bromochloroacetic-acid and Hyperplasia

We report a case of a prostatic adenocarcinoma that showed diffuse aberrant p63 expression in the secretory cells and review the literature and differential diagnosis. p63-positive prostatic adenocarcinoma is rare and is typically encountered when working up an atypical focus with basal markers and α-methylacyl coenzyme A racemase. These carcinomas have unusual morphologic features such as atrophic cytoplasm and basaloid morphology. The differential diagnosis includes basal cell hyperplasia and basal cell carcinoma; morphologic features such as the presence of small, infiltrative acini with nuclear atypia, lack of high-molecular-weight cytokeratin expression, and positive α-methylacyl coenzyme A racemase and prostate-specific antigen expression can help distinguish a p63-positive prostatic adenocarcinoma from atypical basal cell proliferations. Current controversies regarding the grading, prognosis, and molecular profile of p63-positive prostatic adenocarcinomas are also discussed.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Carcinoma, Basal Cell; Cell Proliferation; Diagnosis, Differential; Humans; Hyperplasia; Keratins; Male; Membrane Proteins; Neoplasm Grading; Prognosis; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Racemases and Epimerases

Increasingly more coherent data on the molecular characteristics of benign breast lesions and breast cancer precursors have led to the delineation of new multistep pathways of breast cancer progression through genotypic-phenotypic correlations. It has become apparent that oestrogen receptor (ER)-positive and -negative breast lesions are fundamentally distinct diseases. Within the ER-positive group, histological grade is strongly associated with the number and complexity of genetic abnormalities in breast cancer cells. Genomic analyses of high-grade ER-positive breast cancers have revealed that a substantial proportion of these tumours harbour the characteristic genetic aberrations found in low-grade ER-positive disease, suggesting that at least a subgroup of high-grade ER-positive breast cancers may originate from low-grade lesions. The ER-negative group is more complex and heterogeneous, comprising distinct molecular entities, including basal-like, HER2 and molecular apocrine lesions. Importantly, the type and pattern of genetic aberrations found in ER-negative cancers differ from those of ER-positive disease. Here, we review the available molecular data on breast cancer risk indicator and precursor lesions, the putative mechanisms of progression from in situ to invasive disease, and propose a revised model of breast cancer evolution based on the molecular characteristics of distinct subtypes of in situ and invasive breast cancers.

Topics: Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Disease Progression; Female; Humans; Hyperplasia; Keratins; Metaplasia; Models, Biological; Neoplasm Invasiveness; Neoplasms, Hormone-Dependent; Precancerous Conditions; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Risk Factors

Pathways to breast cancer have been difficult to define using morphology alone. Although epithelial hyperplasia of usual type (HUT) is associated with moderately elevated breast cancer risk, molecular evidence placing it in a cancer precursor pathway is not clear-cut. Recent evidence suggests that small numbers of cytokeratin 5/6 positive cells are precursors of separate lineages which acquire either cytokeratin 8/18/19 or smooth muscle actin (SMA) and cytokeratin 14 on separate pathways to fully differentiated epithelial and myoepithelial phenotypes (and may ultimately lose cytokeratin 5/6 expression). Immunohistochemistry shows that most HUT have a mixed precursor phenotype resembling normal breast with co-expression of cytokeratin 5/6, 8/18/19 and SMA, in contrast to atypical ductal hyperplasia (ADH) and ductal carcinoma in situ which typically have a 'mature' luminal phenotype positive for cytokeratin 8/18/19 but lacking cytokeratin 5/6 expression. While this supports the idea of a biological discontinuity between HUT and ADH/DCIS, caution is called for in the diagnostic use of these reagents until greater experience has been accumulated, and other published data do show features of HUT intermediate between normal breast lobules and ADH.

Topics: Breast; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Cell Transformation, Neoplastic; Epithelium; Female; Humans; Hyperplasia; Keratins; Loss of Heterozygosity; Neoplasm Invasiveness; Neoplasm Staging; Phenotype; Precancerous Conditions

One of the major diagnostic challenges in prostate needle biopsy interpretation is definitive establishment of a malignant diagnosis based on a minimal or limited amount of carcinoma in needle biopsy tissue. Major and minor diagnostic criteria should be used for interpretation of small foci of carcinoma. The constellation of findings and a combination of the major and minor diagnostic criteria permit a definitive diagnosis of focal adenocarcinoma. The differential diagnosis of minimal prostatic adenocarcinoma in needle biopsy tissue is broad and includes many benign lesions. The benign entities most likelty to be misdiagnosed as minimal prostatic adenocarcinoma are atypical adenomatous hyperplasia (adenosis) and atrophy. High-grade prostatic intraepithelial neoplasia and a descriptive diagnosis of focal glandular atypia or atypical small acinar proliferation also should be considered before diagnosing minimal adenocarcinoma. The most valuable adjunctive study for the diagnosis of minimal adenocarcinoma is immunohistochemistry using antibody 34 beta E12, reactive against basal cell-specific high-molecular-weight cytokeratins. Most cases can be diagnosed based on H&E-stained sections without this immunostain. Most minimal carcinomas in prostate needle biopsy tissue are of intermediate histologic grade, and most are indicative of pathologically significant carcinoma in the whole prostate gland.

Topics: Adenocarcinoma; Atrophy; Biopsy, Needle; Diagnosis, Differential; Humans; Hyperplasia; Immunohistochemistry; Keratins; Male; Prostatic Neoplasms

Proliferation of preexisting bile ducts, ductular metaplasia of hepatocytes and proliferation and differentiation of liver stem cells are discussed in the pathogenesis of neoductular structures in the liver. Under the condition of experimental bile duct obstruction and in extrahepatic bile duct stenosis neoductular structures are first the result of proliferation and sprouting of preexisting ducts and cholangioles. Especially in later stages of cholestasis but also in other chronic progredient liver diseases such as chronic alcoholic liver disease and chronic active hepatitis periportal hepatocytes may show a phenotypic shift towards ductular epithelia. In postnatal liver diseases hepatocytes first express keratin 7 and later keratin 19 during ductular transdifferentiation. This is in contrast to embryonal cholangiogenesis. In alpha-1-antitrypsin-deficiency, hemochromatosis, Wilson's disease, and chronic active hepatitis B cellular deposites typically located in hepatocytes such as alpha-1-AT, siderin, copper, HBs-Ag, and HBc-Ag can also be found in neoductular cells close to hepatocytes. These deposites seem to be retained during the ductular transdifferentiation of hepatocytes. Expression of bile duct-type integrin subtypes and TGF beta 1 in neoductular cells are involved in the changing parenchymal/mesenchymal interplay during neoductogenesis, resulting in periductular basal membrane and periductular fibrosis. In FNH the ductular transdifferentiation of hepatocytes is integrated in the histogenesis of micronodules and portal tract equivalents of these tumor-like lesions. Ductular structures in hepatoblastomas and especially in combined hepatocellular and cholangiocarcinomas (CHCC) may reflect the common embryologic derivation of hepatocytes and biliary epithelia. Non-neoplastic liver tissue in resection specimens of our CHCC showed a lower rate of cirrhosis, and a significantly higher Ki 67-LI of neoductular cells compared to liver tissue in resection specimens of HCC and liver metastases. 3 of 10 CHCC had developed in alpha-1-AT-deficiency, in which this protease-inhibitor was predominantly retained in periportal hepatocytes. These findings in non-neoplastic tumor-bearing liver tissue suggest that CHCC include a special histogenic type of primary liver carcinoma which in analogy to some experimental liver tumors might develop from periportal parenchymal cells.

Topics: alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Animals; Bile Ducts; Bile Ducts, Extrahepatic; Carcinoma, Hepatocellular; Cell Differentiation; Cell Division; Cholangiocarcinoma; Cholestasis; Copper; Hepatitis B Core Antigens; Hepatitis B Surface Antigens; Hepatoblastoma; Humans; Hyperplasia; Keratins; Liver; Liver Diseases; Liver Neoplasms; Metaplasia

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benzoyl Peroxide; Cheek; Cocarcinogenesis; Cricetinae; Hyperplasia; Keratins; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; Precancerous Conditions; Tetradecanoylphorbol Acetate

Polyclonal and monoclonal antibodies to cytokeratin polypeptides were used to study the expression of these intermediate filament proteins in normal, squamous metaplastic, and neoplastic epithelium of the uterine cervix, in order to investigate the morphogenesis of early epithelial changes preceding cervical squamous cell carcinoma. A polyclonal keratin antiserum showed a positive reaction in all different epithelial cell types of the uterine cervix. A positive reaction was also found in subcolumnar reserve cell hyperplasia, in squamous metaplastic and dysplastic cells, and in (squamous) carcinoma in situ. A monoclonal antibody specific for columnar epithelium (RGE 53) gave a positive reaction in endocervical columnar cells and in some immature metaplastic cells but was negative in subcolumnar reserve cells, squamous (metaplastic) cells, dysplastic cells, and most cases of carcinoma in situ. Another monoclonal cytokeratin antibody (RKSE 60) pointed to early keratinization in light microscopically nonkeratinizing squamous (metaplastic) and dysplastic epithelium. A possible overlap in staining patterns of RGE 53 and RKSE 60 was seen in some cases of immature metaplasia. Morphologic changes occurring in the transformation zone upon dedifferentiation are accompanied by alterations in cytokeratin expression. Similarities in cytokeratin expression were found between dysplasia and carcinoma in situ on one hand and subcolumnar reserve cell hyperplasia and squamous metaplasia on the other. This study favors an epithelial origin and a squamoid nature of subcolumnar reserve cells.

Topics: Adult; Antibodies, Monoclonal; Carcinoma in Situ; Cervix Uteri; Female; Humans; Hyperplasia; Keratins; Metaplasia; Middle Aged; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Topics: Animals; Carcinoma; Cytoplasm; Digestive System; Embryonic and Fetal Development; Epidermal Cells; Female; Humans; Hyperplasia; Keratins; Male; Melanocytes; Neuroblastoma; Neurosecretory Systems; Rats; Skin; Skin Neoplasms

Topics: Alkynes; Animals; Cell Differentiation; Cytoplasmic Granules; Epidermis; Hair; Hyperplasia; Keratins; Phorbol Esters; Phorbols; Protein Biosynthesis; Tetradecanoylphorbol Acetate; Time Factors; Tretinoin

Topics: Adolescent; Adult; Age Factors; Aged; Candidiasis, Oral; Child; Female; Follow-Up Studies; Humans; Hyperplasia; Keratins; Keratosis; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Nicotine; Precancerous Conditions; Retrospective Studies; Sex Factors; Smoking; Stomatitis

Topics: Animals; Carcinogens; Cell Differentiation; Cell Division; Cell Survival; Cell Transformation, Neoplastic; Epidermal Cells; Epidermis; Growth Inhibitors; Hematopoietic Stem Cells; Homeostasis; Hyperplasia; Keratins; Metaplasia; Mice; Mitogens; Models, Biological; Phorbol Esters; Skin Neoplasms; Wound Healing

Topics: Adenylyl Cyclases; Cyclic AMP; Epidermis; Epinephrine; Growth Inhibitors; Homeostasis; Humans; Hyperplasia; Keratins; Mitosis; Phosphoric Diester Hydrolases; Psoriasis; Skin

Topics: Age Factors; Carcinoma, Squamous Cell; Cell Membrane; Cell Nucleus; Cervix Mucus; Cervix Uteri; Chromatin; Cytoplasm; Female; Herpes Simplex; Humans; Hyperplasia; Inflammation; Keratins; Metaplasia; Pregnancy; Trichomonas Infections

Five cases of a heretofore unreported rare variant of thymic carcinoma characterized by a striking resemblance to adamantinoma of the mandible are described. The tumors occurred in 4 women and 1 man aged 58 to 76 years (mean: 67.8 y); they arose in the anterior mediastinum and measured from 5.3 to 12.0 cm in greatest diameter (mean: 8.9 cm). Presenting symptoms included chest pain, shortness of breath, and in 2 patients, pleural effusion. One tumor was asymptomatic and discovered incidentally. Histologically, the tumors were extensively desmoplastic, and the cellular proliferation was characterized by multiple islands of squamous epithelium with striking peripheral palisading of nuclei and central areas containing clear cells resembling a stellate reticulum. Areas of preexisting spindle cell thymoma were identified in 2 cases; these areas gradually merged with the higher-grade component of the lesion. Cystic changes were noted in 3 cases. Immunohistochemical studies in 3 cases showed the tumor cells were positive for cytokeratins, p40 and p63, and all showed a high proliferation rate (>50% nuclear positivity) with Ki-67. Next-generation sequencing was performed in 2 cases that showed amplification of the AKT1 gene (copy numbers 6 and 13). Clinical follow-up in 3 patients showed recurrence and metastasis after 1 and 2 years; 1 patient passed away 2 years after diagnosis due to the tumor. Desmoplastic adamantinoma-like thymic carcinoma represents an unusual histologic variant of thymic carcinoma that needs to be distinguished from metastases from similar tumors to the mediastinum.

Topics: Adamantinoma; Aged; Ameloblastoma; Biomarkers, Tumor; Epithelium; Female; Humans; Hyperplasia; Keratins; Male; Middle Aged; Thymoma; Thymus Neoplasms

Pigmented extramammary Paget disease (PEMPD) is a rare intraepithelial carcinoma which can clinically resemble other pigmented neoplasms. Similarities to melanoma on dermoscopy, histopathology, and reflectance confocal microscopy (RCM) increase the risk of misdiagnosis and, consequently, mismanagement. Here, we describe a case of a 67-year-old African American woman with a large, pigmented axillary patch that exhibited features of melanoma on RCM, guiding the clinician to perform an excisional biopsy. While traditional histopathology resembled melanoma, immunohistochemistry staining was performed and revealed PEMPD. We highlight an uncommon clinical presentation of PEMPD disease and identify morphologic mimickers of melanoma on RCM-as well as differentiating features.

Topics: Aged; Axilla; Biopsy; Black or African American; Dermoscopy; Diagnosis, Differential; Diagnostic Errors; Female; Humans; Hyperpigmentation; Hyperplasia; Immunohistochemistry; Keratins; Melanocytes; Melanoma; Microscopy, Confocal; Paget Disease, Extramammary

Heck's disease (focal or multifocal epithelial hyperplasia) is a benign, rare condition of the skin and mucous membranes induced by human papillomavirus (HPV) infection. Other entities that can induce large papillomatous lesions that involve the mucous membranes and skin include condyloma acuminatum, which is sexually transmitted, and white sponge nevus, often due to a mutation of cytokeratin 4 or 13. Six cases diagnosed as either Heck's disease (n = 2) or white sponge nevus (n = 4) and 6 oral condyloma were compared on histologic grounds and analyzed in situ for HPV DNA, including HPVs 6,11, and 13, as well as cytokeratins 4 and 13. Each case showed marked acanthosis, and para/hyperkeratosis. More variable histologic findings included rete ridge elongation, keratinocyte degeneration, and perinuclear halos. High copy HPV 13 DNA was evident in the squamous cells towards the surface in the two cases diagnosed as Heck's disease and in two cases diagnosed as white sponge nevus on clinical grounds. HPV 6/11 was found in each of the six condyloma. Marked decrease in either cytokeratin 4 or 13 was evident in the two cases diagnosed as white sponge nevus that were HPV DNA negative. It is concluded that in situ hybridization analyses including HPVs 6, 11, and 13 as well as immunohistochemistry for cytokeratins 4 and 13 can differentiate Heck's disease from condyloma and white sponge nevus, which can be difficult to differentiate on clinical and histologic grounds.

Topics: Adult; Biomarkers; Cell Differentiation; Condylomata Acuminata; DNA, Viral; Female; Focal Epithelial Hyperplasia; Humans; Hyperplasia; In Situ Hybridization; Keratins; Leukokeratosis, Hereditary Mucosal; Male; Middle Aged; Nevus; Papilloma; Papillomaviridae; Papillomavirus Infections; Skin

We report a case of vimentin-positive early gastric adenocarcinoma arising in a hyperplastic polyp (HP). A 72-year-old Japanese man was admitted for the detailed examination of a gastric polyp. He had a subtotal gastrectomy due to acute abdomen 12 years ago. Upper endoscopy revealed a pedunculated polyp measuring approximately 2 cm on the greater curvature of upper body of the remnant stomach. Magnifying endoscopy revealed that the microsurface pattern was irregular and partially absent accompanied with irregular microvessels at the upper end of the polyp. We speculated that the lesion was an adenocarcinoma arising in the HP. Endoscopic submucosal dissection (ESD) was performed. Histological examination of the ESD specimen revealed that the lesion consisted of well- to poorly differentiated adenocarcinoma at the protruding lesion and foveolar hyperplastic epithelia at the base of the polyp. Immunohistochemically, most of tumor cells that comprised poorly-differentiated adenocarcinoma were positive for both cytokeratin and vimentin. Although carcinomas have occasionally been found in HPs, the histological features of the present case are considered extremely unusual. To the best of our knowledge, this is the first case of vimentin-positive early gastric carcinoma arising in a HP.

Topics: Adenocarcinoma; Aged; Endoscopic Mucosal Resection; Humans; Hyperplasia; Keratins; Male; Polyps; Stomach Diseases; Stomach Neoplasms; Vimentin

Epithelial sheath neuroma is a rarely recognized but established entity in the medical literature. First described in 2000 by Requena et al, there have only been 7 published cases to date, mostly in female patients and presenting as symptomatic solitary lesions on the back without a known history of trauma. In 2006, Beer et al described and reviewed a dozen cases in which epithelial sheath neuroma-like features were seen in the advent of a surgical procedure, which was termed "re-excision perineural invasion" and attributed to possible eccrine duct implantation during surgery. Our case is a 66-year-old male patient who underwent an excision of a melanocytic neoplasm in which a reactive epithelial sheath neuroma was incidentally discovered in the excision specimen, adjacent to the biopsy site cicatrix. Histologically, there was benign cutaneous nerve hyperplasia with a proliferation of squamous epithelium in intimate apposition to the nerve bundles in the superficial dermis. We postulate that the process active in the formation of re-excision perineural invasion is the same as in epithelial sheath neuroma and that minor trauma not appreciable on histologic examination is responsible in the latter entity. We performed IL-6 staining and documented that IL-6 was upregulated at the interface of the nerve and reactive epithelium, but was absent in nerves distant from the site of surgery, suggesting that IL-6 may be essential to the lesion's development. The recognition of reactive epithelial sheath neuroma including the subcategory of re-excision perineural invasion is crucial for the dermatopathologist to prevent mislabeling this reactive entity as a perineural squamous cell carcinoma, which has clinical consequences for the patient such as wider re-excision and radiation treatment. Additionally, we have identified a potential pathophysiologic basis for this lesion.

Topics: Adult; Aged; Aged, 80 and over; Back; Biomarkers, Tumor; Biopsy; Cicatrix; Dysplastic Nevus Syndrome; Epithelial Cells; Female; Fluorescent Antibody Technique; Humans; Hyperplasia; Interleukin-6; Keratins; Male; Middle Aged; Neoplasm Invasiveness; Neuroma; Peripheral Nerves; Skin Neoplasms; Up-Regulation

Multipotent stromal cells (MSCs) are envisioned as a powerful therapeutic tool. As they home into tumors, secrete trophic and vasculogenic factors, and suppress immune response their role in carcinogenesis is a matter of controversy. Worldwide oral squamous cell carcinoma (OSCC) is the fifth most common epithelial cancer. Our aim was to determine whether MSC administration at precancerous stage modifies the natural progression of OSCC. OSCC was induced in Syrian hamsters by topical application of DMBA in the buccal pouch. At papilloma stage, the vehicle or 3×10

Topics: Animals; Apoptosis; Bone Marrow Cells; Carcinoma, Squamous Cell; Caspase 3; Cell Dedifferentiation; Cell Line, Tumor; Cell Proliferation; Cricetinae; Disease Progression; Down-Regulation; Epithelial Cells; Female; Hyperplasia; Immunophenotyping; Keratins; Ki-67 Antigen; Leukocyte Common Antigens; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mesocricetus; Mouth Neoplasms; Papilloma; Phenotype; Transcriptome; Transplantation, Homologous

Granular cell tumor is a rare benign tumor that can present a pseudoepitheliomatous hyperplasia of the covering epithelium. This lesion is not encapsulated and can be characterized by a pseudo invasive growth pattern, represented by the tumoral cells that infiltrate between adjacent connective tissue elements. Diagnostic difficulties may arise because histopathological features of the pronounced pseudoepitheliomatous hyperplasia can be confused with a well-differentiated oral squamous cell carcinoma. The aim of this case report is to demonstrate the role of an immunohistochemical panel in the diagnosis of a granular cell tumor in the tongue with clinical and microscopic features resembling an oral squamous cell carcinoma.. A 44-year-old white man with a history of heavy smoking and alcohol abuse presented an ulcerated nodular lesion in the dorsum of the tongue. The lesion was asymptomatic with fast growth. The clinical diagnosis was an oral squamous cell carcinoma. An incisional biopsy was performed and the ensuing histopathological analysis showed a pseudoepitheliomatous hyperplasia in the overlying epithelium mimicking the invasion of epithelial tumor cells into the connective tissue as in an oral squamous cell carcinoma. Immunohistochemical antibodies (S-100, vimentin, CD68, p53, Ki-67, E-cadherin, collagen IV and cytokeratin AE1/AE3) were used to characterize molecular aspects of the lesion. Strong staining of S-100 protein, CD68, vimentin, E-cadherin and low proliferative activity observed with Ki-67 expression confirmed the diagnosis of a granular cell tumor. The patient was submitted to surgical excision of the whole lesion. At a 12-month check-up, there was no evidence of recurrence.. This case report showed that the immunohistochemical profile was helpful in determining the clinical behavior of the tumor and establishing the final diagnosis with appropriate treatment.

Topics: Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cadherins; Carcinoma, Squamous Cell; Collagen Type IV; Granular Cell Tumor; Humans; Hyperplasia; Immunohistochemistry; Keratins; Ki-67 Antigen; Male; S100 Proteins; Tongue; Tongue Neoplasms; Tumor Suppressor Protein p53; Vimentin

Granular cell tumor (GCT) of the oral cavity is a benign lesion. Half of oral GCTs demonstrate pseudocarcinomatous hyperplasia (PCH) of the mucosa which can mimic invasive islands of oral squamous cell carcinoma (SCC). Such similarity can be confusing when diagnosing or evaluating the two conditions, potentially leading to misdiagnosis or misclassification. Indeed, several misdiagnosed cases of oral GCT have been reported in the literature as OSCC or malignant oral GCT that resulted in unnecessary aggressive treatment for the affected patients. The aim of this study was to investigate if the cytokeratin pattern of the PCH can help in differentiating GCT from oral SCC. To distinguish between these two entities, we examined 12 patient specimens of oral GCT-PCH and oral SCC histologically and via immunohistochemistry (IHC) for CK13, CK17 and P75. The results suggest that the cytokeratin profile of PCH is similar to that of oral SCC. Therefore, consideration of IHC findings for epithelial markers alone may lead to erroneous diagnosis; thus, the presence of the granular tumor underneath the PCH and its immunopositivity for P75 or other neural definition markers can be essential to identify the underlying tumor and exclude oral SCC. Finally we recommend more studies on the molecular biology of PCH to understand how it can mimic oral SCC histologically without harboring its malignant phenotype clinically, which could have significant translational potential for understanding invasive oral SCC.

Topics: Biomarkers, Tumor; Carcinoma, Squamous Cell; Diagnosis, Differential; Granular Cell Tumor; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Mouth Neoplasms; Neoplasm Staging; Prognosis

Although Warthin's tumor is one of the common tumors of the salivary glands, Warthin's tumors with a prominent component of nodular oncocytic hyperplasia reminiscent of oncocytoma are rare. Here we report such a tumor, measuring 3 cm in diameter, found in the parotid gland of an 81-year-old man. Histologically, approximately 70% of the mass was a component of nodular oncocytic proliferation, and the remaining portion was a component of conventional Warthin's tumor. We performed immunohistochemical analysis to explore what factors determined the morphogenesis of the two components in the single mass. Cytokeratin (CK) 5÷6-positive tumor cells, which represent basal cells, were aligned in a layer in the conventional Warthin's tumor component, whereas they were localized around blood vessels in the nodular oncocytic hyperplasia component. Immunostaining for CD34 showed that capillaries were sparsely present beneath the bilayered epithelia in the former component, while blood vessels resembling sinusoids separated the trabeculae of the tumor cells in the latter component. Ki-67 labeling index was slightly higher in the latter component. Double immunostaining for CK5÷6 and Ki-67 revealed that most of Ki-67-positive proliferating tumor cells were CK5÷6-positive, suggesting that CK5÷6-positive population contained proliferative progenitor cells of the tumor. These findings imply that the regional difference in the distribution pattern and proliferative activity of CK5÷6-positive putative progenitor cells along with the difference in the pattern of vascular network occurred during the tumorigenic process of the tumor and determined one region to become conventional Warthin's tumor morphology and the other to become nodular oncocytic hyperplasia.

Topics: Adenolymphoma; Adenoma, Oxyphilic; Aged, 80 and over; Humans; Hyperplasia; Immunohistochemistry; Keratins; Ki-67 Antigen; Male; Parotid Neoplasms; Stromal Cells

Diagnostic criteria that have been specified for unicystic ameloblastomas (UAs) are not always helpful to differentiate these cystic tumors from common odontogenic cysts. The aim of this study therefore was to identify additional histopathological features (other than the features considered for the diagnosis of UA at present) that would be helpful to differentiate UA from odontogenic cysts.. One hundred histopathologically confirmed unicystic ameloblastomas and 20 cases each of radicular, inflamed dentigerous and non-inflamed dentigerous cysts were selected. Histopathological features of the UAs that are not used as diagnostic criteria at present were identified.. Hyperplastic arcading epithelial proliferations with stellate-reticulum-like and vacuolated cells were always seen associated with inflammation in odontogenic cysts, while in UA plexiform-like areas were also seen without inflammation (P < 0.001). In addition, a spiky rete pattern was observed in non-inflamed UA while this pattern was observed only in inflamed odontogenic cysts. Furthermore, spiky retes together with subepithelial hyalinization were usually observed in UAs while only subepithelial hyalinization was observed in non-inflamed dentigerous cysts.. Combinations of histopathological features were identified to differentiate non-inflamed UA from common odontogenic cysts. However, presence of inflammatory changes in UA precludes the use of features identified in the present study for diagnostic purposes.

Topics: Ameloblastoma; Ameloblasts; Connective Tissue; Dentigerous Cyst; Diagnosis, Differential; Epithelial Cells; Epithelium; Female; Humans; Hyalin; Hyperplasia; Inflammation; Keratins; Male; Radicular Cyst; Vacuoles; Young Adult

Cancer chemoprevention is defined as the use of chemicals or dietary components to block, inhibit, or reverse the development of cancer in normal or pre-neoplastic tissue. Mentha extract (ME) has antioxidant and antiperoxidant properties. This study was held to investigate the protective and anticancer effect of Mentha leaves aqueous extract on oral epithelium of mice tongues.. A total of 80 Egyptian albino mice were divided into three groups. Group I served as control (not subjected to any kind of treatment), and groups II and III were subjected to two-stage chemical carcinogenesis through topical application of dimethylbenz[a]anthracene (DMBA) followed by formaldehyde on dorsal and ventral surfaces of tongues for 9 weeks. Mentha leaves extract was administrated to group III at the same time of cancer induction. Histological changes were assessed in H&E sections at 3-week intervals. The anticarcinogenic effect of Mentha piperita was tested using immunostain with anticaspase antibody.. The oral administration of ME reduced the appearance of dysplastic cellular changes with 61% and inhibited tumor incidence with 100%. Group I showed moderate-to-strong cytoplasmic caspase expression. At 6-week interval, group II showed weak-to-moderate caspase expression, while sections from group III showed moderate-to-strong caspase expression. High significant statistical difference in the total score of caspase 3 expression was found between specimens obtained from animals sacrificed at 6 weeks in groups I, II, and III (P = 0.001**).. Our study demonstrated that Mentha piperita has inhibited the initiation and promotion of oral dysplastic lesions.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antioxidants; Basement Membrane; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell; Caspase 3; Chemoprevention; Connective Tissue; Epithelium; Formaldehyde; Hyperplasia; Keratins; Male; Mentha piperita; Mice; Phytotherapy; Plant Extracts; Protective Agents; Tongue; Tongue Neoplasms

Keratins are structural marker proteins with tissue specific expression; however, recent reports indicate their involvement in cancer progression. Previous study from our lab revealed deregulation of many genes related to structural molecular integrity including KRT76. Here we evaluate the role of KRT76 downregulation in oral precancer and cancer development.. We evaluated KRT76 expression by qRT-PCR in normal and tumor tissues of the oral cavity. We also analyzed K76 expression by immunohistochemistry in normal, oral precancerous lesion (OPL), oral squamous cell carcinoma (OSCC) and in hamster model of oral carcinogenesis. Further, functional implication of KRT76 loss was confirmed using KRT76-knockout (KO) mice.. We observed a strong association of reduced K76 expression with increased risk of OPL and OSCC development. The buccal epithelium of DMBA treated hamsters showed a similar trend. Oral cavity of KRT76-KO mice showed preneoplastic changes in the gingivobuccal epithelium while no pathological changes were observed in KRT76 negative tissues such as tongue.. The present study demonstrates loss of KRT76 in oral carcinogenesis. The KRT76-KO mice data underlines the potential of KRT76 being an early event although this loss is not sufficient to drive the development of oral cancers. Thus, future studies to investigate the contributing role of KRT76 in light of other tumor driving events are warranted.

Topics: Adult; Animals; Carcinogenesis; Carcinoma, Squamous Cell; Cricetinae; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Hyperplasia; Immunohistochemistry; Keratins; Male; Mice; Mice, Knockout; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Neoplasm Grading; Neoplasm Staging; Prognosis; Reproducibility of Results

The development of the Cre recombinase-controlled (Cre/LoxP) technique allows the manipulation of specific tumorigenic genes, temporarily and spatially. Our original intention of this study was to investigate the role of Kras and p53 in the development of urinary bladder cancer. First, to validate the effect of intravesical delivery on Cre recombination (Adeno-Cre), we examined activity and expression of β-galactosidase in the bladder of control ROSA transgenic mice. The results confirmed specific recombination as evidenced by β-galactosidase activity in the bladder urothelium of these mice. Then, we administered the same adenovirus into the bladder of double transgenic Kras(LSLG12D/+). p53(fl/fl) mice. The virus solution was held in place by a distal urethral retention suture for 2 hours. To our surprise, there was a rapid development of a spindle-cell tumor with sarcoma characteristics near the suture site, within the pelvic area but outside the urinary track. Since we did not see any detectable β-galactosidase in the area outside of the bladder in the validating (control) experiment, we interpreted that this sarcoma formation was likely due to transduction by Adeno-Cre in the soft tissue of the suture site. To avoid the loss of skin integrity associated with the retention suture, we transitioned to an alternative technique without suture to retain the Adeno-Cre into the bladder cavity. Interestingly, although multiple Adeno-Cre treatments were applied, only urothelial hyperplasia but not carcinogenesis was observed in the subsequent experiments of up to 6 months. In conclusion, we observed that the simultaneous inactivation of p53 and activation of Kras induces quick formation of spindle-cell sarcoma in the soft tissues adjacent to the bladder but slow formation of urothelial hyperplasia inside the bladder. These results strongly suggest that the effect of oncogene regulation to produce either hyperplasia or carcinogenesis greatly depends on the tissue type.

Topics: Adenoviridae; Animals; beta-Galactosidase; Breeding; Female; Fluorescent Antibody Technique; Genotype; Hyperplasia; Integrases; Keratins; Magnetic Resonance Imaging; Mice; Mice, Transgenic; Organ Specificity; Proto-Oncogene Proteins p21(ras); Reproducibility of Results; RNA, Untranslated; Sarcoma; Staining and Labeling; Tumor Suppressor Protein p53; Urinary Bladder; Urothelium

Our previous studies showed that topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is very effective for oral verrucous hyperplasia (OVH) and relatively less effective for oral leukoplakia (OL) lesions. Nevertheless, there has been no report on the association of the expression of apoptosis-related proteins in OVH and OL biopsy tissues prior to PDT with PDT treatment outcomes.. This study used immunohistochemistry to evaluate whether the expression of Bak, Mcl-1, caspase-3, caspase-8, caspase-9, p53, p21, or PCNA protein in biopsy specimens of OVH and OL lesions could be used to predict the clinical outcomes of 18 OVH and 40 OL lesions treated with topical ALA-PDT. The marker labeling score (LS) was defined as labeling index (positive cells/total cells) multiplied by staining intensity. The lesions after ALA-PDT treatment were divided into complete response (CR) group and partial or no response (PR/NR) group.. The mean Bak LS and the mean Bak/Mcl-1 LS ratio were significantly higher in the CR group than in the PR/NR group. However, there was no significant difference in the Mcl-1, caspase-3, caspase-8, caspase-9, p53, p21, or PCNA protein LS between the CR and PR/NR groups.. We conclude that the Bak LS or Bak/Mcl-1 LS ratio may be a useful biomarker to predict the clinical outcomes of OVH and OL lesions treated with topical ALA-PDT. Pre-PDT epithelial cell levels of Mcl-1, caspase-3, caspase-8, caspase-9, p53, p21, and PCNA may not have a significant influence on the clinical outcome of OVH and OL lesions treated with topical ALA-PDT.

Topics: Adult; Aged; Aminolevulinic Acid; bcl-2 Homologous Antagonist-Killer Protein; Biomarkers; Biopsy; Caspase 3; Caspase 8; Caspase 9; Cyclin-Dependent Kinase Inhibitor p21; Epithelial Cells; Female; Humans; Hyperplasia; Keratins; Leukoplakia, Oral; Male; Middle Aged; Mouth Mucosa; Myeloid Cell Leukemia Sequence 1 Protein; Photochemotherapy; Photosensitizing Agents; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-bcl-2; Remission Induction; Treatment Outcome; Tumor Suppressor Protein p53; Young Adult

Current insight into the histopathological course of events during disease progression in hidradenitis suppurativa (HS) is fragmentary.. To identify histological alterations and leucocyte subsets in normal-appearing perilesional skin, and early and chronic HS lesions.. In this observational study we examined eight perilesional skin samples, and six early and 10 chronic prototypic HS lesions, as well as skin samples from four healthy donors using in situ immunostaining.. Perilesional skin showed mild psoriasiform hyperplasia and follicular plugging as well as a low-grade influx of tryptase-positive mast cells, CD3+ T cells, CD138+ plasma cells and factor XIIIa+ dendritic cells. In early HS lesions, neutrophilic abscess formation and influx of mainly macrophages, monocytes and dendritic cells predominated. In chronic disease, the infiltrate expanded with markedly increased frequencies of CD20+ and CD79a+ B cells and CD138+ plasma cells. As in early lesions, free keratin fibres were detected in the dermis and within giant cells. Single detached keratinocytes and strands of follicular epithelium were observed in the dermis, the latter frequently expressing Ki67, indicative of active proliferation.. Psoriasiform hyperplasia, follicular plugging and low-grade leucocytic infiltration are already present in normal-appearing perilesional skin. Keratin fibres in the dermis are associated with clinical disease. Early lesions are characterized by neutrophilic abscess formation and influx of mainly histiocytes, and chronic lesions mainly by expansion of B cells and plasma cells in 'pseudo' follicles. Proliferating strands of follicular epithelium may initiate fistula formation. Mast cells are increased in all stages of HS including perilesional skin.

Topics: Acute Disease; Cell Proliferation; Chronic Disease; Epidermis; Hidradenitis Suppurativa; Humans; Hyperplasia; Immunohistochemistry; Immunophenotyping; Keratins; Leukocytes; Skin

Adenoid basal hyperplasia is an underrecognized cervical lesion, resembling adenoid basal carcinoma, except the absence of deep invasion into the stroma. We report a series of 10 cases, all extending less than 1 mm from the basement membrane. Our results support the hypothesis that adenoid basal hyperplasia arises from reserve cells of the cervix. Lesions were found close to the squamocolumnar junction, in continuity with the nearby subcolumnar reserve cells. They shared the same morphology and immunoprofile using a panel of 4 antibodies (keratin 5/6, keratin 14, keratin 7 and p63) designed to differentiate reserve cells from mature squamous cells and endocervical columnar cells. We detected no human papillomavirus infection by in situ hybridization targeting high-risk human papillomavirus, which was concordant with the absence of immunohistochemical p16 expression. We demonstrated human papillomavirus infection in 4 (80%) of 5 adenoid basal carcinoma, which is in the same range as previous studies (88%). Thus, adenoid basal hyperplasia should be distinguished from adenoid basal carcinoma because they imply different risk of human papillomavirus infection and of subsequent association with high-grade invasive carcinoma. In our series, the most reliable morphological parameters to differentiate adenoid basal hyperplasia from adenoid basal carcinoma were the depth of the lesion and the size of the lesion nests. Furthermore, squamous differentiation was rare in adenoid basal hyperplasia and constant in adenoid basal carcinoma. Finally, any mitotic activity and/or an increase of Ki67 labeling index should raise the hypothesis of adenoid basal carcinoma.

Topics: Adult; Aged; Carcinoma, Adenoid Cystic; Carcinoma, Basal Cell; Cervix Uteri; Epithelial Cells; Female; Humans; Hyperplasia; Keratins; Middle Aged; Uterine Cervical Neoplasms

This study aimed to make a nationwide clinicopathological study of oncocytic lesions in the ophthalmic region and to characterize their cytokeratin (CK) expression.. All histologically diagnosed oncocytic lesions in the ophthalmic region registered in Denmark over a 25-year period were collected and re-evaluated using a monoclonal antimitochondrial antibody (MU213-UC). Clinical data were registered. Immunohistochemical characterization was performed with a panel of anti-CK antibodies.. A total of 34 oncocytic lesions were identified and reviewed. The incidence that required surgical intervention in the Danish population could be approximated to 0.3 lesions per million capita per year. Patient ages ranged from 45 years to 89 years, with a peak incidence in the eighth decade. Female patients were twice as common as male. Lesions were typically described as red–brown, cystic and slow-growing. The antimitochondrial antibody MU213-UC produced a distinct and intense immunostaining of all oncocytic lesions and was found to be useful in substantiating oncocytic differentiation. Twenty-six of the lesions originated in the caruncle, three in the conjunctiva, two in the lacrimal sac, one at the semilunar plica, one on the eyelid margin and one peripunctally. Lesions were histologically classified as adenoma (oncocytoma) (26), hyperplasia (4) and metaplasia (4). Fourteen oncocytic lesions representing different locations and differentiation were further evaluated for CK expression. Basal-type oncocytic cells reacted with antibodies against CK 5 ⁄ 6, CK 7, CK 8, CK 13, CK 14, CK 17, CK 18 and CK 19, and suprabasal cells with CK 4, CK 7, CK 8, CK 18 and CK 19. Antibodies against CK 1+10 and CK 20 showed no reaction.. Oncocytic lesions of the ophthalmic region most frequently present as caruncular oncocytomas. The CK profile is similar to the lacrimal- and accessory lacrimal gland duct elements and supports the theory that these lesions originate in the lacrimal- and accessory lacrimal glands.

Topics: Adenoma, Oxyphilic; Aged; Aged, 80 and over; Denmark; Eye; Eye Neoplasms; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Male; Metaplasia; Middle Aged

An examination was performed on 16 intraductal proliferative breast lesions diagnosed as intraductal papillomas (IP) or usual ductal hyperplasia (UDH), which were followed up for more than 3 years. An immunohistochemical marker panel combining myoepithelial markers, high-molecular-weight keratin (HMWK) and neuroendocrine markers was used. Two of 11 IP cases were re-evaluated as atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). These cases developed breast cancer after the first operation. One IP case showed repeated recurrences. None of the other IP and UDH cases had breast cancer or recurrence. The ADH, DCIS and the recurrent IP showing a solid growth lacked myoepithelia, but the recurrent IP expressed HMWK, immunohistochemically. Interestingly, these three lesions were weakly positive for neuroendocrine markers. All other IPs and UDHs, including lesions having solid components, were negative for neuroendocrine markers, and most of them were positive for myoepithelial markers and/or HMWK. A combination of the above immunohistochemical markers seems useful to evaluate intraductal proliferative lesions and to predict their prognosis. In particular, intraductal proliferative lesions with solid components exhibiting positivity for neuroendocrine markers should be followed up carefully to monitor breast cancer risk or recurrence.

Topics: Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Breast Neoplasms, Male; Carcinoma, Intraductal, Noninfiltrating; Chromogranin A; Diagnosis, Differential; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Male; Membrane Proteins; Microfilament Proteins; Middle Aged; Neoplasm Recurrence, Local; Papilloma, Intraductal; Prognosis; Smooth Muscle Myosins

Interobserver reproducibility in the diagnosis of benign intraductal proliferative lesions has been poor. The aims of the study were to investigate the inter- and intraobserver variability and the impact of the addition of an immunostain for high- and low-molecular weight keratins on the variability. Nine pathologists reviewed 81 cases of breast proliferative lesions in three stages and assigned each of the lesions to one of the following three diagnoses: usual ductal hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ. Hematoxylin and eosin slides and corresponding slides stained with ADH-5 cocktail (cytokeratins (CK) 5, 14. 7, 18 and p63) by immunohistochemistry were evaluated. Concordance was evaluated at each stage of the study. The interobserver agreement among the nine pathologists for diagnosing the 81 proliferative breast lesions was fair (κ-value=0.34). The intraobserver κ-value ranged from 0.56 to 0.88 (moderate to strong). Complete agreement among nine pathologists was achieved in only nine (11%) cases, at least eight agreed in 20 (25%) cases and seven or more agreed in 38 (47%) cases. Following immunohistochemical stain, a significant improvement in the interobserver concordance (overall κ-value=0.50) was observed (P=0.015). There was a significant reduction in the total number of atypical ductal hyperplasia diagnosis made by nine pathologists after the use of ADH-5 immunostain. Atypical ductal hyperplasia still remains a diagnostic dilemma with wide variation in both inter- and intraobserver reproducibility among pathologists. The addition of an immunohistochemical stain led to a significant improvement in the concordance rate. More importantly, there was an 8% decrease in the number of lesions classified as atypical ductal hyperplasia in favor of usual hyperplasia; in clinical practice, this could lead to a decrease in the number of surgeries carried out for intraductal proliferative lesions.

Topics: Biomarkers, Tumor; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Observer Variation; Precancerous Conditions; Reproducibility of Results

Retinoids play an important role in skin homeostasis and when administered topically cause skin hyperplasia, abnormal epidermal differentiation and inflammation. Thyroidal status in humans also influences skin morphology and function and we have recently shown that the thyroid hormone receptors (TRs) are required for a normal proliferative response to 12-O-tetradecanolyphorbol-13-acetate (TPA) in mice.. We have compared the epidermal response of mice lacking the thyroid hormone receptor binding isoforms TRα1 and TRβ to retinoids and TPA. Reduced hyperplasia and a decreased number of proliferating cells in the basal layer in response to 9-cis-RA and TPA were found in the epidermis of TR-deficient mice. Nuclear levels of proteins important for cell proliferation were altered, and expression of keratins 5 and 6 was also reduced, concomitantly with the decreased number of epidermal cell layers. In control mice the retinoid (but not TPA) induced parakeratosis and diminished expression of keratin 10 and loricrin, markers of early and terminal epidermal differentiation, respectively. This reduction was more accentuated in the TR deficient animals, whereas they did not present parakeratosis. Therefore, TRs modulate both the proliferative response to retinoids and their inhibitory effects on skin differentiation. Reduced proliferation, which was reversed upon thyroxine treatment, was also found in hypothyroid mice, demonstrating that thyroid hormone binding to TRs is required for the normal response to retinoids. In addition, the mRNA levels of the pro-inflammatory cytokines TNFα and IL-6 and the chemotactic proteins S1008A and S1008B were significantly elevated in the skin of TR knock-out mice after TPA or 9-cis-RA treatment and immune cell infiltration was also enhanced.. Since retinoids are commonly used for the treatment of skin disorders, these results demonstrating that TRs regulate skin proliferation, differentiation and inflammation in response to these compounds could have not only physiological but also therapeutic implications.

Topics: Alitretinoin; Animals; Blotting, Western; Cell Differentiation; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Epidermis; Female; Hyperplasia; Hypothyroidism; Interleukin-6; Keratins; Lymphocytes; Macrophages; Male; Mice; Mice, Knockout; Retinoids; Reverse Transcriptase Polymerase Chain Reaction; Skin; Tetradecanoylphorbol Acetate; Thyroid Hormone Receptors alpha; Thyroid Hormone Receptors beta; Tretinoin; Tumor Necrosis Factor-alpha

The purpose of this study was to evaluate the immunohistochemical profile of cytokeratins (Ck) in pseudoepitheliomatous hyperplasia of cutaneous leishmaniasis (CL).. The tissue samples, with pseudoepitheliomatous hyperplasia, were collected from 37 patients (age 6-85 years old) with indolent ulcers in skin confirmed as CL. The lesions were submitted to immunolabeling for Ck pairs 4-13, 5-14, and 6-16.. In the 37 CL cases, Ck4 and Ck13 staining were, in the majority of cases, negative. Of them, 33 and 35 cases were negative for Ck4 and Ck13, respectively. The Ck4 immunostaining was found in basal and parabasal layers, and Ck13 was viewed in the basal compartment of epithelium. Ck5 was found in 29 cases distributed homogeneously in all layers. Ck14 and Ck6 were found in all samples in all layers, and Ck16 was positive for all cases but heterogeneously found in the basal layer.. In summary, we noticed that the pattern of some Ck staining in pseudoepitheliomatous hyperplasia in CL lesions revealed intense epithelial reinforcement, protection, and proliferation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cell Proliferation; Child; Epithelium; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Leishmaniasis, Cutaneous; Male; Middle Aged; Skin; Young Adult

A case of benign reactive pseudo-glandular mesothelial hyperplasia arising in the context of chronic vaginitis in presented: morphological and immunohistochemical investigations and differential diagnoses are described.

Topics: Cell Proliferation; Diagnosis, Differential; Humans; Hyperplasia; Keratins; Male; Testicular Diseases; Testicular Hydrocele; Testicular Neoplasms; Young Adult

To investigate the pathological diagnostic features and the differential diagnosis of radial sclerosing lesions of the breast.. Morphological observation and immunohistochemistry were applied to forty-four cases of radial sclerosing lesions of the breast.. All forty-four patients were females, the mean age was 40.3 years (range 17 to 54 years). In the 31 consultation cases, 13 were misdiagnosed as carcinoma. The lesions had a radiating outline, and a central scar area where squeezed or pressed irregular shaped tubules were frequently seen. Dilated tubules and proliferated ducts or lobules were seen radically arranged at the periphery accompanied sometimes with the apocrine glands or columnar cell metaplasia and hyperplasia. Aside, there were 14 cases displaying necroses and 8 cases showing atypical ductal hyperplasia. Immunostaining showed myoepithelial cells around the pseudo-infiltrating tubules, and the florid proliferating epithelial cells were positive for CK5/6.. Radial sclerosing lesions of the breast possess characteristic histological features, and may be misdiagnosed as carcinoma. The lesions should be differentiated from ductal carcinoma in situ, lobular neoplasia, tubular carcinoma and invasive ductal carcinoma.

Topics: Adenocarcinoma; Adolescent; Adult; Breast; Breast Diseases; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Diagnosis, Differential; Diagnostic Errors; Female; Humans; Hyperplasia; Keratin-14; Keratin-5; Keratins; Middle Aged; Sclerosis; Young Adult

To investigate the role of the Chinese herbal medicine Xianhuayin on the reversal of 7,12-dimethylbenz[a]anthracene (DMBA)-induced premalignant mucosal lesions in the oral buccal pouch of golden hamsters.. The animals were randomly divided into a non-diseased control group (n=5) and an experimental group including 50 animals in which the buccal mucosa had been painted with DMBA (0.5% in acetone) to generate an oral mucosa premalignant lesion. Animals in the experimental group were further divided into Xianhuayin-treated group (n=30), untreated premalignant lesion group (n=10) and normal saline (NS)-treated group (n=10). The cheek (buccal) pouch mucosa of the golden hamsters in each group was observed with light and electron microscopy eight weeks after intragastric administration with NS or Xianhuayin.. In the non-diseased control group, the buccal mucosa was keratinized and stratified squamous epithelium under a light microscope. In the untreated premalignant lesion group, variable degrees of epithelial dysplasia was observed. The irregular epithelial mucosa gradually became distinct in the Xianhuayin-treated group. Scanning electronic microscopic (SEM) analysis showed that surface of the cells exhibited honeycomb structures in the hamster of untreated-group. The cells were morphologically irregular, overlapped and loosened in the untreated premalignant lesion group. Most of the cell surface exhibited honeycomb structure in the Xianhuayin-treated group. Transmission electronic microscopic (TEM) analysis showed that buccal mucosal epithelial cells were morphologically regular in the non-diseased control group. Desmosomes and tonofibrils were reduced and the nucleus was morphologically irregular in the untreated premalignant lesion group. In the Xianhuayin-treated group, the widening intercellular gap was gradually reduced, desmosomes and the cells becoming morphologically regular. No significant difference was observed between the hamsters in NS-treated group and those in the untreated premalignant lesion group. Significant therapeutic efficacy was observed in the group receiving Xianhuayin.. Xianhuayin is effective in the reversal of DMBA-induced premalignant lesions in the buccal pouch of golden hamsters.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Amomum; Animals; Anticarcinogenic Agents; Carcinogens; Carthamus tinctorius; Cell Nucleus; Cricetinae; Desmosomes; Disease Models, Animal; Drugs, Chinese Herbal; Epithelial Cells; Epithelium; Glycyrrhiza; Hyperplasia; Intercellular Junctions; Intermediate Filaments; Keratins; Mesocricetus; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Mouth Mucosa; Mouth Neoplasms; Philodendron; Poria; Precancerous Conditions; Random Allocation; Sodium Chloride

Basaloid skin tumors, including basal cell carcinoma (BCC) and basaloid follicular hamartoma, are associated with aberrant Hedgehog (Hh) signaling and, in the case of BCC, an expanding set of genetic variants including keratin 5 (encoded by KRT5), an intermediate filament-forming protein. We here show that genetic ablation of keratin 17 (Krt17) protein, which is induced in basaloid skin tumors and co-polymerizes with Krt5 in vivo, delays basaloid follicular hamartoma tumor initiation and growth in mice with constitutive Hh signaling in epidermis. This delay is preceded by a reduced inflammation and a polarization of inflammatory cytokines from a Th1- and Th17-dominated profile to a Th2-dominated profile. Absence of Krt17 also attenuates hyperplasia and inflammation in models of acute dermatitis. Re-expression of Krt17 in Gli2(tg); Krt17(-/-) keratinocytes induces select Th1 chemokines that have established roles in BCC. Our findings establish an immunomodulatory role for Krt17 in Hh driven basaloid skin tumors that could impact additional tumor settings, psoriasis and wound repair.

Topics: Animals; Blotting, Western; Carcinoma, Basal Cell; Ear; Epithelial Cells; Female; Hamartoma; Hedgehog Proteins; Hyperplasia; Immunoprecipitation; Keratinocytes; Keratins; Kruppel-Like Transcription Factors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin Neoplasms; Zinc Finger Protein Gli2

Oral verrucous hyperplasia (OVH) and oral erythroleukoplakia (OEL) are two oral precancerous lesions with relatively high malignant transformation potential. One of the best cancer prevention strategies is to use a conservative and effective treatment modality to eliminate oral precancers to stop their further malignant transformation. Our previous studies have shown that the topical 5-aminolevulinic acid-mediated photodynamic therapy (topical ALA-PDT) using the 635-nm light-emitting diode (LED) light is very effective for OVH and OEL lesions.. Because the laser machine is a more-popular light source than the LED device in PDT clinics, in this study 40 OVH and 40 OEL lesions were treated once a week with the same PDT protocol but using the 635-nm laser light to evaluate whether this laser light-mediated topical ALA-PDT was also effective for OVH and OEL lesions.. We found that all the 40 OVH lesions exhibited complete response (CR) after an average of 3.6 PDT treatments. Of the 40 OEL lesions, 38 showed CR after an average of 3.4 PDT treatments and two showed partial response (PR). Better PDT outcomes were significantly associated with OVH and OEL lesions with the smaller size, pink to red color, epithelial dysplasia, or thinner surface keratin layer.. This study indicates that the laser light-mediated topical ALA-PDT is also very effective for OVH and OEL lesions. Therefore, we suggest that topical ALA-PDT using either the LED or laser light may serve as the first-line treatment of choice for OVH and OEL lesions.

Topics: Adult; Aged; Aged, 80 and over; Aminolevulinic Acid; Biopsy; Carcinoma in Situ; Erythroplasia; Female; Humans; Hyperplasia; Keratins; Leukoplakia, Oral; Low-Level Light Therapy; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Photochemotherapy; Photosensitizing Agents; Precancerous Conditions; Remission Induction; Treatment Outcome

We describe 3 cases of nonneoplastic signet-ring cell change in ulcerated mucosa, 2 of them in the gallbladder and 1 in an endocervical polyp. In the gallbladder cases, there were focal collections of signet-ring cells both on the mucosal surface and within the lumen of tubules, whereas in the endocervical polyp, the signet-ring cell aggregates were entirely confined to the mucosal surface. In all 3 cases, the signet-ring cells were positive for Mayer's mucicarmine and immunoreactive for keratin AE1/AE3. The lack of nuclear atypicality, the arrangement in superficial and intraluminal nests, and the admixture with histiocytes and other inflammatory cells are in keeping with the interpretation that the signet-ring cells are disrupted mucosal goblet cells exhibiting hyperplastic and degenerative changes. A review of the literature disclosed only other 2 previously reported cases of benign signet-ring cell changes in the gallbladder and none--to the best of our knowledge--in an endocervical polyp. Awareness of this phenomenon is of importance to avoid a potential overdiagnosis of signet-ring cell adenocarcinoma.

Topics: Adult; Carcinoma, Signet Ring Cell; Cervix Uteri; Diagnosis, Differential; Diagnostic Errors; Female; Gallbladder Diseases; Humans; Hyperplasia; Keratins; Male; Middle Aged; Mucous Membrane; Polyps; Ulcer; Uterine Cervical Diseases; Young Adult

The definition of atypical ductal hyperplasia (ADH) encompasses qualitative and quantitative criteria. Qualitative criteria include cytological and architectural features similar to those of low grade ductal carcinoma in situ (DCIS), the quantitative criteria are characterized by metric features (2 mm or 2 ductules) or by the confines of lobules. In this article we discuss the morphology of ADH, the status of ADH in the low grade pathway of breast carcinoma development and its clinical significance. Furthermore, we comment some special forms of atypical epithelial proliferations of the ductal type.

Topics: Biopsy; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; Cell Division; Epithelial Cells; Female; Humans; Hyperplasia; Keratins; Loss of Heterozygosity

Proliferative epithelial breast lesions include a wide variety of benign hyperplastic and noninvasive neoplastic lesions, as well as invasive carcinomas. Mammographically these lesions may show microcalcifications, architectural distortions or mass lesions. The task of the pathologist begins with a preoperative diagnosis by means of minimally invasive biopsy. His diagnosis forms the basis for not only the radiological-pathological correlation diagnosis, but also for the management of benign proliferative breast disease lesions, as well as therapeutic decisions in the case of malignant lesions.In daily practice, immunohistochemistry is the method of choice for clarifying difficult cases. The aim of this chapter is to describe the relevant markers in breast pathology and to provide an algorithmic approach to different proliferative breast disease lesions.

Topics: Biomarkers; Biopsy; Breast Diseases; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Basal Cell; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Diagnosis, Differential; Epithelium; Female; Fibrocystic Breast Disease; Humans; Hyperplasia; Immunohistochemistry; Keratins

Intercalated duct lesions (IDLs) are rare, poorly understood and not well-studied lesions that have been associated with a small number of epithelial-myoepithelial carcinomas (EMC) and basal cell adenomas. To examine the nature of IDLs and their association with salivary gland tumors, we reviewed 34 lesions in 32 patients. The IDLs were stained with CK7, estrogen receptors (ER), progesterone receptors, lysozyme, S100, calponin, and CK14. The patients ranged in age from 19 to 80 years (mean 53.8) with a 1.7:1 female predominance. The majorities of IDLs were parotid lesions (82%), were small and nodular (average size 3.1 mm) and showed 3 architectural patterns: hyperplasia (20), adenoma (9), and hybrid forms (5). In 59% of cases, IDLs were seen in conjunction with another salivary gland tumor, most commonly basal cell adenoma (8 cases), followed by EMC (3 cases). One case showed a combination of intercalated duct hyperplasia and basal cell adenoma. The IDLs stained diffusely with CK7 (100%) and S100 (73%) and focally for ER (91%) and lysozyme (100%). Calponin and CK14 highlighted a thin myoepithelial cell layer around all ducts (100%). Normal intercalated ducts were also consistently positive for CK7 and lysozyme, and focally for ER, but were S100 negative. In summary, IDLs have a variety of patterns ranging from hyperplasia to adenoma with hybrid lesions and share morphologic and immunophenotypic features with normal intercalated ducts. There is an association with basal cell adenomas and EMC, which lends credence to their role as a putative precursor lesion.

Topics: Adenoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Calcium-Binding Proteins; Calponins; Female; Humans; Hyperplasia; Keratins; Male; Microfilament Proteins; Middle Aged; Muramidase; Neoplasms, Multiple Primary; Parotid Gland; Receptors, Steroid; S100 Proteins; Salivary Ducts; Salivary Gland Neoplasms; Submandibular Gland; Young Adult

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Papillary; Cell Nucleus; Diagnosis, Differential; Female; Humans; Hyperplasia; Keratins; Membrane Proteins; Neoplasm Proteins; Neoplasms, Multiple Primary; Papilloma

To investigate the changing regular of specific cytokeratin (CK) markers expressing in human pseudoepitheliomatous hyperplasia (PEH), keloids (Ke) and hypertrophic scar (HS) lesion, and to explore the correlation between such changes and the different outcomes of wound repair.. Histopathology and immunohistochemistry (IHC) double staining methods were used in samples of human PEH, Ke, HS and NS to determine the distribution characteristics and changing regularity of CKs in epidermal tissues.. No CK8&18 and CK17 expressed in epidermis of NS group, while CK8&18(+) cells and CK17(+) cells were detected in epidermis of active-stage Ke, HS and PEH. The quantities of CK8&18(+) cells and CK17(+) cells ranked as follows: PEH > Ke > HS and HS > Ke > PEH (P < 0.05). CK19(+) cells and CK5&6(+) cells expressed similar changing trend, while reverse trend of CK10(+) cells was detected in epidermal cells, with local epidermal hyperplasia, cells morphological changes and sub-epidermal inflammatory reaction.. Different degree of de-differentiation and terminal differentiation imbalance are found in epidermal cells of active-stage PEH, Ke and HS, which hint the correlation between the abnormal proliferation and differentiation of epidermal cells and the different outcomes of wound repair.

Topics: Adolescent; Adult; Aged; Cell Differentiation; Cell Proliferation; Child; Child, Preschool; Cicatrix; Epidermis; Epithelial Cells; Female; Humans; Hyperplasia; Infant; Keratins; Male; Middle Aged; Wound Healing; Young Adult

This study investigated the clinical and pathological findings of lung disease in tuberous sclerosis complex (TSC) as previously reported in Japan.. The clinical and pathological findings in 15 patients diagnosed as having multifocal micronodular pneumocyte hyperplasia (MMPH) with TSC were analysed.. The majority of patients (80%) were women and the mean age was 37 years. Three patients had a family history of TSC. The radiological findings were small multiple nodular shadows with ground-glass opacity randomly distributed in the bilateral whole-lung fields in most patients. Differentiation from multiple atypical adenomatous hyperplasia or metastatic lung cancer was necessary in most patients. In 11 patients, the diagnostic method used to identify pulmonary lesions of MMPH with TSC was VAT. Among the complications of MMPH with TSC, lymphangioleiomyomatosis was recognized in 53% of patients. The prognosis was comparatively good because only one patient died of respiratory failure. The histological findings were papillary or tubular proliferation of type II pneumocytes without nuclear atypia lining the thickened alveolar septa and lymphocyte infiltration. Immunohistochemical staining for cytokeratin, and surfactant proteins A and B was positive in alveolar lining cells of all MMPH lesions. However, staining for HMB-45, alpha-smooth muscle actin, p53, carcinoembryonic antigen and hormonal receptor was negative in most patients.. Surgical investigation and immunohistochemical staining for pathological markers are useful for diagnosing MMPH when the radiological findings indicate multiple micronodules with ground-glass opacity in patients with TSC.

Topics: Adult; Diagnosis, Differential; Disease Progression; Female; Humans; Hyperplasia; Immunohistochemistry; Incidence; Japan; Keratins; Lung; Male; Middle Aged; Multiple Pulmonary Nodules; Retrospective Studies; Tuberous Sclerosis; Young Adult

Sensitive to apoptosis gene (SAG)/regulator of cullins-2/RING box protein 2 is a stress-responsive RING component of Skp-1/Cullins/F-box protein E3 ubiquitin ligase. When overexpressed, SAG inhibits apoptosis induced by reactive oxygen species or hypoxia. Here, we report that SAG overexpression inhibits ultraviolet (UV) B-induced apoptosis in mouse JB6 epidermal cells. Using a transgenic mouse model, in which SAG expression was targeted primarily to epidermis by a K14 promoter, we showed that, at the early stage of UVB skin carcinogenesis (10 weeks post-UVB exposure), c-Jun, p27, p53, c-Fos and cyclin D1 were strongly induced. While having no effect on UVB-induced p53, c-Fos and cyclin D1, SAG-transgenic expression reduced the levels of c-Jun and p27 and inhibited AP-1 activity. The net outcome of SAG-mediated inhibition of c-Jun/AP-1 (pro-tumor promotion) and of p27 (antiproliferation) increased skin hyperplasia, with no apparent effect on apoptosis, as evidenced by increased skin thickness, and increased rate of DNA synthesis, but hardly any apoptosis. Although skin hyperplasia was promoted, SAG-transgenic expression had no significant effect on tumor formation in the later stage of UVB carcinogenesis. Thus, by simultaneously targeting c-Jun and p27, SAG accelerates UVB-induced skin hyperplasia, but not carcinogenesis.

Topics: Animals; Cell Line; Epidermis; Humans; Hyperplasia; In Situ Nick-End Labeling; Keratins; Lung; Mice; Mice, Transgenic; Proliferating Cell Nuclear Antigen; Promoter Regions, Genetic; Radionuclide Imaging; Skin; Skin Neoplasms; Transcription Factor AP-1; Ubiquitin-Protein Ligases; Ubiquitination; Ultraviolet Rays

To assess the impact of cytokeratin (CK) 5/6 and E-cadherin immunohistochemistry on diagnostic agreement of non-invasive proliferative breast lesions.. Twenty pathologists classified 105 cases of non-invasive proliferative breast lesions into 10 diagnostic categories. One haematoxylin and eosin (H&E) slide of each case was analysed on a first round and one H&E slide with corresponding CK5/6 and E-cadherin immunohistochemistry was analysed on a second round. Interobserver reproducibility for category-specific and management-specific lesions was measured on each round. CK5/6 and E-cadherin had little impact on diagnostic agreement, which remained moderate between the first and second rounds (overall kappa coefficients of 0.47 and 0.53, respectively, P = NS). Levels of agreement slightly improved for lesions with specific CK5/6 and E-cadherin immunoprofiles (usual ductal hyperplasia, atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, non-high-grade ductal carcinoma in situ), but the differences observed were not statistically significant. However, diagnostic agreement improved when lesions were grouped according to their management category (overall kappa coefficients of 0.58 and 0.66 in the first and second rounds, respectively).. CK5/6 and E-cadherin immunohistochemistry has little impact on interobserver reproducibility for non-invasive breast lesions. Diagnostic agreement can, however, be improved by grouping lesions in management categories.

Topics: Biomarkers, Tumor; Breast; Breast Neoplasms; Cadherins; Carcinoma, Intraductal, Noninfiltrating; Diagnosis, Differential; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins

Keratinocytes and fibroblasts isolated from dysplastic oral lesions were combined to provide a renewable source of epithelia. A dysplasia-scoring index was devised to compare the architectural and cytological features and used together with robust immunophenotyping to show that the engineered epithelia showed most of the characteristics of the clinical lesions. The strains of dysplastic oral keratinocytes with an extended or immortal lifespan provided a reproducible resource of epithelia showing mild (DOK), moderate (POE9n) or severe (D20) dysplasia when maintained under defined conditions. The dysplasia score was influenced by growth conditions, with KGF polarizing proliferation to the basal layer and reducing the severity of dysplasia. When compared to the normal counterparts, dysplasia-associated fibroblasts expressed MMP9, secreted more HGF, increased the dysplasia score for epithelia generated with mortal dysplastic keratinocytes and induced morphological changes in normal keratinocytes, highlighting the role of the microenvironment in determining the phenotype of dysplastic epithelia.

Topics: Culture Media, Conditioned; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Humans; Hyperplasia; Immunohistochemistry; Keratinocytes; Keratins; Leukoplakia, Oral; Linear Models; Mouth Mucosa; Precancerous Conditions; Tissue Engineering

The transcription factor Gata3 is crucially involved in epidermis and hair follicle differentiation. Yet, little is known about how Gata3 co-ordinates stem cell lineage determination in skin, what pathways are involved and how Gata3 differentially regulates distinct cell populations within the hair follicle. Here, we describe a conditional Gata3-/- mouse (K14-Gata3-/-) in which Gata3 is specifically deleted in epidermis and hair follicles. K14-Gata3-/- mice show aberrant postnatal growth and development, delayed hair growth and maintenance, abnormal hair follicle organization and irregular pigmentation. After the first hair cycle, the germinative layer surrounding the dermal papilla was not restored; instead, proliferation was pronounced in basal epidermal cells. Transcriptome analysis of laser-dissected K14-Gata3-/- hair follicles revealed mitosis, epithelial differentiation and the Notch, Wnt and BMP signaling pathways to be significantly overrepresented. Elucidation of these pathways at the RNA and protein levels and physiologic endpoints suggests that Gata3 integrates diverse signaling networks to regulate the balance between hair follicle and epidermal cell fates.

Topics: Animals; Animals, Newborn; Bone Morphogenetic Proteins; Cell Cycle; Cell Proliferation; Embryonic Development; Epidermis; Female; Fibroblast Growth Factors; GATA3 Transcription Factor; Hair Follicle; Hyperkeratosis, Epidermolytic; Hyperplasia; Keratinocytes; Keratins; Mice; Mice, Knockout; Mice, Transgenic; Phenotype; Pregnancy; Receptor, Notch1; Signal Transduction; Stem Cells; Transcription, Genetic; Wnt Proteins

Papillary breast lesions remain a source of diagnostic confusion because the full range of epithelial proliferations may arise within, or secondarily involve, papilloma. The expression of p63 and high-molecular-weight cytokeratins (HMWCK) was studied simultaneously in 33 papillary lesions including intraductal papilloma (IP, n = 10), atypical papilloma (AP, n = 8) and intraductal papillary carcinoma (IPC, n = 15) by double immunostaining. The myoepithelial cell nuclei were stained dark brown whereas the cytoplasms of usual ductal hyperplasia (UDH) and myoepithelium were stained purple. The myoepithelial layer was recognized as a dark brown dotted line at the epithelial stromal junction in all IP (10/10), most AP (7/8) and some IPC (7/15), suggesting that the retained myoepithelial layer in the papillary processes does not necessarily guarantee benignity. However, the malignant epithelial cells in AP and IPC were typically recognized as monotonous populations unstained with either chromogen. These monotonous cells contrasted with the proliferating cells of UDH in papilloma, which had intense purple cytoplasm in a mosaic-like fashion. The present data suggest that the double immunostaining with the two popular antibodies p63 and HMWCK is a useful tool for reproducible classification of papillary breast lesions.

Topics: Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Papillary; DNA-Binding Proteins; Female; Fluorescent Antibody Technique, Direct; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Mammary Glands, Human; Middle Aged; Molecular Weight; Papilloma, Intraductal; Retrospective Studies; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins

We examined myoepithelial status in intraductal papillary carcinoma (IPC) along with the expression of high-molecular weight cytokeratin (HMWK) and neuroendocrine markers, with special reference to the differential diagnosis of solid intraductal papillary carcinoma(SIPC) and intraductal papilloma with usual ductal hyperplasia (IP-UDH). Twenty-six (93%) of the twenty-eight intraductal papillomas (IP) had myoepithelial cells in >70% of the epithelial-stromal interface of the intraluminal proliferating component. Six (29%) of twenty-one SIPC had almost complete myoepithelial layer like IP-UDH at the epithelial-stromal interface. HMWK (34 beta E-12) was diffusely positive in 14 (93%) of 15 IP-UDH, but 16 (76%) of 21 SIPC were completely negative for HMWK. Neuroendocrine markers were positive in 14 (67%) of SIPC, but all 28 IPs were completely negative. If only the presence of myoepithelial cells is emphasized as a benign hallmark, about 30% of SIPCs may be underdiagnosed as IP-UDH. However, by using a combination of myoepithelial markers, HMWK, and neuroendocrine markers, all of the 36 solid intraductal papillary lesions were properly classified as benign and malignant. Solid intraductal papillary lesions meeting at least two of the following criteria are highly likely to be malignant: (1) absence of myoepithelial cells(<10% of epithelial-stromal interface of intraluminal proliferating component), (2) negative HMWK(<10%), (3) positive neuroendocrine markers (>10%).

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Papillary; Diagnosis, Differential; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Mammary Glands, Human; Middle Aged; Molecular Weight; Nerve Tissue Proteins; Papilloma, Intraductal

Topics: Aged; Biopsy; Calbindin 2; Diagnosis, Differential; Epithelium; Gene Expression Regulation; Humans; Hyperplasia; Incidental Findings; Keratins; Lymph Nodes; Lymphoma; Male; S100 Calcium Binding Protein G

Clear-cell acanthoma (CCA) has been reported to be a benign epidermal neoplasm; however, several authors have suggested alternative differentiation as well as other nosologic categories, including a reactive dermatosis. Fourteen CCAs, ten tricholemmomas, and seven cases of psoriasis were reviewed with conventional microscopy, periodic acid-Schiff stains, and immunohistochemical stains. Twelve of fourteen (86%) CCAs were associated with underlying or adjacent conditions. The CCAs stained immunohistochemically in a pattern similar to normal epidermis and psoriasis. Tricholemmomas stained in a distinctly different pattern with MNF116 and NGFR/p75. These cases demonstrate CCA in settings that reflect chronic inflammation, primarily scars and stasis dermatitis, and with an immunophenotype that parallels psoriasis. These findings support the contention that CCA does not show outer follicular sheath (tricholemmal) differentiation. Furthermore, these cases lend additional support to the contention that CCA represents a psoriasiform reaction pattern, which, in appropriately taken biopsies, usually has a demonstrable associated condition. Nonetheless, the precise nosology of this phenomenon has yet to be elucidated completely.

Topics: Acanthoma; Adult; Aged; Aged, 80 and over; Cicatrix; Dermatitis; Epidermis; Female; Hair Follicle; Hidradenitis Suppurativa; Humans; Hyperplasia; Keratins; Keratosis, Seborrheic; Male; Middle Aged; Molecular Weight; Neoplasms, Basal Cell; Nerve Tissue Proteins; Psoriasis; Receptors, Nerve Growth Factor; Skin; Skin Neoplasms

The authors report two examples of nodular hyperplasia of the Bartholin gland. Each occurred in the vulva, close to the introitus of women aged 33 and 49 years, who presented with slightly painful lesions that were clinically thought to be cysts. Grossly, both masses exhibited a multilobular architecture, were elastic, were gray in color, and measured 4 cm and 3.2 cm in greatest dimension. On microscopic examination, the lesions looked similar and exhibited an increased number of secretory acini, with maintenance of the normal duct-acinar relationship--features compatible with nodular hyperplasia. Rare dilated ducts were observed, and intraluminal inspissated secretions were occasionally seen. In one case, there were a focal mild inflammatory infiltrate, squamous metaplasia of larger ducts, and rare ruptured ducts with extravasated stromal mucin. Clonality analysis performed in one case revealed a monoclonal pattern, suggesting that the lesion may be a neoplastic process rather than simple reactive hyperplasia.

Topics: Actins; Adult; Bartholin's Glands; Calcium-Binding Proteins; Calponins; Clone Cells; Collagen; Cytoplasm; Dilatation, Pathologic; Female; Humans; Hyperplasia; Keratins; Membrane Proteins; Metaplasia; Microfilament Proteins; Middle Aged; Mucins; Muscle Proteins; Receptors, Androgen; S100 Proteins

Humans with selected mutations in the vitamin D receptor (VDR) and mouse models lacking VDR develop alopecia. Mice null for the Vdr gene are born with a normal coat of hair, but fail to initiate normal hair follicle cycling. In this study, we examined the morphology of the hair follicle of the Vdr null mouse during days 13-22 when the hair follicle normally initiates and completes the first catagen. We then explored the possibility that the abnormality in hair follicle cycling was associated with abnormal expression of hairless (Hr), a putative transcriptional regulator known to regulate hair follicle cycling and recently shown to regulate VDR transcriptional activity. Our results demonstrate the progressive deterioration of the hair follicle through catagen. Comparable to VDR, Hr was found in the basal cells of the epidermis and ORS of the hair follicle. However, Hr was also found in the IRS and matrix of the follicle, regions with little or no VDR. Hr levels increased during catagen, reaching a peak by day 19. Levels of Hr were greater in the Vdr null mice compared to wildtype controls, results confirmed by quantitative RT-PCR. We conclude that lack of VDR causes disruption of hair follicle structure during the first catagen resulting in failure of subsequent hair follicle cycling. These changes are associated with increased expression of Hr, suggesting a role for VDR in regulating Hr expression. Both Hr and VDR are required for normal hair follicle cycling.

Topics: Alkaline Phosphatase; Alopecia; Animals; Collagen Type I; Collagen Type I, alpha 1 Chain; Disease Progression; Epidermis; Fibroblasts; Gene Expression; Hair Follicle; Hyperplasia; Keratin-15; Keratin-5; Keratinocytes; Keratins; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Scanning; Proliferating Cell Nuclear Antigen; Receptors, Calcitriol; Skin; Transcription Factors

We previously showed that the EP2 knockout mice were resistant to chemically induced skin carcinogenesis. The purpose of this study was to investigate the role of the overexpression of the EP2 receptor in mouse skin carcinogenesis. To determine the effect of overexpression of EP2, we used EP2 transgenic (TG) mice and wild-type (WT) mice in a DMBA (7,12-dimethylbenz[alpha]anthracene)/TPA (12-O-tetradecanoylphorbol-13-acetate) two-stage carcinogenesis protocol. EP2 TG mice developed significantly more tumors compared with WT mice. Overexpression of the EP2 receptor increased TPA-induced keratinocyte proliferation both in vivo and in vitro. In addition, the epidermis of EP2 TG mice 48 h after topical TPA treatment was significantly thicker compared to that of WT mice. EP2 TG mice showed significantly increased cyclic adenosine monophosphate levels in the epidermis after prostaglandin E2 (PGE2) treatment. The inflammatory response to TPA was increased in EP2 TG mice, as demonstrated by an increased number of macrophages in the dermis. Tumors and 7 x TPA-treated and DMBA-TPA-treated (6 weeks) skins from EP2 TG mice produced more blood vessels than those of WT mice as determined by CD-31 immunostaining. Vascular endothelial growth factor (VEGF) protein expression was significantly increased in squamous cell carcinoma (SCC) samples from EP2 TG mice compared that of WT mice. There was, however, no difference in the number of apoptotic cells in tumors from WT and EP2 TG mice. Together, our results suggest that the overexpression of the EP2 receptor plays a significant role in the protumorigenic action of PGE2 in mouse skin.

Topics: Animals; Animals, Newborn; Bromodeoxyuridine; Carcinoma, Squamous Cell; Cattle; Cell Culture Techniques; Cell Proliferation; Female; Humans; Hyperplasia; Inflammation; Keratinocytes; Keratins; Mice; Mice, Transgenic; Neovascularization, Pathologic; Polymerase Chain Reaction; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype; Skin Neoplasms; Tetradecanoylphorbol Acetate; Up-Regulation

Ductopenia is observed in end-stage human cholestatic diseases. The limited capability of cholangiocytes for proliferation is suggested to be the principal reason. Recently, bone marrow cells (BMCs) have been reported to behave as hepatic stem cells; however, their capability to differentiate into cholangiocytes in cholestasis remains unclear.. Normal mice were lethally irradiated to suppress the proliferation of self-BMCs; thereafter, the BMCs from enhanced green fluorescent protein (EGFP)-transgenic mice were transferred to recipients. Chronic cholestasis was induced by 0.1%alpha-naphtylisothiocyanate (ANIT) feeding. The proliferation of cholangiocytes and oval cells was assessed morphologically and immunohistchemically (cytokeratin-7 (CK-7), A6). Proliferative activity (proliferating cell nuclear antigen (PCNA) protein expression), hepatic growth factor (HGF) receptor (c-Met), stem cell factor receptor (c-kit), Notch2 and Hes1 expression were also evaluated.. Marked cholangiocyte proliferation was observed in ANIT-fed mice. However, no EGFP/CK-7 double positive cells were identified in any of the liver specimens after BMCs transfer (Tx). In hepatic parenchyma, there were scattered EGFP-positive cells, although none of them were positive for CK-7.. In spite of the significant ductular proliferations after ANIT feeding, no EGFP-positive cholangiocytes were confirmed by any other means in this chronic cholestasis model. Thus, different from hepatocytes, BMCs Tx seems not to contribute to the differentiation of cholangiocytes. Future studies are feasible to clarify the origin of proliferative cholangiocytes observed in this chronic cholestatic ductular hyperplasia model.

Topics: 1-Naphthylisothiocyanate; Animals; Basic Helix-Loop-Helix Transcription Factors; Bile Ducts; Bone Marrow Cells; Bone Marrow Transplantation; Cell Differentiation; Cell Proliferation; Cholestasis; Disease Models, Animal; Female; Gene Expression Regulation; Green Fluorescent Proteins; Homeodomain Proteins; Hyperplasia; Keratin-7; Keratins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; Protein-Tyrosine Kinases; Receptors, Notch; Regeneration; Transcription Factor HES-1

Topics: Actins; Antigens, Neoplasm; Desmin; Diagnosis, Differential; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Lung; Lung Neoplasms; Lymphangioleiomyomatosis; Melanoma-Specific Antigens; Middle Aged; Muscle, Smooth; Neoplasm Proteins; Nuclear Proteins; Receptors, Estrogen; Receptors, Progesterone; Thyroid Nuclear Factor 1; Transcription Factors; Tuberous Sclerosis

Topics: Biomarkers, Tumor; Child; Diagnosis, Differential; Female; Humans; Hyperplasia; Keratins; Pigment Epithelium of Eye; Retinal Neoplasms

The histological diagnosis is critical for the postsurgical management and follow-up of thyroid malignancies. The differential diagnosis between papillary carcinoma and hyperfunctioning lesions, either with papillary hyperplasia or with a follicular architecture, can create real diagnostic difficulty. The aim of this study was to evaluate the expression of several antibodies considered to be markers of malignancy in malignant and hyperfunctioning thyroid neoplasms and to include the most effective of them in a diagnostic panel.. One hundred resected thyroid nodules--58 hyperfunctioning benign lesions and 42 papillary carcinomas (14 follicular variant, 14 macrofollicular variant and 14 classic type)--were immunohistochemically studied for HBME-1, galectin-3, cytokeratin (CK) 19 and RET-proto-oncogene. HBME-1 and galectin-3 showed 92.8% and 89% sensitivity, respectively, and their coexpression was present in 36 out of 42 papillary carcinomas (85.7%) and absent in non-malignant lesions. Their association increased sensitivity to 94.7% and the diagnostic accuracy to 97.9% and involved the highest number of cases (95%) in comparison with two other panels including, respectively, three (HBME-1, galectin-3, CK19) and all four antibodies.. An immunohistochemical panel consisting of HBME-1 and galectin-3 can make a correct distinction between malignant and hyperfunctioning thyroid neoplasms with high diagnostic accuracy.

Topics: Biomarkers, Tumor; Carcinoma, Papillary; Diagnosis, Differential; Galectin 3; Humans; Hyperplasia; Immunohistochemistry; Keratins; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Reproducibility of Results; Sensitivity and Specificity; Thyroid Gland; Thyroid Neoplasms

The solid papillary variant of ductal carcinoma in situ is an uncommon entity, which usually presents in the seventh or eighth decade and may be associated with invasive mucinous carcinoma. Solid papillary ductal carcinoma in situ (SP-DCIS) shares many morphological features with usual ductal hyperplasia (UDH) involving a papilloma: papillary architecture, solid growth, cellular streaming, and low-grade nuclear features. These similarities can make the distinction between these 2 entities challenging. Recent studies have demonstrated that immunohistochemical staining for cytokeratin 5/6 can distinguish UDH from conventional forms of ductal carcinoma in situ. Most of the epithelial cells of UDH express cytokeratin 5/6, but the tumor cells of ductal carcinoma in situ do not. We tested the hypothesis that the results of staining for cytokeratin 5/6 can distinguish UDH from the solid papillary variant of ductal carcinoma in situ. Immunohistochemical staining of 14 cases of SP-DCIS and 9 cases of UDH (4 involving papillomas) was performed using cytokeratin 5/6 antibody clone D5/16 B4. Strong cytoplasmic or membrane staining was considered positive. The hyperplastic cells in all cases of UDH showed strong staining for cytokeratin 5/6. The percentage of positive cells ranged from 50% to 80%. None of the SP-DCIS tumor cells stained for cytokeratin 5/6; however, many cases did show staining of occasional entrapped, benign epithelial, and myoepithelial cells. We conclude that the absence of strong cytokeratin 5/6 expression by SP-DCIS distinguishes it from its morphological mimic, UDH. Pathologists must guard against misinterpreting SP-DCIS as UDH in those cases in which the carcinoma cells engulf cytokeratin 5/6-expressing residual, native epithelial cells.

Topics: Biomarkers, Tumor; Breast; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Papillary; Diagnosis, Differential; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Precancerous Conditions

Paracoccidioidomycosis (Pmycosis) is one the most prevalent deep systemic mycoses in Latin America. It is characterized by granulomatous inflammation and pseudoepitheliomatous hyperplasia. Cytokeratins (CKs) are a group of intermediate filaments of epithelial cells and their expression varies according to the epithelium type, differentiation and pathological processes. This study describes cytokeratin expression as examined by immunohistochemistry, in 28 cases of oral Pmycosis involving the buccal mucosa, lip, gingiva and hard palate. Expression of CKs in the basal layer of the epithelium in pseudoepitheliomatous hyperplasia of Pmycosis was similar to that in normal oral mucosa (NOM), but in Pmycosis CK1 and CK10 were not expressed in the spinous and superficial layers of the lip, gingiva or hard palate, and, in the spinous and superficial layers of the lip and buccal mucosa, CK14 was positive in contrast to NOM where it was negative. In Pmycosis, CK6 was more frequently expressed in the spinous layer of the lip, gingiva and hard palate, but nevertheless CK16 expression was decreased in the spinous and superficial layers of the gingiva and hard palate. We conclude that pseudoepitheliomatous hyperplasia in oral Pmycosis shows a different pattern of CK expression, particularly CKs 1, 10 and 14, compared with NOM.

Topics: Gingiva; Humans; Hyperplasia; Immunohistochemistry; Keratins; Lip; Mouth Diseases; Mouth Mucosa; Palate, Hard; Paracoccidioidomycosis

S100 proteins were reported to be involved in different biological activities such as transduction of intracellular calcium signalling. It has been reported that each member of the S100 protein family exhibits a distinct tissue-specific pattern of expression. Furthermore, altered S100 protein expression and function correlate with many diseases. The expression of S100A1 was reported to be increased in different tissue with hyperplasia. The external auditory canal cholesteatoma (EACC) is a benign hyperplasia of the auditory meatal skin. However, without treatment, EACC destroys adjacent tissue. Seventeen EACC specimens were collected and investigated immunohistochemically against S100A1. Normal auditory meatal skin served as control. In the EACC, S100A1 showed a more homogeneous staining pattern, positively expressed throughout the epithelial layers. The keratin debris showed no detectable expression of S100A1. In the auditory meatal skin (control), S100A1 was only expressed in the basal layer of the epithelium. We showed that there are different staining patterns in normal auditory meatal skin, middle ear cholesteatoma and external auditory canal cholesteatomas. The immunoreactivity increased with the stage of the disease. Contrary to that reported previously in the middle ear cholesteatomas, the reactivity was strongest in the upper epithelial layers. In our collective, the epithelial matrix of the EACC showed strong reactivity throughout all the layers. Surprisingly, there is no study regarding the connection between growth factors and S100A1. In previous experiments we showed significant increase of growth factors in EACC. This correlates with our new data concerning S100A1. This is the first study to show the different reactivity pattern of S100A1 in the external auditory canal cholesteatoma.

Topics: Adult; Aged; Cholesteatoma; Ear Canal; Ear Diseases; Female; Gene Expression Regulation; Humans; Hyperplasia; Immunohistochemistry; Keratins; Male; Middle Aged; S100 Proteins; Signal Transduction

The inducible form of cyclooxygenase (COX), COX-2, is up-regulated in many epithelial cancers and its prostaglandin products increase proliferation, enhance angiogenesis, and inhibit apoptosis in several tissues. Pharmacologic inhibition and genetic deletion studies showed a marked reduction of tumor development in colon and skin. COX-2 has also been strongly implicated in urinary bladder cancer primarily by studies with nonselective COX- and COX-2-selective inhibitors. We now show that forced expression of COX-2, under the control of a keratin 5 promoter, is sufficient to cause transitional cell hyperplasia (TCH) in 17% and 75% of the heterozygous and homozygous transgenic lines, respectively, in an age-dependent manner. TCH was strongly associated with inflammation, primarily nodules of B lymphocytes; some T cells and macrophage infiltration were also observed. Additionally, transitional cell carcinoma was observed in approximately 10% of the K5.COX-2 transgenic mice; no TCH or transitional cell carcinoma was observed in wild-type bladders. Immunohistochemistry for vascular proliferation and vascular endothelial growth factor showed significant increases above that in wild-type urinary bladders. Our results suggest that overexpression of COX-2 is sufficient to cause hyperplasia and carcinomas in the urinary bladder. Therefore, inhibition of COX-2 should continue to be pursued as a potential chemopreventive and therapeutic strategy.

Topics: Animals; B-Lymphocytes; Carcinoma, Transitional Cell; Cell Proliferation; Cyclooxygenase 2; Gene Expression Regulation, Enzymologic; Humans; Hyperplasia; Inflammation; Keratin-15; Keratin-5; Keratins; Macrophages; Membrane Proteins; Mice; Mice, Transgenic; Neoplasm Staging; Promoter Regions, Genetic; Prostaglandin-Endoperoxide Synthases; T-Lymphocytes; Transcription, Genetic; Urinary Bladder; Urinary Bladder Neoplasms; Vascular Endothelial Growth Factor A

Exposure of skin to excessive ultraviolet-B (UVB) radiation causes epidermal hyperproliferation that leads to epidermal hyperplasia, however, it is not yet clear exactly how these responses progress.. We attempted to clarify the response patterns involved with epidermal hyperproliferation following UVB radiation.. UVB was irradiated at 2 minimal erythema doses (MED) to human back skin and epidermal morphologic changes were evaluated using in vivo confocal laser microscopy. Skin biopsy specimens were collected from exposed and from non-exposed regions, and were subjected to histochemical and immunohistochemical analysis.. The in vivo confocal laser microscopic analysis showed that UVB-induced epidermal hyperplasia was prominent at the epidermal rete ridges. Further, 3 days after UVB exposure, numerous Ki67-positive epidermal cells were observed in the epidermal rete ridges, but not in the epidermis at the top of the dermal papilla. These results suggest that cells highly responsive to UVB exist in the epidermal rete ridges and that their hyperproliferation leads to elongation of the epidermal rete ridges. In contrast, the number of keratin 10-positive basal cells, known as transitional cells, was increased throughout the epidermis, suggesting that an upward migration of keratinocytes from the epidermal basal layer occurred regardless of their location. However, diffusion of melanin to the suprabasal layers was markedly observed in epidermal regions above the dermal papillae, suggesting the occurrence of strong upper cell movement at this position.. Based on our results, we conclude that differences in keratinocyte responses to UVB radiation exist in cells located in the undulating epidermal basal layer.

Topics: Adult; Back; Cell Division; Cell Movement; Coloring Agents; Eosine Yellowish-(YS); Epidermis; Fluorescent Dyes; Hematoxylin; Histocytochemistry; Humans; Hyperplasia; Immunohistochemistry; Keratin-10; Keratinocytes; Keratins; Ki-67 Antigen; Male; Microscopy, Confocal; Silver Nitrate; Staining and Labeling; Ultraviolet Rays

Abnormal follicular keratinization is involved in comedogenesis in acne vulgaris. We recently demonstrated that calcium influx into epidermal keratinocytes is associated with impaired skin barrier function and epidermal proliferation. Based on these results, we hypothesized that sebum components affect calcium dynamics in the keratinocyte and consequently induce abnormal keratinization. To test this idea, we first observed the effects of topical application of sebum components, triglycerides (triolein), saturated fatty acids (palmitic acid and stearic acid), and unsaturated fatty acids (oleic acid and palmitoleic acid) on hairless mouse skin. Neither triglyceride nor saturated fatty acids affected the skin surface morphology or epidermal proliferation. On the other hand, application of unsaturated fatty acids, oleic acid, and palmitoleic acid induced scaly skin, abnormal keratinization, and epidermal hyperplasia. Application of triglycerides and saturated fatty acids on cultured human keratinocytes did not affect the intracellular calcium concentration ([Ca(2+)](i)), whereas unsaturated fatty acids increased the [Ca(2+)](i) of the keratinocytes. Moreover, application of oleic acid on hairless mouse skin induced an abnormal calcium distribution in the epidermis. These results suggest that unsaturated fatty acids in sebum alter the calcium dynamics in epidermal keratinocytes and induce abnormal follicular keratinization.

Topics: Acne Vulgaris; Animals; Calcium; Cell Differentiation; Epidermis; Fatty Acids, Unsaturated; Hyperplasia; Keratinocytes; Keratins; Male; Mice; Mice, Hairless

To identify differentially expressed genes during the development of oral malignancy, differential display, northern blotting, reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical analyses were undertaken using oral squamous cell carcinoma (OSCC) and leukoplakia tissues. Significantly higher levels of keratin (Ker)-14 and -17 mRNAs, combined with lower levels of Ker-4, Ker-13 and transglutaminase 3 (TG-3) transcripts, were observed in OSCC and severely dysplastic tissues, whereas this expression profile was reversed in hyperplasia and in mild to moderate dysplasia. The expression of Ker-4 and Ker-13 was elevated in density-arrested OSCC cell lines (Ca9-22, HSC-2, -3 and -4) but the expression of Ker-17 mRNA was elevated in these cells, regardless of the growth conditions. In addition, Ker-4 and Ker-13 proteins were predominantly expressed in moderate dysplasia and hyperplasia, whereas Ker-17 was markedly expressed in OSCC tissues. The expression patterns of these genes could therefore be an important determinant of the manifestation of oral malignancy.

Topics: Adult; Aged; Aged, 80 and over; Calcium-Binding Proteins; Carcinoma, Squamous Cell; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Humans; Hyperplasia; Immunoenzyme Techniques; Keratin-14; Keratins; Leukoplakia, Oral; Male; Middle Aged; Mouth Neoplasms; Neoplasm Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Transglutaminases; Tumor Cells, Cultured

Cystic fibrosis airways are recurrently exposed to noxious stimuli, leading to epithelial injury. Previous reports suggest that cystic fibrosis airway epithelia may respond to injury by increasing proliferation.. We sought to determine the characteristics of the proliferating cell population in cystic fibrosis airways.. Six cystic fibrosis and six normal lung sections from lung transplant recipients or lung surgery were obtained from the Duke Hospital pathology archives. Sections containing bronchi were evaluated for epithelial cell proliferation using immunohistochemistry for a nuclear proliferation antigen, Ki-67, and image analysis; immunohistochemistry for basal cells using a cytokeratin 5/14 antibody; and immunohistochemistry for the epidermal growth factor receptor and ErbB2, two receptor tyrosine kinases implicated in epithelial proliferation and differentiation.. Overall, cystic fibrosis sections had a greater proliferation index than control sections with 25.1 +/- 2.1% positively staining nuclei/total nuclei compared with control sections, 4.6 +/- 0.9% (p = 0.002). In cystic fibrosis sections only, there were areas of hyperplastic cuboidal cells adjacent to normal pseudostratified columnar epithelial sections; in these areas of epithelial hyperplasia, there was uniform Ki-67 staining, indicating a zone of proliferating cells. The proliferating cell population also expressed the basal cell cytokeratins 5/14 and epidermal growth factor receptor. Expression of ErbB2 was diminished in the proliferating cells.. Our results suggest that basal-like cells, expressing the epidermal growth factor receptor, constitute the proliferating cell population in cystic fibrosis airways.

Topics: Adolescent; Adult; Basement Membrane; Biopsy; Bronchi; Case-Control Studies; Cell Count; Cell Proliferation; Child, Preschool; Cystic Fibrosis; ErbB Receptors; Female; Goblet Cells; Humans; Hyperplasia; Image Cytometry; Immunohistochemistry; Infant; Keratins; Ki-67 Antigen; Male; Middle Aged; Photomicrography; Receptor, ErbB-2; Respiratory Mucosa

Overwhelming evidence has demonstrated tobacco smoke (TS) is causally associated with various types of cancers, especially lung cancer. Sustained epithelial cell hyperplasia and squamous metaplasia are considered as preneoplastic lesions during the formation of lung cancer. The cellular and molecular mechanisms leading to lung cancer due to TS are not clear. Mitogen-activated protein kinases (MAPK)/activator protein-1 (AP-1) can be activated by various stimuli and play a critical role in the control of cell proliferation and differentiation. To date, information on the response of the MAPK/AP-1 pathway during hyperplasia and squamous metaplasia induced by TS is lacking. We therefore investigated the effects of TS on the development of epithelial hyperplasia and squamous metaplasia, regulation of MAPK/AP-1 activation, and expression of AP-1-regulated cell cycle proteins and differentiation markers in the lungs of rats. Exposure of rats to TS (30 mg/m(3) or 80 mg/m(3), 6 h/day, 3 days/week for 14 weeks) dramatically induced cell proliferation and squamous metaplasia in a dose-dependent manner, effects that paralleled the activation of AP-1-DNA binding activity. Phosphorylated ERK1/2, JNK, p38 and ERK5 were significantly increased by exposure to TS, indicating the activation of these MAPK pathways. Expression of Jun and Fos proteins were differentially regulated by TS. TS upregulated the expression of AP-1-dependent cell cycle proteins including cyclin D1 and proliferating cell nuclear antigen (PCNA). Among the AP-1-dependent cell differentiation markers, keratin 5 and 14 were upregulated, while loricrin, filaggrin and involucrin were downregulated following TS exposure. These findings suggest the important role of MAPK/AP-1 pathway in TS-induced pathogenesis, thus providing new insights into the molecular mechanisms of TS-associated lung diseases including lung cancers.

Topics: Animals; Cell Proliferation; Cyclin D1; Enzyme Activation; Filaggrin Proteins; Hyperplasia; Intermediate Filament Proteins; JNK Mitogen-Activated Protein Kinases; Keratins; Lung Neoplasms; Male; Membrane Proteins; Metaplasia; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proliferating Cell Nuclear Antigen; Protein Precursors; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Rats, Inbred WKY; Signal Transduction; Smoking; Transcription Factor AP-1

Genetically engineered mouse models with altered oncogene or tumor suppressor gene activity have been utilized recently for carcinogen identification. The v-rasHa transgenic Tg.AC mouse, with its enhanced susceptibility to skin tumorigenesis, is thought to be well suited for examining the carcinogenicity of topically applied agents. Tg.AC mice were used to examine the carcinogenicity of SEPA 0009, a rationally designed organic molecule designed to enhance drug penetration through the skin. Fifty mg SEPA 0009/kg body weight, 1500 mg SEPA 0009/kg body weight, or the vehicle alone was applied daily to the skin of Tg.AC mice. Nontransgenic FVB/N mice were also treated with the vehicle alone or 1500 mg SEPA 0009. Daily application of a high-dose of SEPA 0009 caused severe and chronic irritation by 1 week that was maintained throughout the experiment. The irritation was accompanied by increased proliferation, increased apoptosis, and expression of the wound-associated keratin 6. High-dose SEPA 0009 induced squamous papillomas in Tg.AC, but not in nontransgenic mice, by 6 weeks. In mice treated with the high dose SEPA 0009, transgene expression was detected in papillomas at week 9, well after the onset of skin irritation and hyperplasia. In contrast, low-dose SEPA 0009 was not irritating to the skin and did not induce papillomas. Thus, SEPA 0009-induced tumorigenesis was associated with chronic and severe irritation. We propose that SEPA 0009-induced tumorigenesis in Tg.AC mice proceeds through an indirect mechanism that is secondary to cutaneous irritation.

Topics: Animals; Carcinogenicity Tests; Carcinogens; Cell Death; Cell Proliferation; Dermatitis, Irritant; Dioxolanes; Dose-Response Relationship, Drug; Epidermis; Female; Gene Expression; Genes, ras; Hyperplasia; Keratin-6; Keratinocytes; Keratins; Mice; Mice, Transgenic; Papilloma; Precancerous Conditions; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors

Protein kinase C epsilon (PKCepsilon) overexpressing transgenic (PKCepsilon Tg) mice develop papilloma-independent squamous cell carcinomas (SCC) elicited by 7,12-dimethylbenz[a]anthracene (DMBA) tumor initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) tumor promotion. We examined whether epidermal cell turnover kinetics was altered during the development of SCC in PKCepsilon Tg mice. Dorsal skin samples were fixed for histological examination. A single application of TPA resulted in extensive infiltration of polymorphonuclear neutrophils (PMNs) into the epidermis at 24 h after TPA treatment in PKCepsilon Tg mice while wild-type (WT) mouse skin showed focal infiltration by PMNs. Complete epidermal necrosis was observed at 48 h in PKCepsilon Tg mice only; at 72 h, epidermal cell regeneration beginning from hair follicles was observed in PKCepsilon Tg mice. Since the first TPA treatment to DMBA-initiated PKCepsilon Tg mouse skin led to epidermal destruction analogous to skin abrasion, we propose the papilloma-independent phenotype may be explained by death of initiated interfollicular cells originally destined to become papillomas. Epidermal destruction did not occur after multiple doses of TPA, presumably reflecting adaptation of epidermis to chronic TPA treatment. Prolonged hyperplasia in the hair follicle may result in the early neoplastic lesions originally described by Jansen et al. (2001) by expanding initiated cells in the hair follicles resulting in the subsequent development of SCC.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma, Squamous Cell; Cell Death; Cell Differentiation; Cell Proliferation; Chemotaxis, Leukocyte; Cocarcinogenesis; Disease Models, Animal; Epidermis; Female; Hair Follicle; Hyperplasia; Keratin-10; Keratinocytes; Keratins; Mice; Mice, Transgenic; Neutrophils; Phenotype; Precancerous Conditions; Protein Kinase C-epsilon; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors

We report the historical, clinical and histopathological characteristics of skin lesions in biopsies from 37 heavy draught horses with chronic pastern dermatitis. The skin lesions were divided into four macroscopic groups: scaling (group I, n=5), hyperkeratotic and hyperplastic plaque-like lesions (group II, n=14), nodular skin masses (group III, n=16) and verrucous skin lesions (group IV, n=2). The principal histological findings were hyperkeratosis and epidermal hyperplasia. There was a gradual increase in epidermal hyperplasia from groups I to IV, suggesting that the lesions represent different stages of disease. In all cases, there was perivascular dermatitis dominated by T lymphocytes with an increase in MHC class II-positive dendritic-like cells. Immunohistochemical labelling for cytokeratins CK5/6(4), CK10 and CK14 indicated a change in their expression pattern. This correlated with the degree of epidermal hyperplasia, indicating abnormal differentiation of keratinocytes. There was a statistically significant correlation between the severity of skin lesions and several other factors including increasing age, increasing cannon circumference, prominence of anatomical structures such as fetlock tufts of hairs, ergots and chestnuts, and bulges in the fetlock region.

Topics: Age Factors; Animals; Biopsy; Breeding; Cell Division; Epidermis; Epithelial Cells; Female; Foot Dermatoses; Horse Diseases; Horses; Hyperplasia; Immunohistochemistry; Keratins; Ki-67 Antigen; Male; Prevalence; Risk Factors; Severity of Illness Index; Sex Factors; Skin

To investigate the relationship between the formation of pseudoepitheliomatous hyperplasia (PEH) and the mechanism of loss of some components from the basement membrane in epithelial interstitial junction (EIJ) in the treatment of cutaneous wounds, when formation of PEH lesion was induced.. Morphological change in epithelial tissue was observed with histopathologic method and electronic microscopy in 11 specimens of PEH lesions and 6 specimens of normal skin adjacent to PEH (PEH-N) from 11 patients with injured skin. The expression characteristics and distribution of pan-cytokeratin (p-CK), matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-9, proliferating cell nuclear antigen (PCNA), epithelial cadherin(E-Cad) and beta-catenin(beta-Cat) in EMJ were detected with immunohistochemical methods.. Epithelial cells expressing P-CK presented squamous epithelialization and extended into deep layer of mesenchyma. In epithelium-mesenchyma junction, where IV type collagen and laminin were weakly expressed, the protein contents of p-CK, E-Cad, MMP-2, MMP-3 MMP-9 were decreased, whilst the immunochemical staining of beta-Cat and PCNA was apparently increased. In the junction, epithelial basal cells were observed to migrate and to depart from basal membrane; epithelial islands and isolated epithelial cells expressing p-CK in mesenchyma could be observed. Ultrastructural observation revealed deformation of epithelial basal cells, increment of nucleus/cytoplasm ratio, loosened intercellular junctions, decrement of electronic density of BM and derangement of BM structure could be observed.. Reduction in the capability of epithelial basal cells adhesion, differentiation and formation of basement membrane and cytokeratin in PEH associated with wound may be the crucial cause which controls epithelial cells migration into mesenchyma. That the contents of ColIV and LN were decreased may not be associated with MMPs, but with enhancement of the ratio of beta-Cat/E-Cad signal might be the important mechanism of dedifferentiation of epithelial basal cells and the loss of ability of structure formation and cellular migration.

Topics: Basement Membrane; beta Catenin; Cadherins; Cytoskeletal Proteins; Epithelium; Humans; Hyperplasia; Immunohistochemistry; Keratins; Matrix Metalloproteinases; Proliferating Cell Nuclear Antigen; Skin; Trans-Activators

This investigation, though initially designed to examine the possible influence of the Bcl-2 protein on the node-metastasizing capacity of breast carcinomas, was amplified to study the expression of this anti-apoptotic protein in normal breast lobules and hyperplastic lesions. We examined paraffin sections of 508 breast carcinomas, stained for Bcl-2, estrogen (ER) and progesterone receptors (PgR) and epithelial membrane antigen, and occasionally for other antigens as well. Only a few cells showing a strong Bcl-2 positivity spotted the tubulo-lobular units of normal resting glands, whereas such cells were relatively numerous in atrophic lobules, and very scarce in the terminally differentiated lactating breast. Columnar and usual types of hyperplasia were exclusively, or almost exclusively, composed of Bcl-2(+), ER(+) and PgR(+) cells. The foci of carcinoma in situ and those of invasive carcinomas were respectively 83% and 66% positive for Bcl-2 in at least 25% of their cells. Even among the invasive carcinomas, Bcl-2(+) cases included 83% and 87% of the ER(+) and PgR(+) cases, respectively (p=0.0001). Though there was a statistically significant inverse relation between Bcl-2 and tumor grade (p=0.0001), no significant association was found between Bcl-2 and lymph node stage. In conclusion, we suggest that normal, hyperplastic and neoplastic breast epithelial cells expressing the anti-apoptotic protein Bcl-2 are immature cells that ought to form part of the stem-cell subpopulation, which is committed to the development and to the maintenance of the normal gland and which gives rise to hyperplastic and neoplastic disorders when its proliferation is deregulated. In ductal proliferative changes Bcl-2 assays may be useful for diagnostic but not for prognostic purposes.

Topics: Aged; Apoptosis; Breast; Breast Neoplasms; Carcinoma; Cell Division; Gene Expression Regulation, Neoplastic; Humans; Hyperplasia; Immunohistochemistry; Keratins; Middle Aged; Neoplasm Metastasis; Proto-Oncogene Proteins c-bcl-2; Receptors, Estrogen; Receptors, Progesterone; Stem Cells

In routine examination of liver biopsies isolated ductular hyperplasia (IDH) may be the only histopathological change. Here we describe the clinical and immunophenotypic features of a number of cases retrospectively identified reviewing consecutive liver biopsies from five Italian centers over 4 years.. We reviewed 1235 cases biopsied for chronic liver disease (1078 for viral hepatitis). Records of cases fulfilling the inclusion criteria for IDH were reviewed to identify possible aetiologies. Biopsies showing IDH and control biopsies were studied by immunohistochemistry for cytokeratin-7, epithelial-membrane-antigen (EMA), neural-cell-adhesion-molecule (NCAM), Ki-67.. Out of 70 biopsies fulfilling IDH criteria, 16 (22.8%) were of unknown aetiology. Patients with idiopathic IDH (age 38.2+/-11 years) were asymptomatic with mild, long-lasting ALT and/or gammaGT increases. A significant increase of well-differentiated (EMA-positive; NCAM-negative) bile ductules localized at the portal interface and inside the lobule was found in idiopathic IDH.. Idiopathic IDH was present in 10% of adults biopsied for persistent mild liver function test abnormalities unrelated to viral hepatitis. In contrast with the ductular reaction seen in many forms of liver disease, it is characterized by well-differentiated hyperplastic ductules in absence of significant inflammation, and may represent a non-specific pattern of reaction to mild liver damages.

Topics: Adolescent; Adult; Bile Ducts, Intrahepatic; Case-Control Studies; Female; Humans; Hyperplasia; Keratin-7; Keratins; Liver Function Tests; Male; Middle Aged; Mucin-1; Neural Cell Adhesion Molecules; Retrospective Studies

Population-based oral cancer screening appears to be a promising health promotion strategy (especially in high-risk individuals) with significant increases in quality-adjusted life years saved. However, the current protocol, conventional visual inspection, and palpation of oral soft tissues for the early detection of pre-malignant or malignant changes, appears to be deficient. The adjunctive application of technology to highlight such lesions may increase the diagnostic yield. The purpose of this pilot study was to collect data, which might support the hypothesis that oral soft tissues exhibit features similar to the cervical epithelium following an acetic acid wash and visual inspection under chemiluminescent illumination. The data provides strong evidence to support the hypothesis. Epithelium with hyperkeratinization, hyperparakeratinization, and/or chronic inflammatory infiltrate reflects the diffuse, low-level, blue-white chemiluminescent light more strongly and appears amplified. Similarly, epithelium with an altered nuclear-cytoplasmic ratio also reflects the diffuse, low-level, blue-white chemiluminescent light. In such cases, the lesions become clinically discernible and appear "acetowhite." Large-scale studies are required to further refine issues related to the selectivity and specificity of the technology.

Topics: Acetic Acid; Adolescent; Adult; Aged; Cell Nucleus; Cytoplasm; Epithelium; Female; Humans; Hyperplasia; Indicators and Reagents; Keratins; Leukoplakia, Oral; Luminescent Measurements; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Pilot Projects; Precancerous Conditions; Sensitivity and Specificity

The Bmx gene, a member of the Tec family of nonreceptor protein tyrosine kinases, is expressed in arterial endothelium and in certain hematopoietic and epithelial cells. Previous in vitro studies have implicated Bmx signaling in cell migration and survival and suggested that it contributes to the progression of prostate carcinomas. However, the function of Bmx in normal tissues in vivo is unknown. We show here that Bmx expression is induced in skin keratinocytes during wound healing. To analyze the role of Bmx in epidermal keratinocytes in vivo, we generated transgenic mice overexpressing Bmx in the skin. We show that Bmx overexpression accelerates keratinocyte proliferation and wound reepithelialization. Bmx expression also induces chronic inflammation and angiogenesis in the skin, and gene expression profiling suggests that this occurs via cytokine-mediated recruitment of inflammatory cells. Our studies provide the first data on Bmx function in vivo and form the basis of evaluation of its role in epithelial neoplasia.

Topics: Animals; Base Sequence; Cell Differentiation; DNA; Gene Expression; Humans; Hyperplasia; Inflammation Mediators; Keratin-14; Keratinocytes; Keratins; Mice; Mice, Transgenic; Neovascularization, Pathologic; Promoter Regions, Genetic; Protein-Tyrosine Kinases; Skin; Wound Healing

The aim of the present study was to explore cell biological characteristics of normal breast, benign proliferative breast diseases and noninvasive breast malignancies based on the recently published adult progenitor cell concept from our group. Here, we investigated the proliferative activity of CK5/14(+), CK8/18/19(+) and alpha-smooth muscle actin(+) cellular phenotypes encountered in normal mammary gland, in a series of usual ductal hyperplasias and early malignant breast diseases, such as atypical ductal and lobular hyperplasias, as well as ductal and lobular in situ carcinomas. Immunohistochemical double labeling was performed on frozen sections from diagnostic breast biopsies by using antibodies to basal cytokeratins (CK5/14), glandular cytokeratins (CK8/18/19), smooth muscle actin and the Ki-67 antigen (MIB1). Normal breast tissues and usual ductal hyperplasias were characterized by a heterogeneous cellular composition of the growth fraction. The proliferative cell compartment consisted of CK8/18/19(+) glandular and, in a variable proportion, CK5/14(+) progenitor phenotypes. In contrast, noninvasive breast malignancies were composed of a monotonous proliferation of CK 8/18/19(+) neoplastic glandular cells. These findings indicate a significant role of progenitor cells in the development of benign proliferative breast diseases and lend support to the view that malignant transformation in the human breast usually occurs in a cell committed to the glandular lineage. Our results provide cell kinetic support to the functional progenitor cell hypothesis, and we propose this concept as an operative model for understanding benign proliferative and malignant breast diseases.

Topics: Actins; Adult; Aged; Breast; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Lobular; Cell Proliferation; Female; Humans; Hyperplasia; Immunohistochemistry; Keratin-14; Keratin-5; Keratins; Ki-67 Antigen; Mammary Glands, Human; Middle Aged; Muscle, Smooth

To investigate the abnormalities of human epiderm in keloids and hypertrophic scars.. Biopsies from ten untreated keloids (duration of disease 3 - 30 years) and ten hypertrophic scars (duration of disease 6 - 10 months) and five normal adult skin specimens. Total RNA was isolated from normal adult skin. A cDNA fragment (base 5941 - 6481 bp) of the full-length human Tenascin-C cDNA was synthesized by polymerase chain reaction and subcloned in pGEM-T-easy. Dioxigen-labeled anti-sense and sense probes were synthesized by using a Sp6/T7 in vitro RNA synthesis kit in the present of Dig-UTP. In situ hybridization was performed on 4% paraformaldehyde-fixed and wax-embedded sections of keloids and hypertrophic scars. NBT-NCIP was used in color detection. Immunohistochemical procedure. The sections were incubated with antibodies (anti-Tenascin-C, anti-CK-16 and anti-Ki-67). Ultrasensitive Streptavidin Peroxidase staining was performed following established procedures.. The study show that the proliferation of epidermal keratinocytes in keloids and hypertrophic scars is very clear. The expressions of Tenascin-C mRNA in keloids epidermal keratinocytes markedly increased in contrast with epidermal keratinocytes of hypertrophic scars and adult skin. The CK-16 and Ki-67 stainings significantly enhanced in the epidermal keratinocytes of keloids and hypertrophic scars.. The different expressions of Tenascin-C, CK-16 and Ki-67 among normal adult skin, keloids and hypertrophic scars show the abnormalities of epidermal keratinocytes proliferation and differentiation in keloids and hypertrophic scars.

Topics: Cicatrix, Hypertrophic; Epidermis; Female; Humans; Hyperplasia; Immunohistochemistry; In Situ Hybridization; Keloid; Keratins; Ki-67 Antigen; Male; Tenascin

To evaluate the expression of cytokeratins in intraductal proliferative lesions of breast, including usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH), ductal carcinoma-in-situ (DCIS) and its role in differential diagnosis.. Ninety two cases of paraffin-embedded lesional breast tissue, 30 cases of frozen samples, cell cultures of hyperplastic ductal cells and 2 invasive ductal carcinoma cell lines (T47D and MCF-7) were used for this study. Immunohistochemistry was performed using EnVision method for 34betaE12, CK8 and CK14.. The percentage of 34betaE12-positivity in paraffin-embedded samples of UDH, ADH, DCIS and invasive ductal carcinoma (IDC) was found to be 95.2%, 33.3%, 19.2% and 12.5% respectively. In frozen tissues, all UDH cases and 55% of IDC cases expressed 34betaE12. The primary UDH cell cultures and T47D cell line were also 34betaE12-positive, whereas MCF7 cell line showed negative staining. The expression rate of CK8 and CK14 in UDH was also different from that in ADH and DCIS.. 34betaE12 can be useful in differential diagnosis of intraductal proliferative lesions of the breast. However application of this cytokeratin stain in intraoperative frozen sections is relatively limited. The expression patterns of CK8 and CK14 are also helpful in the differential diagnosis of similar lesions.

Topics: Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Cell Line, Tumor; Diagnosis, Differential; Female; Humans; Hyperplasia; Keratins; Precancerous Conditions

Diagnostic utility of E-cadherin (E-CD) and cytokeratin (CK) subtype profiling in effusion cytology was investigated, employing immunocytochemistry on cellblock sections available from 211 metastatic carcinomas (MC), 6 mesotheliomas and 73 reactive mesothelial hyperplasias (MH). E-CD and monoclonal carcinoembryonic antigen (mCEA) stained 85% (120/141) and 65% (138/211) of MC, respectively. E-CD staining of MC was frequently heterogeneous (76/120) and absent in all anaplastic carcinomas (0/2). E-CD stained none (0/57) of MH while mCEA and epithelial membrane antigen (EMA) stained 12% (9/73) and 32% (16/32) of MH, respectively. Of 6 mesotheliomas, E-CD focally stained in 2 while mCEA stained none and EMA stained all. CK20 and CK17 stained none of MH or mesotheliomas. CK20 stained 15% of MC and CK 17 stained 22% of MC. CK5/6 and high molecular weight CK stained all mesotheliomas, 56% and 88% of MH, 26% and 39% of MC, respectively. MC showed predominant CK7+/20-expression, with the exceptions of MC from mucinous type of colon/rectum and ovary showing predominant CK20 positive. E-CD may be a useful positive marker for MC in effusion cytology, although it may focally stain in some mesotheliomas. Any positive staining for CK20 of MC suggests MC from the gastrointestinal tract or ovary among others.

Topics: Biomarkers, Tumor; Cadherins; Carcinoma; Diagnosis, Differential; Epithelium; Humans; Hyperplasia; Immunohistochemistry; Keratins; Mesothelioma

Monoclonal antibody 34betaE12 (Ck34betaE12) recognizes a set of cytokeratins (1, 5, 10, 14) expressed in normal stratified squamous epithelium. We have recently reported its expression in squamous cell carcinoma and basaloid carcinoma, in contrast to large cell neuroendocrine carcinoma, an entity with overlapping morphological features with basaloid carcinoma. We have now examined the role of Ck34betaE12 in discriminating between neuroendocrine and non-neuroendocrine proliferations.. We performed an immunohistochemical study of 228 cases, comprising the whole spectrum of lung neuroendocrine proliferations and tumours. All cases of neuroendocrine cell hyperplasia (n = 15), tumorlet (n = 23), typical carcinoid (n = 27) and atypical carcinoid (n = 23) were completely negative for Ck34betaE12. Although the neuroendocrine cells of small cell lung carcinoma and large cell neuroendocrine carcinoma were consistently negative, a strong and diffuse positive staining was found in the non-neuroendocrine components of combined small cell carcinoma (three of eight cases) and combined large cell neuroendocrine carcinoma (11 of 12 cases). In addition, scattered Ck34betaE12+ cells were noted in 11 of 64 (17%) large cell neuroendocrine carcinoma and in seven of 56 (12.5%) small cell carcinoma, which were not obviously histologically combined. This heterogeneity of high-grade neuroendocrine tumours was not observed in carcinoids which lack Ck34betaE12 clusters of reactive cells. There was mutual exclusion between expression of neuroendocrine markers and that of Ck34betaE12.. We conclude that 34betaE12 expression excludes the neuroendocrine nature of tumour cells and uncovers the real frequency of combined forms in high-grade neuroendocrine tumours.

Topics: Biomarkers, Tumor; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Fluorescent Antibody Technique, Indirect; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Lung Neoplasms

12-O-Tetradecanoylphorbol-13-acetate (TPA) was applied to the back skin of v-Ha-ras (TG-AC) female transgenic mice at a dose of 2.5 microg/200 microl twice a week for 9 weeks. The back skin was then exposed to blue light (wavelength, 470 nm; irradiance, 5.7 mW/cm2) for 1 h daily for 9 weeks. The mice to which TPA was applied developed skin tumors at 6 weeks after the start of application. The tumor incidence rates at 6, 7, 8 and 9 weeks after the start of application were 70%, 80%, 100% and 100%, respectively, and the numbers of tumors 1 mm or more in diameter were 1, 5, 10 and 19, respectively. In the mice that were exposed to blue light after TPA application, the tumor incidence rates were 10%, 40%, 60% and 80%, respectively, and the numbers of tumors 1 mm or more in diameter were 0, 2, 5 and 9, respectively. Histopathological examination of the skin revealed that TPA application induced diffuse hyperplasia, exaggerated keratinization, and papillomas in all 10 mice. A localized form of epidermal hyperplasia was also observed in 4 mice. The incidence rate of papillomas in the mice that were exposed to blue light after TPA application was lower and the degree of exaggerated keratinization was greater. Exaggerated keratinization was considered to represent a regressive change following exposure. These findings suggest that exposure to blue light may be a promising new approach in the treatment of skin tumors.

Topics: Animals; Epidermis; Female; Genes, ras; Hyperplasia; Keratins; Mice; Mice, Transgenic; Oncogene Protein p21(ras); Papilloma; Phototherapy; Precancerous Conditions; Recombinant Fusion Proteins; Skin Diseases; Skin Neoplasms; Tetradecanoylphorbol Acetate; Weight Gain

Previous studies have shown that basal-type cytokeratins (CKs) can distinguish usual ductal hyperplasia (UDH) from the spectrum of atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS). Indeed, expression of these CKs is weak or absent in ADH, DCIS and LCIS. However, the diagnostic usefulness of D5/16B4 antibody (anti-CK5/6) has never been compared with that of 34betaE12 antibody (anti-CK1/5/10/14). We performed immunostaining of CK 5/6 and CK1/5/10/14 on 100 breast lesions, including UDH ( n=31), ADH ( n=5), DCIS ( n=54) and LCIS ( n=10). Abundant immunostaining was observed in all UDH using both antibodies. Four of five of the ADH cases showed less than 5% of CK5/6 stained cells, the remaining case showed 30% of labeled cells. With 34betaE12 antibody, three of five of the ADH cases showed less than 5% labeled cells, while two cases showed more than 30% of stained cells. None of the 54 DCIS or the 10 LCIS was labeled by D5/16B4, while a lack of 34betaE12 immunostaining was observed in only 15 of 54 DCIS and 2 of 10 LCIS. We confirmed that D5/16B4 antibody directed against CK5/6 is useful in distinguishing UDH from the spectrum of ADH/DCIS/LCIS. We also demonstrated that D5/16B4 is far a more specific marker than 34betaE12 antibody.

Topics: Biomarkers, Tumor; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Cell Count; Female; Humans; Hyperplasia; Immunohistochemistry; Keratin-5; Keratins; Sensitivity and Specificity

A frequent genetic alteration found in premalignant stages of pancreatic adenocarcinoma is K-ras oncogene point mutation. The mechanistic basis for the inability of K-ras mutation to transform pancreatic ductal cells is unclear, although cooperating events with p16 inactivation, p53 mutation, and SMAD 4 mutation are recognized to be necessary. We have generated a novel mouse model in which the cytokeratin 19 promoter, specifically active in pancreatic ductal cells but not other cell types of the pancreas, is fused to mutant K-ras. This is of direct relevance to human pancreatic cancer because premalignant lesions are found specifically in ductal cells. There is dramatic periductal lymphocytic infiltration in the pancreata of transgenic mice, predominantly CD4+ T lymphocytes, which may act as an adaptive immune response to activated ras-mediated signaling. In addition, gene array analysis reveals an induction of N-cadherin in transgenic mice pancreatic ductal cells, the significance of which relates to promotion of cell adhesion and deterrence of cell migration. Apart from these important biological considerations, there is parallel activity of the cytokeratin 19 promoter in the stem cell region of the gastric epithelium, namely in mucous neck cells. Activated K-ras in this context causes mucous neck cell hyperplasia, a precursor to gastric adenocarcinoma. There is concomitant parietal cell decrease, which is a key step toward gastric adenocarcinoma. Taken together, we have defined how mutant K-ras signaling modulates important molecular events in the initiating events of pancreatic and gastric carcinogenesis.

Topics: Adenocarcinoma; Animals; Carcinoma, Pancreatic Ductal; Cell Transformation, Neoplastic; Gastric Mucosa; Genes, ras; Humans; Hyperplasia; Keratins; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Transgenic; Mutation; Pancreatic Neoplasms; Precancerous Conditions; Promoter Regions, Genetic; Stomach Neoplasms; Transfection; Tumor Cells, Cultured

The histopathology of papillary thyroid hyperplasia and papillary thyroid carcinoma is similar enough to cause a diagnostic dilemma in a few cases. Both lesions may have papillary fronds with fibrovascular cores, nuclear crowding, and nuclear anisocytosis. Formalin- fixed paraffin-embedded tissues from 30 randomly selected patients with papillary thyroid hyperplasia and an equal number from patients with papillary thyroid carcinoma were analyzed for expression of cytokeratin 19 (CK19), galectin-3, and HBME-1. Cases of papillary thyroid carcinoma had moderate to strong CK19, galectin-3, and HBME-1 reactivity although both CK19 and galectin-3 showed positive staining in a significant number of nonneoplastic thyroid cases. HBME-1 was uncommon in the nonneoplastic cases. These results indicate that HBME-1 may be useful in helping to distinguish papillary thyroid carcinoma from hyperplasia in diagnostically difficult cases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Papillary; Diagnosis, Differential; Female; Galectin 3; Humans; Hyperplasia; Immunohistochemistry; Keratins; Male; Middle Aged; Thyroid Diseases; Thyroid Neoplasms

Human papillomaviruses (HPVs) are the causative agent of warts. Infections with high-risk HPVs are associated with anogenital and head and neck cancers. One of the viral genes responsible for HPV's oncogenic activity is E6. Mice expressing the HPV-16 E6 protein in their epidermis (K14E6(WT)) develop epithelial hyperplasia and squamous carcinomas. Numerous cellular proteins interact with E6, some of which can be grouped based on common amino acid motifs in their E6-binding domains. One such group, the PDZ partners, including hDLG, hSCRIBBLE, MUPP1, and MAGI, bind to the carboxy-terminal four amino acids of E6 through their PDZ domains. E6's interaction with the PDZ partners leads to their degradation. Additionally, E6's binding to PDZ proteins has been correlated with its ability to transform baby rat kidney cells in tissue culture and to confer tumorigenicity onto cells in xenograft experiments. To address whether the ability of E6 to bind PDZ domain partners is necessary for E6 to confer epithelial hyperproliferation in vivo, we generated transgenic mice that express in stratified squamous epithelia a mutant of E6 lacking the last six amino acids at its carboxyl terminus, E6(Delta 146-151), from the human keratin 14 (K14) promoter. The K14E6(Delta 146-151) mice exhibit a radiation response similar to that of the K14E6(WT) mice, demonstrating that this protein, as predicted, retains an ability to inactivate p53. However, the K14E6(Delta 146-151) mice fail to display epithelial hyperplasia. These results indicate that an interaction of E6 with PDZ partners is necessary for its induction of epithelial hyperplasia.

Topics: Adaptor Proteins, Signal Transducing; Animals; Carrier Proteins; Cell Transformation, Neoplastic; Discs Large Homolog 1 Protein; DNA Damage; Guanylate Kinases; Humans; Hyperplasia; Keratin-14; Keratins; Ligands; Membrane Proteins; Mice; Mice, Transgenic; Oncogene Proteins, Viral; Papillomaviridae; Proliferating Cell Nuclear Antigen; Proteins; Rats; Repressor Proteins; Skin Neoplasms

Gain-of-function mutations in SMO have been implicated in constitutive activation of the hedgehog signaling pathway in human basal cell carcinomas (BCCs). We used a truncated keratin 5 (DeltaK5) promoter to assess the potential role of the human M2SMO mutant in BCC development in adult transgenic mice. DeltaK5-M2SMO mouse epidermis is hyperproliferative, ex presses BCC protein markers and gives rise to numerous epithelial downgrowths invading the underlying dermis. Lesions strikingly similar to human basaloid follicular hamartomas develop, but BCCs do not arise even in elderly mice. Hedgehog target gene transcripts were only modestly upregulated in mouse and human follicular hamartomas, in contrast to the high levels detected in BCCs. Cyclins D1 and D2 were selectively upregulated in mouse BCCs. Our data suggest that the levels of hedgehog pathway activation and G(1) cyclins are major determinants of tumor phenotype in skin, and strongly implicate deregulated hedgehog signaling in the genesis of human basaloid follicular hamartomas. Expression of an activated SMO mutant in keratinocytes appears to be insufficient for the development and/or maintenance of full-blown BCCs.

Topics: Alopecia; Animals; Carcinoma, Basal Cell; Cell Differentiation; Hamartoma; Hedgehog Proteins; Humans; Hyperplasia; Keratin-15; Keratin-5; Keratinocytes; Keratins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Phenotype; Promoter Regions, Genetic; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Signal Transduction; Skin Neoplasms; Smoothened Receptor; Trans-Activators

Adenomyoma and adenomyomatous hyperplasia of the Vaterian system are consistently benign lesions. Clinically, adenomyoma mimics frequently ampullary adenoma or carcinoma, and biopsy analysis is often difficult. The histogenesis of ampullary adenomyoma and adenomyomatous hyperplasia is still subject to debate. We present a retrospective study of clinicopathological features of 13 cases of surgically resected ampullary adenomyoma. The age of our patients was between 38 and 78 years (mean: 63 y). The preoperative diagnosis was ampullary tumor or tumor of the head of the pancreas. On macroscopy, a white, firm lesion of the ampullary wall was observed; its size ranged between 10 and 30 mm. Histologically the lesion consisted of multiple glandular structures surrounded by a fibroblastic/myofibroblastic proliferation, resulting in a "pseudo-hypertrophy" of the Vaterian system. The immunophenotype of the epithelial component was cytokeratin 7+/cytokeratin 20-, similar to that of the normal biliary and pancreatic duct system. The epithelial cells exhibited low proliferative activity. The hyperplastic myofibroblastic cells expressed smooth muscle actin. A complete pancreatic heterotopy contiguous with the adenomyoma was noted in three cases. Adenomyoma and adenomyomatous hyperplasia of the Vaterian system are benign lesions frequently treated by extensive surgery because of long-term biliary obstruction. The clinicopathological characteristics suggest either a reactive and/or a malformative, nonneoplastic nature for this lesion, which could, in some cases, develop from heterotopic pancreas. The immunophenotype of epithelial cells may be a useful tool for differentiating it from ampullary adenoma on biopsy specimens.

Topics: Adenomyoma; Adult; Aged; Ampulla of Vater; Biomarkers, Tumor; Common Bile Duct Neoplasms; Female; Humans; Hyperplasia; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Male; Middle Aged; Pancreaticoduodenectomy; Retrospective Studies; Treatment Outcome

The significant increase in oral cancer mortality necessitates further research on the mechanisms of tumorigenesis. It was the aim of this study to compare the permeability, lipid composition and histopathological characteristics of oral leukoplakia with non-lesional specimens of the same region in 30 cases as well as 11 specimens originating from healthy control buccal mucosa. The permeability (Kp) of tissue biopsies to tritiated nitrosonornicotine was determined in a continuous through-flow perfusion system, lipids were extracted and identified by thin-layer chromatography, and thickness of epithelium and keratin layer assessed by histopathological methods. Results of the measurements showed that the permeability to the tobacco carcinogen, nitrosonornicotine for leukoplakic tissue was higher than for normal control buccal specimens. Non-lesional areas of buccal mucosa, adjacent to leukoplakias, showed hyperplasia and significantly higher permeability values than both leukoplakic and normal buccal control mucosa. The lipid content of the non-lesional sites was intermediate between the increased values of the leukoplakic lesion and of normal control mucosa. The data strongly suggest that the presence of tobacco in the oral cavity may bring about generalized changes even in regions that do not show leukoplakia.

Topics: Adult; Aged; Alcohol Drinking; Analysis of Variance; Carcinogens; Chromatography, Thin Layer; Epithelium; Female; Humans; Hyperplasia; Keratins; Leukoplakia, Oral; Lipids; Male; Middle Aged; Mouth Mucosa; Nitrosamines; Permeability; Smoking

Topics: Antigens, CD; Antigens, Differentiation, B-Lymphocyte; Cell Adhesion Molecules; Child; DNA-Binding Proteins; Humans; Hyperplasia; Immunohistochemistry; Keratins; Lectins; Myasthenia Gravis; Nerve Tissue Proteins; Nuclear Proteins; Receptors, Steroid; Receptors, Thyroid Hormone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sialic Acid Binding Ig-like Lectin 2; Thymoma; Thymus Gland; Transforming Growth Factor beta; Transforming Growth Factor beta1

During evolution, placental mammals appear to have lost cyclobutane pyrimidine dimer (CPD) photolyase, an enzyme that efficiently removes UV-induced CPDs from DNA in a light-dependent manner. As a consequence, they have to rely solely on the more complex, and for this lesion less efficient, nucleotide excision repair pathway. To assess the contribution of poor repair of CPDs to various biological effects of UV, we generated mice expressing a marsupial CPD photolyase transgene. Expression from the ubiquitous beta-actin promoter allowed rapid repair of CPDs in epidermis and dermis. UV-exposed cultured dermal fibroblasts from these mice displayed superior survival when treated with photoreactivating light. Moreover, photoreactivation of CPDs in intact skin dramatically reduced acute UV effects like erythema (sunburn), hyperplasia and apoptosis. Mice expressing the photolyase from keratin 14 promoter photo reactivate CPDs in basal and early differentiating keratinocytes only. Strikingly, in these animals, the anti-apoptotic effect appears to extend to other skin compartments, suggesting the presence of intercellular apoptotic signals. Thus, providing mice with CPD photolyase significantly improves repair and uncovers the biological effects of CPD lesions.

Topics: Actins; Animals; Apoptosis; Cells, Cultured; Deoxyribodipyrimidine Photo-Lyase; DNA; DNA Damage; DNA Repair; Epidermis; Erythema; Fibroblasts; Glutathione Transferase; Humans; Hyperplasia; Keratinocytes; Keratins; Macropodidae; Mice; Mice, Transgenic; Promoter Regions, Genetic; Pyrimidine Dimers; Radiation Injuries, Experimental; Radiation Tolerance; Recombinant Fusion Proteins; Skin; Transgenes; Ultraviolet Rays

Topics: Biopsy, Needle; E2F6 Transcription Factor; Endothelium, Vascular; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Middle Aged; Paraganglioma; Platelet Endothelial Cell Adhesion Molecule-1; Repressor Proteins; Thyroglobulin; Thyroid Neoplasms; Transcription Factors

An unusual case of an odontogenic cyst with verrucous proliferation is described in a 13-year-old girl. This histologically distinctive odontogenic cyst variant does not appear to have been reported previously. The cyst was characterised by a series of verrucous projections in the lumen with hypergranulosis and cells resembling koilocytes, raising the possibility of a viral aetiology. However, no evidence of human papillomavirus (HPV) was found using immunohistochemistry and polymerase chain reaction (PCR) amplification.

Topics: Adolescent; Cell Division; Epithelial Cells; Female; Humans; Hyperplasia; Keratins; Maxillary Diseases; Mitosis; Odontogenic Cysts; Papillomaviridae; Warts

The distinction of basal cell hyperplasia (BCH) from carcinoma or high-grade prostatic intraepithelial neoplasia may be difficult. We reviewed 25 cases of BCH with unusual features and identified four distinct groups: BCH with intracytoplasmic globules (five cases); BCH with calcifications (eight cases), including one with globules; BCH with squamous features (three cases); and cribriform BCH (nine cases), including two cases with globules. A total of five cases contained prominent nucleoli and/or cytologic atypia. Hyaline cytoplasmic globules have not been described in any other prostatic entity and appear diagnostic of BCH. Calcifications observed in BCH were psammomatous, differing from the fine stippled calcifications occasionally seen in areas of comedonecrosis within high-grade prostatic carcinoma. Basal cell hyperplasia with squamous features differed from squamous differentiation in carcinomas (adenosquamous carcinoma) and from benign foci of squamous differentiation seen associated with either prostatic infarcts or with hormonal therapy. Whereas cribriform prostatic intraepithelial neoplasia and cribriform cancer glands represent a single glandular unit with punched out lumina, many of the glands within a focus of cribriform BCH appeared as fused individual BCH glands. The use of cytokeratin 34betaE12 can help in difficult cases. In cribriform BCH high-molecular-weight cytokeratin shows multilayered staining of the basal cells in some of the glands and a continuous layer of immunoreactivity. Cribriform prostatic intraepithelial neoplasia demonstrates an interrupted immunoreactive single cell layer of basal cells. Recognition of the architectural and cytologic features of unusual morphologies of BCH can be used to facilitate its diagnosis and differentiation from prostatic carcinoma and high-grade prostatic intraepithelial neoplasia.

Topics: Carcinoma, Adenosquamous; Diagnosis, Differential; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Prostate; Prostatic Intraepithelial Neoplasia; Prostatic Neoplasms

Transgenic mice were developed to study the role of c-src in epithelial tumorigenesis through targeted expression of a constitutively active form of murine c-src (src(529)). Src(529) was targeted to the interfollicular epidermis with the human keratin 1 (HK1) promoter. The skin phenotype of these mice was characterized by exaggerated epidermal hyperplasia and hyperkeratosis within the first week after birth. The severity of this phenotype correlated with overall src kinase activity, both of which subsided with age. Treatment of adult HK1.src(529) transgenic mice with the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate resulted in an increase in epidermal hyperplasia and labeling index significantly greater than that seen in nontransgenic littermates. In addition, HK1.src(529) transgenic mice developed papillomas earlier and in significantly greater numbers compared with nontransgenic littermates in a standard initiation-promotion experiment. The data support the hypothesis that activation of c-src kinase plays a role in skin tumor promotion.

Topics: Animals; Carcinogens; Epidermis; Hyperplasia; Keratins; Kinetics; Mice; Mice, Transgenic; Mutation; Promoter Regions, Genetic; Proto-Oncogene Proteins pp60(c-src); Skin Neoplasms; Tetradecanoylphorbol Acetate

Ionic fluxes are important for critical aspects of keratinocyte differentiation, including synthesis of differentiation-specific proteins, enzymatic catalysis of protein cross-linking, post-transcriptional processing of profilaggrin, and lipid secretion. The epithelial sodium channel is expressed in epidermis and the expression of its alpha and beta subunits is enhanced as keratinocytes differentiate. In order to ascertain the role of the epithelial sodium channel in epidermal differentiation, we examined skin of mice in which the epithelial sodium channel alpha subunit had been deleted. Newborn -/- mice, in which the alpha subunit had been completely inactivated, demonstrated epithelial hyperplasia, abnormal nuclei, premature secretion of lipids, and abnormal keratohyaline granules. In addition, immunohistochemistry demonstrated that expression of the differentiation markers K1, K6, and involucrin were abnormal. These data suggest that the epithelial sodium channel modulates ionic signaling for specific aspects of epidermal differentiation, such as synthesis or processing of differentiation- specific proteins, and lipid secretion.

Topics: Animals; Biopsy; Cell Differentiation; Epidermal Cells; Epidermis; Epithelial Sodium Channels; Gene Expression; Hyperplasia; Keratinocytes; Keratins; Lipid Metabolism; Mice; Mice, Knockout; Microscopy, Electron; Protein Precursors; Sodium; Sodium Channels

To characterize, at the histopathologic and molecular levels, the irradiated epidermis in cases of human skin fibrosis induced by radiotherapy.. Surgical samples were obtained from 6 patients who had developed cutaneous fibronecrotic lesions from 7 months to 27 years after irradiation. The proliferation and differentiation status of the irradiated epidermis was characterized with specific markers using immunohistochemical methods.. All samples presented with hyperplasia of the epidermis associated with local inflammation. The scar epidermis exhibited an increased expression of proliferating cell nuclear antigen, which revealed hyperproliferation of keratinocytes. Furthermore, an abnormal differentiation was found, characterized by the expression of K6 and K16, and by alterations in protein amounts and localization of cytokeratins, involucrin, and transforming growth factor-beta1.. These results demonstrate that late damage of irradiated skin is not only characterized by fibrosis in the dermis but also by hyperplasia in the epidermis. This hyperplasia was due to both hyperproliferation and abnormal differentiation of keratinocytes.

Topics: Adult; Aged; Cell Differentiation; Cell Division; Cicatrix; Female; Humans; Hyperplasia; Integrins; Keratinocytes; Keratins; Male; Middle Aged; Proliferating Cell Nuclear Antigen; Radiation Injuries; Skin; Transforming Growth Factor beta

Three cases of Spitz nevus of the tongue associated with pseudoepitheliomatous hyperplasia are reported: two occurring in children and one in an adult. The location at an unusual site and the complex pattern resulting from the intimate admixture of the neoplastic melanocytic component and the hyperplastic keratinocytic component led in each case to consider diagnoses such as malignant melanoma and invasive squamous cell carcinoma. Staining for S-100 protein and keratin was useful to identify and separate the two components. Spitz nevus of the tongue carries some intriguing similarities with granular cell tumor, suggesting a possible histogenetic and pathogenetic relationship.

Topics: Adult; Biomarkers, Tumor; Child; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Male; Neoplasm Proteins; Nevus, Epithelioid and Spindle Cell; S100 Proteins; Skin Neoplasms; Tongue Neoplasms

The regulation of apoptotic cell death may have a profound effect on the pathogenesis and progression of colon cancer. Survivin, a member of the inhibitor of apoptosis gene family, has been detected in fetal tissue and in a variety of human malignancies. In the current study, we investigated survivin expression by an immunohistochemical approach in benign, hyperplastic, premalignant, and malignant lesions of the colon. Survivin was detected in all cases of normal colonic mucosa (20/20), hyperplastic polyps (20/20), adenomatous polyps (20/20), and in both well differentiated and moderately differentiated colonic adenocarcinomas (20/20). In the normal colonic mucosa, survivin expression was mostly restricted to the base of the colonic crypts. All epithelial cells showed uniformly intense staining for survivin in hyperplastic polyps. By contrast, adenomas and adenocarcinomas showed a heterogeneous staining pattern with cell-to-cell, gland-to-gland, and regional variability in the intensity of survivin staining. In contrast to the basal preponderance of staining in normal colonic mucosa, numerous survivin positive cells were present at the luminal surface of hyperplastic polyps, adenomatous polyps, and adenocarcinomas. In conclusion, the expression of survivin is not a specific marker of adenocarcinoma of the colon but does show characteristic and reproducible patterns of expression in non-neoplastic proliferative lesions and in normal colonic mucosa.

Topics: Colon; Colonic Neoplasms; HeLa Cells; Humans; Hyperplasia; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Intestinal Mucosa; Keratins; Ki-67 Antigen; Microtubule-Associated Proteins; Neoplasm Proteins; Protein Biosynthesis; Survivin

Corn1 is an autosomal recessive mutation characterized by corneal epithelial hyperplasia and stromal neovascularization. The aim of the present study is to examine the expression patterns of specific epithelial and stromal proteins in corn/corn1 mutant mice.. Immunohistochemistry with antibodies directed against keratins 1, 4, 5, 12, and 14 as well as loricrin, filaggrin, and involucrin were performed in corn1/corn1 and wild type, A.By/SnJ strain, mice at 4 weeks of age. Western blot hybridization was performed to confirm the presence of involucrin in corneas. In situ and northern blot hybridization were used to evaluate the expression of keratin 12, lumican, and keratocan in these mice.. In corn1/corn1 mice, focal areas of corneal epithelial hyperplasia alternate with epithelium with normal appearance. Both regions of normal and hyperplastic corneal epithelium were labeled by anti-keratin 12 antibodies through all corneal epithelial layers. The anti-keratin 14 antibody only labeled the basal cell layer in normal epithelial areas, whereas it labeled both basal and suprabasal cell layers in hyperplastic areas. In wild type mice, anti-keratin 12 antibodies labeled all corneal epithelial layers, whereas anti-keratin 14 labeled the basal corneal epithelial cells only. Positive staining by anti-involucrin antibody was demonstrated in the basal corneal epithelial layer of wild type mice and normal areas of corn1/corn1 mice. Similarly, as observed with anti-keratin 14 antibody, the anti-involucrin antibody labeled both basal and suprabasal cell layers of hyperplastic corneal epithelium of corn1/corn1 mice. Antibodies against keratin 1, keratin 4, loricrin, and fillagrin did not label the corneas of wild type mice or corn1/corn1 mice. Northern hybridization indicated that the expressions of keratocan and lumican mRNA levels were up regulated in corn1/corn1 mice, but keratin 12 mRNA remained similar to that of the wild type mice. In situ hybridization revealed that the lumican mRNA was detected in epithelial and stromal cells of corn1/corn1 mice, whereas keratocan mRNA was only detected in stromal cells.. Hyperproliferative epithelial cells of corn1/corn1 mice have increased levels of expression of keratin 14 and involucrin, but do not exhibit the phenotypical characteristics of cornification. These observations indicate that factors associated with the phenotypes of corn1/corn1 mice do not alter the cornea-type epithelial differentiation of keratin 12 expression, but cause aberrant expression of lumican by corneal epithelial cells.

Topics: Animals; Blotting, Northern; Blotting, Western; Chondroitin Sulfate Proteoglycans; Corneal Neovascularization; Corneal Stroma; Epithelium, Corneal; Eye Proteins; Fibroblasts; Filaggrin Proteins; Gene Expression; Hyperplasia; In Situ Hybridization; Intermediate Filament Proteins; Keratan Sulfate; Keratins; Lumican; Membrane Proteins; Mice; Mice, Mutant Strains; Protein Precursors; RNA, Messenger

Epidermal changes overlying dermatofibromas (DFs) have been described as ranging from psoriasiform simple hyperplasia to basaloid hyperplasia sometimes morphologically indistinguishable from superficial basal cell carcinoma (BCC). To characterize epidermal hyperplasia overlying DFs and to determine its association with the disease process, we examined 30 cases of DF showing hyperplastic epidermis. We used nine immunohistochemical markers associated with keratinocyte proliferation or differentiation. In DFs, the dermal metallothionein (MT) expression and immunophenotypic changes with regard to epidermal differentiation varied depending on the stage of lesional evolution of the DFs. Immunostaining for epidermal growth factor receptor (EGFR), MT, and keratin 6 (K6) increased in simple hyperplastic epidermis (SHE) overlying DFs (n = 11), whereas it gradually diminished in basaloid hyperplastic epidermis (BHE) overlying DFs (n = 19). In SHE, there was a significant increase in K14 expression. Among 19 BHE cases, 12 showed premature expression of involucrin and delayed appearance of K1 along with aberrant expression of K14. Conversely, the remaining 7 BHE cases showed a pattern of involucrin and K1 similar to that of normal skin coinciding with decreased or absent dermal MT expression. Loricrin and filaggrin expression in all DFs was the same as that of normal skin. Based on the sparse positivity of Ki-67 in the hyperplastic epidermis overlying DFs, we found that the biologic ability of BHE and SHE was not apparent in the hyperproliferative state observed in psoriasis and BCC. These results suggest that the dermal fibrohistiocytic process may trigger the induction of SHE overlying DFs by an unknown mechanism and then mediate both the abnormal keratinocyte differentiation and the transformation of SHE to BHE through the evolution of the dermal lesions.

Topics: Biomarkers; Carcinoma, Basal Cell; Cell Differentiation; Cell Division; Epidermis; ErbB Receptors; Filaggrin Proteins; Histiocytoma, Benign Fibrous; Humans; Hyperplasia; Immunoenzyme Techniques; Keratinocytes; Keratins; Metallothionein; Precancerous Conditions; Psoriasis; Skin Neoplasms

Pachyonychia congenita type 2 is an inherited ectodermal dysplasia characterized by hypertrophic nail dystrophy and multiple pilosebaceous cysts. Focal nonepidermolytic palmoplantar keratoderma, natal teeth, and pili torti may also be present. Epithelial tissues affected in pachyonychia congenita type 2 express the keratin pair K6b/K17. Here, we report three novel heterozygous mutations in the K17 gene (KRT17A) in patients presenting with pachyonychia congenita type 2. These mutations, R94-98del (deletion of the peptide sequence RLASY) and missense mutations R94P and L95Q, are all within the 1A domain hotspot for pathogenic keratin mutations.

Topics: Base Sequence; Child, Preschool; Ectodermal Dysplasia; Female; Gene Deletion; Humans; Hyperplasia; Keratins; Molecular Sequence Data; Mutation; Mutation, Missense; Nails

In prostanoid biosynthesis, the first two steps are catalyzed by cyclooxygenases (COX). In mice and humans, deregulated expression of COX-2, but not of COX-1, is characteristic of epithelial tumors, including squamous cell carcinomas of skin. To explore the function of COX-2 in epidermis, a keratin 5 promoter was used to direct COX-2 expression to the basal cells of interfollicular epidermis and the pilosebaceous appendage of transgenic mouse skin. COX-2 overexpression in the expected locations, resulting in increased prostaglandin levels in epidermis and plasma, correlated with a pronounced skin phenotype. Heterozygous transgenic mice exhibited a reduced hair follicle density. Moreover, postnatally hair follicle morphogenesis and thinning of interfollicular dorsal epidermis were delayed. Adult transgenics showed a body-site-dependent sparse coat of greasy hair, the latter caused by sebaceous gland hyperplasia and increased epicutaneous sebum levels. In tail skin, hyperplasia of scale epidermis reflecting an increased number of viable and cornified cell layers was observed. Hyperplasia was a result of a disturbed program of epidermal differentiation rather than an increased proliferation rate, as reflected by the strong suppression of keratin 10, involucrin, and loricrin expression in suprabasal cells. Further pathological signs were loss of cell polarity, mainly of basal keratinocytes, epidermal invaginations into the dermis, and formation of horn perls. Invaginating hyperplastic lobes were surrounded by CD31-positive vessels. These results demonstrate a causal relationship between transgenic COX-2 expression in basal keratinocytes and epidermal hyperplasia as well as dysplastic features at discrete body sites.

Topics: Aging; Animals; Cattle; Cell Differentiation; Cell Division; Cyclooxygenase 2; Epidermis; Hair; Hair Follicle; Heterozygote; Hyperplasia; Isoenzymes; Keratins; Membrane Proteins; Mice; Mice, Transgenic; Phenotype; Promoter Regions, Genetic; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Protein Precursors; Reverse Transcriptase Polymerase Chain Reaction; Sebaceous Glands; Skin

The beta-catenin/TCF signaling pathway is essential for the maintenance of epithelial stem cells in the small intestine. c-Myc a downstream target of beta-catenin/TCF (ref. 2), can induce differentiation of epidermal stem cells in vitro. To determine the role of c-Myc in epidermal stem cells in vivo, we have targeted expression of human MYC2 to the hair follicles and the basal layer of mouse epidermis using a keratin 14 vector (K14.MYC2). Adult K14.MYC2 mice gradually lose their hair and develop spontaneous ulcerated lesions due to a severe impairment in wound healing; their keratinocytes show impaired migration in response to wounding. The expression of beta1 integrin, which is preferentially expressed in epidermal stem cells is unusually low in the epidermis of K14.MYC2 mice. Label-retaining analysis to identify epidermal stem cells reveals a 75% reduction in the number of stem cells in 3-month-old K14.MYC2 mice, compared with wildtype mice. We conclude that deregulated expression of c-Myc in stem cells reduces beta1 integrin expression, which is essential to both keratinocyte migration and stem cell maintenance.

Topics: Animals; Bromodeoxyuridine; Cell Division; Cell Movement; Cells, Cultured; Gene Expression Regulation, Developmental; Hyperplasia; Integrin beta1; Keratin-14; Keratinocytes; Keratins; Mice; Mice, Transgenic; Proto-Oncogene Proteins c-myc; Skin; Stem Cells; Wound Healing

Telomerase transgenics are an important tool to assess the role of telomerase in cancer, as well as to evaluate the potential use of telomerase for gene therapy of age-associated diseases. Here, we have targeted the expression of the catalytic component of mouse telomerase, mTERT, to basal keratinocytes using the bovine keratin 5 promoter. These telomerase-transgenic mice are viable and show histologically normal stratified epithelia with high levels of telomerase activity and normal telomere length. Interestingly, the epidermis of these mice is highly responsive to the mitogenic effects of phorbol esters, and it is more susceptible than that of wild-type littermates to the development skin tumors upon chemical carcinogenesis. The epidermis of telomerase-transgenic mice also shows an increased wound-healing rate compared with wild-type littermates. These results suggest that, contrary to the general assumption, telomerase actively promotes proliferation in cells that have sufficiently long telomeres and unravel potential risks of gene therapy for age-associated diseases based on telomerase upregulation.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Catalytic Domain; Cattle; DNA-Binding Proteins; Female; Gastric Mucosa; Genes, p53; Genetic Therapy; Hyperplasia; Keratinocytes; Keratins; Mice; Mice, Knockout; Mice, Transgenic; Mouth Mucosa; Neoplasms, Experimental; Papilloma; Protein Subunits; RNA; Skin; Skin Neoplasms; Stomach; Telomerase; Telomere; Tetradecanoylphorbol Acetate; Vagina; Wound Healing

Topics: Carcinoembryonic Antigen; Epithelial Cells; Hair Follicle; Humans; Hyperplasia; Keratins; Keratoacanthoma; Melanoma; Mouth Mucosa; Skin; Skin Neoplasms

In a previous report we have described the effects of expression of D-type cyclins in epithelial tissues of transgenic mice. To study the involvement of the D-type cyclin partner cyclin-dependent kinase 4 (CDK4) in epithelial growth and differentiation, transgenic mice were generated carrying the CDK4 gene under the control of a keratin 5 promoter. As expected, transgenic mice showed expression of CDK4 in the epidermal basal-cell layer. Epidermal proliferation increased dramatically and basal cell hyperplasia and hypertrophy were observed. The hyperproliferative phenotype of these transgenic mice was independent of D-type cyclin expression because no overexpression of these proteins was detected. CDK4 and CDK2 kinase activities increased in transgenic animals and were associated with elevated binding of p27(Kip1) to CDK4. Expression of CDK4 in the epidermis results in an increased spinous layer compared with normal epidermis, and a mild hyperkeratosis in the cornified layer. In addition to epidermal changes, severe dermal fibrosis was observed and part of the subcutaneous adipose tissue was replaced by connective tissue. Also, abnormal expression of keratin 6 associated with the hyperproliferative phenotype was observed in transgenic epidermis. This model provides in vivo evidence for the role of CDK4 as a mediator of proliferation in epithelial cells independent of D-type cyclin expression.

Topics: Animals; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; Cyclins; Epidermis; Fibrosis; Humans; Hyperplasia; Hypertrophy; Keratins; Mice; Mice, Transgenic; Proto-Oncogene Proteins; Retinoblastoma Protein; Skin; Skin Physiological Phenomena

The murine genome is known to have two keratin 6 (K6) genes, mouse K6 (MK6)a and MK6b. These genes display a complex expression pattern with constitutive expression in the epithelia of oral mucosa, hair follicles, and nail beds. We generated mice deficient for both genes through embryonic stem cell technology. The majority of MK6a/b-/- mice die of starvation within the first two weeks of life. This is due to a localized disintegration of the dorsal tongue epithelium, which results in the build up of a plaque of cell debris that severely impairs feeding. However, approximately 25% of MK6a/b-/- mice survive to adulthood. Remarkably, the surviving MK6a/b-/- mice have normal hair and nails. To our surprise, we discovered MK6 staining both in the hair follicle and the nail bed of MK6a/b-/- mice, indicating the presence of a third MK6 gene. We cloned this previously unknown murine keratin gene and found it to be highly homologous to human K6hf, which is expressed in hair follicles. We therefore termed this gene MK6 hair follicle (MK6hf). The presence of MK6hf in the MK6a/b-/- follicles and nails offers an explanation for the absence of hair and nail defects in MK6a/b-/- animals.

Topics: Animals; Epithelial Cells; Gene Deletion; Hair Diseases; Hyperplasia; Isomerism; Keratins; Mice; Mice, Knockout; Microscopy, Electron; Molecular Sequence Data; Mouth Diseases; Nail Diseases; Phenotype; Sequence Homology, Amino Acid; Skin; Starvation; Tongue; Wound Healing

Seventeen examples of a variant of ductal carcinoma in situ (DCIS) composed exclusively or predominantly of spindle cells arranged in fascicles, whorls, and solid sheets are described. The fascicular arrangement of the spindle cells simulates the "streaming" phenomenon associated with ordinary intraductal epithelial hyperplasia (IDH). This process also resembles the myoid, solid form of intraductal myoepithelial proliferation. The women ranged in age from 38 years to 79 years with a mean age of 59.3 years. Five patients presented with a palpable mass. The remaining tumors were discovered using mammography. The radiological appearances of the lesions raised concern for carcinoma, but there were no distinctive mammographic findings to suggest an unusual variant of DCIS. Cytological preparations were suspicious for malignancy in two patients and were reported as malignant in another case. Sixteen patients were treated with wide local excision, and one woman had a partial mastectomy. The tumors measured from 3 mm to 15 mm (mean 8.65 mm). In three cases, minute foci of stromal invasion were associated with the spindle cell DCIS. In another specimen, a 2.7-cm invasive ductal carcinoma of no special type was identified in an area away from the foci of the spindle cell DCIS. None of the patients has experienced recurrence or metastasis during the relatively short mean follow-up period of 16.2 months (range 4-77 months). Spindle cell DCIS is distinguished from the streaming pattern of ordinary IDH by its solid growth pattern, lack of secondary spaces or peripheral fenestrations, uniformity of appearance and distribution of nuclei, cytological atypia in the range of low to intermediate-grade DCIS, and negative immunoreaction with CK-34betaE12 (HMW-CK903). When fenestrations are present, they are evident in areas of cribriform DCIS that merge with the solid, spindle cell areas in hybrid ducts harboring both patterns. This admixture, with conventional cribriform DCIS, and the association with foci of invasive ductal carcinoma in some cases further help recognition and confirmation of this lesion as in situ carcinoma. When there is no transition from the spindle cells to recognizable cribriform DCIS, distinction from intraductal myoepithelial hyperplasia (myoepitheliosis) requires immunostains for actin and S-100 protein. Recognition of this pattern of DCIS is important in order to avoid its frequent misclassification as a benign lesion.

Topics: Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Intraductal, Noninfiltrating; Cell Division; Diagnosis, Differential; Endothelium; Female; Follow-Up Studies; Humans; Hyperplasia; Immunohistochemistry; Keratins; Mammography; Middle Aged; Treatment Outcome

Lobular endocervical glandular hyperplasia of the uterine cervix is a rare pseudoneoplastic lesion of the uterine cervix, described recently. Our aim was to characterize the clinicopathological and immunohistochemical features of lobular endocervical glandular hyperplasia, to elucidate its pyloric gland phenotype, and to distinguish it from adenoma malignum of the uterine cervix.. Nine cases of lobular endocervical glandular hyperplasia were studied histologically and immunohistochemically. The average age of the nine patients was 48.8 years (range 38-64 years). Six cases were found incidentally, whereas in three cases a watery vaginal discharge and imaging studies suggested adenoma malignum preoperatively. Microscopically, lobular endocervical glandular hyperplasia ranged from 1 mm to 20 mm (mean 6.8 mm) in the largest horizontal extent and 1 mm to 10 mm (mean 3.9 mm) in depth, and was characterized by lobular arrangements of small glands composed of low columnar cells with pale eosinophilic cytoplasm and bland nuclei. Three cases showed a pseudo-invasive growth. Intracytoplasmic mucin was predominantly PAS-positive, and seven cases showed immunoreactivity for M-GGMC-1, an antibody that reacts with pyloric gland-type mucin. Only focal and faint reactivity for CEA was seen, and ER was negative in all cases. The cytokeratin profile was CK7+/20- in all cases, in keeping with their Müllerian derivation. All three lesions examined contained chromogranin-positive endocrine cells. After surgery all patients are well without recurrent disease (mean follow-up was 48.4 months).. Lobular endocervical glandular hyperplasia is a morphologically distinct pseudoneoplastic glandular lesion, which has unique phenotypic characteristics shared by pyloric glands of the stomach. Although most are found incidentally, some cases may show clinical and radiological features resembling those of adenoma malignum.

Topics: Adenocarcinoma, Mucinous; Adult; Carcinoembryonic Antigen; Cervix Uteri; Chromogranin A; Chromogranins; Diagnosis, Differential; Female; Gastric Mucosa; Humans; Hyperplasia; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Metaplasia; Middle Aged; Mucins; Receptors, Estrogen; Uterine Cervical Neoplasms

Immunostaining with monoclonal antibody (MoAb) hepatocyte paraffin 1 (Hep Par 1) and an MoAb to cytokeratin 7 (CK7) was performed on 105 formalin-fixed, paraffin-embedded canine hyperplastic and neoplastic hepatic lesions. Hep Par 1 was detected in 12/12 hyperplastic nodules, 17/17 hepatocellular adenomas, and 37/40 hepatocellular carcinomas. The staining was disseminated, granular, and cytoplasmic. This antibody did not react with normal or neoplastic biliary epithelium. Other hepatic tumors or tumors metastatic to the liver did not bind Hep Par 1 except one metastatic intestinal carcinoma. MoAb to CK 7 stained all hyperplastic biliary epithelium and benign cholangiocellular tumors (5/5) and 14/18 cholangiocellular carcinomas. One hepatocellular carcinoma had cells positive for both Hep Par 1 and CK 7. Liver was the only normal tissue tested that reacted with MoAb Hep Par 1. Only five nonhepatic tumors (one adrenocortical carcinoma, one interstitial cell tumor of the testis, one melanoma, and two salivary adenocarcinomas) of 277 tumors tested had focal/multifocal staining for Hep Par 1. Prolonged fixation did not alter the staining with Hep Par 1. We conclude that Hep Par 1 is a specific and sensitive marker for canine hepatocellular tumors and allows distinction between hepatocellular and biliary neoplasms.

Topics: Adenoma, Liver Cell; Animals; Antibodies, Monoclonal; Bile Duct Neoplasms; Carcinoma, Hepatocellular; Dog Diseases; Dogs; Hyperplasia; Immunohistochemistry; Keratin-7; Keratins; Liver; Liver Neoplasms; Retrospective Studies

Solitary papillary hyperplastic thyroid nodules (SPHTNs) are frequently encountered in children and teenagers. Although the histologic features are well described, to the best of our knowledge, cytologic findings have not been reported.. To review the cytologic features of histologically proven SPHTNs and to identify the potential diagnostic pitfalls in cytologic diagnosis.. Fine-needle aspiration cytology of 3 histologically proven SPHTNs was reviewed.. Two girls and 1 boy (ages 11, 12, and 15 years) were affected. The cytologic diagnosis in all 3 cases was suspicious for papillary thyroid carcinoma (PTC). The spectrum of cytologic findings included broad flat sheets and 3-dimensional clusters with fire flares. There was mild to moderate nuclear pleomorphism and nuclear atypia. Short nonbranching papillae with transgressing vessels shown to represent hyperplastic papillae on histologic sections were identified in all cases. The background contained giant cells, histiocytes, and watery and inspissated colloid. Although nuclear grooves were identified in occasional cells, intranuclear inclusions were absent. A cell block section (1 case) and histologic sections of SPHTNs (2 cases) were immunohistochemically negative for cytokeratin 19.. Fine-needle aspiration of SPHTNs may be difficult to interpret accurately and can result in false-positive diagnosis of PTC. Although it shares several cytologic features with PTC, the presence of fire flares and short nonbranching papillae, as well as lack of intranuclear inclusions and watery and inspissated colloid in SPHTN appear to be useful features that are helpful in distinguishing SPHTN from PTC. Negative immunohistochemical staining for cytokeratin 19 is useful in excluding a diagnosis of PTC.

Topics: Adolescent; Biomarkers, Tumor; Biopsy, Needle; Carcinoma, Papillary; Child; Diagnosis, Differential; Female; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Thyroid Nodule

According to current concepts, benign proliferative breast disease (BPBD) is a direct precursor of breast cancer, in a spectrum ranging from ductal hyperplasia to overtly invasive carcinoma. In this study, comparative genomic hybridization (CGH) was used to screen ductal hyperplasia and other BPBD lesions and ductal carcinoma in situ (DCIS) for common genomic abnormalities, to test the relationship between these hyperplastic and neoplastic lesions. Immunohistochemistry for cytokeratin 5/6 was used as a diagnostic adjunct to distinguish ductal hyperplasia from DCIS. A total of 42 cases of BPBD comprising ductal hyperplasia of the usual type (n=14), papilloma (n=22), tubular adenoma (n=3), and adenosis (n=3), as well as 52 cases of DCIS, were studied. All cases of BPBD consistently displayed the presence of a subpopulation of cytokeratin 5/6-expressing basal-type cells within the proliferative lesion, whereas all of the non-high-grade and most of the high-grade DCIS lesions lacked cytokeratin 5/6-positive cells. Whereas gross genomic alterations, as determined by CGH, were undetectable in BPBD, distinct genetic changes characterized all cases of DCIS, with one exception. These results confirm the usefulness of cytokeratin 5/6 immunohistology in the diagnosis of BPBD and neoplastic breast lesions and support the view that BPBD and DCIS are not closely related entities and that BPBD is not an obligate direct precursor of DCIS.

Topics: Adenoma; Breast Diseases; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Chromosome Aberrations; Female; Fibrocystic Breast Disease; Humans; Hyperplasia; In Situ Hybridization, Fluorescence; Keratins; Molecular Weight; Nucleic Acid Hybridization; Papilloma, Intraductal; Precancerous Conditions

Fine-needle aspiration (FNA) of the adrenal is a useful modality for the evaluation of primary and metastatic neoplasms. Until now, however, few reliable markers existed for the positive identification of adrenal cortical cells. Originally studied as a melanoma marker, Melan-A, as detected by the murine monoclonal antibody, A103, has gained recent attention as a marker for steroid-producing cells. Formalin-fixed, paraffin-embedded cell blocks from 24 adrenal FNA specimens were stained for cytokeratins (AE1/AE3) and Melan-A (A103). Seven of 8 cases containing normal, hyperplastic, and neoplastic adrenal cortical cells were positive for A103. Among 16 cases of metastatic carcinoma, tumor cells in 14 samples were positive for cytokeratins but negative for A103. The A103 monoclonal antibody is a sensitive marker for the identification of normal, hyperplastic, and neoplastic adrenal cortical cells in cell blocks of adrenal FNA specimens. With the exception of melanoma, A103 reactivity is restricted to adrenal cortical and other steroid-producing cells. A103 should be used routinely for the evaluation of FNA specimens of adrenal mass lesions.

Topics: Adrenal Cortex; Adrenal Cortex Neoplasms; Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Biomarkers, Tumor; Biopsy, Needle; Cell Nucleus; Humans; Hyperplasia; Immunohistochemistry; Keratins; MART-1 Antigen; Melanoma; Mice; Neoplasm Proteins

Although there is experimental evidence supporting the involvement of angiogenesis in the pathogenesis of breast cancer, the exact nature and effects of interaction between human breast epithelial cells (HBECs) and endothelial cells (ECs) have not been described thus far. This approach requires an assay system that permits growth and differentiation of both epithelial and endothelial cells. Here, we report the development of a three-dimensional in vitro culture system that supports growth and functional differentiation of preneoplastic HBECs and ECs and recapitulates estrogen-induced in vivo effects on angiogenesis and the proliferative potential of MCF10AT xenografts. MCF10A and MCF10AT1-EIII8 (referred to as EIII8) cell lines used in this study are normal or produce preneoplastic lesions, respectively. When MCF10A or EIII8 cells are seeded on reconstituted basement membrane (Matrigel), both lines organize into a three-dimensional tubular network of cells; however, tubes produced by EIII8 cells appear multicellular in contrast to unicellular structures formed by MCF10A cells. However, when MCF10A or EIII8 cells are cocultured with human umbilical vein endothelial cells (HUVECs) on Matrigel, rather than interacting with extracellular matrix, the ECs exhibit preferential adherence to epithelial cells. Although both MCF10A and EIII8 cells provide preferential substrate for EC attachment, only EIII8 cells facilitate sustained proliferation of ECs for prolonged periods that are visualized as "endothelial cell enriched spots," which express factor VIII-related antigen. At regions of endothelial-enriched spots, preneoplastic HBECs undergo branching ductal-alveolar morphogenesis that produce mucin, express cytokeratins, and proliferating cell nuclear antigen. The presence of actively proliferating and functional endothelial cells is essential for ductal-alveolar morphogenesis of preneoplastic HBECs because without ECs, the epithelial cells formed only tubular structures. This ability to establish functional ECs and ductal-alveolar morphogenesis is facilitated only by preneoplastic HBECs because normal MCF10A cells fail to elicit similar effects. Thus, a cause-effect relationship that is mutually beneficial exists between EC and preneoplastic HBECs that is critical for generation of functional vascular networks and local proliferative ductal alveolar outgrowths with invasive potential. Both these processes are augmented by estrogen, whereas antiestrogens inhibit

Topics: Basement Membrane; Breast; Breast Neoplasms; Cell Differentiation; Cell Division; Cells, Cultured; Coculture Techniques; Collagen; Culture Media, Conditioned; Drug Combinations; Endothelial Growth Factors; Endothelium, Vascular; Epithelial Cells; Estrogens; Female; Humans; Hyperplasia; Interleukin-8; Keratins; Laminin; Lymphokines; Matrix Metalloproteinase 2; Mucins; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Proteoglycans; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Umbilical Veins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Anti-CEA, anti-vimentin, CAM5.2, BerEp4, Leu-M1 and anti-EMA were applied to effusions from 36 mesotheliomas, 53 adenocarcinomas and 24 reactive mesothelial proliferations. Stepwise logistic regression analysis selected three criteria of major importance for distinguishing between adenocarcinoma and mesothelioma: BerEp4, CEA and EMA accentuated at the cell membrane (mEMA), these three being of similar diagnostic value. The pattern BerEp4-, CEA- and mEMA+ was fully predictive for mesothelioma (sensitivity 47%), whereas the opposite pattern was fully predictive for adenocarcinoma (sensitivity 80%). Only EMA seemed to distinguish between mesotheliosis and mesothelioma. Comparison of reactivity in cytological and histological material from the same mesotheliomas showed similar staining frequencies for CEA and CAM5.2, with some random variation for Leu-M1 and EMA, whereas vimentin and BerEp4 reactivity was more frequent in cytological specimens.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antibodies, Neoplasm; Antibody Specificity; Antigens, Neoplasm; Antigens, Surface; Biomarkers; Biomarkers, Tumor; Carcinoembryonic Antigen; Diagnosis, Differential; Epithelium; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Lewis X Antigen; Logistic Models; Lung Neoplasms; Mesothelioma; Mucin-1; Neoplasm Proteins; Pleural Effusion, Malignant; Sensitivity and Specificity; Vimentin

We report a case of cutaneous malignant melanoma associated with extensive pseudoepitheliomatous hyperplasia. Pseudoepitheliomatous hyperplasia may mimic squamous cell carcinoma and may complicate the diagnosis of cutaneous melanoma. This diagnostic pitfall is important to both recognize and be cognizant of, so as to avoid diagnostic errors. The observation of the pseudoepitheliomatous hyperplasia, in this case with an extensive proliferation of eccrine ducts, provides further evidence that cutaneous pseudoepitheliomatous hyperplasia arises within the eccrine apparatus.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Squamous Cell; Diagnosis, Differential; Eccrine Glands; Epithelial Cells; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Melanoma; Skin; Skin Neoplasms

Mucous cells in the respiratory tract contribute to the maintenance of the normal epithelial cell population via mechanisms of cell proliferation and differentiation. Mucous cell hyperplasia often occurs as a basic response to injury in the tracheobronchial epithelium. These cells are also thought to be involved in the histogenesis of epidermoid metaplasia. A typical biochemical feature of these cells is mucus secretion. Aberrant glycosylation or under-glycosylation of mucins is well known in cancer; however, the specific role played by mucin genes is at present unclear. To provide information regarding the expression of these genes in squamous metaplasia and squamous cell carcinoma, we analyzed and compared the expression of MUC1-MUC7 genes by in situ hybridization in control respiratory mucosa and lesions associated with neoplasia (hyperplasia, metaplasia and dysplasia) and squamous cell carcinomas. MUC4 was expressed independently of mucus secretion since it was expressed weakly by basal cells and probably by ciliated cells as well as collecting ducts, epidermoid metaplasia with complete squamous cell differentiation, and most of epidermoid carcinomas even well differentiated and keratinized. In squamous metaplasia and dysplasia, MUC4 gene expression was diffuse and less intense than in normal epithelium. MUC5AC was overexpressed in dysplasia as well as in mucous cell and basal cell hyperplasia and undetectable when squamous differentiation was achieved.

Topics: Biomarkers, Tumor; Bronchi; Carcinoma, Squamous Cell; Epithelium; Gene Expression; Histocytochemistry; Humans; Hyperplasia; In Situ Hybridization; Keratins; Mucin 5AC; Mucin-1; Mucin-2; Mucin-4; Mucin-5B; Mucins; Mucous Membrane; Respiratory System; RNA, Messenger; Salivary Proteins and Peptides

We describe a patient with hyperplastic mesothelial cells localized to mediastinal lymph node sinuses. These mesothelial cells were originally misdiagnosed as metastatic carcinoma, and the patient received radiotherapy. Histologic review, immunohistochemistry, and ultrastructural studies confirmed mesothelial cell origin. These nodal mesothelial cells were associated with pericardial and pleural effusions. Extranodal lymphatics also contained hyperplastic mesothelial cells, confirming their mode of lymphatic transport to node sinuses. This finding supports the theory that hyperplastic mesothelial cells derive from reactive serosal mesothelium and are dislodged into draining lymphatics. This is the first report, to our knowledge, that demonstrates the pathogenetic significance of this lymphatic transport mechanism. Awareness of intralymphatic and nodal benign hyperplastic mesothelial cells and their mimicry of invasive malignant neoplasms is important for accurate diagnoses and appropriate therapy.

Topics: Adipose Tissue; Calcinosis; Diagnosis, Differential; Epithelium; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Neoplasms, Unknown Primary

In 1999, the World Health Organization (WHO) published a new classification of papillary urothelial tumors of the urinary bladder. Intended to represent a reproducible, easy-to-use classification system that better separates patients with true malignancies (bladder cancer) from those patients who are at an increased risk for developing bladder cancer, problems in the differential diagnosis of various lesions remained. Probably the most critical distinction is between papillomas, papillary urothelial neoplasms of low malignant potential (lmp), and grade I papillary carcinomas. Conversely, problems in the distinction between reactive atypia, atypia of unknown significance, and dysplasia, as well as the distinction of dysplasia from carcinoma in situ (CIS), are unresolved. Whether urothelial basal cell status assessment on hematoxylin and eosin-stained slides completed by cytokeratin immunohistochemistry with anticytokeratin clone 34betaE12 may help to improve some of the previously mentioned diagnostic dilemmas was investigated. Basal cell status assessment was helpful in the differentiation between dysplasia and CIS. In dysplasia, CK IHC showed a predominantly basal labeling pattern, whereas in CIS, labeling of all urothelial layers was seen. Basal cell status assessment could separate 2 groups of pTa GIb papillary carcinoma. Group 1 with a continuous basal CK labeling and a low MIB-1 labeling index (LI) was compared with group 2, with a diffuse labeling pattern and a significantly higher MIB-1 LI. Whether group 1 carcinomas should better be assigned to the group of papillary urothelial neoplasms of lmp is discussed.

Topics: Antigens, Nuclear; Biopsy; Carcinoma, Papillary; Diagnosis, Differential; Humans; Hyperplasia; Immunohistochemistry; Keratins; Ki-67 Antigen; Nuclear Proteins; Papilloma; Urinary Bladder Neoplasms; Urothelium; World Health Organization

Alternative models using fish species have been tested in liver toxicity and carcinogenesis bioassays. Similar models have not been developed for skin. The brown bullhead (Ameiurus nebulosus) has shown potential as a model for skin carcinogenesis studies due to its sensitivity to environmental chemical pollutants. The present study is an initial morphologic and biochemical characterization of the normal and neoplastic brown bullhead skin to assess its suitability as a model of skin carcinogenesis. Brown bullhead were removed from Back River in the Chesapeake Bay region, an area historically polluted with heavy metals and polycyclic aromatic hydrocarbons. Histology, histochemistry, and electron microscopy were used to stage the morphologic development and progression of neoplasia in skin. The distribution of keratin, a family of structural proteins with altered expression in mammalian tumorigenesis, was analyzed with one and two dimensional gel electrophoresis and nitrocellulose blots of extracts from normal skin. Keratin expression in skin and other organs was also assessed with immunohistochemistry using AE1, AE3, and PCK 26 antibodies, and the proliferation index in skin and neoplasms with PCNA antibody. Skin lesions appeared to progress from hyperplasia through carcinoma, and the proliferation index was increased in papilloma. Also in papilloma, intercellular interdigitations appeared increased and desmosomes decreased which may in future studies correlate with changes in expression of other molecular markers of neoplastic progression. Both Type I and Type II keratin subfamilies were detected in skin using gel electrophoresis with the complimentary keratin blot-binding assay. For further development of the brown bullhead model, future studies can compare and relate these baseline data to alterations in expression of keratin and other markers in fish neoplasms and to molecular events which occur in man.

Topics: Animals; Carcinogenicity Tests; Electrophoresis, Polyacrylamide Gel; Epithelium; Fishes; Histocytochemistry; Hydrocarbons, Aromatic; Hyperplasia; Keratins; Lip; Metals, Heavy; Microscopy, Electron; Papilloma; Proliferating Cell Nuclear Antigen; Skin Neoplasms; Water Pollutants, Chemical

This study was performed to determine the diagnostic value of keratin 5/6 (CK 5/6) immunophenotyping on routinely processed breast tissues.. Six hundred and ninety-nine breast lesions, including normal tissues as well as benign and malignant lesions in 321 formalin-fixed, paraffin-embedded samples from 158 different patients were investigated immunohistochemically, following wet autoclave pre-treatment for antigen retrieval. In normal breast tissues, both myoepithelial and luminal epithelial cells expressed CK 5/6 in varying amounts. While myoepithelial immunoreactivity was most pronounced in the duct system, luminal epithelial immunoreactivity was strongest in the terminal duct lobular units. In ductal hyperplasias (DH), luminal epithelial cells predominantly revealed CK 5/6 immunoreaction. In contrast, neoplastic epithelial cells in atypical ductal and lobular hyperplasias (ADH and ALH) lacked such an expression, whereas in ductal in-situ carcinomas (DCIS) and in infiltrating ductal carcinomas 3.7% and 7.7%, of the cases respectively, showed positive immunostaining for CK 5/6.. Immunophenotyping of keratin 5/6 expression can be helpful in the diagnosis of atypical hyperplasias and in-situ carcinomas of the breast. It is particularly valuable in the differential diagnosis between benign and atypical proliferative lesions.

Topics: Breast; Breast Neoplasms; Carcinoma in Situ; Cell Division; Diagnosis, Differential; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Neoplasm Invasiveness

The aims of this study were to ascertain the incidence of intercalated duct hyperplasia in association with cases of epithelial-myoepithelial carcinoma (EMC), and to explore a possible relationship between them and hybrid carcinomas of salivary glands.. Seven cases of EMC with sufficient surrounding non-tumour parotid were examined. Three cases contained foci of intercalated duct hyperplasia adjacent to the tumour. One of the cases was a hybrid tumour composed of EMC and mucoepidermoid carcinoma. The hyperplastic intercalated ducts formed multiple foci within the salivary parenchyma and were composed of bland, uniform ducts. Cytological atypia was not identified.. Intercalated duct hyperplasia may be a precursor lesion to EMC. Furthermore, it may also explain why EMC is frequently associated with other salivary gland carcinomas, so-called hybrid tumours, as well as sharing histological features with adenoid cystic carcinoma. Recognition of the latter is of particular importance because adenoid cystic carcinoma carries a poor prognosis.

Topics: Actins; Biomarkers; Carcinoma; Humans; Hyperplasia; Immunohistochemistry; Keratins; Muscles; Neoplasms, Multiple Primary; S100 Proteins; Salivary Ducts; Salivary Gland Neoplasms

The erbB family of receptor tyrosine kinases, which consists of the epidermal growth factor receptor (EGFr/erbB1), erbB2 (neu), erbB3 and erbB4, has been shown to be important for both normal development as well as neoplasia. The expression of rat erbB2 was targeted to the basal layer of mouse epidermis with the bovine keratin 5 promoter. Overexpression of wild type rat erbB2 in the basal layer of epidermis led to alopecia, follicular hyperplasia and sebaceous gland enlargement as well as hyperplasia of the interfollicular epidermis. Spontaneous papillomas, some of which converted to squamous cell carcinomas, arose in homozygous erbB2 transgenic mice as early as 6 weeks of age with >90% incidence by 6 months. Analysis of several proliferation/differentiation markers indicated that erbB2 overexpression led to epidermal hyperproliferation and a possible delay in epidermal differentiation. Transgenic mice were also hypersensitive to the proliferative effects of the skin tumor promoter, 12-0-tetradecanoylphorbol-13-acetate (TPA) and were more sensitive to two-stage carcinogenesis. Elevations in EGFr and erbB2 protein as well as erbB2:EGFr and erbB2:erbB3 heterodimers were observed in skin of the erbB2 transgenic mice. Phosphotyrosine levels of the EGFr, erbB2 and erbB3 proteins were also elevated. These results indicate an important role for erbB2 signaling in epidermal growth, development and neoplasia. Oncogene (2000) 19, 4243 - 4254

Topics: Animals; Carcinogens; Carcinoma, Squamous Cell; Cattle; Cell Differentiation; Cell Division; Cell Transformation, Neoplastic; Cocarcinogenesis; Dimerization; Disease Progression; Epidermis; ErbB Receptors; Female; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Genes, ras; Genes, Synthetic; Hyperplasia; Keratins; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Neoplasm Proteins; Papilloma; Phosphorylation; Promoter Regions, Genetic; Protein Processing, Post-Translational; Rats; Receptor, ErbB-2; Receptor, ErbB-3; Recombinant Fusion Proteins; Signal Transduction; Skin Neoplasms; Tetradecanoylphorbol Acetate; Transgenes

Myofibroblasts are the primary cells responsible for increased matrix deposition in hepatic fibrosis. Activation of hepatic stellate cells and portal fibroblasts to myofibroblasts during cholestatic liver injury is accompanied by increased expression of the activation marker, alpha-smooth muscle actin (SMA), and collagen genes. In contrast to our understanding of injury, the cellular mechanisms of liver repair are not well defined. This study was designed to examine the morphological relationship between bile duct hyperplasia, matrix deposition and myofibroblast phenotype in a model of chronic cholestatic liver injury and repair.. Reversible extrahepatic obstruction was accomplished in rats using a soft vessel loop suspended from the anterior abdominal wall: duct manipulation alone was performed in sham-operated controls. After 7 days, rats were either sacrificed or decompressed by release of the loop and subsequently sacrificed 2-10 days after reversal. Liver sections were obtained for in situ hybridization for procollagen alpha1(I) mRNA, immunohistochemical staining for SMA and cytokeratin 19, and histochemical staining for reticulin.. Cholestatic livers demonstrated bile duct hyperplasia, which reversed to normal within 10 days after decompression. Fibrosis was also substantially reduced during this period. SMA-positive myofibroblasts were abundant and localized to regions adjacent to proliferating ducts and excess matrix in the obstructed animals. Decompressed livers showed a dramatic time-dependent reduction in the number of SMA-positive cells and in the expression of procollagen I mRNA.. Our results show that the disappearance of bile duct hyperplasia after biliary decompression is accompanied by a similarly rapid loss of SMA-positive myofibroblasts. Both cellular events may abrogate enhanced matrix synthesis and allow repair to occur.

Topics: Actins; Alanine Transaminase; Animals; Bile Ducts; Bilirubin; Cholestasis, Extrahepatic; Chronic Disease; Disease Models, Animal; Extracellular Matrix; Fibroblasts; gamma-Glutamyltransferase; Histocytochemistry; Hyperplasia; Keratins; Liver; Liver Cirrhosis, Experimental; Liver Regeneration; Male; Procollagen; Rats; Rats, Sprague-Dawley; Reticulin; RNA, Messenger

Clara cell 10-kDa protein (CC10) is an inhibitor of phospholipase A2 and binds to phosphatidylinositol. It may therefore interfere with intracellular signal transduction. Bronchial CC10-reactive cells have been described by several authors. In contrast to the bronchiolar CC10-containing Clara cell, which is a progenitor cell of terminally differentiated airway epithelium, the role of bronchial CC10-reactive cells remains to be elucidated. We assessed the number of bronchial CC10-reactive cells in relation to cytokeratin (CK) expression and proliferative activity in normal, hyperplastic and squamous metaplastic epithelium. Sixty-five human bronchial mucosal specimens were investigated immunohistochemically for CK expression (CK7, CK13 and CK5/6), proliferative activity (MIB-1) and number of CC10-reactive epithelia. The proliferation fraction of CC10-reactive cells was assessed with double staining for MIB-1 and CC10. The proliferation index of the epithelium differed significantly between normal, hyperplastic and metaplastic epithelium. The number of CC10-reactive cells was inversely related to the epithelial proliferation. Bronchial CC10-reactive cells showed no proliferative activity as assessed using immunohistochemical double staining for CC10 and MIB-1. In contrast to normal and hyperplastic epithelium, squamous metaplasia disclosed CK5/6 in all epithelial layers, a loss of CK7 and a gain of CK13. We conclude that CC10-reactive cells have no progenitor role in the bronchial mucosa. However, because the proliferative activity is inversely related to the number of CC10-reactive cells, the CC10 protein may play a role in the regulation of epithelial repair. Squamous metaplasia most likely originates from basal cells.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Nuclear; Bronchi; Cell Count; Cell Division; Enzyme Inhibitors; Epithelial Cells; Epithelium; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Ki-67 Antigen; Male; Metaplasia; Middle Aged; Nuclear Proteins; Phospholipases A; Phospholipases A2; Proteins; Respiratory Mucosa; Uteroglobin

Clomiphene citrate is chemically related to non-steroidal estrogens, and has antiestrogenic properties. It is used in the treatment of anovulatory female infertility and its therapeutic effect mainly depends on inhibiting the negative feedback effects of endogenous estrogen by stimulating the gonadotropin releasing hormone. Today, it is also used in the treatment of male infertility.. In this study the effects of clomiphene citrate on skin maturation in neonatal rats were investigated.. Forty Spraque-Dawley female newborn rats were separated into two control and two experimental groups (n = 10). One day after birth. experimental newborn rats were given clomphene citrate subcutaneously in a dosage of 100 mg/kg/day for five days. The first experimental group of rats were anesthetised at 21 days whereas the second experimental group of rats were then anestetised on day 28. Biopsies were taken immediately from the perineal skin. Histopathological assessments were made and compared with their control groups.. In both the experimental groups of newborn rats, increased keratinization and irregular hypertrophy were observed in the epidermal cells. Disorganization of the basal layer cells and hyperplasia were found to be more prominent in the first experimental group and dermal fibrosis and lymphohistiocytic inflammatory cell infiltration were especially prominent around the sebaceous glands in the second experimental group.. The administration of clomiphene citrate in newborn rats showed impaired skin maturation.

Topics: Animals; Animals, Newborn; Clomiphene; Epidermis; Female; Fibrosis; Histiocytes; Hyperplasia; Keratins; Lymphocytes; Rats; Rats, Sprague-Dawley; Sebaceous Glands; Skin

The dithiocarbamates are known to cause dermatitis, conjunctivitis, rhinitis, pharyngitis and bronchitis in humans. The experimental group received Propineb (obtained from Bayer) concentrations of 400 ppm in distilled water five days a week (treatment time three weeks) administered orally by gasric pit. Acute oral LD50 for male rats has been found to be 8,500 mg/kg (Worthing, 1983). The control group (n = 10) received only distilled water. At ultrasonographical examination, there were no resorbed fetuses or stillborns during or after propineb administration. It can be clearly seen that the body weights of the experimental group of litters are lower than those of the control group (p < 0.001). However, the mean length of the experimental litters was identical to the control group of litters (p > 0.05). Under microscopical examination, increased keratinization and hyperplasia were observed in the epidermal cells.

Topics: Animals; Animals, Newborn; Biopsy; Body Weight; Epidermis; Female; Fungicides, Industrial; Hyperplasia; Keratins; Male; Maternal-Fetal Exchange; Pregnancy; Rats; Rats, Wistar; Skin; Teratogens; Ultrasonography, Prenatal; Zineb

The expression of keratins and filaggrin by keratinocytes is a highly regulated process and depends on their state of differentiation and proliferation. As such, these proteins can be used as markers to determine if keratinocyte differentiation is normal. Mutant cpdm/cpdm mice develop a chronic skin disease characterized by epidermal hyperplasia and inflammation. Immunohistochemical staining for the basal keratins K5 and K14 revealed expression in the basal and suprabasal cell layers. The expression of K1 and K10 was reduced and limited to the outer layers of the stratum spinosum. Keratin 6 was expressed in the suprabasal layers of affected skin, and throughout all layers in severely affected skin. Filaggrin was present in the stratum granulosum which had variable thickness. These results indicate that the differentiation of keratinocytes in cpdm/cpdm mice was normal. The altered distribution and expression of keratins in comparison with the skin of control mice was the result of hyperproliferation.

Topics: Animals; Chronic Disease; Dermatitis; Filaggrin Proteins; Hyperplasia; Immunohistochemistry; Intermediate Filament Proteins; Keratinocytes; Keratins; Mice; Mice, Inbred C57BL; Mutation; Skin

Aural cholesteatoma has different morphologic and biologic characteristics from the normal epithelial cells.. The exact pathophysiology of aural cholesteatoma has not been proved. There are certain factors that can be involved in the development of the aural cholesteatoma, which makes it necessary to find the morphologic and biologic changes in aural cholesteatoma.. The animal model of aural cholesteatoma was induced in gerbils with the external auditory canal (EAC) ligation method. Using immunohistochemical method, the distribution of cytokeratin and the binding patterns of lectin were observed to show the biologic and morphologic changes that take place in aural cholesteatomas.. The successful induction rate was 86.7%. The cytokeratin distribution of aural cholesteatoma was similar to that of EAC but different from that of the middle ear mucosa. The cytokeratin distribution in the cholesteatoma did not change with the different duration of EAC ligation. The results of the lectin-binding study indicate that the mucin-type cells are mainly distributed in the suprabasal cells of aural cholesteatoma and that the basal cells of cholesteatoma lack a D-galactosyl sugar residue.. This study suggests that the origin of aural cholesteatoma may be the external auditory canal epidermal cells, and the characteristics of these cells do not change once the cholesteatoma develops. This study also suggests that cholesteatoma has different biologic nature from that of the normal epithelial cell, especially in the basal cells.

Topics: Animals; Cholesteatoma, Middle Ear; Disease Models, Animal; Ear Canal; Gerbillinae; Hyperplasia; Immunohistochemistry; Keratins; Lectins; Ligation; Substrate Specificity; Time Factors

This investigation was undertaken to further study cyclosporin A (CsA)-induced gingival overgrowth. Thirty mg/kg/d of vehicle or CsA solutions were given orally to 6-wk-old male Sprague-Dawley rats. After 4, 9, 14 and 19 wk 2 control and 2 experimental rats were anaesthetized, tissues fixed by intracardiac perfusion of fixative solution and jaws processed for Epon inclusion. Histological and ultrastructural studies conducted in a gingival portion (free gingiva) revealed the presence of hyalinization areas and of multinucleated cells (MCs) containing collagen fibrils (connective tissue), of amorphous areas and disorders of keratinization (epithelia). Histomorphometric evaluation indicated that in the CsA rats the mean cross-sectional area of the free gingiva was 2.52-fold increased compared to the controls. The connective tissue comprised 41.43% of this area (instead of 31.49% in controls). Additional histomorphometric evaluation was performed in 3 groups of free gingival portions: control (C group), CsA-non-respondent (CsA-nR) and CsA-respondent (CsA-R). The cross-sectional gingival areas studied were slightly lower than the mean area of all the control sites previously defined (groups C and CsA-nR) or showed the higher degrees of enlargement (CsA-R). In the CsA-R group the mean cross-sectioned area of the vessel profiles was increased and the number of fibroblast profiles decreased. In the CsA-nR group the number of vessel profiles and that of MCs profiles were increased. In the epithelia of the CsA-R group were increased (a) keratinized epithelia: thickness; thickness of the inner and of the outer compartments; surface area of spinous cell profiles; (b) oral gingival epithelium: number of cell layers (inner compartment); (c) oral sulcular epithelium: surface area of granular cell profiles; (d) junctional epithelium: thickness; number of cell layers. These results indicate that (a) the CsA induced modifications are not limited to enlarged gingiva (b) the overgrowth of the GCT is the result of a vasodilatation and of an increase in the volume of the extracellular matrix and (c) the increase of the epithelial thickness is mainly the result of a cell hypertrophy in the keratinized epithelia and of a cell hyperplasia in the junctional epithelium.

Topics: Anatomy, Cross-Sectional; Animals; Cell Count; Collagen; Connective Tissue; Cyclosporine; Epithelial Attachment; Epithelium; Extracellular Matrix; Fibroblasts; Follow-Up Studies; Gingiva; Gingival Overgrowth; Hyalin; Hyperplasia; Immunosuppressive Agents; Keratins; Male; Microscopy, Electron; Pharmaceutical Vehicles; Rats; Rats, Sprague-Dawley; Vasodilation

To validate histological criteria for the grading of epithelial hyperplastic laryngeal lesions (EHHL) (dysplastic laryngeal lesions), we used a system that had been devised and tested in Ljubljana, Slovenia over many years and was felt to be more appropriate to laryngeal pathology than is the commonly-used model of intraepithelial neoplasia in the cervix.. Vocal cord biopsies of 45 patients with a broad spectrum of EHLL were reviewed. Detailed histological criteria were formulated for each of the four grades of EHLL in the Ljubljana classification, comprising simple hyperplasia (benign spinous layer augmentation), abnormal hyperplasia (benign basal and parabasal layer augmentation), atypical hyperplasia (risky for malignancy) and carcinoma in situ (actually malignant, but without invasion).. Using these criteria a high degree of concordance of histological diagnoses of grading levels for the Ljubljana classification was achieved between the pathologists of the Working Group. The system was found to be more precise for routine diagnostic work than the others in vogue. The different grades of the Ljubljana classification correspond to significantly different levels yielded in each grade by the semiobjective methods of quantitative morphometry and immunohistochemistry.

Topics: Epithelium; Humans; Hyperplasia; Keratins; Laryngeal Diseases; Laryngeal Mucosa; Laryngeal Neoplasms; Multicenter Studies as Topic; Precancerous Conditions; Slovenia

It is not clear, whether the so-called basal cells of the salivary striated ducts are an independent cell-type distinct from myoepithelial cells, making characterization of the cell proliferation typical of the duct lesions in Sjögren-type sialadenitis/benign lymphoepithelial lesion (BLEL) difficult. An immunohistochemical investigation including different cytokeratin subtypes, alpha-actin, Ki-67 and Bcl-2 was directed at the epithelial cytoskeleton in normal parotid parenchyma (n=8), BLEL (n=12), HIV-associated lymphoepithelial cysts (n=8) and palatine tonsils (n=8). There are profound morphological and functional differences between basal and myoepithelial cells in the normal salivary duct. Development of duct lesions in BLEL arises from basal cell hyperplasia of striated ducts with aberrant differentiation into a multi-layered and reticulated epithelium, characterized by profound alteration of the cytokeratin pattern. This functionally inferior, metaplastic epithelium is similar to the lymphoepithelial crypt epithelium of palatine tonsils. The often postulated participation of myoepithelial cells in duct lesions of Sjögren disease/BLEL cannot be supported. We regard the designations lymphoepithelial lesion and lymphoepithelial metaplasia as the most appropriate.

Topics: Adolescent; Adult; Aged; Biomarkers; Cytoskeleton; Epithelial Cells; Female; HIV Infections; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Lymphocele; Male; Middle Aged; Palatine Tonsil; Parotid Diseases; Parotid Gland; Salivary Ducts; Sialadenitis; Sjogren's Syndrome

Eight hepatic atypical adenomatous hyperplasias (AH), 30 hepatocellular carcinomas (HCC) consisting of 11 well-, 13 moderately and six poorly differentiated HCC, and 10 intrahepatic cholangiocarcinomas (CC) were investigated immunohistochemically with anti-alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), CA19-9, epithelial membrane antigen (EMA), and cytokeratins (CK) 18 and 19 antibodies. Immunostaining was regarded as positive when more than 5% of cells were stained. Alpha-fetoprotein was positive, although focally, in five (17%) of 30 HCC but negative in all AH and CC. Carcinoembryonic antigen (polyclonal antibody) did not stain the cytoplasm of all AH and HCC, but stained two (25%) of eight AH and 10 (33%) of 30 HCC in a bile canalicular staining manner. Carcinoembryonic antigen showed intracytoplasmic or luminal border staining in six (60%) of 10 CC. CA19-9 was negative in all AH and HCC, while six (60%) of 10 CC were positive for CA19-9. Epithelial membrane antigen was positive in one (13%) of eight AH, seven (23%) of 30 HCC and in all 10 cases of CC. Cytokeratin 18 was positive in all AH, HCC and CC. Cytokeratin 19 was negative in both AH and HCC, whereas it stained the cytoplasm of tumor cells in all CC diffusely and intensely. These results suggest that immunostaining of AFP, CEA, CA19-9, EMA, CK18 and CK19 are not useful in the differential diagnosis between AH and well-differentiated HCC, and that CK19 is the most suitable reagent for the differential diagnosis between HCC and CC.

Topics: Adenoma; alpha-Fetoproteins; Biomarkers, Tumor; CA-19-9 Antigen; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Cholangiocarcinoma; Diagnosis, Differential; Humans; Hyperplasia; Immunohistochemistry; Keratins; Liver; Liver Neoplasms; Mucin-1; Precancerous Conditions; Predictive Value of Tests; Prognosis

The ErbB2 receptor tyrosine kinase (RTK) is expressed in basal cells of squamous epithelia and the outer root sheath of hair follicles. We previously showed that constitutive expression of activated ErbB2 directed to these sites in the skin by the keratin 14 (K14) promoter produces prominent hair follicle abnormalities and striking skin hyperplasia in transgenic mice. However, perinatal lethality precluded the establishment of a transgenic line for analysis of ErbB2 function in adult animals. To investigate the significance of ErbB2 signaling in epithelial tissues during and post development, we developed a K14-rtTA/TetRE-ErbB2 'Tet-On' bitransgenic mouse system. These mice were normal until the ErbB2 transgene was induced by exposure to doxycycline (Dox). Prenatal induction resulted in perinatal death. Postnatally, ErbB2 transgene expression was observed at 4 h after the initiation of Dox, and reached a plateau at 24 h. Skin hyperplasia followed after 2 days and these changes reverted to normal upon Dox withdrawal. In adults, as in the neonates, prolonged ErbB2 induction caused prominent skin and hair follicle hyperplasias. Severe hyperplasias in the cornea, eye lids, tongue and esophagus were also observed. ErbB2 transgene induction was accompanied by increased expression of TGFalpha, a ligand of epidermal growth factor receptor (EGFR), and to a lesser extent, EGFR, further enhancing RTK signal transduction. We conclude that ErbB2 plays important roles in both development and maintenance of hair follicles and diverse squamous epithelia and that this ligand-inducible and tissue-specific 'Tet-On' transgenic mouse system provides a means to study transgenes with perinatal toxicity.

Topics: Animals; Animals, Newborn; Cell Division; Cornea; Doxycycline; Epidermis; ErbB Receptors; Esophagus; Genes, erbB-2; Hair Follicle; Hyperplasia; Keratins; Mice; Mice, Transgenic; Oncogene Proteins v-erbB; Organ Specificity; RNA, Messenger; Tongue; Transforming Growth Factor alpha; Transgenes; Up-Regulation

The 9-cis-retinoic acid (9cRA) is an endogenous ligand of retinoid X nuclear receptors (RXRs). Although the epidermis contains five times more RXRs than RARs, little is known on the activity of topical 9cRA. In order to circumvent surface isomerization of topically applied 9cRA into all-trans-retinoic acid (atRA), we used topical 9-cis-retinaldehyde (9cRAL) as a precursor of 9cRA, hypothesizing that keratinocytes would metabolize 9cRAL into 9-cis-retinoic acid (9cRA). Retinoid content was determined by HPLC analysis of mouse tail skin that had been washed after the application of 9cRAL (0.05% for 14 days) to evaluate the metabolites produced within the epidermis. Biologic activities of 9cRAL and atRAL were analysed by assessing hyperplastic and metaplastic responses, by determining epidermal thickness and the levels of mRNAs encoding for specific keratins. atRAL and derived retinoids were found in skin treated with either atRAL or 9cRAL. The metabolite pattern obtained with 9cRAL was similar to that obtained with atRAL except the presence in 9cRAL samples of an unidentified nonpolar metabolite. However, treatment with 9cRAL yielded higher atRAL and lower retinyl ester concentrations. The biologic activities (hyperplastic and metaplastic responses) resulting from topical application of 9cRAL were lower than those induced by atRAL or atRA at similar concentrations. Taken together, these data show that topical 9cRAL does not deliver significant amounts of 9cRA and exerts less biologic activity than atRAL. Contrary to atRAL, 9cRAL does not appear therefore as a pertinent candidate for topical use in humans.

Topics: Administration, Topical; Alitretinoin; Animals; Gene Expression; Hyperplasia; Keratins; Metaplasia; Mice; Mice, Inbred C57BL; Retinaldehyde; Retinoids; RNA, Messenger; Skin; Stereoisomerism; Tail; Tretinoin

Matrix metalloproteinases (MMPs) are invariably upregulated in the stromal compartment of epithelial cancers and appear to promote invasion and metastasis. Here we report that phenotypically normal mammary epithelial cells with tetracycline-regulated expression of MMP3/stromelysin-1 (Str1) form epithelial glandular structures in vivo without Str1 but form invasive mesenchymal-like tumors with Str1. Once initiated, the tumors become independent of continued Str1 expression. Str1 also promotes spontaneous premalignant changes and malignant conversion in mammary glands of transgenic mice. These changes are blocked by coexpression of a TIMP1 transgene. The premalignant and malignant lesions have stereotyped genomic changes unlike those seen in other murine mammary cancer models. These data indicate that Str1 influences tumor initiation and alters neoplastic risk.

Topics: Animals; Antineoplastic Agents; Carcinogenicity Tests; Cell Differentiation; Cells, Cultured; Epithelial Cells; Female; Fibrosis; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genome; Humans; Hyperplasia; Keratins; Mammary Neoplasms, Experimental; Matrix Metalloproteinase 3; Mesoderm; Mice; Mice, SCID; Mice, Transgenic; Pregnancy; Stromal Cells; Tissue Inhibitor of Metalloproteinase-1; Vimentin

The purpose of this study was to determine whether any clinical or histopathologic variables are associated with the severity of epithelial change in lesions of actinic cheilitis.. A total of 152 acceptable cases of actinic cheilitis were identified from 66,067 cases accessioned from February 1989 to June 1998. For each case, the clinical information supplied by the submitting practitioner at the time of the biopsy and 8 histopathologic variables were evaluated.. The following 5 histopathologic variables were positively correlated with an increased degree of epithelial change: acanthosis, basophilic change within the connective tissue, the presence of inflammation within the connective tissue, perivascular inflammation, and thickness of the keratin layer. None of the clinical variables was associated with an increased degree of epithelial change.. The presence of any of the aforementioned histopathologic changes should prompt a close evaluation of the lesion for the presence of either epithelial dysplasia or carcinoma.

Topics: Age Factors; Biopsy; Blood Vessels; Cellulitis; Cheilitis; Connective Tissue; Epithelium; Female; Humans; Hyperplasia; Keratins; Lip; Male; Middle Aged; Oral Ulcer; Recurrence; Sex Factors

c-Myc overexpression has been associated with several types of human cancers. To study the role of c-myc in epidermal differentiation and carcinogenesis, a transgenic mouse model was created to overexpress c-Myc in the epidermis. Human c-myc 2 cDNA was subcloned into a 6.5 kb mouse loricrin expression vector, ML.myc2. This loricrin promoter primarily directs expression in the epidermis in both proliferating and differentiated keratinocytes. On day 4, ML.myc2 transgenic pups develop a hyperkeratotic phenotype, which progressively worsens until day 7. Upon histological analysis, both hyperplasia and hyperkeratosis were evident. Bromodeoxyuridine (BrdU) incorporation revealed that transgenic mice had a threefold increase in the number of proliferating cells as compared with a normal littermate. Proliferative cells in the ML.myc2 epidermis were also found to be suprabasal, suggesting an inhibition of terminal differentiation in keratinocytes. Inhibition of terminal differentiation by c-Myc overexpression was further suggested by aberrant expression of differentiation markers, keratin 1, keratin 6, loricrin, and filaggrin in ML.myc2 transgenic mice. Interestingly, ML.myc2 keratinocytes exhibit a reduced sensitivity to UV-B induced apoptosis, in vivo. In vitro studies reveal the reduced sensitivity of ML.myc2 keratinocytes to UV-B irradiation is growth factor dependent. These findings provide evidence that overexpression of c-Myc in the epidermis induces proliferation, inhibits terminal differentiation and decreases the sensitivity of keratinocytes to UV-B induced apoptosis.

Topics: Animals; Animals, Newborn; Apoptosis; Biomarkers; Cell Differentiation; Cell Division; Epidermis; Female; Filaggrin Proteins; Genes, myc; Growth Substances; Humans; Hyperplasia; Intermediate Filament Proteins; Keratins; Keratosis; Male; Membrane Proteins; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Mice, Transgenic; Ultraviolet Rays

Most of the double immunostaining protocols that have been introduced so far have been developed for application on fresh frozen material or based on different species antibodies. In liver tissue, general problems of double immunostaining techniques are further complicated by tissue-specific difficulties, such as necrosis or high intracellular protein content. To assess a reliable double immunostaining protocol for archived, paraffin embedded liver tissue, different protocols based on the use of same species primary antibodies were evaluated in terms of sensitivity, specificity and non-specific background staining in pathological liver specimens. We compared peroxidase-anti-peroxidase, alkaline phosphatase-anti-alkaline phosphatase (PAP/APAP), labelled-avidin-biotin (LAB/LAB) and digoxigenin-anti-digoxigenin (dig-a-dig/PAP) techniques using different cytokeratin antibodies and an antibody against PCNA. Comparison of the double immunostaining techniques revealed a high sensitivity and specificity in all procedures. Sections, which were stained employing PAP/APAP-technique, displayed a higher background staining compared to sections which were treated with the LAB/LAB or dig-a-dig/PAP protocol. In contrast to the dig-a-dig/PAP protocol, the LAB/LAB technique provides a better time/cost relationship. Therefore, we would like to recommend a modified LAB/LAB protocol for simultaneous detection of different antigens in archived liver tissue.

Topics: Animals; Antibodies; Cell Membrane; Humans; Hyperplasia; Immunoenzyme Techniques; Immunohistochemistry; Keratins; Liver; Liver Cirrhosis; Mice; Paraffin Embedding; Proliferating Cell Nuclear Antigen; Staining and Labeling

Immunohistochemistry with monospecific antibodies was used to study the expression patterns of cytokeratins (Cks) and vimentin in non-dysplastic lesions of the oral cavity, including lichen planus and fibromas. In hyperplastic lesions, Ck expression did not deviate significantly from the normal non-keratinizing squamous epithelium of the oral cavity. Hyperkeratotic lesions showed pronounced aberrations in their Ck profile. These lesions were characterized by extended expression of the keratinization marker Ck 10, the basal cell Ck 14 and the hyperproliferation-associated Ck 16 in the suprabasal compartment. The stratification markers Cks 4 and 13 showed a decreased expression. Coexpression of Cks and vimentin was found in lesions having accumulations of inflammatory cells in the subepithelial cell layer. These changes are felt to characterize benign mucosal lesions without dysplasia and might be helpful for distinguishing these lesions from potentially malignant ones.

Topics: Antibodies, Monoclonal; Cell Division; Epithelial Cells; Epithelium; Fibroma; Gene Expression Regulation; Humans; Hyperplasia; Immunohistochemistry; Intermediate Filament Proteins; Keratins; Leukoplakia, Oral; Lichen Planus, Oral; Mouth Diseases; Mouth Mucosa; Mouth Neoplasms; Vimentin

Intradermal administration of concanavalin A, a potent T-cell mitogen, into an ear lap resulted in activation of chondrogenesis and stimulation of epidermis proliferation. This proliferation is sometimes invasive in character (pearls and epidermal nests form in the underlying connective tissue) but never turns into true cancerous lesions. This reaction can be delayed, but not prevented, by the prostaglandin inhibitor indomethacin. Stimulation of epidermis proliferation was also caused by administration of other immunomodulators, such as carrageenan type IV, Moloney sarcoma development, and rarely in the course of GvHr, but to much lesser degree than with concanavalin A. It is suggested that the same growth factors, which are mediators of local chondrocyte stimulation, are also mediators of keratinocyte activation.

Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bone Marrow Transplantation; Carrageenan; Chondrocytes; Concanavalin A; Drug Eruptions; Ear Diseases; Ear Neoplasms; Ear, External; Epidermis; Epithelium; Female; Graft vs Host Reaction; Hyperplasia; Hypertrophy; Indomethacin; Keratinocytes; Keratins; Male; Mice; Mice, Inbred BALB C; Mice, Inbred CBA; Mice, Inbred DBA; Mice, Inbred ICR; Mice, SCID; Moloney murine sarcoma virus; Precancerous Conditions; Sarcoma, Experimental; Transplantation, Heterotopic

Of the 20 known cytokeratins, CK-19 is expressed in normal urothelium, whereas the recently identified CK-20 is expressed in urothelial carcinoma cells but not in normal urothelial cells. The aim of this study was to examine whether CK-20 expression could serve as a noninvasive test in which malignant urothelial cells in urine are detected and monitored.. In the current study, the authors used reverse transcriptase-polymerase chain reaction (RT-PCR) methods to determine the expression of CK-20 in cells separated from the urine of patients with bladder carcinoma. Cells were obtained from the urine of 87 patients divided into the following 2 groups: 1) 14 healthy volunteers without any known history of transitional cell carcinoma (TCC), and 2) 73 patients with hematuria suspected for TCC of the bladder. For control purposes, CK-20 expression was examined in cells of 1) bladder carcinoma tumors of 5 patients, 2) blood of either patients with bladder carcinoma (n = 5) or healthy controls (n = 5), and 3) three different cell lines. RNA of the various cell pellets was extracted and RT-PCR was performed with CK-20 and CK-19 primers (CK-19 was used as a marker for normal epithelial cells).. CK-20 amplification band (370 bp) was obtained with mRNA extracted from TCC cells of either bladder tumor or HT-29 line (a CK-20 colon carcinoma line). Sensitivity of the method was found to be 91%, whereas specificity was 67%. Among the 7 false-positive cases, 3 showed atypia, 3 hyperplasia, and 1 metaplasia, and 2 underwent previously successful TCC tumor removals, suggesting that the CK-20 test also responded to premalignant lesions. No false-positive cases were found in the healthy control group. No other preparation, including blood of the patients of with TCC, showed the CK-20 amplification band.. These results indicate that CK-20 is a potential biomarker for noninvasive detection of bladder carcinoma by assaying uroepithelial cells from the voided urine specimen with RT-PCR.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Transitional Cell; False Positive Reactions; Female; Gene Expression Regulation, Neoplastic; Hematuria; HT29 Cells; Humans; Hyperplasia; Keratins; Male; Metaplasia; Middle Aged; Polymerase Chain Reaction; Precancerous Conditions; RNA, Messenger; Sensitivity and Specificity; Transcription, Genetic; Tumor Cells, Cultured; Urinary Bladder; Urinary Bladder Neoplasms; Urothelium

Transgenic mice were developed to explore the role of the erbB2 during epithelial homeostasis and tumorigenesis, through targeted expression of the neu oncogene (neu*). Expression of a neu* cDNA was targeted to the basal layer of skin epidermis as well as other epithelial tissues of transgenic mice via the bovine keratin 5 promoter. Two transgenic founders were obtained that were morphologically distinguishable from non-transgenic littermates by their visibly thickened skin and patchy hair growth by day 3 after birth. The presence of the transgene was confirmed by polymerase chain reaction analysis of tail DNA and immunofluorescence analysis of neu* protein in skin sections. Histological evaluation revealed significant hyperplasia of the follicular and interfollicular epidermis, the abnormal presence of horny material in the dermis and hypodermis, and a dramatic increase in epidermal proliferation. Many areas of the dermis involving this abnormal epithelial proliferation exhibited a squamous cell carcinoma-like appearance. In addition, there was unusual proliferation of the sebaceous glands. One founder died at day 14 and the other at day 20. The latter founder had two papillomas at the time of death. Additional phenotypic changes resulting from the expression of neu* in other tissues included hyperkeratosis in the forestomach and esophagus. In addition, there was a lack of distinction of the cortical-medullary boundaries and an increased rate of cell death in lymphocytes in the thymus. The phenotypic changes in these other tissues correlated with transgene expression. The data suggest that erbB2 signaling has an important role in epidermal proliferation. In addition, the data provide strong support for a role for erbB2 signaling during epidermal carcinogenesis in mouse skin.

Topics: Animals; Female; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Hair Follicle; Homeostasis; Hyperplasia; Keratins; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Neoplasm Proteins; Papilloma; Promoter Regions, Genetic; Skin Neoplasms; Stomach; Thymus Gland; Transgenes

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by mental retardation, seizures, and central nervous system and visceral hamartomas. Pulmonary involvement manifesting as lymphangioleiomyomatosis (LAM) occurs in 1% of patients (all women) with TSC. Micronodular pneumocyte hyperplasia also has been described as a rare pulmonary manifestation of TSC. We report 14 patients with micronodular pneumocyte hyperplasia (MNPH). The patients ranged in age from 23 to 57 years (mean 37.5). There were 12 women and 2 men. Nine of the patients (one man and eight women) had documented clinical manifestations of TSC: seven with LAM, two without LAM (including one man). Of the five patients who did not have TSC, three had LAM and two did not (including one man). Histologically, all 14 cases demonstrated multiple well-demarcated nodules usually measuring up to 8 mm in size, but most were 1-3 mm. The nodules were produced by a proliferation of enlarged cytologically benign type II pneumocytes, with an associated increase in alveolar macrophages and interstitial reticulin. Immunoperoxidase studies showed the type II pneumocytes within lesions to be reactive with antibodies to cytokeratin (four of four), epithelial membrane antigen (EMA) (five of five), and surfactant apoprotein B (8 of 10). HMB-45 was negative in the MNPH lesions in all nine cases studied. Follow-up was available in 9 of 10 living patients and ranged from 1 to 14 years (mean 6 years). Nine patients are alive; six are clinically stable and three have repeated pneumothoraces related to LAM. Four patients have died. None of the deaths were attributable to MNPH. MNPH appears to be a hamartomatous proliferation occurring most frequently in patients with tuberous sclerosis, is separable from and not a manifestation of LAM, has been observed to occur in men, and, like other hamartomas of tuberous sclerosis, does not appear to possess malignant potential.

Topics: Adult; Biomarkers; Female; Humans; Hyperplasia; Immunohistochemistry; In Situ Hybridization; Keratins; Lung; Lymphangioleiomyomatosis; Male; Middle Aged; Repressor Proteins; RNA, Messenger; Tomography, X-Ray Computed; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

By introducing certain irritants into the middle ear it is possible to produce cholesteatoma. Propylene glycol, the main agent used for this purpose, produces a long-standing inflammation that causes hyperplasia and migration of the epithelium through an intact tympanic membrane. In the present investigation topical prednisolone was used in order to inhibit the production of cholesteatoma. The results indicate that there is a marked decrease in inflammation and hence experimental cholesteatoma production when prednisolone is administered into the middle ear.

Topics: Animals; Anti-Inflammatory Agents; Cell Movement; Cholesteatoma, Middle Ear; Ear, Middle; Epithelium; Fibrosis; Glucocorticoids; Granulation Tissue; Hyperplasia; Inflammation; Injections; Irritants; Keratins; Otitis Media; Prednisolone; Propylene Glycol; Rats; Rats, Wistar; Temporal Bone; Tympanic Membrane

In cell culture studies, overexpression of the E2F1 transcription factor has been shown to stimulate proliferation, induce apoptosis, and cooperate with an activated ras gene to oncogenically transform primary rodent cells. To study the effect of increased E2F1 activity on epithelial growth and tumorigenesis in vivo, transgenic mice expressing E2F1 under the control of a keratin 5 (K5) promoter were generated. Expression of E2F1 in the epidermis results in hyperplasia but does not inhibit terminal differentiation. In a transgenic line expressing high levels of E2F1, mice have decreased hair growth likely as a result of aberrant apoptosis in developing hair follicles. Coexpression of a cyclin D1 transgene with E2F1 augments epidermal hyperplasia and further disrupts hair follicle development suggesting that hypophosphorylated Rb antagonizes the proliferative and apoptotic-promoting activities of E2F1. Finally, the E2F1 transgene is found to cooperate with a v-Ha-ras transgene to induce skin tumors in double transgenic animals. These findings confirm that many of the activities ascribed to E2F1 through in vitro studies can be reproduced in vivo and demonstrate for the first time that deregulated E2F activity can contribute to tumor development.

Topics: Animals; Animals, Newborn; Apoptosis; Carrier Proteins; Cell Cycle Proteins; Cell Division; Crosses, Genetic; DNA-Binding Proteins; E2F Transcription Factors; E2F1 Transcription Factor; Epidermis; Gene Expression Regulation; Genes, ras; Hair; Humans; Hyperplasia; Keratinocytes; Keratins; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Retinoblastoma-Binding Protein 1; Skin; Skin Neoplasms; Transcription Factor DP1; Transcription Factors; Transfection

Desmin is a marker of smooth and striated muscle, but evidence is accumulating that it may be expressed by human mesothelium. The aim of this study was to describe desmin expression in normal, reactive, and hyperplastic peritoneal mesothelium, and to evaluate its potential use as a marker for differentiating between epithelial and mesothelial proliferations. We immunohistochemically studied 27 tissue specimens (from 22 patients) with reactive mesothelium, including omentum (n = 14), fallopian tubes (n = 7), ovaries (n = 3), ascitic fluid (n = 1), and peritoneal washings (n = 2). Ovarian surface epithelium (OSE) from 9 cases and 28 ovarian surface epithelial tumors was evaluated for comparison. The desmin expression pattern in the mesothelium, which was similar to but less consistent than that of cytokeratins, was evident in flat and reactive mesothelium, including hyperplastic mesothelial sheets and mesothelium entrapped in clefts. Mesothelial pseudoglandular structures, present in three cases, were predominantly negative for desmin. Desmin expression was observed in the OSE in 4 of 9 cases but not in any mullerian-derived epithelium or mullerian type tumor. Thus, in contrast to cytokeratins, desmin discriminated mesothelial cells from mullerian type epithelia. Compared with vimentin, desmin discriminated mesothelial cells from other tissues except muscle cells. We conclude that desmin may be used in addition to cytokeratins and vimentin as a marker of peritoneal mesothelium.

Topics: Ascitic Fluid; Desmin; Epithelium; Fallopian Tubes; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Omentum; Ovary; Peritoneum; Vimentin

We report six cases of hyperplastic mesothelial cells located in the sinuses of lymph nodes. All patients but one had a concurrent serosal fluid collection (two pericardial, two pleural, one abdominal) at the time of the lymph node biopsy. All effusions cleared with treatment of the underlying disorder, which included lymphoproliferative processes, congestive heart failure, and inflammatory diseases (Dressler syndrome, vasculitis, and glomerulonephritis). Four cases were associated with vascular prominence of the involved nodal sinuses, a feature that may reflect the cause of the underlying effusion or support the transient persistence of benign mesothelial cells in lymph nodes. Two cases were characterized by distention of the nodal sinuses by sheets of mitotically active mesothelial cells. The differential diagnosis includes metastatic carcinoma, keratin-positive dendritic cells native to lymph nodes, and metastatic malignant mesothelioma. Because the latter shares both clinical and morphological features with cases of benign mesothelial cells in lymph nodes, we believe that this distinction may not always be possible in a given biopsy specimen and therefore that careful clinical follow-up is required in such cases.

Topics: Actins; Adolescent; Adult; Biomarkers, Tumor; Carcinoma; Dendritic Cells; Diagnosis, Differential; Epithelium; Female; Glomerulonephritis; Heart Failure; Humans; Hyperplasia; Immunohistochemistry; Keratins; Lymph Nodes; Lymphoproliferative Disorders; Male; Mesothelioma; Middle Aged; Platelet Endothelial Cell Adhesion Molecule-1; Vasculitis

The erbB-2 proto-oncogene belongs to a receptor tyrosine kinase family that includes the epidermal growth factor receptor, erbB-2, erbB-3, and erbB-4. erbB-2 is expressed in basal cells of the squamous epithelia and the outer root sheath of the hair follicles, but its function in epidermal development has not been well studied. To investigate its role in the skin, we created transgenic mice harboring an activated erbB-2 oncogene under the control of the human keratin 14 promoter. The keratin 14 promoter directed its expression to cells in which erbB-2 is normally expressed, whereas the activated receptor gene ensured increased signaling. All transgenic founder mice exhibited extensive and striking skin phenotype, including epidermal hyperplasia, preneoplasia, papilloma, hyperkeratosis, and dyskeratosis. The majority of the hair follicles were replaced by bizarre hyperproliferative intradermal squamous invaginations, whereas the rest of the follicles exhibited severe hyperplasia and disorganization. All but one of the transgenic mice died before or shortly after birth, probably as a consequence of defects in the skin and esophagus. These observations demonstrate that the skin is sensitive to erbB-2 signaling, suggesting an important role for this receptor tyrosine kinase in epidermal growth, differentiation, and hair follicle morphogenesis.

Topics: Animals; Animals, Newborn; Cell Differentiation; Cell Division; Epidermis; Epithelium; Esophagus; Female; Filaggrin Proteins; Gene Targeting; Genes, erbB-2; Hair Follicle; Hyperplasia; Intermediate Filament Proteins; Keratin-14; Keratins; Male; Mice; Mice, Transgenic; Phenotype; Proliferating Cell Nuclear Antigen; Promoter Regions, Genetic; Proto-Oncogene Mas; Receptor, ErbB-2; RNA, Messenger; Skin

Retinoids and phorbol esters have profound effects on proliferation and differentiation of epidermal keratinocytes when applied topically on rodent skin. Since both agents also modulate gap junction (GJ)-mediated cell-cell communication, we have examined the effects of all-trans retinoic acid (RA) and 12-O-tetradecanoylphorbol-13-acetate (TPA) on the expression of alpha1 (Cx43) and beta2 (Cx26) connexins, the two major gap junction gene products in mature rat epidermis. In fully differentiated, mature epidermis, alpha1 is expressed in the lower, less differentiated portion, while beta2 is localized in upper, more differentiated layers. Dorsal skin of 21-day old rats was treated topically with a single dose of RA, TPA or vehicle alone and used for histological and molecular analyses at different time points. Keratinocytes in interfollicular epidermis were examined for proliferation and differentiation using specific antibodies for keratins (K10, K14) and proliferating cell nuclear antigen (PCNA). An increase in epidermal thickness was noticed within 4 hours after the application of RA or TPA. This increase, however, appeared to be primarily due to hypertrophy, since no substantial changes were observed in the proliferative index of epidermal keratinocytes. PCNA immunoreactivity significantly increased after 8 hours treatment of RA or TPA, suggesting a hyperproliferative growth response. Epidermal hyperplasia was confirmed by monitoring the expression patterns of K10 and K14 in RA- or TPA-treated skin. RA-induced hyperplasia lasted longer as compared to TPA induction. Changes in keratin phenotypes were paralleled by an increase in alpha1 and beta2 connexin expression as well as their colocalization in same epidermal layers. Differences in hyperplastic growth response kinetics were also confirmed at the connexin level, with beta2 antigen sustained for longer and at higher levels in suprabasal layers of RA-treated skin. Overall, this type of connexin expression resembled that observed in the non-differentiated rat epidermis during embryonic development. An increase in alpha1 and beta2 connexin abundance was also observed at the protein and RNA levels. At 96 hours after RA or TPA treatment, expression of both connexins was similar to that of the control epidermis. Taken together, these findings suggest that a higher level of GJ-mediated cell-cell communication, is required for the maintenance of homeostasis during periods of rapid epidermal growth and differen

Topics: Animals; Antineoplastic Agents; Carcinogens; Cell Differentiation; Connexin 26; Connexin 43; Connexins; Epidermis; Gap Junctions; Gene Expression; Hyperplasia; Keratinocytes; Keratins; Rats; Rats, Wistar; RNA, Messenger; Tetradecanoylphorbol Acetate; Tretinoin

Upregulation of keratinocyte-derived VEGF-A expression has recently been established in non-neoplastic processes of skin such as wound healing, blistering diseases and psoriasis, as well as in skin neoplasia. To further characterize the effects of VEGF-A in skin in vivo, we have developed transgenic mice expressing the mouse VEGF120 under the control of a 2.4 kb 5' fragment of keratin K6 gene regulatory sequences that confers transgene inducibility upon hyperproliferative stimuli. As expected from the inducible nature of the transgene, two of the three founder mice obtained (V27 and V208), showed no apparent phenotype. However, one founder (V2), mosaic for transgene integration, developed scattered red spots throughout the skin at birth. The transgenic offspring derived from this founder developed a striking phenotype characterized by swelling and erythema, resulting in early postnatal lethality. Histological examination of the skin of these transgenics demonstrated highly increased vascularization and edema leading to disruption of skin architecture. Expression of the transgene was silent in adult animals of lines derived from founders V27 and V208. Phorbol ester-induced hyperplasia resulted in transgene induction and increased cutaneous vascularization in adult transgenic mice of these lines. Skin carcinogenesis experiments performed on hemizygous crosses of V208 mice with activated H-ras-carrying transgenic mice (TG.AC) resulted in accelerated papilloma development and increased tumor burden. Previous results from our laboratory showed that VEGF upregulation is a major angiogenic stimulus in mouse epidermal carcinogenesis. By overexpressing VEGF in the skin of transgenic mice we now move a step further toward showing that VEGF-mediated angiogenesis is a rate-limiting step in the genesis of premalignant lesions, such as mouse skin papilloma. Our transgenic mice constitute an interesting model system for in vivo study of the cutaneous angiogenic process and its relevance in tumorigenesis and other skin diseases.

Topics: Animals; Capillary Permeability; Endothelial Growth Factors; Genes, ras; Hyperplasia; Keratins; Lymphokines; Mice; Mice, Transgenic; Neovascularization, Pathologic; Neovascularization, Physiologic; Papilloma; Precancerous Conditions; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Regulatory Sequences, Nucleic Acid; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Keratins are intermediate filaments of epithelial cells. Mutations in keratin genes expressed in skin lead to human disorders, including epidermolysis bullosa simplex and epidermolytic hyperkeratosis. We examined the role of keratin 4 (K4) in maintaining the integrity of internal epithelial linings by using gene targeting to generate mice containing a null mutation in the epithelial K4 gene. Homozygous mice that do not express K4 develop a spectrum of phenotypes that affect several organs which express K4 including the esophagus, tongue, and cornea. The cellular phenotypes include basal hyperplasia, lack of maturation, hyperkeratosis, atypical nuclei, perinuclear clearing, and cell degeneration. These results are consistent with the notion that K4 is required for internal epithelial cell integrity. As mutations in K4 in humans lead to a disorder called white sponge nevus, the K4-deficient mice may serve as models for white sponge nevus and for understanding the role of K4 in cellular proliferation and differentiation.

Topics: Aging; Animals; DNA Primers; Epithelial Cells; Epithelium, Corneal; Esophagus; Female; Humans; Hyperplasia; Keratins; Male; Melanins; Mice; Mice, Inbred C57BL; Mice, Knockout; Polymerase Chain Reaction; Reference Values; Skin; Tongue

Two cases of mesothelial/monocytic incidental cardiac excrescences in a 66-year-old female and an 80-year-old male are presented. Lesions had solid and tubular pattern formations which were composed of two predominant cell types of histiocytoid cells and cuboidal cells arranged in strips. The histiocytoid cells were round and had well-defined nuclei with prominent nuclear grooves. They had a low nuclear to cytoplasmic ratio. There were no atypical mitoses. Immunohistochemically, these cells were positive for leukocyte common antigen (LCA) and CD68 (KP-1) but negative for keratin. The cuboidal cells were present in strips, had haphazardly arranged surface microvilli and had small round non-cleaved nuclei. These cells were positive for keratin but negative for LCA, CD68, p53, proliferative cell nuclear antigen, alpha-smooth muscle actin, Factor VIII, epithelial membranous antigen and vimentin. These lesions are probably reactive because of their heterogeneous components; an expected feature for an essentially artifactual lesion that is related to cardiac surgery and invasive catheterization. Immunohistochemical studies are useful for avoiding misdiagnosis of neoplasms.

Topics: Aged; Aged, 80 and over; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers, Tumor; Epithelium; Female; Heart Diseases; Histiocytes; Humans; Hyperplasia; Iatrogenic Disease; Immunohistochemistry; Keratins; Leukocyte Common Antigens; Male; Monocytes; Myocardium

Cytokeratin (CK) patterns and albumin messenger RNA (mRNA) are investigated in 24 patients with benign hepatic lesions (7 patients with focal nodular hyperplasia [FNH], 10 with hepatocellular adenomas [HA], 1 with biliary hamartoma, 4 with biliary cysts, 2 with cystadenomas) and in 8 patients with cystadenocarcinoma, a rare liver malignancy. The lesions and surrounding tissue of the hepatocytic components expressed CK 8 and 18 at immunohistochemistry, whereas the biliary elements evidenced CK 8 and 18 and CK 7 and 19. The albumin mRNA, as detected by in situ hybridization (ISH), revealed different distributions in the hepatocytes of FNH and HA. In the benign biliary lesions, the normal hepatocytes surrounding the tumors expressed albumin mRNA, whereas the biliary structures did not. Interestingly, in the cystadenocarcinomas, albumin mRNA was observed not only in the hepatocytes of residual parenchyma, but also in neoplastic bile duct cells lining the carcinomatous cysts; no signal was identified in the nonneoplastic biliary elements. This indicates that cystadenocarcinomas have a mixed biological phenotype and suggests they could arise either from pluripotent cells or from neoplastic cells that reacquire epigenetic features. Our results suggest two possible diagnostic applications for albumin ISH: on routine sections, it could represent an important tool for distinguishing between cystadenoma and cystadenocarcinoma; and on fine needle biopsy specimens, it could reduce uncertainty between FNH and HA.

Topics: Adenoma; Adolescent; Adult; Aged; Albumins; Biliary Tract Neoplasms; Biomarkers, Tumor; Cell Differentiation; Cystadenocarcinoma; Cystadenoma; Cysts; Diagnosis, Differential; Female; Gene Expression; Hamartoma; Humans; Hyperplasia; Immunoenzyme Techniques; In Situ Hybridization; Keratins; Liver; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Neoplasm Proteins; Phenotype; Protein Isoforms; RNA Probes; RNA, Complementary; RNA, Messenger; RNA, Neoplasm; Stem Cells

Differences in the expression of cytokeratins (CK) in specimens obtained from snuff-affected oral epithelium of the maxillary vestibular sulcus and clinically normal sulcular epithelium were studied by indirect immunofluorescence staining with a panel of monoclonal antibodies (MAbs). CK 14, a marker of stratified squamous epithelium was not seen expressed in 3/11 of the snuff user's specimens. Terminal differentiation markers, typical of cornified epithelia (CK 1, 9, 10 and 11), were detected suprabasally in the snuff user's keratosis but not in the normal control epithelium. The use of snuff seemed to change the CK staining pattern of the mucosa so that it resembles more that of a cornified type of epithelium. Simple epithelial-type CK were included in the study in order to establish the CK profile of the snuff-induced keratosis, for comparison with normal and dysplastic lesions. MAb to CK 7 and 19 showed reactivity in the basal cells and suprabasally whereas the monospecific MAb anti-CK 7 showed suprabasal staining both in the control and affected epithelia. By using MAbs, we found no immunoreactivity against CK 18 either in normal or affected epithelia, whereas we found suprabasal reaction (5/11) against CK 8 in the snuff user's epithelia. The two MAbs demonstrating the expression of CK 19, normally confined to the basal cells of the stratified squamous epithelium, showed variable patterns of expression both in basal cells and suprabasally in the snuff lesions. The results show that use of oral snuff causes some alterations in the CK expression pattern of the affected epithelium. Whether the alterations are indicative of a premalignant change is, however, uncertain. The results encourage further studies on the subject.

Topics: Adult; Antibodies, Monoclonal; Biomarkers; Biopsy; Epithelium; Fluorescein-5-isothiocyanate; Fluorescent Antibody Technique, Direct; Fluorescent Dyes; Gene Expression Regulation; Humans; Hyperplasia; Keratins; Leukoplakia, Oral; Male; Mouth Mucosa; Plants, Toxic; Precancerous Conditions; Tobacco, Smokeless

Transgenic animals were developed to assess the role of insulin-like growth factor 1 (IGF-1) in skin growth, differentiation and organization, as well as its importance in tumor formation. Expression of a human IGF-1 cDNA was targeted to the interfollicular epidermis of transgenic mice using a human keratin 1 promoter construct (HK1). Transgenic animals (HK1.IGF-1 mice) could be identified at birth by early ear unfolding and excessive ear and skin growth compared to non-transgenic littermates. Further examination of the skin from these mice showed epidermal hyperplasia and hyperkeratosis, marked thickening of the dermis and hypodermis, and early hair follicle generation in newborns. The severity of this phenotype correlated with transgene expression both of which subsided with age. Adult HK1.IGF-1 mice developed spontaneous tumors following treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) alone and exhibited an exaggerated epidermal proliferative response following treatment with the tumor promoter compared to non transgenic littermates. Additionally, HK1.IGF-1 transgenic mice developed papillomas faster and in markedly greater numbers compared to non-transgenic littermates in standard initiation-promotion experiments. The data presented suggest an important role for IGF-1 in the process of multistage carcinogenesis in mouse skin.

Topics: Animals; Carcinogens; Epidermis; Fluorescent Antibody Technique, Indirect; Humans; Hyperplasia; Insulin-Like Growth Factor I; Keratins; Mice; Mice, Transgenic; Neoplasms, Experimental; Skin Abnormalities; Skin Neoplasms; Tetradecanoylphorbol Acetate

Squamous carcinoma of the larynx arises from pre-existing lesions, the so-called "preneoplastic lesions". Hyperplastic lesions represent a part of their spectrum, from both clinical and biological points of view. On morphologic grounds, the most characteristic feature with prognostic value in the evaluation of preneoplastic lesions is dysplasia. It is not only nuclear alterations that are seen in the process of malignant transformation, the cytoplasmic pattern of cytokeratins changes through neoplastic progression, with a progressive reduction of the molecular weight of the produced species. Dysplasia also associates with gross alterations of the DNA content. This is in agreement with our finding of alterations of genes participating in the control of the cell cycle, p53 and p21(WAF1/cip1). p53 overexpression is detected in non-invasive squamous lesions (even in the absence of obvious dysplasia) and p21(WAF1/cip1) shows a dramatic change in the pattern of expression in dysplastic epithelium compared with the normal. However, not all genes participating in the control of the cell cycle are altered in early lesions. Overexpression of cyclin D1, a common phenomenon in advanced carcinomas, is not likely to participate in the early phases of neoplastic development.

Topics: Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Cyclin D1; Cyclin-Dependent Kinases; Cyclins; DNA, Neoplasm; Epithelium; Genes, p53; Humans; Hyperplasia; Keratins; Laryngeal Diseases; Laryngeal Mucosa; Laryngeal Neoplasms; Oncogene Proteins; Precancerous Conditions

Leukoplakia is only a descriptive clinical term designating a white patch or plaque of the mucosa and must be complemented by histology. On the other hand, keratosis is an exclusively histological term denoting pathological production and accumulation of keratin on the surface of the laryngeal epithelium. Leukoplakia is usually keratosis, but not always. Keratosis can mask various epithelial changes, from simple hyperplasia to invasive squamous carcinoma and is only the superficially visible manifestation of an underlying pathological process. Keratosis means total replacement of superficial epithelial cells by keratin filaments, and dissolution of the nuclei. When nuclei are retained in keratinized cells, the process is termed parakeratosis. Therefore, keratosis can be classified as a separate entity only when histopathological examination reveals superficial keratotic changes accompanying a normal squamous epithelium. To identify the presence of keratosis in various benign laryngeal entities divided according to severity of epithelial abnormalities, and to determine whether keratosis has any prognostic value, we performed a retrospective analysis on bioptic material on 4,291 tissue specimens over a period of 15 years. Our results suggest that keratosis must be considered as only one sign of the disorder within the complex of other pathological changes and not as a distinct pathological entity. For this very reason, keratinization of the epithelial surface was not included among significant parameters used for the grading of epithelial changes into the particular group according to Kambic-Lenart classification.

Topics: Epithelium; Humans; Hyperplasia; Keratins; Laryngeal Diseases; Laryngeal Mucosa; Laryngeal Neoplasms; Leukoplakia; Prognosis; Retrospective Studies

This report describes two examples of nodular histiocytic/ mesothelial hyperplasia as seen in transbronchial biopsy that initially led to serious consideration of neuroendocrine neoplasm or meningioma. The biopsies showed nodular collections of cohesive polygonal or round cells with ovoid or deeply grooved nuclei and a moderate amount of finely granular cytoplasm. Nuclear pleomorphism was mild. Immunohistochemical studies showed few cells staining for cytokeratin and the mesothelial marker HBME-1, whereas most cells were decorated by the histiocytic marker PG-M1 (CD68). This lesion appears to be identical to nodular mesothelial hyperplasia as described in hernia sacs and mesothelial/monocytic incidental cardiac excrescences, and we propose modifying the designation to "nodular histiocytic/mesothelial hyperplasia" to take into account the marked predominance of histiocytes over mesothelial cells. The clues to recognition of the true nature of the lesion are clinicopathologic correlation and identification of strips of low cuboidal (mesothelial) cells in the vicinity, and the diagnosis can be further confirmed by immunohistochemical staining. Nodular histiocytic/mesothelial hyperplasia probably results from irritation to the mesothelial lining by various causes leading to focal aggregation of histiocytes within retraction pockets or crevices of the serosal cavity.

Topics: Biopsy; Bronchi; Bronchoscopy; Diagnosis, Differential; Female; Humans; Hyperplasia; Keratins; Male; Middle Aged; Neoplasms, Mesothelial; Neutrophils; Thoracoscopy

The aim of this study was to investigate prospectively the epithelialization process in the healing temporalis myofascial flap (TMF). Eight cats underwent maxillectomy and immediate reconstruction with TMF. They were killed at the determined time and the reconstructed maxillae were processed for examination by light microscopy and scanning electron microscopy. Results revealed that epithelialization of the healing TMF was initiated by hyperplastic changes followed by active migration of epithelial cells deriving from the wound margins. The partial maxillectomy wound was completely covered by a smooth oral mucosa at postoperative week 24. The mucosa had histological and ultrastructural features different from normal palatal mucosa.

Topics: Animals; Cats; Cell Movement; Collagen; Connective Tissue; Edema; Elastin; Epithelium; Fascia; Granulation Tissue; Hyperplasia; Inflammation; Keratins; Lymphocytes; Macrophages; Maxilla; Microscopy, Electron, Scanning; Mouth; Mouth Mucosa; Plasma Cells; Prospective Studies; Regeneration; Surgical Flaps; Temporal Muscle; Wound Healing

It is generally recognized that epithelial cytokeratins (CKs) are expressed in tissue-specific patterns and reflect differentiation, functional specialization, and pathological alterations of the cells. Differential epithelial cell types can thus be distinguished from each other by their selective expression of particular sets of CKs. To determine the characteristics of metaplastic and hyperplastic changes of alveolar-lining epithelial cells in the lungs of idiopathic pulmonary fibrosis (IPF), the expression of individual CKs was studied immunohistochemically using monospecific anti-CK monoclonal antibodies (anti-CKs 7, 8, 10, 13, 14, 16, 17, 18, 19). Biopsy specimens from 17 patients with IPF and normal lung tissues (NL) from seven patients with lung cancer were studied. In the IPF specimens, several kinds of altered epithelial cells were observed, which showed characteristic changes in CK expression compared with NL, especially CKs 8, 14, and 17. Hyperplastic type II cells expressed increased CKs 7, 8, and 19, but not CK 17; flattened or stratified squamous metaplastic cells expressed increased CKs 17 and 14, co-expressed with CKs 7, 8, and 19; bronchiolar metaplastic cells expressed increased CKs 7, 8, and 19, co-expressed with CKs 14 and 17; cuboidal metaplastic cells expressed increased CKs 7, 8, 17, and 19. The quantification of individual CKs in the tissues by enzyme-linked immunosorbent assay revealed increased expression of CKs 8, 14, and 17 in IPF lung tissues compared with NL. These results were consistent with the immunohistochemical observations. The hyperplastic and bronchiolar metaplastic phenotypes were characterized by their increased expression of simple CKs without CK alteration. The squamous metaplastic phenotype showed CK alterations, with the appearance of CKs 17 and 14. Epithelial cells are thus altered not only in shape, but possibly also in differentiation and function, with potential implications for the pathogenesis of IPF.

Topics: Aged; Enzyme-Linked Immunosorbent Assay; Epithelium; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Male; Metaplasia; Middle Aged; Pulmonary Alveoli; Pulmonary Fibrosis

The rat treated with bile duct ligation (BDL) and furan is a unique animal model of massive bile ductular hyperplasia in which normal liver parenchyma is largely replaced with well-differentiated proliferated bile ductules. We have now developed a simple cell isolation procedure to obtain and culture viable bile ductular epithelial cells in high numbers and with a high degree of purity from the livers of BDL/furan-treated rats. Primary monolayer cell cultures were readily established when the isolated bile ductular epithelial cells were cultured in plastic tissue culture wells coated with rat tail tendon type I collagen plus bovine plasma fibronectin. Under these conditions, epidermal growth factor (EGF) was mitogenic for the cultured cells, and they retained phenotypic features typical of hyperplastic bile ductular epithelium but did not show evidence of ductal morphogenesis in vitro. In contrast, when the isolated bile ductular cells were cultured for 7 to 16 days in the presence of 25 ng EGF/mL and 10% fetal bovine serum on type I collagen gels, they formed into branching ductal structures whose ultrastructural features very closely resembled those of polarized hyperplastic bile ductules/ducts in vivo. Histological preparations of these gel cultures further showed that numerous ductal structures with defined lumens were present. Phenotypically, these ductal structures were completely surrounded by a thickened basement membrane that was strongly immunoreactive for laminin. Like their in vivo biliary cell counterparts, the epithelial cells comprising these ductal structures in culture also exhibited strong immunocytochemical staining reactions for cytokeratins 8 and 19, for glutathione S-transferase pi 7, and for luminal gamma-glutamyl transpeptidase, but they did not express immunoreactive albumin or alpha-fetoprotein. Occasional epithelial cells of the ductal structures, when examined in 10-day-old primary gel culture, showed strong nuclear staining for incorporated 5-bromo-2'deoxyuridine, indicating active cell proliferation. Our results support the development of a novel biliary epithelial cell culture model that has the potential of serving as a powerful tool for investigation of factors that regulate hyperplastic bile ductular morphogenesis, cell proliferation, and polarized cell functions in a structural form in vitro that mimics that of hyperplastic bile ductules induced in vivo.

Topics: Animals; Bile Ducts; Biomarkers; Cattle; Cell Culture Techniques; Cell Division; Cell Nucleus; Cell Polarity; Cell Separation; Cells, Cultured; Collagen; Epidermal Growth Factor; Epithelial Cells; Epithelium; Fibronectins; gamma-Glutamyltransferase; Glutathione Transferase; Hyperplasia; Immunohistochemistry; Keratins; Laminin; Liver; Male; Models, Biological; Rats; Rats, Inbred F344; Time Factors

The increased glucose uptake seen in cancer cells correlates with the expression of human erythrocyte glucose transporter (Glut1) protein in certain human malignancies.. Our purpose was to determine Glut1 expression in cutaneous neoplasms.. A polyclonal anti-Glut1 antibody (MYM) and a standard ABC immunoperoxidase technique were used to determine Glut1 expression in invasive squamous cell carcinomas (SCCs), SCC in situ, basal cell carcinomas (BCCs), melanomas, actinic keratoses (AKs), seborrheic keratoses, common acquired nevi, and scars with regenerative epidermal hyperplasia.. All of the cases of SCC in situ, 14 of 15 (93%) of the SCC, and 13 of 15 AKs (87%) showed intense membranous staining for Glut1. Glut1 staining was present in the epidermis of 8 of 15 scars (53%) but was not detected in any BCC, even in areas of focal keratinization and squamous metaplasia. Glut1 reactivity was absent in the melanomas and seborrheic keratoses.. Glut1 expression in a cutaneous lesion strongly suggests a proliferative lesion of the squamous cell type.

Topics: Antibodies; Carcinoma in Situ; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cell Division; Cicatrix; Dermatitis, Seborrheic; Epidermis; Epithelial Cells; Gene Expression Regulation, Neoplastic; Glucose; Glucose Transporter Type 1; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Keratosis; Melanoma; Monosaccharide Transport Proteins; Neoplasm Invasiveness; Nevus; Regeneration; Skin Neoplasms

A 33-year-old Japanese woman presented with a black papule on a pigmented lesion which had been on her right thigh since her early childhood. A hematoxylin-eosin-stained section revealed a sharply demarcated, acanthotic epidermis composed of enlarged clear cells, which stained positively for epithelial membrane antigen and negatively for carcinoembryonic antigen. With antikeratin antibodies, the tumor cells stained for AE1 and AE3, but did not stain for CAM5.2. They contained abundant glycogen. Histologically, we diagnosed the case as a clear cell acanthoma which developed in the pre-existing epidermal nevus. This is the second such case in the literature.

Topics: Adult; Female; Glycogen; Humans; Hyperplasia; Keratins; Mucin-1; Nevus, Pigmented; Skin Neoplasms

Clomiphene citrate is a nonsteroid antiestrogen which is widely used in the therapy of receptor-positive estrogen for the induction of ovulation. Clomiphene citrate was given subcutaneously to newly born rats with daily injections of 100 mg/kg for 5 days. Changes caused by the clomiphene citrate in vaginas of female rats were investigated at 28 and 35 days. Depending upon the effect of the clomiphene citrate, histopathological changes such as papillary development at keratinization, increase in vaginal epithelium, and observation of polygonal shaped nodular cells in stroma were considered as important findings. It should be emphasised that clomiphene citrate used for induction of ovulation caused these abnormalities in the vagina of rats.

Topics: Animals; Animals, Newborn; Cell Division; Clomiphene; Epithelial Cells; Female; Hyperplasia; Keratins; Rats; Stromal Cells; Vagina

Ligand-mediated activation of the insulin-like growth factor 1 (IGF-1) receptor is critical for epidermal keratinocyte proliferation in vitro, and its expression in normal and psoriatic epidermis suggests that it might regulate keratinocyte proliferation in vivo. In this study, we used a monoclonal antibody (alpha-IR3) that binds to the alpha-chain of this receptor to study its expression (i) in other epithelial cell types in human skin and (ii) in growth-activated epidermis associated with various cutaneous pathologies. In normal skin, IGF-1 receptors were expressed by basal epidermal keratinocytes as well as by basal-like or undifferentiated germinative epithelial cells associated with the follicular outer root sheath, sebaceous glands, and the hair matrix. There was minimal IGF-1 receptor expression in differentiating outer root sheath, hair shaft, and sebaceous epithelial cells. IGF-1 receptor expression in non-growth-activated epidermis of long-standing seborrheic keratoses was confined to the basal epidermal layer, as in normal epidermis. In contrast, hyperplastic epidermis undergoing "regenerative" differentiation (keratin 16+, Ki67+ suprabasal keratinocytes) from psoriasis, chronic skin wounds, and plaques of mycosis fungoides consistently showed increased expression of IGF-1 receptor. In these conditions, the region of expanded IGF-1 receptor expression delimited the epidermal zone of keratinocyte proliferation. In cultured keratinocytes, the subcellular localization of the IGF-1 receptor could be modulated from plasma membranes to the cell cytoplasm by ligand binding, suggesting that the in vivo cytoplasmic staining occasionally observed represents internalization of receptors following ligand stimulation. Our results suggest that cell surface IGF-1 receptors are widely expressed by epithelial cells with proliferative potential, that receptor expression can be modulated with differing epidermal growth states, and that these receptors are largely downregulated in highly differentiated epithelial cells.

Topics: Cell Division; Eccrine Glands; Epidermal Cells; Epidermis; Epithelial Cells; Epithelium; Humans; Hyperplasia; Immunohistochemistry; In Vitro Techniques; Keratinocytes; Keratins; Receptor, IGF Type 1; Skin; Skin Diseases

To study the involvement of cyclin D1 in epithelial growth and differentiation and its putative role as an oncogene in skin, transgenic mice were developed carrying the human cyclin D1 gene driven by a bovine keratin 5 promoter. As expected, all squamous epithelia including skin, oral mucosa, trachea, vaginal epithelium, and the epithelial compartment of the thymus expressed aberrant levels of cyclin D1. The rate of epidermal proliferation increased dramatically in transgenic mice, which also showed basal cell hyperplasia. However, epidermal differentiation was unaffected, as shown by normal growth arrest of newborn primary keratinocytes in response to high extracellular calcium. Moreover, an unexpected phenotype was observed in the thymus. Transgenic mice developed a severe thymic hyperplasia that caused premature death due to cardio-respiratory failure within 4 months of age. By 14 weeks, the thymi of transgenic mice increased in weight up to 40-fold, representing 10% of total body weight. The hyperplastic thymi had normal histology revealing a well-differentiated cortex and medulla, which supported an apparently normal T-cell developmental program based on the distribution of thymocyte subsets. These results suggest that proliferation and differentiation of epithelial cells are under independent genetic controls in these organs and that cyclin D1 can modulate epithelial proliferation without altering the initiation of differentiation programs. No spontaneous development of epithelial tumors or thymic lymphomas was perceived in transgenic mice during their first 8 months of life, although they continue under observation. This model provides in vivo evidence of the action of cyclin D1 as a pure mediator of proliferation in epithelial cells.

Topics: Aging; Animals; Base Sequence; Body Weight; Cattle; Cell Division; Crosses, Genetic; Cyclin D1; Cyclins; DNA Primers; Epidermis; Epithelium; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Mice, Transgenic; Molecular Sequence Data; Oncogene Proteins; Organ Size; Polymerase Chain Reaction; Promoter Regions, Genetic; Restriction Mapping; T-Lymphocyte Subsets; T-Lymphocytes; Thymus Gland; Vagina

Retinaldehyde, a natural metabolite of beta-carotene and retinol, has been proposed recently for topical use in humans. Because retinaldehyde does not bind to retinoid nuclear receptors, its biologic activity should result from enzymatic transformation by epidermal keratinocytes into ligands for these receptors, such as all-trans retinoic acid and 9-cis-retinoic acid. In this study, we analyzed by high performance liquid chromatography the type and amounts of tissue retinoids as well as several biologic activities resulting from topical application of either retinaldehyde or all-trans retinoic acid on mouse tail skin. Biologic activities of all-trans retinoic acid and retinaldehyde were qualitatively identical in metaplastic parameters (induction of orthokeratosis, reduction of keratin 65-kDa mRNA, increase in filaggrin and loricrin mRNAs) and hyperplastic parameters (increase in epidermal thickness, increase in bromodeoxyuridine (BrdU)-positive cells, increase in keratin 50-kDa mRNA, and reduction in keratin 70-kDa mRNA). Some quantitative differences, not all in favor of all-trans retinoic acid, were found in several indices. Cellular retinoic acid-binding protein II and cellular retinol-binding protein I mRNAs were increased by both topical retinaldehyde and all-trans retinoic acid. Whereas all-trans retinoic acid, 9-cis-retinoic acid, and 13-cis-retinoic acid were not detectable (limit 5 ng/g) in vehicle-treated skin, 0.05% retinaldehyde-treated skin contained 13 +/- 6.9 ng/g wet tissue of all-trans retinoic acid (mean +/- SD), 12.6 +/- 5.9 ng/g 13-cis-retinoic acid, and no 9-cis-retinoic acid. In contrast, 9-cis-retinoic acid was detectable in 0.05% of all-trans retinoic acid-treated skin, which also contained 25-fold more all-trans retinoic acid and 5-fold more 13-cis-retinoic acid than retinaldehyde-treated skin. Our results show that topical retinaldehyde is transformed in vivo into all-trans retinoic acid by mouse epidermis. The small amounts of ligand for retinoic acid nuclear receptors thus produced are sufficient to induce biologic effects similar to those resulting from the topical application of the ligand itself in much higher concentration.

Topics: Administration, Topical; Animals; Filaggrin Proteins; Hyperplasia; Keratins; Mice; Mice, Inbred C57BL; Receptors, Retinoic Acid; Retinaldehyde; Retinol-Binding Proteins; Retinol-Binding Proteins, Cellular; Skin; Tretinoin

The purpose of this study was to investigate the distribution of epithelial cells and the fate of the basement membrane along the root surface of rat molars during cementogenesis, and to test the hypothesis that the Hertwig's epithelial root sheath (HERS) cells remain on the root surface if mineralization is inhibited. To demonstrate the HERS cells and basement membrane, immunohistochemistry with antibodies against keratin and laminin were used. The dentin matrix mineralization was inhibited by a single injection of 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP). A modified Gomori staining method was used to monitor the inhibition of mineral formation in dentin and cementum. Paraffin sections were stained with haematoxylin-eosin, and freeze-dried sections were used for Gomori and immunohistochemical stainings. We found that the formation of acellular cementum was suppressed above the dentin with inhibited mineralization. Instead, a hyperplastic matrix, different from acellular cementum, covered the dentin. This hyperplastic cementum had keratin- and laminin-positive cells incorporated; such cells were never incorporated in normal acellular cementum. The later formation of cellular cementum correlated, in controls, with the disappearance of HERS cells from the root surface. Treatment with HEBP resulted in a persistent presence of epithelial cells, interpreted as an inhibition of their disappearance. In conclusion, there is evidence that the cells of HERS are involved in the development of both acellular and cellular cementum. The developmental processes of these tissues appear in some way to be influenced by or associated with the initial mineralization of the dentin.

Topics: Animals; Basement Membrane; Cell Differentiation; Cementogenesis; Dental Cementum; Dentin; Epithelial Cells; Etidronic Acid; Freeze Drying; Hyperplasia; Immunohistochemistry; Keratins; Laminin; Odontogenesis; Rats; Rats, Sprague-Dawley; Tooth Calcification; Tooth Root

By using the subtractive hybridization method, two complementary DNA clones differently expressed in rat normal esophageal epithelium and squamous cell carcinoma induced by administration of precursors of N-nitrososarcosine ethyl ester were isolated. A rat homologue of the human 50-kDa type I cytokeratin 14 was cloned for the first time and shown to be expressed preferentially in squamous cell papillomas and carcinomas, whereas it was weakly expressed or absent in normal squamous epithelial cells and in hyperplastic lesions. A rat homologue of the mouse 57-kDa type II cytokeratin showed strong expression in both normal and tumor tissues. These results are well consistent with the reported alteration of keratin subspecies in human esophageal cancers, therefore, encouraging us to use this experimental system as a model for human esophageal carcinogenesis.

Topics: Animals; Carcinogens; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; DNA, Complementary; Esophageal Diseases; Esophageal Neoplasms; Esophagus; Humans; Hyperplasia; In Situ Hybridization; Keratins; Mice; Neoplasm Proteins; Nitrosamines; Papilloma; Precancerous Conditions; Rats; Rats, Wistar; Recombinant Proteins; Subtraction Technique

The effect of sodium lauryl sulphate (SLS) on cytokeratin (CK) gene expression in hamster cheek pouch epithelium was studied with a hybridohistochemical technique. Using specific human anti-sense RNA probes, the plausible hamster mRNA counterparts for these human CK mRNAs were localized by detection of heterologous hybrids. In comparison with normal epithelium, the expression and distribution pattern of CK mRNAs in the hamster cheek pouch were obviously changed after application of SLS. There was a decreased expression of CK mRNAs in the hyperplastic basal layer, and increased expression in the hypertrophic granular layer. Strikingly, hybridization with the human CK 18 cRNA probe revealed an additionally expressed CK mRNA in the SLS-treated epithelium that was not found in the untreated epithelium. The present study indicates that cRNA probes for human CK mRNAs can be used successfully, not only to distinguish between different hamster CK mRNAs but also to investigate changes in CK gene expression upon the induction of non-neoplastic and neoplastic alterations in the hamster cheek pouch model. This may help elucidate the molecular changes involved in epithelial pathologies.

Topics: Animals; Cheek; Cricetinae; Detergents; Epithelium; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Histocytochemistry; Humans; Hybridomas; Hyperplasia; Hypertrophy; In Situ Hybridization; Keratins; Male; Mesocricetus; Mouth Mucosa; Mouth Neoplasms; RNA Probes; RNA, Antisense; RNA, Complementary; RNA, Messenger; Sodium Dodecyl Sulfate; Surface-Active Agents

Keratins are the major structural proteins of keratinocytes, which are the most abundant cell type in the mammalian epidermis. Mutations in epidermal keratin genes have been shown to cause severe blistering skin abnormalities. One such disease, epidermolytic hyperkeratosis (EHK), also known as bullous congenital ichthyosiform erythroderma, occurs as a result of mutations in highly conserved regions of keratins K1 and K10. Patients with EHK first exhibit erythroderma with severe blistering, which later is replaced by thick patches of scaly skin. To assess the effect of a mutated K1 gene on skin biology and to produce an animal model for EHK, we removed 60 residues from the 2B segment of HK1 and observed the effects of its expression in the epidermis of transgenic mice. Phenotypes of the resultant mice closely resembled those observed in the human disease, first with epidermal blisters, then later with hyperkeratotic lesions. In neonatal mice homozygous for the transgene, the skin was thicker, with an increased labeling index, and the spinous cells showed a collapse of the keratin filament network around the nuclei, suggesting that a critical concentration of the mutant HK1, over the endogenous MK1, was required to disrupt the structural integrity of the spinous cells. Additionally, footpad epithelium, which is devoid of hair follicles, showed blistering in the spinous layer, suggesting that hair follicles can stabilize or protect the epidermis from trauma. Blisters were not evident in adult mice, but instead they showed a thick, scaly hyperkeratotic skin with increased mitosis, resulting in an increased number of corneocytes and granular cells. Irregularly shaped keratohyalin granules were also observed. To date, this is the only transgenic model to show the typical morphology found in the adult form of EHK.

Topics: Age Factors; Animals; Animals, Newborn; Disease Models, Animal; Epidermis; Epithelium; Female; Humans; Hyperkeratosis, Epidermolytic; Hyperplasia; Keratins; Male; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Mice, Transgenic; Mutation; Phenotype; Skin; Transgenes

Isoforms of the transmembrane glycoprotein CD44, which are generated by alternative splicing of nine variant exons, have been implicated in tumor cell adhesion, invasion and metastatic spread and may be indicators of the degree of tumor differentiation. Since little is known about the distribution of CD44 in non-neoplastic neuroendocrine cell types, we systematically investigated 42 samples of tissue from different organs, including the pituitary gland, thyroid, parathyroid, adrenal gland, lung, pancreas, stomach, duodenum, jejunum, ileum, appendix, and colon, immunohistochemically for the expression of CD44 standard and variant exon-encoded gene products (CD44v3, v4, v5, v6, v9). Furthermore, double immunolabeling for CD44 and a variety of peptide hormones was applied to characterize the different neuroendocrine cell types. Our results show that neuroendocrine cells derived from the neuroectoderm lack CD44 immunoreactivity. However, those originated from the endoderm exhibit a variable CD44 immunostaining which is related to their anatomical localization and the degree of differentiation irrespective of the hormone produced. Furthermore, we demonstrate that CD44 positive neuroendocrine cells predominantly express CD44 isoforms of the epithelial type and that hyperplastic clusters of neuroendocrine cells of pancreatic ducts express CD44 most probably as a sign of dedifferentiation.

Topics: Adrenal Glands; Alternative Splicing; Antigens, Nuclear; Autoantigens; Biomarkers, Tumor; Cell Differentiation; Digestive System; Exons; Gene Expression Regulation, Neoplastic; Genetic Heterogeneity; Humans; Hyaluronan Receptors; Hyperplasia; Immunohistochemistry; Intermediate Filament Proteins; Isomerism; Keratin-20; Keratins; Neurosecretory Systems; Nuclear Proteins; Pancreas; Parathyroid Glands; Thyroid Gland

Long-Evans (Eker) rats carry a mutation that predisposes them to develop spontaneous renal cell tumors of two morphologic patterns: solid chromophilic masses or cystic lesions lined by eosinophilic cells. Previous studies have suggested that these tumors arise from the proximal tubules. In the present study, lectin-binding characteristics and cytokeratin expression of various stages of hereditary rat renal epithelial neoplasia were examined to localize the portion of the nephron from which tumors arise. Lectin-binding histochemistry has been used as a marker of cell surface glycoprotein expression, thought to be important in the differentiation of benign from malignant epithelial lesions and in the determination of their cell of origin. The presence or absence of keratin intermediate filaments in the rat nephron has been used to identify nephron segments. The polyclonal antibody to high- and low-molecular-weight cytokeratin stained the cells of the collecting ducts but not the proximal or distal tubules. Binding to the proximal tubules by the lectins Conavalia ensiformis (Con A), Dolichas biflorus, Ricinus communis (RCA-1), and Triticum vulgare and to the distal tubules by Con A, RCA-1, Arachis hypogaea (PNA) with and without neuraminidase, and the antibody for cytokeratins was demonstrated. The lectin binding and cytokeratin staining patterns of rat hereditary renal cell carcinoma, adenoma and the preneoplastic lesions of atypical tubules and hyperplasias suggest that cystic adenomas arise from the distal nephron, principally the collecting duct, whereas the solid atypical tubules, hyperplasias, and adenomas arise from the proximal nephron, principally the proximal tubule.

Topics: Adenoma; Animals; Biomarkers, Tumor; Carcinoma, Renal Cell; Concanavalin A; Histocytochemistry; Hyperplasia; Immunohistochemistry; Keratins; Kidney Neoplasms; Kidney Tubules, Distal; Kidney Tubules, Proximal; Lectins; Male; Plant Lectins; Precancerous Conditions; Rats; Rodent Diseases; Wheat Germ Agglutinins

Weanling male Sprague-Dawley rats were fed a diet containing 0.4 parts/10(6) zinc and controls were fed an identical diet supplemented with 40 parts/10(6) zinc. After 9, 18 and 27 days of zinc deficiency, specimens were excised from cheek epithelium and processed for transmission electron microscopy to study the concentration of membrane-coating granules (MCG). Their concentration was increased in the granular-cell layers of the zinc-deficient epithelium and became significantly greater after 18 and 27 days than 9 days of deficiency. MCGs appeared in the parakeratinized layers of zinc-deficient epithelium and their concentration became significantly greater after 27 days in comparison with 9 and 18 days of deficiency. Thus the intracellular retention of MCGs was increased in the granular and parakeratinized layers with the increase in time of zinc deficiency.

Topics: Animals; Animals, Newborn; Basement Membrane; Cheek; Cytoplasmic Granules; Epithelial Cells; Epithelium; Extracellular Space; Humans; Hyperplasia; Intracellular Membranes; Keratinocytes; Keratins; Leukoplakia, Oral; Male; Microscopy, Electron; Mouth Mucosa; Rats; Rats, Sprague-Dawley; Time Factors; Zinc

In normal adult pseudostratified human nasal surface epithelium, the cystic fibrosis transmembrane conductance regulator (CFTR) is localized to the apical domain of the ciliated cells, whereas in cystic fibrosis (CF), the mutated delta F 508 CFTR exhibits an abnormal cytoplasmic localization. Frequent airway injuries either in CF or non-CF patients may induce a remodeling of the surface epithelium characterized by a change in the morphological structure from normal columnar pseudostratified epithelium to either basal cell hyperplasia, mucous cell hyperplasia, or squamous metaplasia.. The localization of CFTR parallel to markers of cell differentiation, such as cytokeratin 14 (CK14, a marker of basal cells), cytokeratin 18 (CK 18, a marker of ciliated and mucous cells), cytokeratin 13 (CK13, a marker of squamous metaplasia cells), and desmoplakins (DP) 1 and 2 (markers of desmosomes) was analyzed by indirect immunofluorescence.. In normal pseudostratified epithelium, CFTR was detected at the apical plasma membrane of the ciliated cells, CK14 was identified in basal cells of focal areas, CK18 was localized in both ciliated and mucous cells, CK 13 was detected in all basal cells, and DP 1 and 2 were preferentially detected at the interface between columnar and basal cells. In basal cell hyperplasia, CFTR was poorly expressed in the cytoplasm of the more superficial cells, CK14 and CK13 were localized in basal cell multilayers, CK18 labeling was present in the more superficial cell layers, and DP 1 and 2 were preferentially detected at the interface between the more basal cells. In squamous metaplasia, CFTR labeling was either very low or even undetectable, CK14 was found in focal areas of the more basal cell layers, CK18 labeling was either very low or undetectable, CK13 expression was restricted to the flattened cells toward the epithelial surface, and DP 1&2 were intensively present between all the epithelial cells.. These results suggest that the localization of CFTR in human nasal surface epithelium is related to the differentiation state of this epithelium. Abnormally low expression of the CFTR protein may not only be caused by CFTR gene mutations but can also be associated with airway surface epithelium dedifferentiation and remodeling.

Topics: Adult; Aged; Aged, 80 and over; Cell Differentiation; Cystic Fibrosis Transmembrane Conductance Regulator; Cytoskeletal Proteins; Desmoplakins; Epithelial Cells; Epithelium; Fluorescent Antibody Technique; Humans; Hyperplasia; Immunohistochemistry; Keratins; Membrane Proteins; Middle Aged; Mutation; Nasal Mucosa; Nasal Polyps

A total of 291 enlarged lymph nodes showing a range of reactive-inflammatory processes, primary and metastatic neoplasms were studied to determine the distribution and immunoprofile of their cytokeratin-positive interstitial reticulum cells (CIRC) in comparison with normal nodes. In 258/291 nodes (89%), CIRC numbers were distinctly increased in the subcapsular, paracortical and, occasionally, in the medullary zones; often, these increased CIRC formed networks around follicles, sinuses and vessels. CIRC had comparatively small, irregularly shaped bodies and dendritic processes; occasionally, giant forms were noted. CIRC contained cytokeratins (CK) 8 and 18 but not 19, as shown by immunohistochemistry, and by gel electrophoresis with subsequent immunoblotting. They co-expressed vimentin consistently, alpha-smooth-muscle actin frequently, and desmin less frequently. They did not contain desmoplakins, Factor VIII, S-100, LCA, B and T lymphocyte- and macrophage-associated antigens, chromogranin A, synaptophysin or the A-80 glycoprotein. We found no clear correlation between the increased CIRC and given nodal disease processes. However, CIRC were most abundant in nodes free of but draining malignant tumours; bizarre CIRC assemblies were noted in HIV lymphadenopathy. CIRC appear to represent a subset of the so-called "fibroblastic reticulum cells" of lymph nodes. Their function remains undetermined; their increase in diverse lymphadenopathies suggests that they partake in nodal reactions to injury. It remains unclear whether the increase in CIRC relative number is due to proliferation or to CK gene induction processes but their presence and potential capability to undergo hyperplasia with dysplastic forms should alert pathologists to possible diagnostic pitfalls. In addition, we discuss that CIRC may undergo transformation and represent the "cell of origin" of certain CK-positive tumours restricted to lymph nodes.

Topics: Cytoskeletal Proteins; Dendritic Cells; Humans; Hyperplasia; Immunohistochemistry; Keratins; Lymph Nodes; Lymphangitis; Lymphatic Diseases; Lymphoma; Microscopy, Fluorescence; Neoplasms

We report on six patients with tumours of visceral organs (three patients with endometrial adenocarcinoma with squamous cell differentiation, one patient with atypical hyperplasia of endometrium, and two patients with adenocarcinoma of the colon with squamous cell differentiation), where unquestionable differentiation into shadow cells was observed. In all six cases the shadow cells were found mostly in the morules of immature squamous cells. The shadow cells were morphologically identical, on the light microscopical and ultrastructural level, to similar cells found in pilomatricomas. They were often accompanied by granulomatous giant cell reaction and calcification.

Topics: Adenocarcinoma; Adult; Carcinoma, Squamous Cell; Cell Differentiation; Colonic Neoplasms; Endometrial Neoplasms; Endometrium; Female; Humans; Hyperplasia; Keratins; Male; Microscopy, Electron; Middle Aged; Uterine Neoplasms; Uterus

Transgenic mice that expressed v-fos exclusively in the epidermis by means of a human keratin K1-based targeting vector (HK1.fos) developed preneoplastic epidermal hyperplasia and hyperkeratosis after long latency and an associated wound promotion stimulus. To assess the requirements for papilloma formation and malignant conversion and determine the sensitivity to a chemical promotion stimulus, HK1.fos mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). HK1.fos mice were sensitive to TPA promotion but developed papillomas only after long latency (20-30 weeks of promotion) and in relatively few numbers per animal, suggesting the necessity of an additional genetic event prior to overt lesion formation. Consistent with this idea, at 60 weeks, on cessation of TPA promotion, these HK1.fos TPA-papillomas were found to be autonomous, TPA-independent tumors which persisted, grew larger, and converted to malignancy. Analysis of HK1.fos tumor RNA and DNA identified endogenous c-rasHa mutations at codons 12 and 61 in papillomas and carcinomas; however, no p53 tumor suppressor gene mutations were detected. These data indicate that epidermal expression of v-fos induces sensitivity to TPA promotion, but since additional genetic events, such as endogenous c-rasHa activation, appear to be required in tumorigenesis, v-fos may predominantly play a role in the mechanism of promotion to achieve papilloma autonomy and TPA independence. Furthermore, spontaneous malignant conversion in this model does not appear to involve mutations in the p53 tumor suppressor gene.

Topics: Animals; Base Sequence; Biomarkers; Carcinoma; Cell Differentiation; Cell Transformation, Neoplastic; DNA, Neoplasm; Epidermis; Gene Expression Regulation, Neoplastic; Genes, fos; Genes, p53; Genes, ras; Hyperplasia; Keratins; Keratosis; Mice; Mice, Transgenic; Molecular Sequence Data; Mutation; Oncogene Proteins v-fos; Papilloma; ras Proteins; RNA, Neoplasm; Tetradecanoylphorbol Acetate

Ninety-three male breast specimens have been examined for the presence of pseudoangiomatous hyperplasia of the mammary stroma which has hitherto been described almost exclusively in females. Forty-four cases (47.4%) showed some degree of hyperplasia, varying from small microscopic foci to extensive change involving 90% of the mammary tissue. All but one were found in association with gynaecomastia, early and intermediate stage. The association between pseudoangiomatous hyperplasia and benign proliferative lesions mirrors that reported in the female breast, and our findings suggest that the change may represent a stage in the maturation of newly formed mammary stroma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Breast; Cell Adhesion Molecules; Fat Necrosis; Gynecomastia; Humans; Hyperplasia; Keratins; Male; Membrane Glycoproteins; Middle Aged; Mucin-1; Mucins; Platelet Endothelial Cell Adhesion Molecule-1; Vimentin; von Willebrand Factor

The suprabasal keratin 6 (K6) is remarkable among the keratins as, in addition to being constitutively expressed in different stratified epithelia, it is induced in epidermis under hyperproliferative conditions, such as benign or malignant tumors, psoriasis, and wound healing. In addition, this keratin is also induced in skin treated with 12-O-tetradecanoylphorbol-13-acetate or retinoic acid (RA). These characteristics make the study of K6 regulatory elements an especially interesting issue, in particular because these elements could be useful in designing gene constructs for the therapy of skin diseases. We have analyzed by mobility shift and footprinting experiments the cell type-specific enhancer of the bovine K6 beta gene (Blessing, M., Jorcano, J. L., and Franke, W. W. (1989) EMBO J. 8, 117-126) and have identified an AP-2-like element, two AP-1 elements (one of them composite), and a retinoic acid-responsive element (RARE). Mutagenesis experiments and cotransfections with retinoic acid receptors show that the RARE mediates enhancer activation by RA. Chloramphenicol acetyltransferase assays show that under normal culture conditions, the AP-1 element retains most of the enhancer transcriptional activity, while the RARE and AP-2 are weakly active. However, following RA treatment, the AP-1 element is repressed and the RARE is activated, resulting in an overall stimulation of the enhancer by RA in the BMGE+H cells used in our study. These results explain in part the complex and sometimes contradictory response of keratin 6 to hyperproliferative stimuli.

Topics: Animals; Base Sequence; Cattle; Cell Division; Cells, Cultured; DNA; Enhancer Elements, Genetic; Gene Expression Regulation; Humans; Hyperplasia; Keratins; Molecular Sequence Data; Nuclear Proteins; Protein Binding; Sequence Homology, Nucleic Acid; Skin; Tetradecanoylphorbol Acetate; Tretinoin

The nature of clear cell acanthoma has not been clarified, although many hypotheses have been proposed, including a benign neoplasm derived from epidermis or the acrosyringium, or a non-specific dermatosis. In this study, seven cases of clear cell acanthoma were analysed by immunohistochemical techniques, using various monoclonal antikeratin antibodies, and antibodies against filaggrin, involucrin and epithelial membrane antigen. Different immunoreactivities were noted between clear cell acanthoma and a normal eccrine gland, including the acrosyringium. Immunoreactivities of clear cell acanthoma were almost identical to those of normal epidermis, although some antibodies gave a different staining pattern between clear cell acanthoma and normal epidermis. The expression of cytokeratins in psoriatic epidermis has been reported to change as a result of abnormal differentiation or maturation. Clear cell acanthoma showed a similar staining pattern to inflammatory dermatoses such as psoriasis vulgaris, lichen planus and discoid lupus erythematosus. We speculate that clear cell acanthoma is a localized form of inflammatory dermatosis rather than a neoplasm.

Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Epidermis; Filaggrin Proteins; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Membrane Glycoproteins; Mucin-1; Mucins; Protein Precursors

Borderline nodule (BN) in the cirrhotic liver is considered to be a precancerous lesion leading to hepatocellular carcinoma (HCC). We investigated the distribution of cytokeratin 19 (CK 19)-positive biliary cells, recognizable by a monoclonal antibody AE1, in normal livers, chronic active hepatitis, cirrhosis, BN, and small HCC. The CK 19-positive biliary cells in the hepatic parenchyma were clearly divisible into two types (I and II). Type I cells were located within the hepatic parenchyma as small clusters forming small tubules (intraparenchymal ductules). Type II cells were bile ductules located in the peripheral rim of the hepatic lobules or hepatocellular lesions (peripheral ductular reaction) and were continuous with proliferated bile ductules in fibrous septae or portal tracts. In chronic active hepatitis and regenerative nodules of cirrhosis, a few type I cells and a variable number of type II cells were present. In the BN, all cases harbored a few type I cells as well as a variable number of type II cells. The type II cells in the BN were fewer in number and more randomly distributed than those in chronic active hepatitis and cirrhosis. Malignant foci in some BNs lacked CK 19-positive biliary cells. In small HCC, no CK 19-positive biliary cells were found; instead, AE1-positive HCC cells were present in three cases (17%). Although a great majority of type I cells corresponded to intraparenchymal ductules, some type I cells in the BN were composed of rather large tubules considered as interlobular bile ducts.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenoma; Biomarkers, Tumor; Carcinoma, Hepatocellular; Humans; Hyperplasia; Keratins; Liver; Liver Cirrhosis; Liver Neoplasms; Precancerous Conditions

In this study, the histological, cytological, and electron microscopical features of cervical atypical reserve cell hyperplasia are presented. The most important feature of atypical reserve cells in smears is the absence of cytoplasm. Thus, they must be recognized on the absence and not on the presence of a feature, which makes identifying these cells a controversial issue. These stripped nuclei are erroneously believed to be degenerated cylindrical cells, and accordingly are ignored. The atypical reserve cell nuclei are easily damaged in the smear process; however, the MIB-1 staining shows that these disrupted nuclei are derived from proliferating cells. In a follow-up histological study of cases diagnosed as mild dysplasia in a smear, it was found that the presence of MIB-1 positive staining atypical reserve cells was closely related to the development of carcinoma in situ. Recognizing the atypical reserve cells and observing their proliferating activity in a smear might prove to be more important than focusing on the better-known dysplastic cells.

Topics: Antibodies, Monoclonal; Biomarkers; Carcinoma in Situ; Cervix Uteri; Female; Humans; Hyperplasia; Keratins; Ki-67 Antigen; Neoplasm Proteins; Nuclear Proteins; Precancerous Conditions; Uterine Cervical Neoplasms; Vaginal Smears

Nevus sebaceus, considered to be a hamartoma, is known to develop several secondary hyperplastic and neoplastic proliferations. By the use of immunohistochemical studies, we were able to describe a sometimes very striking increase of Merkel cells in nine of 19 nevi sebacei. Only nevi sebacei that formed follicular germ structures and trichoblastomas showed a Merkel cell hyperplasia. In the hyperplastic epidermis of some cases a slight hyperplasia of singular Merkel cells was observed. In foci with follicular germs and trichoblastomas, however, the Merkel cells were much more abundant and sometimes arranged in clusters. Merkel cell hyperplasia is likely to represent another facet of hamartomatous hyperplasia in nevi sebacei. Our observation that trichoblastomas in nevus sebaceus possess, as a rule, hyperplasia of Merkel cells, might be an additional aid to distinguish these tumors from basal cell carcinomas, which are usually devoid of Merkel cells. Furthermore, our findings are a hint that development of follicular germs and trichoblastomas in nevi sebacei may be promoted by Merkel cells.

Topics: Adolescent; Carcinoma, Basal Cell; Cell Count; Child; Chromogranin A; Chromogranins; Coloring Agents; Diagnosis, Differential; Epidermis; Hair Follicle; Hamartoma; Humans; Hyperplasia; Immunohistochemistry; Keratins; Merkel Cells; Neoplasms, Basal Cell; Skin; Skin Abnormalities; Skin Neoplasms

The prostatic epithelium is composed of three distinct cell populations: secretory luminal, basal, and endocrine-paracrine cells. It is currently unknown whether these basic epithelial cell types are related in a hierarchical pathway of differentiation or are independent and separate entities. In the present study we used double-label techniques for cell-specific markers to search for multidirectional differentiation in normal, hyperplastic, and neoplastic prostate tissue. In normal and hyperplastic conditions subsets of basal cells revealed synchronous expression of basal cell-specific cytokeratins and the prostate-specific antigen, indicating intermediate differentiation between basal and secretory luminal cell types. Furthermore, endocrine-paracrine cells of the closed type focally showed simultaneous expression of chromogranin A and basal cell-specific cytokeratins. These findings highlight the phenotypic plasticity of the basal cell layer in the human prostate. In prostatic adenocarcinoma co-expression of exocrine (prostate-specific antigen) and endocrine (chromogranin A) markers was detected frequently in subsets of malignant cells. Conversely, this amphicrine phenotype was rarely found in hyperplastic glands. The occurrence of multidirectional differentiation within the prostatic endocrine cell system may indicate that endocrine-paracine cells derive from pluripotent stem cells of endodermal origin. Furthermore, the phenotypic plasticity of basal cells suggests that this epithelial compartment houses stem cell populations that give rise to all epithelial cell lineages encountered in the normal, hyperplastic, and neoplastic human prostate.

Topics: Adenocarcinoma; Biomarkers; Biomarkers, Tumor; Cell Differentiation; Chromogranin A; Chromogranins; Humans; Hyperplasia; Keratins; Male; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms; Reference Values

Monoclonal antibodies to human stratifying keratin (StK), simple keratin (SK), broad spectrum keratin (BSK) and vimentin were applied to 47 canine mammary tumours (three benign hyperplasia, 26 benign mammary tumours, one malignant mixed tumour, two malignant complex tumours, seven lobular carcinomas, three papillary carcinomas and five squamous cell carcinomas). In benign hyperplasia the SK antibody reacted with acinar and duct epithelial cells; the StK and BSK antibodies reacted strongly with duct epithelial cells in the canine mammary tumours expressed mainly keratins of stratified epithelia rather than those of simple epithelia. Myoepithelial cells in complex and mixed tumours can express StK and vimentin. The finding might be helpful in the assessment of complex tumours where stromal reactions may be confused with myoepithelial neoplastic proliferation. Stromal mesenchymal tissues, including precartilage in complex tumours, and clearly differentiated myoepithelial cells always stained positively for vimentin. Occasional carcinoma cells stained positively for vimentin.

Topics: Animals; Antibodies, Monoclonal; Carcinoma; Carcinoma, Lobular; Carcinoma, Papillary; Carcinoma, Squamous Cell; Dog Diseases; Dogs; Female; Hyperplasia; Immunohistochemistry; Keratins; Mammary Glands, Animal; Mammary Neoplasms, Animal; Vimentin

The effects of four different hyperplastic agents and of the carcinogen DMBA on cytokeratin expression in hamster cheek pouch epithelia were compared. Reversible hyperplasia was produced by the application of either oil of turpentine, vitamin A or TPA. No hyperplastic changes were produced by application of EPP. Apart from the transient appearance of a 45 kDa cytokeratin in one group treated with vitamin A, the immunohistochemical staining patterns and immunoblot profiles of cytokeratins from cheek pouches treated with each of the hyperplastic agents were identical to controls. Following application of DMBA, the cytokeratins stained with increased intensity in the spinous and granular cell layers. This was associated with increased amounts of 42-56 kDa cytokeratins and decreased production of 62-75 kDa cytokeratins. Monoclonal antibody AE1 detected a 45 kDa cytokeratin in extracts of DMBA-treated epithelia that was not detected in untreated epithelial extracts. Monoclonal antibody AE3 detected an additional 54 kDa cytokeratin band in extracts of DMBA-treated epithelia. These cytokeratin changes were present in preneoplastic epithelia and maintained in neoplastic epithelia.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Alkynes; Animals; Cricetinae; Diterpenes; Epithelium; Gene Expression Regulation, Neoplastic; Hyperplasia; Immunoblotting; Immunohistochemistry; Keratins; Male; Molecular Weight; Mouth Mucosa; Mouth Neoplasms; Precancerous Conditions; Retinyl Esters; Tetradecanoylphorbol Acetate; Turpentine; Vitamin A

The pathologic diagnosis of thyroid tumors is often difficult and subjective. Immunohistochemical markers including high molecular weight cytokeratin (HMW-CK), cytokeratin-19 (CK-19) and epithelial membrane antigen have been suggested to be helpful in the distinction of various types of thyroid neoplasia. We collected frozen and/or paraffin-embedded tissues from a total of 116 surgically resected thyroids including 31 nodular hyperplasias, 18 follicular adenomas, 48 papillary carcinomas and 19 follicular carcinomas, stained them for HMW-CK, CK-19 and epithelial membrane antigen, and graded the results on a scale from 0 to 3+. Although little staining for HMW-CK was seen in paraffin-embedded tissues, different results were obtained when both HMW-CK and CK-19 were tested on frozen tissues. In papillary carcinomas, including the follicular variant of papillary carcinoma, diffuse positivity for these antigens was seen immunohistochemically, and these antigens significantly distinguished papillary carcinomas from follicular neoplasms and nodular hyperplasias. Focal staining for epithelial membrane antigen was found in all pathological processes; thus this marker was not useful. We conclude that HMW-CK and CK-19 are useful in the distinction of papillary carcinomas from follicular adenomas, follicular carcinomas, and nodular hyperplasias when applied to frozen tissues. We recommend that samples of thyroid follicular nodules be frozen, and retrieved if necessary to aid in the differential diagnosis of these tumors.

Topics: Adenocarcinoma, Follicular; Adenoma; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma, Papillary; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Membrane Glycoproteins; Molecular Weight; Mucin-1; Thyroid Neoplasms

Injection transgenesis was used to study the long-term effects of excess insulin-like growth factor II on mouse growth and differentiation. By using a construct in which the coding region of the mouse insulin like growth factor II gene (Igf-2) was placed under the control of a keratin gene promoter, four transgenic lines were established, all of which displayed overgrowth of the skin as judged by wrinkling. In addition to high levels of expression in the skin, transgene transcripts were also present in the alimentary canal and uterus. At most of the sites of transgene expression the cell number (DNA content) was greatly increased, indicating a local action of the excess insulin-like growth factor II on cell multiplication. Adult total live weight was slightly increased and there was no macroscopic evidence of tumor formation. The characteristics of these transgenic mice indicate distinct local and systemic actions for insulin-like growth factor II.

Topics: Aging; Animals; Cattle; Cell Division; DNA; Female; Hyperplasia; Insulin-Like Growth Factor II; Keratins; Male; Mice; Mice, Transgenic; Organ Specificity; Promoter Regions, Genetic; Skin Aging; Transcription, Genetic

Retinoic acid (RA) modulates epidermal homeostasis and affects differentiation-associated proteins such as keratin K1 and filaggrin. Because results from in vitro and in vivo studies have been conflicting with respect to RA effects on keratinization, we examined the terminal differentiation of epidermal cell cohorts after RA stimulation in vivo. Pulse-labelling with 5-bromo-2-deoxyuridine (BrdU) was performed by intraperitoneal injection of mice immediately or at 16 h after a single topical application of 100 nmol RA. The cell cohort labelled at the time of RA application consisted of previously unperturbed cells exposed to RA after initiation of S-phase, whereas the cohort labelled 16 h after RA application consisted of cells stimulated into the S-phase by RA. These two cohorts of partially synchronized cells were followed for up to 72 h after BrdU labelling. Such labelling combined with keratin K1 or filaggrin expression was scored by paired immunofluorescence staining of skin sections. The onset of keratin K1 expression was unchanged in both series after RA treatment, while filaggrin appeared earlier than in controls. The differential effect of RA on the maturation markers was related to the proliferative activity, the increased cell turnover, and the shortened epidermal transit time. The onset of keratin expression appeared to be regulated before the postmitotic period, whereas filaggrin expression appeared to be regulated during the late phase of the maturation process, thus being influenced by the actual epidermal kinetics and structural alterations. These results suggested that the effect of RA on epidermal differentiation is secondary to its effect on proliferation, as determined by the altered cellular age distribution following regenerative proliferation.

Topics: Administration, Topical; Animals; Cell Differentiation; Cell Division; Epidermis; Filaggrin Proteins; Hyperplasia; Intermediate Filament Proteins; Keratins; Mice; Mice, Hairless; Tretinoin

We report that keratin 8 (mK8) gene disruption causes colorectal hyperplasia in FVB/N mice. The intestinal lesions affect uniformly the cecum, colon, and rectum but not the small intestine. The elongation of the crypts is accompanied by an inflammation of the lamina propria and submucosa. Hepatic, renal, and pancreatic functions tested in clinical assays are within nonpathological range, suggesting that the major defect lies in colonic epithelial cells. Still, small but consistent elevation in the hepatic enzymes alanine (AST) and asparate (ALT) aminotransferase are observed, along with a 70% increase in spleen weight. No homozygous mouse line has been established, because of a markedly reduced fertility of the mK8-/- females. Previously, we reported that the mK8- targeted mutation causes embryonic lethality in (C57B1/6x129Sv) mice. This strong effect of the genetic background on the mK8- mutant phenotype emphasizes the importance of using several inbred mouse strains to reveal the polygenic contribution to mutant phenotypes. Our results demonstrate that genetic modifiers of K8/K18 filament functions, with profound effects on embryogenesis and gut functional integrity, are differentially active in the FVB/N and C57B1/6 genetic backgrounds. More importantly, the increase in mK8-/- gut epithelial cell number, rather than cell disruption, contrasts with the known function of epidermal keratins in providing mechanical strength.

Topics: Aging; Animals; Base Sequence; Cecum; Colon; Crosses, Genetic; DNA Primers; Female; Fertility; Genotype; Homozygote; Hyperplasia; Infertility, Female; Keratins; Litter Size; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Molecular Sequence Data; Polymerase Chain Reaction; Pregnancy; Rectum

Nail pathology shares some common features with skin pathology, but it also has its own peculiar aspects. The anatomical and physiological characteristics of the nail unit probably play a major role in determining these pathological differences. Although the presence of keratohyaline granules is a normal feature of the skin, there is no granular layer in the normal nail matrix. As a consequence, nail matrix hypergranulosis should be considered a separate entity from skin hypergranulosis. In our review of 150 longitudinal nail biopsy specimens, keratohyaline granules were seen in the nail matrix of 24 cases of lichen planus, 29 cases of spongiotic trachyonychia, 10 cases of psoriasis, and three cases of Hallopeau acrodermatitis. In all cases, the presence of keratohyaline granules was associated with the absence of the normal keratogenous zone. Similar nail matrix features were detectable in three cases of malignant melanoma, two cases of primary systemic amyloidosis, and one case of histiocytoid hemangioma compressing the nail matrix. Our data suggest that inflammatory and compressive insults to the nail matrix cause both disappearance of the keratogenous zone and matrix keratinization with the formation of keratohyaline granules. Skin hypergranulosis reflects a hyperplasia of a normal skin component. In the nail matrix, however, hypergranulosis represents the appearance of structures not normally present. Nail matrix hypergranulosis should be considered a pattern of nail matrix reaction to different inflammatory insults. It is therefore more analogous to epidermal parakeratosis than to epidermal hypergranulosis.

Topics: Acrodermatitis; Amyloidosis; Biopsy; Epidermis; Epithelium; Hemangioma; Humans; Hyalin; Hyperplasia; Keratins; Keratosis; Lichen Planus; Melanoma; Nail Diseases; Nails; Onychomycosis; Psoriasis

We examined the expression of carcinoembryonic antigen (CEA) and cytokeratin (CK) as well as the sialo- and sulphomucin content of 40 hyperplastic polyps (HPs), 6 mixed hyperplastic-adenomatous polyps, 30 adenomas and 40 adenocarcinomas of the colorectum. HPs showed a positive CEA expression in 95% of cases and a decreased sialo- and sulphomucin content compared with normal mucosa. Similar changes were observed in adenomas with low-grade dysplasia. The increase in CEA expression from HPs and adenomas to carcinomas was accompanied by a reduction of sialo- and sulphomucins with about three fourths of carcinomas being sialo- and sulphomucin negative. Oncofetal antigen expression concomitant with mucin changes observed in HPs may indicate impaired cellular maturation at a functional level before dysplastic changes become visible. CEA and CK positive macrophages were found in carcinomas predominantly at sites of tumor disruption and necrosis as well as within veins and lymphatic vessels. Our findings suggest that macrophages may play a role in CEA and CK release into the circulation and thus may be determinants of tumor marker serum levels.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adenomatous Polyps; Biomarkers, Tumor; Carcinoembryonic Antigen; Cell Transformation, Neoplastic; Colon; Colonic Polyps; Colorectal Neoplasms; Humans; Hyperplasia; Keratins; Macrophages; Mucins; Necrosis; Neoplastic Cells, Circulating; Precancerous Conditions; Rectum

To determine if hyperplastic and neoplastic lesions from medaka showed similar immunoreactivity to intermediate filament antibodies as the tissues of origin, two week old medaka were exposed to 10 or 20 mg/L of methylazoxymethanol acetate for two hours and transferred to clean water for up to six months. Using a streptavidin peroxidase method, paraffin embedded Bouins fixed neoplasms were incubated with cytokeratin, vimentin, or neurofilament antibodies. Like their nonneoplastic cellular counterparts, hepatocellular carcinoma, pancreatic acinar carcinoma and mesenchymal neoplasms including hemangioma and hemangiopericytoma reacted negatively to cytokeratin antibodies. Cholangiocarcinoma, mesothelioma, and proliferative lesions containing biliary epithelial cells reacted positively to cytokeratin antibodies. All neoplasms and proliferative lesions were negative with vimentin and neurofilament antibodies. These data indicate that while some epithelial neoplasms showed cytokeratin reactivity similar to the parent tissues, additional markers are needed to identify mesenchymal tissues and neoplasms.

Topics: Adenoma, Liver Cell; Animals; Antibodies; Carcinogens; Carcinoma, Acinar Cell; Carcinoma, Hepatocellular; Cell Division; Cholangiocarcinoma; Hemangioma; Hemangiopericytoma; Hyperplasia; Immunohistochemistry; Intermediate Filaments; Keratins; Liver; Liver Neoplasms; Methylazoxymethanol Acetate; Neurofilament Proteins; Oryzias; Pancreas; Pancreatic Neoplasms; Vimentin

Basic fibroblast growth factor (bFGF) can stimulate the proliferation and differentiation of keratinocytes, fibroblasts, and endothelial cells. These cells are involved during the healing of tympanic membrane (TM) perforations. Light and electron microscopy examinations were used to study the histology of TM healing after application of 400 ng of bFGF on the perforation. The progress of healing is accelerated, but the basic healing process is unchanged, i.e., epithelial proliferation first closes the perforation and is then followed by connective tissue growth. There is more connective tissue in the TM receiving bFGF, and extracellular fibers are better oriented. No significant increase of neoangiogenesis was detected in the treated TM. In the nonperforated area of treated TM, an extensive hyperplasia of the submucosal connective tissue is observed. These results demonstrate that bFGF can produce a TM scar containing more connective tissue, which may be of benefit in the prevention of atrophic healed TM.

Topics: Animals; Basement Membrane; Cell Division; Connective Tissue; Epithelium; Exudates and Transudates; Fibrin; Fibroblast Growth Factor 2; Fibroblasts; Hyperplasia; Hypertrophy; Keratins; Male; Microscopy, Electron; Neutrophils; Rats; Rats, Sprague-Dawley; Tympanic Membrane; Wound Healing

The regulatory elements of the human keratin K1 gene have been used to target expression of the v-Ha-ras oncogene exclusively in the epidermis of transgenic mice. We developed 12 transgenic mouse lines that express the HK1.ras transgene, producing epidermal hyperplasia in neonates and hyperkeratosis in juveniles. Eventually this skin phenotype diminished but with time adult animals developed papillomas that could persist or regress. The rate and frequency of tumorigenesis appeared to be limited, which suggests that v-Ha-ras requires a second or even third event to elicit and maintain a benign phenotype in transgenic mice. Since in certain transgenic lines papillomas appeared at wound sites, it appears that the promotion stimulus from wounding may be a second event. We envision that such transgenic mice that express v-Ha-ras in the epidermis will become a powerful model for assessing how environmental and molecular factors affect the process of multistage skin carcinogenesis in vivo, as well as a model for evaluating novel therapeutic protocols.

Topics: Aging; Animals; Bacteriophage lambda; Base Sequence; Cell Transformation, Neoplastic; Disease Models, Animal; Female; Fluorescent Antibody Technique; Gene Expression; Gene Expression Regulation, Neoplastic; Genes, ras; Genetic Techniques; Hyperplasia; Keratins; Keratosis; Male; Mice; Mice, Transgenic; Molecular Sequence Data; Papilloma; Polymerase Chain Reaction; Regulatory Sequences, Nucleic Acid; RNA, Neoplasm; Skin Neoplasms

Human basal epithelium (myoepithelium)-specific (312C8-1) and luminal epithelium-specific (13H5) cytokeratin antibodies were applied to frozen sections of normal canine mammary tissues (seven), benign adenomas and hyperplasias (five), mixed tumors (12), and adenocarcinomas (18) to determine if epithelial subsets could be discriminated by the use of an avidin biotin peroxidase complex immunohistochemical procedure. The 312C8-1 and 13H5 antibodies were consistently reactive with basal and luminal epithelium, respectively, in the normal mammary gland (7/7) and in benign adenomas and hyperplasias (5/5). Mixed mammary tumors had similar basal and luminal epithelial reactivity and also had proliferating spindle-shaped stromal cells that were reactive with 312C8-1 (10/12) and 13H5 (4/12). The adenocarcinomas were subclassified into basal, luminal, and basal/luminal on the basis of 312C8-1 reactivity (4/18), 13H5 reactivity (2/18), and dual reactivity with mutually exclusive anatomic distribution (11/18), respectively. Those tumors with dual immunoreactivity were indicative of noninvasive carcinomas. Dogs with neoplasms that were reactive with 312C8-1 and nonreactive with 13H5 had local recurrence or distant metastasis within 2 weeks to 6 months after diagnosis. Other antibodies used for comparison were pan cytokeratin AE1/AE3, actin HHF35, and vimentin. 312C8-1 and 13H5 antibodies are specific for canine mammary basal and luminal epithelium, respectively, and by employing these antibodies, the origin and differentiation of canine mammary neoplasms can be determined more accurately than on the basis of hematoxylin and eosin-stained tissue alone.

Topics: Actins; Adenocarcinoma; Adenoma; Animals; Dog Diseases; Dogs; Female; Hyperplasia; Immunohistochemistry; Keratins; Mammary Glands, Animal; Mammary Neoplasms, Animal; Vimentin

Cholera toxin causes reversible epidermal hyperplasia. We observed maximal thickness of the epidermis on the fourth day after treatment and a return to pretreatment values by day 7. The increase in thickness occurred in the basal and intermediate layers, with these layers becoming two to three times thicker than those of normal epidermis. The time sequence of epidermal proliferation was studied using bromodeoxyuridine (BrdU) labelling. We observed a maximum number of labelled basal cells within the first 24 h. Only a few cells were labelled 7 days after toxin injection. Griffonia simplicifolia-IB4 (GSA-IB4), Ulex europaeus-I (UEA-I) and Griffonia simplicifolia-II (GSA-II) lectins were used for the analysis of epidermal cell differentiation in the tissue sections. To study keratinocyte differentiation, further immunological staining was performed using two anticytokeratin antibodies, PKK2 and PKK3 mouse monoclonal antibodies. From the immunocytochemical results, we conclude that synchronous differentiation of the epidermis occurs after cholera toxin administration.

Topics: Animals; Cell Differentiation; Cell Division; Cholera Toxin; Hyperplasia; Immunohistochemistry; Keratins; Lectins; Male; Mice; Skin

Female Wistar rats were exposed to different concentrations of a pyrolized pitch condensate and/or carbon black particles and/or a combination of irritant gases for 18 hours/day, 5 days/week for 10 months, followed by a clean air period of up to 20 months. Bronchiolo-alveolar hyperplasia and squamous metaplasia were important components of the resulting lesions. Squamous metaplasia and associated hyperplasia was investigated by routine histology, scanning and transmission electron microscopy, and by immunohistochemical detection of various cytokeratins (CKs). Intensely CK positive squamous metaplasia lacking a distinct stratum spinosum was distinguishable from squamous metaplasia with a distinct stratum spinosum that reacted weakly CK positive or CK negative. The CK positive type was histologically characterized by narrow intercellular spaces, the weakly CK positive or CK negative type had markedly enlarged intercellular spaces. Differentiated hyperplastic epithelium and the normal lung parenchyma reacted CK negative. In poorly differentiated hyperplasia of the alveolar type associated with squamous metaplasia scattered cells with characteristics of squamous differentiation were detected. Ultrastructurally these cells showed increased amounts of filament bundles and immunohistochemically a positive reaction with the CK antibody. These cells were regarded as precursor stages of squamous metaplasia of the lung periphery in rats.

Topics: Animals; Carbon; Female; Hyperplasia; Keratins; Lung; Metaplasia; Microscopy, Electron; Microscopy, Electron, Scanning; Polycyclic Compounds; Rats; Rats, Wistar

A vector, derived from the human K1 keratin gene, has been employed to target v-fos expression exclusively in the epidermis of transgenic mice. Adult transgenic mice expressors (3-4 months) displayed hyperplasia and hyperkeratosis, initially in wounded (tagged) ears, which later became bilateral. This phenotype appeared at other epidermal sites, most notably in the axilla and inguinal areas. This indicates that a second promoting event, such as wounding or friction, is required to elicit these pathological changes. Highly keratotic benign ear lesions and benign squamous papillomas appeared after long latency at sites of phenotypic epidermis. These data suggest that v-fos may be interfering with c-fos function in normal keratinocyte differentiation, but by itself is insufficient to elicit overt benign lesions.

Topics: Alopecia; Animals; Base Sequence; Cell Differentiation; Epidermis; Gene Expression Regulation, Neoplastic; Genes, fos; Hyperplasia; Keratins; Keratosis; Mice; Mice, Transgenic; Molecular Sequence Data; Oncogene Proteins v-fos; Proto-Oncogene Proteins c-fos; Skin Neoplasms

Salivary duct carcinoma (SDC) is a distinctive salivary gland neoplasm morphologically characterized by intraductal and infiltrating components. Most tumors occur in the major salivary glands and demonstrate a propensity for invasive growth with early regional and distant metastases. Therefore, SDC is regarded as a high-grade malignancy in the current classification of salivary gland neoplasms.. In an effort to identify clinically relevant prognostic features, we studied the clinicopathologic and immunohistochemical findings in 15 SDC, with ultrastructural evaluation of three tumors.. Thirteen SDC occurred in the parotid gland, one in the Stensens duct, and one in the palate. Twelve patients were men (ratio of men to women = 4:1). Patients ranged in age from 39 to 81 years (mean = 59 years). Tumor size varied from 1.2 to 6.5 cm (mean = 3.1 cm). An intraductal component was identified in 10 of 14 primary SDC that made up 10% to 95% of the tumor. In three SDC a preexisting pleomorphic adenoma was identified. Immunohistochemical and electron microscopic evaluation showed the SDC to be composed entirely of ductal cells, and one tumor exhibited features of striated duct differentiation.. SDC show a broader clinicopathologic spectrum than previously described. The tumor may arise in a pleomorphic adenoma. The proportion of intraductal and extraductal growth is variable and of prognostic significance. Although the majority of SDC behave in a high-grade fashion, those with a predominant intraductal component of greater than 90% (PID-SDC) and minimally invasive (< 8 mm) SDC in pleomorphic adenoma appear to have a more favorable prognosis.

Topics: Adenoma, Pleomorphic; Adult; Aged; Aged, 80 and over; Carcinoma, Intraductal, Noninfiltrating; Cell Membrane; Cell Nucleus; Cytoplasm; Epithelium; Female; Humans; Hyalin; Hyperplasia; Keratins; Male; Middle Aged; Mitochondria; Neoplasm Invasiveness; Neoplasms, Multiple Primary; Palatal Neoplasms; Parotid Neoplasms

Transgenic mice have been previously established that express v-rasHa or v-fos exclusively in the epidermis by means of a targeting vector based on the human keratin 1 gene (HK1). Epidermal expression of v-rasHa (HK1.ras) or v-fos (HK1.fos) resulted in hyperplasia, hyperkeratosis, and later, in benign tumors. To assess the potential for oncogene cooperation in vivo mating experiments were performed. Resultant HK1.fos/ras mice exhibited an obvious increase in the severity of neonatal and juvenile preneoplastic phenotypes, together with the immediate onset of tumorigenesis as compared to single oncogene sibling controls. The HK1.fos/ras tumors grew aggressively and often compromised the animals by 10-12 weeks. However, tumors remained benign as determined by histotype and specific keratin markers. These data indicate that v-fos can cooperate with an initiating v-rasHa phenotype to generate autonomous papillomas, but additional events are required for malignant conversion.

Topics: Animals; Animals, Newborn; Base Sequence; Cell Transformation, Neoplastic; DNA Primers; Fluorescent Antibody Technique; Genes, fos; Genes, ras; Genetic Vectors; Humans; Hyperplasia; Introns; Keratins; Mice; Mice, Transgenic; Molecular Sequence Data; Papilloma; Polymerase Chain Reaction; Skin; Skin Neoplasms; TATA Box

We examined 142 biopsy specimens of smokeless tobacco-associated oral mucosal lesions from 133 professional baseball players. Four types of epithelial change were observed in the specimens: hyperparakeratosis, hyperorthokeratosis, pale surface staining, and basal cell hyperplasia. These types of epithelial change were associated with the type of smokeless tobacco used (snuff or chewing tobacco) but not with the duration (years) or amount (hours per day) of use. The thickness of hyperkeratosis in a specimen correlated directly with the amount of smokeless tobacco use. The use of snuff was more frequently associated with development of oral mucosal lesions than was the use of chewing tobacco, and snuff appeared to cause a greater variety and severity of epithelial change than did chewing tobacco.

Topics: Adult; Baseball; Cell Nucleus; Epithelium; Humans; Hyperplasia; Keratins; Leukoplakia, Oral; Male; Mouth Diseases; Mouth Mucosa; Plants, Toxic; Time Factors; Tobacco, Smokeless; United States

This study on the different types of epithelial hyperplasia in fibrocystic disease was inspired by the observation of myoepithelial (basocellular) hyperplasia identified by strong expression of S100 protein and a weak reaction with antibodies against cytokeratin (KL1) in cells forming solid and acinar buds. The cells do not contain immunohistochemically detectable actin or desmin. Glandular transformation and proliferation give rise to basocellular circumductal adenosis. Normal breast tissue, 51 cases of fibrocystic disease with mild, florid and atypical hyperplasias, 7 fibroadenomas and 20 cases of carcinoma in situ were studied and a semiquantitative analysis revealed basal buds and adenosis in less than 40% of cases of mild hyperplasia and up to 73% in florid hyperplasia. Epitheliosis is characterized by a heterogeneous cell pattern with cells positive for S100 protein in 30-60%, but in small ducts up to 100% with an immediate connection to the basal cell layer were positive. Carcinoma in situ contained very rare tumour cells positive for S100 protein. The cells expressing S100 protein in terminal ducts, in adenosis and epitheliosis showed only some of the characteristics of myoepithelial cells, since they lack immunoreactivity with antibodies against actin. These basal clear cells are interpreted as transitional or indeterminate cells with features of myoepithelial precursor cells, but with the ability to develop basocellular nodular and glandular hyperplasia in the ductulo-lobular units in cases of adenosis and juvenile fibroadenoma.

Topics: Adenofibroma; Breast; Breast Diseases; Breast Neoplasms; Cell Division; Female; Fibrocystic Breast Disease; Humans; Hyperplasia; Immunohistochemistry; Keratins; Myoepithelioma; S100 Proteins

The distinction between atypical hyperplasia and carcinoma in situ in breast lesions can be difficult. The identification of myoepithelial cell layers may be helpful in establishing a diagnosis of proliferative breast disease vs. intraepithelial neoplasia. We reviewed pathologic material on 20 cases of atypical hyperplasia and 29 cases of carcinoma in situ. Immunohistochemical stains were employed against muscle-specific actin, S-100 protein, and cytokeratin to identify myoepithelial cells and to recognize different staining patterns. In atypical hyperplasia, muscle-specific actin staining identified myoepithelial cells in fine branching fibrovascular layers or as scattered cells between other proliferating cells. This pattern was absent in carcinoma in situ. S-100 protein showed more positive staining in atypical hyperplasia than in carcinoma in situ with patterns distinct from muscle-specific actin. Immunostaining for cytokeratin demonstrated distinctly different patterns between the two lesions. This study suggests that muscle-specific actin, S-100 protein, and cytokeratin in combination may assist in distinguishing proliferative breast disease with atypia from carcinoma in situ.

Topics: Actins; Breast; Breast Neoplasms; Carcinoma in Situ; Diagnosis, Differential; Epithelium; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; S100 Proteins

A retrospective study of 878 biopsy specimens from 692 patients with laryngeal hyperplastic aberrations was performed according to the Kambic-Lenart classification. Special attention was focused on 88 patients with persistent or recurring disease. In these carcinoma developed in 17 (2.4%) patients, 12 (1.7%) of whom had had atypical hyperplasia. We therefore propose that the term precancerosis, which so definitely implies cancer, should be replaced with the expression risky epithelium where nothing is determined in advance, but a careful follow-up of the patients is imperative. In particular cases of laryngeal hyperplastic lesions, mainly in abnormal and in atypical hyperplasias when the tissue specimens are cut tangentially, the exact identification and position of individual epithelial cells is essential. In such cases histochemical and immunohistochemical methods yield more precise evaluation. Lectins and cytokeratins provide good markers of epithelial maturation. These results contribute to a more useful evaluation of laryngeal hyperplastic lesions, crucial for the choice of adequate therapy.

Topics: Adult; Aged; Aged, 80 and over; Cell Transformation, Neoplastic; Female; Follow-Up Studies; Histocytochemistry; Humans; Hyperplasia; Keratins; Laryngeal Mucosa; Lectins; Male; Middle Aged; Retrospective Studies; Vocal Cords

Intrahepatic biliary cell plasticity was investigated in a rat model that combined prior bile ductular cell hyperplasia after bile duct ligation with subsequent CCl4-induced hepatonecrosis. Morphometric analysis of histologic liver sections from rats at 4 to 6 weeks after bile duct ligation and 3 to 5 days after CCl4 demonstrated the total section area to be occupied by near-equal amounts of hyperplastic bile ductular tissue area and hepatonecrotic area. Of particular significance was the unique presence, albeit infrequent, of newly appearing hepatic cell cholangioles composed of both biliary epithelial cells and one or more 'ductular hepatocytes' exclusively within the hyperplastic bile ductular tissue area of liver sections from the bile-duct-ligated/CCl4-treated rats, but not observed in control liver sections. This finding is compatible with the possibility of a 'transdifferentiation' of some hyperplastic biliary epithelial cells into 'ductular hepatocytes' in response to an extreme hepatic injury.

Topics: Animals; Bile Ducts; Carbon Tetrachloride; Cell Differentiation; Hyperplasia; Immunohistochemistry; Keratins; Ligation; Liver; Male; Rats; Rats, Inbred F344

An immunohistochemical study of squamous metaplasia (n = 10), dysplasia (n = 18), squamous cell carcinoma (n = 48) and 3 cases of adenosquamous carcinoma of the uterine cervix with anti-56KD keratin and 68KD keratin antibodies was performed. In the cases of squamous metaplasia, there were two types of staining of which one type had 56KD positive and 68KD negative and another type had both positive. In the cases of dysplasia, there were two types of staining the same as in squamous metaplasia. But in the cases of carcinoma in situ (CIS) (n = 25), there were three types of staining of which the first type had both 56KD and 68KD negative (n = 7), the second type had 56KD positive and 68KD negative (n = 15), and the third type had both 56KD and 68KD positive (n = 3). In invasive carcinoma (n = 23), there were two types of staining the same as in dysplasia of which one type had 56KD positive and 68KD negative (n = 17) and another type had both positive (n = 6). The keratin negative cases in CIS showed morphologically atypical reserve cell hyperplasia composed of atypical small cells with round nuclei and had a small lesion compared with other types. This result suggested that keratin negative CIS was an early form of CIS which was keratin positive. The results indicating that all dysplasia had 56KD keratin positive and CIS had not always 56KD keratin positive suggested that dysplasia was not always a precursor lesion of CIS.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Antibodies, Monoclonal; Carcinoma in Situ; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Cervix Uteri; Female; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Metaplasia; Molecular Weight; Neoplasms, Multiple Primary; Uterine Cervical Neoplasms

The various cytokeratin polypeptides in oral epithelia are expressed in dependence on site and formation of a stratum corneum. Certain cytokeratins occur permanently and others occasionally. In fibrous hyperplasia and Lichen ruber planus, patterns of cytokeratins did not deviate significantly from normal. In some but not all cases of squamous cell carcinoma and leukoplakia studied, marked aberrations of pattern were characterized by (i) appearance of cytokeratin No. 19, (ii) somewhat more frequent occurrence of cytokeratins Nos. 8 and 18, (iii) proteolytic modifications of cytokeratins, and (iv) partial loss of a few site-specific cytokeratins. The aberrations may be taken as additional diagnostic criteria for differentiation between non-aggressive and potentially aggressive leukoplakic lesion, even if they are not correlated with the conventional histological grading of dysplasia.

Topics: Adolescent; Adult; Aged; Carcinoma, Squamous Cell; Female; Gingiva; Humans; Hyperplasia; Keratins; Keratosis; Leukoplakia, Oral; Lichen Planus; Male; Middle Aged; Molecular Weight; Mouth Diseases; Mouth Mucosa; Mouth Neoplasms

Five-month-old male goats were treated with 25 mg diethylstilbestrol dipropionate (DES-DP) by a single intramuscular injection, causing characteristic histological alterations in the peripheral glandular epithelium of the prostate, resulting in squamous metaplasia. Using a panel of monoclonal and polyclonal cytokeratin antibodies on frozen tissue sections of control prostates, we were able to immunohistochemically distinguish between the normal secretory cells, which are positive for cytokeratin 18 as detected with the antibody RGE 53, and the scattered basal cells, which could be specifically stained by the antibody RCK 103. Cytokeratins indicating squamous differentiation, i.e., nos 4 and 13, recognised by the antibodies 6B10 and 1C7, respectively, were found in sporadic cells throughout the normal goat prostate. Profound changes in cytokeratin expression were observed in the metaplastic lesions as compared to control peripheral glandular tissue. In this respect three monoclonal antibodies are of special interest. RCK 103 is immunoreactive with resting and all stages of differentiating basal cells. Antibodies 1C7 and 6B10 strongly stain the squamous cells in the metaplastic lesions, with 1C7 staining all the squamous cells in the lesions except the basal cell layer, and 6B10 being immunoreactive with the same suprabasal cells or the more differentiated cells in the upper strata. As a result the number of cytokeratin 18-positive cells is drastically reduced upon metaplasia. The results indicate that the goat system can be used as a suitable model system to further test the applicability of immunohistochemical methods in meat inspection and toxicological pathology.

Topics: Animals; Antibodies, Monoclonal; Cross Reactions; Diethylstilbestrol; Epithelium; Frozen Sections; Goat Diseases; Goats; Hyperplasia; Immunoenzyme Techniques; Immunohistochemistry; Keratins; Male; Metaplasia; Prostate; Prostatic Neoplasms

Localized absence of epithelial Langerhans cells (LC) has been shown to affect systemic immune responses, allow microbial colonization and play a possible role in carcinogenesis. Because use of smokeless tobacco is associated with abnormal oral mucosal changes and development of carcinoma, we examined lesion and control specimens from 17 current users of smokeless tobacco to determine whether lesions showed changes in LC number or antigen expression. We identified LC by immunohistochemistry with antibodies to the antigens T6, HLA-DR, HLA-DQ, and HLA-DP. Lesion specimens contained fewer LC (means of 6 LC/mm and 10 LC/mm2) than did the corresponding control specimens (means of 14 LC/mm and 30 LC/mm2), and in each pair of lesion and autologous control specimens the reduction in LC was on average 58% (range, 3% to 95%). There were no apparent differences between lesion and control specimens in the number of LC expressing each of the four marker antigens. Reductions in LC occurred in all types of smokeless tobacco-associated lesions, regardless of increased epithelial thickness or changes in keratinization. Our data indicate that smokeless tobacco reduces the number of Langerhans cells at its site of contact with the oral mucosa.

Topics: Antigens, Surface; Cell Count; Cell Nucleus; Epithelium; HLA-DP Antigens; HLA-DQ Antigens; Humans; Hyperplasia; Keratins; Keratosis; Langerhans Cells; Leukoplakia, Oral; Male; Mouth Mucosa; Plants, Toxic; Tobacco, Smokeless; Vacuoles

A survey of 4342 oral pathology reports accumulated over a five-year period was performed. Diagnoses were 1090 irritation fibromas and 116 giant cell fibromas. A statistical comparison was then made between the giant cell fibromas and the irritation fibromas to determine if there were any differences between these two lesions with respect to sex or race predilection, age distribution, or location in the oral cavity. Finally, various staining techniques were performed on the giant cell fibromas in an attempt to ascertain the origin of the giant cells present in these lesions. The results will be discussed in this paper.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Collagen; Epithelium; Female; Fibroma; Giant Cells; Gingival Neoplasms; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Middle Aged; Mouth Neoplasms; Palatal Neoplasms; Tongue Neoplasms

In dyskeratosis congenita, the hyperkeratotic lesions affecting the mucous membranes have a propensity to undergo malignant change. Unfortunately there is presently no reliable method for predicting such an outcome. Oral mucosal biopsies were obtained from a case of dyskeratosis congenita and keratin expression identified using a panel of antikeratin antibodies. Marked changes were found from keratin profiles established for normal oral mucosa. In particular coexpression of three separate type 1 keratins (K16, K10 and K13) were observed in the ventral tongue lesion. The keratin pattern found in the tissue biopsies examined is suggestive of an unusually immature or disturbed state of tissue differentiation, and as such may be indicative of future malignant change.

Topics: Child; Epithelium; Humans; Hyperplasia; Immunohistochemistry; Keratins; Leukoplakia, Oral; Male; Nail Diseases; Rothmund-Thomson Syndrome; Tongue; Tongue Neoplasms

Recognition of premalignant lesions in the oral epithelium has the potential to increase survival rates for squamous cell carcinoma of the oral cavity. It has previously been reported that cytokeratin 19 (CK19), a 40-kd epithelial cytoskeletal protein within the suprabasal squamous epithelium, is a specific marker of moderate-to-severe dysplasia and carcinoma in situ in oral cavity squamous epithelium. In contrast, normal epithelium and hyperplastic lesions reportedly express CK19 only in the basal layer if at all. The authors chose to test and extend this hypothesis by studying suprabasal CK19 expression and dysplasia of the oral cavity and upper aerodigestive tract in paraffin-embedded specimens that had been fixed in alcohol, a superior fixative for the preservation of cytokeratins. The authors examined 56 alcohol-fixed, paraffin-embedded specimens including 37 from the oral cavity, using two antibodies specific for CK19 (Ks19.1 and 4.62), an antibody to the nuclear proliferation marker, proliferating cell nuclear antigen (PCNA) (19A2), and an antibody to the putative tumor suppressor gene, p53 (pAb1801). The lesions were classified as normal, hyperplasia, mild dysplasia, moderate dysplasia, severe dysplasia/carcinoma in situ, or invasive squamous cell carcinoma, following standard histologic criteria. Immunocytochemically stained sections were scored for the presence or absence of suprabasal CK19, suprabasal PCNA, and p53 positivity, regardless of location. The immunostaining patterns of the two anti-CK19 antibodies were essentially equivalent. Except for one laryngeal specimen, normal epithelium, when positive, showed CK19 expression only in scattered cells throughout the basal layer. Proliferating cell nuclear antigen-positive nuclei were found exclusively in the basal layer. In areas of hyperplasia, CK19 immunostaining was absent or confined to the basal layer in 20 of 38 specimens and was expressed in suprabasal cells in 18 of 38 hyperplastic specimens. Proliferating cell nuclear antigen immunostaining in all cases of hyperplasia was limited to the basal layer. Severe dysplasia and carcinoma in situ showed suprabasal CK19 staining in six of nine specimens and no CK19 staining in three of nine specimens. In contrast, suprabasal PCNA immunostaining was found in all dysplasia and carcinoma in situ cases. p53 expression was detected in three of nine severe dysplasia/CIS specimens and was immunocytochemically undetectable in all normal, hyperplasia, an

Topics: Antigens, Neoplasm; Carcinoma, Squamous Cell; Genes, p53; Humans; Hyperplasia; Immunohistochemistry; Keratins; Mouth; Mouth Mucosa; Mouth Neoplasms; Mutation; Nuclear Proteins; Pharynx; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Tissue Fixation

In previous experiments, pretreatment of CD-1 mouse skin with prostratin (12-deoxyphorbol 13-acetate) inhibited hyperplasia, induction of ornithine decarboxylase and edema in response to acute treatment with phorbol 12-myristate 13-acetate (PMA). We report here that prostratin inhibits biological responses induced by multiple (chronic) PMA treatment. A typical chronic treatment schedule consisted of five applications of 3.2 nmol (2 micrograms) PMA at 48 h intervals. Most effective inhibition could be achieved when the first PMA treatment was preceded 48 h before by a lower dose of prostratin (256 nmol = 100 micrograms) and each PMA treatment was preceded 15 min before by a higher dose (2.56 mumol = 1 mg) of prostratin. Under this schedule hyperplasia was completely blocked, as was keratin K6 expression (a marker of hyperproliferative epidermis), whereas myeloperoxidase activity (a marker of neutrophil granulocyte infiltration) was reduced to 36%. 12-Deoxyphorbol 13-phenylacetate (dPP), a non-promoting 12-deoxyphorbol derivative that binds to protein kinase C with two orders of magnitude higher potency than does prostratin, showed the same pattern of inhibition as did prostratin for a single PMA treatment but with a corresponding two orders of magnitude higher potency. In the case of chronic PMA treatment, however, dPP failed to inhibit hyperplasia fully, though it reduced keratin K6 expression and inflammation. Dissociation of K6 expression from hyperplasia was unexpected, since expression of these two responses was thought to be closely coupled. We conclude that 12-deoxyphorbol 13-monoesters are functional antagonists for a class of protein kinase C-mediated responses closely correlated to tumor promotion.

Topics: Animals; Dermatitis, Contact; Drug Antagonism; Enzyme Induction; Hyperplasia; Keratins; Mice; Ornithine Decarboxylase; Peroxidase; Phorbol Esters; Skin; Tetradecanoylphorbol Acetate

The presence of eosinophilic, hyaline globules in association with epithelial hyperplasia was noted in the rete testis of three patients with germ cell tumors. In the more florid examples, this proliferation formed a solid and microcystic pattern that, in association with the hyaline globules, mimicked a yolk sac tumor component. However, the bland cytologic features of the cells and the conformation to the configuration of the rete testis were keys to its reactive nature. A subsequent review of 48 testicular specimens containing well-defined areas of the rete testis showed hyaline globule formation in the rete testis or tubuli recti in 16 of 27 germ cell tumors, one of five other testicular tumors (four stromal tumors and one plasmacytoma), and none of 16 nonneoplastic cases. Many of the cases that had hyaline globules also showed epithelial hyperplasia. Further analysis demonstrated an incidence of rete testis invasion by neoplasm in cases that had hyaline globules, with or without epithelial hyperplasia, that was significantly higher (p less than 0.01) than that seen in neoplastic cases lacking hyaline globules. We concluded that this pseudoneoplastic reaction developed secondary to invasion of the rete testis by tumor. Immunostains supported the nonneoplastic nature of the proliferative lesions and indicated that the globules represented various proteins that had been absorbed from the lumen of the rete testis by the epithelial-lining cells but not successfully secreted.

Topics: Albumins; alpha 1-Antitrypsin; Diagnosis, Differential; Epithelium; Humans; Hyalin; Hyperplasia; Immunohistochemistry; Keratins; Lactalbumin; Male; Mesonephroma; Rete Testis; Testicular Neoplasms; Vimentin

Cell kinetics of reversible and persistent forestomach lesions induced by the genotoxic agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and/or the nongenotoxic antioxidant butylated hydroxyanisole (BHA) was investigated. A total of 184 male F344 rats were divided into four groups: Group 1 given an initial single gastric intubation of MNNG received 2% BHA diet from the third wk to the 26th wk and then basal diet; Group 2 receiving 2% BHA without MNNG initiation; Group 3 given MNNG alone; and Group 4 serving as a nontreated control. Rats were sequentially sacrificed at 6, 16, 26, 30, and 46 wk. Bromodeoxyuridine was administered either as a single i.p. injection (100 mg/kg of body weight) 1 h before killing or continuously via an osmotic minipump (120 micrograms/h) for 1, 3, or 7 days prior to sacrifice, in each case labeled cells being detected by immunohistochemistry. Squamous cell hyperplasia (SCH) and basal cell hyperplasia (BCH), each characterized by different phenotypic keratin expression, were induced in Groups 1 to 3. After withdrawal of BHA, rapid regression of SCH and extremely slow regression of BCH were observed. Papillomas and squamous cell carcinomas developed irreversibly in Group 1 and 3, BHA significantly (P less than 0.01) enhancing the incidence of SCC in Group 1. Flash and continuous bromodeoxyuridine labeling revealed SCH to consist of cells of high mitotic activity and short life span, whereas BCH consisted of cells with low mitotic activity and long life span. In addition, highly labeled areas were observed in SCH after cessation of BHA feeding in Group 1 without regression, and similar lesions were also evident in Group 3. The results suggest that rapid regression of SCH and slow regression of BCH reflect different cell kinetic patterns and that highly labeled areas after release from stimulating agents might be preneoplastic changes related to cancer development.

Topics: Animals; Butylated Hydroxyanisole; DNA; Epithelium; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Methylnitronitrosoguanidine; Precancerous Conditions; Rats; Rats, Inbred F344; Stomach; Stomach Neoplasms; Time Factors

The so-called embryonal hyperplasia of Bowman's capsular epithelium (EHBCE) is a rather specific lesion occurring in kidneys of patients maintained on chronic dialysis. It consists of poorly differentiated cells proliferating around sclerosed or obsolescent glomeruli. In this study, immunohistochemical and ultrastructural characterization of EHBCE was performed. The poorly differentiated cells in the lesion exhibited a positive reaction for vimentin and a negative one for cytokeratin (PKK 1) and epithelial membrane antigen. On ultrastructural examination, specialized junctions between adjoining cells, microvilli-like structures on their surfaces, and immature basal folds were observed. These observations suggest that the cells of EHBCE may be associated with the anlage of glomerular epithelium. The background in which neoplasms like renal cell carcinoma or atypical epithelium of cyst wall develop in end-stage kidneys of adult patients on long-term dialysis may cause such a proliferation of poorly differentiated cells in young or paediatric age group patients.

Topics: Child, Preschool; Epithelium; Fetal Diseases; Humans; Hyperplasia; Immunohistochemistry; Keratins; Kidney Glomerulus; Male; Membrane Glycoproteins; Microscopy, Electron; Mucin-1; Vimentin

Six cases are described of benign thymic cysts of the anterior mediastinum showing focal pseudoepitheliomatous hyperplasia of the lining epithelium. The patients' ages ranged from 11 to 54 years; five cysts occurred in males and one in a female. Histologically, the lesions were characterized by exuberant proliferation of the cyst lining epithelium that grew as sheets and tongues of atypical squamous cells with large, hyperchromatic nuclei, prominent nucleoli, and scattered mitotic figures. The walls of the cyst adjacent to the areas of epithelial proliferation showed abundant hemorrhage, necrosis, and severe inflammatory changes. All cases were treated by local surgical excision. There was no evidence of recurrence or metastases over a follow-up period of up to 8 years (average follow-up, 4 years). It is proposed that pseudoepitheliomatous hyperplasia may develop in thymic cysts as an expression of regeneration of the lining epithelium in response to the inflammatory, hemorrhagic, and necrotizing changes which often accompany these lesions. This should not be mistaken for malignancy, and should be distinguished from the exceptional cases of true thymic neoplasms seen in association with thymic cysts.

Topics: Adult; Child; Epithelium; Female; Follow-Up Studies; Humans; Hyperplasia; Immunoenzyme Techniques; Inflammation; Keratins; Male; Mediastinal Cyst; Middle Aged

Studies on cell lines have greatly improved our understanding of many important biological questions. Generation of cell lines is facilitated by the introduction of immortalizing oncogenes into cell types of interest. One gene known to immortalize many different cell types in vitro encodes the simian virus 40 (SV40) large tumor (T) antigen (TAg). To circumvent the need for gene insertion in vitro to generate cell lines, we created transgenic mice harboring the SV40 TAg gene. Since previous studies have shown that TAg expression in transgenic mice is associated with tumorigenesis and aberrant development, we utilized a thermolabile TAg [from a SV40 strain, tsA58, temperature sensitive (ts) for transformation] to reduce the levels of functional TAg present in vivo. To direct expression to a broad range of tissues, we used the mouse major histocompatibility complex H-2Kb promoter, which is both widely active and can be further induced by interferons. tsA58 TAg mRNA was expressed in tissues of all animals harboring the hybrid construct. Development of all tissues was macroscopically normal except for thymus, which consistently showed hyperplasia. Fibroblast and cytokeratin+ thymic epithelial cultures from these mice were readily established without undergoing crisis and were conditionally immortal in their growth; the degree of conditionality was correlated with the levels of tsA58 TAg detected. One strain of H-2Kb-tsA58 mice has been bred through several generations to homozygosity and transmits a functional copy of the transgene.

Topics: Animals; Blotting, Northern; Blotting, Western; Cell Line; Cell Transformation, Viral; Cloning, Molecular; Epithelium; Fibroblasts; Fluorescent Antibody Technique; Hyperplasia; Interferon-gamma; Keratins; Mice; Mice, Transgenic; Nucleic Acid Hybridization; Promoter Regions, Genetic; RNA; Simian virus 40; Skin; Thymus Gland

Atypical mesothelial hyperplasia encountered in pleural fluid or in a pleural biopsy specimen raises the suspicion that one may be dealing with a diffuse malignant mesothelioma of the pleura. We studied eight cases with cytologic or histologic changes of mesothelial atypia thought to be suspicious for diffuse malignant mesothelioma. In each case, the hyperplasia was associated with a bronchogenic carcinoma in the lung subjacent to the mesothelial hyperplasia. Bronchogenic carcinoma should be added to the list of causes of atypical mesothelial hyperplasia. This combination of reactive and malignant processes should be appreciated, since pleural carcinomatosis and diffuse malignant mesothelioma must be separated for clinical and epidemiologic reasons.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Carcinoma, Bronchogenic; Carcinoma, Squamous Cell; Female; Humans; Hyperplasia; Keratins; Lung; Lung Neoplasms; Male; Middle Aged; Pleura; Pleural Effusion, Malignant

This study demonstrates that the stromal thymus elements of postcapillary venules are the source of desmin-positive mesenchyme from which both myoid and epithelial cells arise. The double staining revealed various degrees of desmin and keratin positivity in the same kind of cells in the medulla as well as in Hassall's corpuscles. Hassall's corpuscles seem to arise from several kinds of cells of which one appears to be monocytogenic and expressed S100 protein.

Topics: Adolescent; Adult; Biomarkers; Cell Differentiation; Cell Fusion; Child; Desmin; Epithelium; Female; Humans; Hyperplasia; Keratins; Male; Monocytes; Myasthenia Gravis; Myoglobin; S100 Proteins; Thymus Gland; Venules

Human liver parenchymal cells have a very simple cytokeratin composition and express only one cytokeratin pair: cytokeratin 8 (a type II cytokeratin, molecular weight 52 kD) and cytokeratin 18 (a type I cytokeratin, molecular weight 45 kD). Intrahepatic bile duct cells contain in addition to cytokeratins 8 and 18 also cytokeratins 7 (a type II cytokeratin, molecular weight 54 kD) and cytokeratin 19 (a type I cytokeratin, molecular weight 40 kD). The paper deals with the cytokeratin expression in various types of benign and malignant primary liver tumors as assessed by immunohistochemical methods or by the use of gel electrophoresis and immunoblotting of cytoskeletal extracts.

Topics: Adenoma, Bile Duct; Biomarkers; Carcinoma, Hepatocellular; Histocytochemistry; Humans; Hyperplasia; Keratins; Liver Diseases; Liver Neoplasms

From a total material of 184 Swedish users of loose packed moist snuff and 68 users of portion-bag packed moist snuff, cases were selected from subgroups based on a four-point clinical grading scale. The selected material for the study comprised 70 cases (ten from each clinical grade group, no Degree 4 lesion was found among portion-bag users). Features recognized in biopsies from these cases together with findings in previous studies correlated well with the use of a four-point scale for the grading of clinical changes, especially in the context of discriminating lesions for which special efforts should be undertaken to make the patient stop or change the snuff dipping habit and for selecting patients in whom regular clinical follow-up including a biopsy should be carried out. In this article is also discussed the labeling of the clinical oral mucosal changes seen at the site where a quid of snuff is regularly placed. The conceptual use of "snuff dippers' lesions" is recommended instead of e.g. snuff-induced leukoplakia.

Topics: Adult; Atrophy; Epithelium; Humans; Hyperplasia; Keratins; Male; Mitosis; Mouth Diseases; Mouth Mucosa; Necrosis; Plants, Toxic; Sweden; Time Factors; Tobacco, Smokeless

The microanatomic organization of focal nodular hyperplasia (FNH) of the liver was analyzed to obtain information about the histogenesis of this tumor-like lesion. All of the 11 examples of FNH studied showed subdivision into multiple pseudolobules, which were characterized by fibrovascular and ductular areas radiating from perilobular septa, and an expanding periphery of normal appearing hepatocytes. Immunohistochemical analysis showed continuous transitions from normal hepatocytes in the periphery of the pseudolobules, which expressed only the keratins 8 and 18, to small hepatocytes and ductular aggregates in the center of the pseudolobules, both of which also expressed the keratins 7 and 19. Ductular metaplasia of hepatocytes was always accompanied by sinusoidal endothelial cells stained by the endothelial markers BMA 120, M 616, and by an increase in collagenous fibers especially of type III. Further development of this fibrovascular and ductular transformation lead to subdivision of the involved pseudolobules. The pseudolobules had similar mean sizes, irrespective of their site in the periphery or the center of the FNHs, showing that proliferation, fibrovascular and ductular transformation and subdivision of these micronodules are a basic histogenetic phenomenon in FNH. The findings indicate that local changes in the interrelations between liver epithelial and mesenchymal cells influence substantially the abnormal but nevertheless regulated growth of liver parenchyma which gives rise to FNH.

Topics: Adult; Aged; Endothelium; Epithelium; Female; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Liver Neoplasms; Male; Microcirculation; Middle Aged

Pachyonychia congenita (PC) is a very rare hereditary disorder of keratinization. Immunohistological findings has so far been lacking. Reported in this paper is a case of Jadassohn-Lewandowsky type PC in a woman aged 18 years on which immunohistological investigations could be performed. Several monoclonal antibodies to filaggrin and keratin were used to stain tissue sections of lesional plantar skin, with a view to studying impairment of epidermal differentiation. While staining patterns comparable to those of normal skin were exhibited by anti-filaggrin and some antikeratins (RPN 1161, A51-B/H4), substantially altered immunostaining was recordable from other anti-keratins. Only superficial vital keratinocytes were stained by RKSE 60 against keratin 10 and K 8.12 against keratins 13 and 16. The authors, in other words, obtained information on expression of keratin 10, normally occurring in all suprabasal keratinocytes, as well as of the basal proliferation keratin 16 in the uppermost vital cell positions of PC lesion. The above results are likely to suggest impairment of keratin expression in cases of PC.

Topics: Adolescent; Epidermis; Female; Filaggrin Proteins; Frozen Sections; Humans; Hyperplasia; Immunohistochemistry; Intermediate Filament Proteins; Keratinocytes; Keratins; Keratoderma, Palmoplantar; Nails, Malformed; Syndrome; Tongue

Hyperplasia in the hamster cheek pouch was examined using 4 different hyperplastic agents: oil of turpentine 50% v/v in liquid paraffin; vitamin A palmitate 10% w/v in liquid paraffin; 12-O-tetradeconyl-phorbol-13-acetate 16nM in acetone; and ethylphenylpropiolate 0.04mM in acetone. Acetone, paraffin and untreated control groups were also examined. Cheek pouches were painted 3 times a week for up to 4 weeks with each solution. Samples were removed and prepared for light microscopy 24 hours after 2 weeks of painting and 24 hours, 6, 12 and 18 weeks after 4 weeks of painting. Hyperplasia was produced by application of turpentine, vitamin A and TPA after 2 weeks of application. Further increases in epithelial width occurred after 4 weeks of painting in the turpentine and vitamin A groups but a decrease was seen in the TPA group. Six weeks (vitamin A and TPA groups) or 12 weeks (turpentine group) after the completion of treatment the epithelium had a normal histological appearance. No differences between the control or EPP treated cheek pouch mucosa could be detected. Turpentine and vitamin A can be used as models of reversible hyperplasia in the hamster cheek pouch.

Topics: Alkynes; Animals; Cell Nucleus; Connective Tissue; Cricetinae; Cytoplasmic Granules; Diterpenes; Epithelium; Hyalin; Hyperplasia; Keratins; Male; Mouth Mucosa; Retinyl Esters; Tetradecanoylphorbol Acetate; Time Factors; Turpentine; Vitamin A

The calcifying odontogenic cyst (COC) is a rare lesion without specific clinical characteristics. Its diagnosis is essentially histopathological showing the presence of ghost cells associated with narrow squamous epithelium, the basal strata of which consist of clearly delineated cells differentiating in areas of the stellate reticulum in a similar way to ameloblastoma. The results of ultrastructural observations of the ghost cells as well as histochemical and immunohistochemical studies suggest that they are the sites of abnormal keratinisation. The aim of this study of one COC mas to locate the stages in epithelial maturation associated with the formation of ghost cells. Six monoclonal antibodies were used; three with a wide spectrum (KL1, AE3, AE1), two with a narrow spectrum against high molecular weight cytokeratins (AE2, AE8) and one against vimentin (M725). Histopathological examination of the COC revealed three different types of cells in the epithelial lining and the epithelial islands; small basal cubic cells surrounding larger ones placed centrally or suprabasally; balloon shaped cells or flattened ghost cells rolled up on themselves to resemble keratinising pearls, or cornifying cells. The ghost cells and cornifying cells had an altered distribution of their cytokeratins demonstrated by the absence of staining of antibodies against cytokeratins. The differentiated cells adjacent to them showed cytokeratins typical of squamous epithelium rather than those associated with the process of keratinization. The coexistence of cornifying and ghost cells testifies to the great potential of odontogenic epithelium to form numerous epithelial islands.

Topics: Adult; Calcinosis; Cell Membrane; Connective Tissue; Epithelium; Fibrosis; Humans; Hyperplasia; Keratins; Male; Odontogenic Tumors; Vimentin

Topics: Animals; Cytoskeleton; Griseofulvin; Hyperplasia; Immunohistochemistry; Intermediate Filament Proteins; Intermediate Filaments; Keratins; Liver; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C3H; Microscopy, Electron; Neoplasm Proteins

Forty-four cases of mesonephric hyperplasia (MH) and two adenocarcinomas arising from mesonephric remnants (MA) in the cervix were compared immunohistochemically with 10 embryonic and fetal mesonephric tissues. The mesonephric cells retained their pattern for intermediate filaments during ontogenesis, as well as in the mature, hyperplastic, and neoplastic states: they expressed cytokeratin 8, cytokeratin 13, and vimentin, the two latter in variable amounts. In embryonic mesonephric tissues, cytokeratin was absent, whereas the staining for vimentin was intense. Fetal mesonephric cells stained for cytokeratin 13 and vimentin, but that staining diminished as maturation progressed. All MH and MA expressed cytokeratin 8, whereas only 20-30% of the cells in MH and 10-20% of carcinomatous mesonephric cells showed positive reactions with anti-cytokeratin 13 and anti-vimentin. CEA was always negative in cells of mesonephric origin. We regard these results to be important, since the reactions with anti-CEA and anti-vimentin enable one to distinguish cervical adenocarcinomas of mesonephric origin from those of endocervical origin, the latter being CEA-positive and vimentin-negative. Clinical studies revealed that approximately 75% of the patients with MH had used oral contraceptives for several years, 46% had precancerous lesions of the cervix, and in 62% the cervical mucosa showed adenomatous microglandular hyperplasia. We believe that hyperplasia of mesonephric remnants in the cervix may occur more often in patients with disturbed hormonal balance. However, the lack of a control population does not enable us to advance this hypothesis with assurance.

Topics: Adult; Aged; Diagnosis, Differential; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Mesonephroma; Mesonephros; Middle Aged; Uterine Cervical Neoplasms; Vimentin

The discrimination of atypical (premalignant) cells from invasive neoplastic cells in primary bladder lesions is a major diagnostic problem in cytopathology and surgical pathology. We have used an animal model of urinary bladder carcinogenesis to determine the specific changes which occur in the expression of certain cytokeratins (CK) during the progression of lesions from regenerative hyperplasia and carcinoma in situ to transitional cell carcinomas. At sequential time points following exposure of the rat bladder epithelium to N-methyl-N-nitrosourea in vivo, immunohistochemical staining of CKs was evaluated in ethanol-fixed samples from the induced urothelial lesions using commercially available anti-CK mouse monoclonal antibodies. Specific changes were found in the expression of CKs 13, 18, and 19 during the neoplastic progression of induced urothelial lesions in the rat. These changes included the reciprocal loss of expression of CK 19 and the reappearance of CK 18 as malignant tumors developed. Invasive cells also did not express CK 13. Our results, based on the rat model, are similar to those reported by others on CK expression in human bladder tumors. Because these changes in CK expression occurred at specific points in the progression of urothelial lesions, the antibodies utilized in this study may be helpful in predicting the invasive potential of cells present in cytopathological specimens and tissue biopsies from human urothelial lesions.

Topics: Animals; Antibodies, Monoclonal; Blotting, Western; Epithelium; Female; Hyperplasia; Immunoenzyme Techniques; Immunohistochemistry; Keratins; Methylnitrosourea; Rats; Rats, Inbred F344; Urinary Bladder; Urinary Bladder Neoplasms

This study was undertaken to explore the expression of keratins in the hamster cheek pouch carcinogenesis model, using monospecific keratin antibodies and a technique that allows immunoblotting analysis of tissues embedded in paraffin. Changes in keratin expression were correlated with histopathological changes and with the expression of the enzyme gamma-glutamyl transpeptidase. The right cheek pouch of 20 male golden Syrian hamsters was treated with 0.5% 7,12-dimethylbenz[a]anthracene for 16 weeks. As previously described by other laboratories, this treatment resulted in hyperplastic and dysplastic lesions and benign and malignant tumors. The keratins assayed in this study were K14 (Mr 55,000), K1 (Mr 67,000), and K13 (Mr 47,000). The normal hamster cheek pouch epithelium expressed K14 in the basal layer and K13 in the suprabasal and differentiated layers, whereas K1 was not detected by either immunohistochemistry or immunoblotting. Concomitant with 7,12-dimethylbenz[a]anthracene-induced hyperplasia, there were some topographical alterations in the distribution of K14. In this case, K14 was no longer restricted to the basal layer but was also expressed in differentiated cells. The same pattern was also observed in dysplastic lesions and in squamous cell carcinoma. Furthermore, expression of the K13 differentiation-associated keratin was preserved in this hyperplastic epithelium during all the stages of carcinogenesis, including either anaplastic or differentiated areas. In contrast, after 2 weeks of 7,12-dimethylbenz[a]anthracene treatment, K1 expression started as a weak and patchy pattern in suprabasal cells, becoming stronger and more homogeneous at 8 and 16 weeks of treatment. However, K1 was almost absent in squamous cell carcinoma, where only small very well differentiated areas were stained. We also observed gamma-glutamyl transpeptidase-positive foci in earlier stages of carcinogenesis, concomitant with the expression of the K1 keratin. However, it was not possible to find a perfect topographical correspondence between the two events. Alterations in the pattern of keratin expression appear to be a common feature during the development of squamous cell carcinoma in different systems and could be an excellent tool to study carcinogenesis and chemoprevention.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Biomarkers, Tumor; Carcinogenicity Tests; Carcinoma, Squamous Cell; Cell Differentiation; Cheek; Cricetinae; Hyperplasia; Keratins; Male; Mesocricetus; Molecular Weight; Mouth Mucosa; Mouth Neoplasms; Reference Values

The BNLF-1 gene of Epstein-Barr virus (EBV) encodes the latent membrane protein (LMP), one of the putative oncogene products of the virus. This gene has been expressed from two different enhancer-promoter constructs in transgenic mice, to determine its biological activity and possible contribution to oncogenesis. While transgenic mice expressing LMP in many tissues demonstrated poor viability, expression of LMP specifically in the epidermis induces a phenotype of hyperplastic dermatosis. Concomitant with the expression of LMP in this tissue (and in the esophagus) is an induction of the expression of a hyperproliferative keratin, K6, at aberrant locations within the epidermis. The epithelial hyperplastic phenotype caused by the LMP-encoding transgenes implies that the LMP plays a role in the acanthotic condition of the tongue epithelium in the human EBV- and HIV-associated syndrome oral hairy leukoplakia, as well as possibly predisposing the nasopharyngeal epithelium to carcinogenesis.

Topics: Animals; Disease Models, Animal; DNA; DNA Probes; Gene Expression; Herpesvirus 4, Human; Humans; Hyperplasia; Keratins; Membrane Proteins; Mice; Mice, Transgenic; Oncogene Proteins, Viral; Oncogenes; Phenotype; Plasmids; Protein-Tyrosine Kinases; Skin; Transcription, Genetic; Viral Matrix Proteins

Proliferation of bile duct-like structures is a hepatic cellular reaction observed in most forms of human liver disease and in a variety of experimental conditions associated with liver injury. Yet the origin, means of initiation, and significance of this hyperplasia are unknown. To clarify these issues we induced bile duct proliferation in rats by ligating the common bile duct and studied (a) hepatic incorporation of [3H]thymidine by histoautoradiography, (b) hepatic morphometry, (c) biliary tree volume using [3H]taurocholate as a marker of biliary transit time, (d) immunohistochemical expression of cytokeratin no. 19, (e) the effect of indomethacin, and (f) the role of increased biliary pressure, in the absence of physiological and biochemical evidence of cholestasis, on [3H]thymidine incorporation by the bile-duct cells. The results have demonstrated that (a) the proliferating bile duct-like cells are products of the extant biliary epithelium and retain its characteristics; (b) bile duct cells divide irrespective of the size of the duct in which they are located and form a system with a lumen continuous with the preexisting one; (c) bile duct proliferation results mainly in elongation, not in circumferential enlargement or sprouting of side branches; (d) portal macrophage infiltration does not play a role in the hyperplastic reaction, and (e) increased biliary pressure is the initiating factor in bile duct cell division. Our results provide evidence that under the present conditions, ductular metaplasia of hepatocytes does not occur and there is no functioning stem cell for biliary epithelial growth segregated in any particular duct size or within the portal connective tissue.

Topics: Animals; Autoradiography; Bile Ducts, Intrahepatic; Cell Division; Cholestasis; Common Bile Duct; Hyperplasia; Indomethacin; Keratins; Ligation; Male; Rats; Rats, Inbred Strains

There are a number of benign, small-acinar lesions in the prostate gland that may be difficult to differentiate from small-acinar adenocarcinoma. An important diagnostic criterion in this differentiation is the loss of the basal layer in small-acinar adenocarcinoma and its preservation in benign conditions. A monoclonal antibody to high-molecular-weight cytokeratins (34 beta E12) has been shown to stain these basal cells preferentially. To assess the usefulness of this antibody in distinguishing benign from malignant small-acinar lesions, we examined 21 cases of small-acinar adenocarcinoma and 47 examples of benign lesions, which included atypical adenomatous hyperplasia, atrophy, post-sclerotic hyperplasia, basal cell hyperplasia, and fibroepithelial nodule. Positive staining with 34 beta E12 was seen in 13/13 cases of atypical adenomatous hyperplasia, although in some cases the staining was weak and focal. Positivity with 34 beta E12 was also demonstrated in all other benign lesions studied. All 21 cases of small-acinar adenocarcinoma showed no reactivity with 34 beta E12. The results suggest that 34 beta E12 is of value in distinguishing between well-differentiated, small-acinar prostatic adenocarcinoma and its mimics. However, care is needed in interpretation of staining in formalin-fixed material due to the variable reactivity, particularly in cases of atypical adenomatous hyperplasia.

Topics: Adenocarcinoma; Adenoma; Antibodies, Monoclonal; Atrophy; Diagnosis, Differential; Evaluation Studies as Topic; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Molecular Weight; Prostate; Prostatic Diseases; Prostatic Neoplasms; Staining and Labeling

Sweat gland abnormalities occur much more frequently than hitherto described in cutaneous graft versus host disease (GVHD). Two patterns of abnormalities were identified in 80 per cent of cases of acute GVHD: a cytopathic pattern consisting of a combination of basal vacuolopathy with or without lymphocytic infiltration and basal cell degeneration, and a proliferative pattern consisting of basal cell hyperplasia. In chronic GVHD, complete sweat gland destruction with fibrosis was commonly observed. Squamous metaplasia and dilation of the sweat glands were less frequently identified. Ki67 immunostaining confirmed proliferative activity in the basal cells of the distal duct. HLA-DR antigens were expressed on the basal cells of the duct and secretory glands in acute GVHD but not in normal skin. Langerhans cells were absent in both normal and abnormal sweat glands. The role of HLA-DR or Langerhans cells in the initiation of GVHD is questioned in the light of the new data and the primary involvement of proliferating cells is confirmed.

Topics: Acute Disease; Adolescent; Adult; Aged; Cell Survival; Child; Child, Preschool; Chronic Disease; Female; Graft vs Host Disease; Humans; Hyperplasia; Keratins; Male; Middle Aged; Skin Diseases; Sweat Glands

Anticytokeratin antibody AE1 was studied immunohistochemically in 56 surgical specimens of esophageal carcinoma. Relationships between morphologic characteristics and AE1 reaction patterns were analyzed in carcinomas and adjacent epithelium. Infiltrating carcinomas had three types of AE1 patterns that paralleled degrees of differentiation. Type 1 pattern was present in well-differentiated carcinomas characterized by cytoplasmic staining of polyhedral cells. Types 2 and 3 were seen in poorly differentiated and undifferentiated carcinomas in different percentages, characterized by all cancer cells stained, with cellular membrane and cytoplasm stained or all unstained, respectively. In normal esophageal epithelium, basal cells were the major population that was AE1 positive. In hyperplasia basal cells showed two kinds of changes, either reduced/lost AE1 staining accompanied by AE1 expression in spinous cells or retained/increased AE1 reactivity. In dysplasia and carcinoma in situ, abnormal cells had reaction patterns in which they lost or increased AE1 expression. Findings indicate that different degrees of differentiation of infiltrating esophageal carcinoma cells have differing expressions of cytokeratins and that monoclonal antibody AE1 can serve as a biomarker identifying early abnormalities in esophageal epithelial cells having increased predisposition to malignancy. Molecular mechanisms of AE1 cytokeratin expression in esophageal epithelium are also discussed.

Topics: Antibodies, Monoclonal; Carcinoma, Squamous Cell; Cell Differentiation; Epithelium; Esophageal Neoplasms; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Staining and Labeling

Epitheliosis is a benign intraluminal proliferation in the breast ducts and lobules that needs to be distinguished from ductal carcinoma in situ (DCIS). The histogenesis and differentiation of cells comprising epitheliosis have been the subject of some controversy. We evaluated the expression of a high-molecular-weight keratin (34 beta E12), muscle-specific actin (HHF-35), and S-100 protein immunoreactivity in formalin-fixed sections of the breast with epitheliosis and DCIS. In 28 of 30 cases of epitheliosis, there was strong HMW keratin immunoreactivity in the streaming sheetlike intraluminal proliferations. In contrast, 35 of 40 cases of DCIS (nonpapillary and papillary) were nonreactive for HMW keratin; the other five were weakly reactive. Furthermore, in 10 cases of DCIS, some ducts had isolated or small aggregates of HMW keratin-positive benign cells on the luminal aspects of the neoplastic proliferation that were reminiscent of a pagetoid pattern. Muscle actin-stained sections were analyzed to assess myoepithelial (ME) cell participation in epitheliosis. Muscle actin-positive ME cells were present at the periphery of the involved ducts but were absent or rare within epitheliosis. The distribution of ME cells--i.e., at the periphery of the spaces involved--was similar in DCIS and epitheliosis. S-100 protein was weakly but relatively consistently expressed by epitheliosis, but all cases of DCIS were negative. Six cases of atypical ductal hyperplasia included in the study were negative for HMW keratin, muscle actin, and S-100 protein. The immunohistochemical profile of epitheliosis indicates that it is primarily an epithelial proliferation with strong HMW keratin and weak S-100 protein expression but without ME cell participation. The distinct differences in HMW keratin expression of epitheliosis and intraductal carcinoma appear to reflect a consistent antigenic difference in these two biologically distinct forms of proliferation.

Topics: Actins; Biomarkers, Tumor; Breast Diseases; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Intraductal, Noninfiltrating; Female; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; S100 Proteins

Expression of cytokeratins (CKs) was investigated immunohistochemically by use of monospecific monoclonal anti-CK antibodies in normal epithelia of pyriform sinus and epithelial lesions such as simple hyperplasia, different degrees of dysplasia, in situ carcinoma, and invasive carcinoma. In normal epithelium, strong expression of CK-19 was consistently observed only in the basal layer as basic CK, while expression of CK-13 showed a completely reverse pattern, being expressed only in suprabasal layers as stratification-related CK. Characteristic changes in expression pattern of these two CKs were observed in accordance with the degree of epithelial disorders and differentiation of carcinoma. Cytokeratin 1, as keratinization-associated CK, was observed only in keratinized cells of hyperplastic epithelia and well-differentiated carcinomas. These findings may be useful in evaluating epithelial disorders and classifying carcinomas more objectively, and may assist earlier detection of carcinoma when used with standard histologic techniques.

Topics: Antibodies, Monoclonal; Biopsy; Epithelium; Humans; Hyperplasia; Immunohistochemistry; Keratins; Laryngeal Neoplasms; Larynx; Molecular Weight

We report four unusual cases of malignant melanoma in which squamous cell carcinoma was strongly considered in the differential diagnosis on routine hematoxylin and eosin-stained sections due to the near absence of melanin and the presence of pseudocarcinomatous hyperplasia. Ultimately, immunohistochemical staining for S-100 protein and keratin established the correct diagnosis of malignant melanoma in all cases.

Topics: Aged; Carcinoma, Squamous Cell; Diagnosis, Differential; Female; Humans; Hyperplasia; Immunohistochemistry; Keratins; Male; Melanoma; Middle Aged; S100 Proteins; Skin; Skin Neoplasms

The expression of cytokeratins in the epithelium of the middle ear and external auditory meatus of the rat was studied on cryosections of ethylenediaminetetraacetic acid-decalcified specimens by use of a panel of monoclonal antibodies. The normal middle ear epithelium revealed a complex cytokeratin profile, including regional differences. The induction of sterile middle ear effusions resulted in increased cytokeratin expression. Infective effusions were accompanied by both quantitative and qualitative changes in the cytokeratin expression patterns. The differences observed between the cytokeratin profiles of external meatal skin and those of middle ear epithelium may form a useful tool for research into cholesteatoma development.

Topics: Animals; Antibodies, Monoclonal; Ear, Middle; Epithelial Cells; Hyperplasia; Hypertrophy; Immunohistochemistry; Keratins; Male; Mucous Membrane; Otitis Media; Rats; Rats, Inbred Strains

Histologic changes induced in SENCAR skin following a single treatment with chrysarobin (1,8-dihydroxy-3-methyl-9-anthrone) exhibited differences in time course from that observed with 12-O-tetradecanoylphorbol-13-acetate (TPA). Although not significantly different, maximum elevations in epidermal thickness, total number of nucleated epidermal cells, and dark basal keratinocytes (DCs) induced by 220 nmol chrysarobin occurred at 96 h after treatment, while those induced by 3.4 nmol TPA occurred at 48 h. Both compounds elicited comparable inflammatory responses. Twice-weekly applications of chrysarobin for 2.5 weeks induced a moderate hyperplasia, increase in total nucleated epidermal cells, and increased DCs at 48 and 96 h after the last treatment, with a higher value for these parameters occurring at 48 h. Interestingly, the magnitude of these changes was similar to that observed after a single application. In contrast, twice-weekly applications of TPA induced a dramatic, potentiated induction of epidermal hyperplasia and DCs. Once-weekly applications of chrysarobin led to a potentiated induction of both hyperplasia and DCs compared to the twice-weekly treatment regimen and also more effectively promoted epidermal papillomas in previously initiated SENCAR mice. Skin sections from mice treated with chrysarobin displayed overt signs of epidermal toxicity including altered basal cell morphology and a decreased number of basal cells per 125 micron of basement membrane. Hyperplasia induced by multiple but not single treatments with chrysarobin and TPA correlated quantitatively with their papilloma promoting activity. In addition, the data suggest that epidermal toxicity may play a role in tumor promotion by anthrones.

Topics: Administration, Cutaneous; Animals; Anthracenes; Carcinogens; Female; Hyperplasia; Keratins; Mice; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors

Psoriasis occurring in a patient with lamellar ichthyosis is reported. Similar self-limited episodes had occurred earlier. On histopathologic examination of a biopsy specimen, an eruptive plaque showed parakeratosis and a reduction in the granular layer. Electrophoretic analysis of the keratins isolated from the epidermis of a plaque showed a reduction in the amount of the 67 kd polypeptide compared to the keratins of ichthyosis epidermis. Both of these findings support the diagnosis of psoriasis. Epilyt, applied daily, was effective in removing scales.

Topics: Adult; Biopsy; Dermatologic Agents; Female; Humans; Hyperplasia; Ichthyosis; Keratins; Psoriasis; Skin

Testicular Leydig cell tumours are able to produce oestrogens and can be induced by exogeneous oestrogen administration. Oestrogen and progesterone receptors, cytokeratin, vimentin, and proliferative activity were determined immunohistologically in human testes in six Leydig cell tumours, 14 cases of Leydig cell hyperplasia, and 13 cases with normal Leydig cells. While both steroid receptors were detected in about 70 per cent of the tumour cells in cryostat sections, no reaction was observed in normal Leydig cells. This supports the hypothesis of an enhanced receptor state in a Leydig cell subpopulation as a basic pathophysiological factor in the development of Leydig cell tumours. On cryostat sections, all tumours co-express cytokeratin and vimentin. Neither the receptors nor the intermediate filaments could be detected reliably in paraffin sections. The low proliferative activity of Leydig cell tumours corresponds to their benign clinical course.

Topics: Adult; Aged; Antibodies, Monoclonal; Cytoskeleton; Humans; Hyperplasia; Intermediate Filaments; Keratins; Leydig Cell Tumor; Leydig Cells; Male; Middle Aged; Receptors, Estrogen; Receptors, Progesterone; Testicular Neoplasms; Vimentin

When cells from normal human epidermis and from the human squamous cell carcinoma line SCC-13 were seeded on floating rafts of collagen and fibroblasts, they stratified and underwent terminal differentiation. Although the program of differentiation in SCC-13 cells was morphologically abnormal, the cultures resembled normal epidermal raft cultures by expressing the terminal differentiation-specific keratins, K1/K10, and by restricting their proliferative capacity to the basal-like cells of the population. In addition, the differentiating cells of both normal and SCC-13 raft cultures expressed keratins K6 and K16, which are not normally expressed in epidermis, but are synthesized suprabasally during wound-healing and in various epidermal diseases associated with hyperproliferation. While the behavior of normal and SCC-13 rafts was quite similar when they were cultured over normal medium, significant biochemical differences began to emerge when the cultures were exposed to retinoic acid. Most notably, while the SCC-13 cultures still stratified extensively, they showed a marked inhibition of both abnormal (K6/K16) and normal (K1/K10) differentiation-associated keratins, concomitantly with an overall disappearance of differentiated phenotype. Surprisingly, the reduction in K6/K16 in retinoid-treated SCC-13 cultures was not accompanied by a decrease in cell proliferation. Using immunohistochemistry combined with [3H]thymidine labeling, we demonstrate that while the expression of K6 and K16 are often associated with hyperproliferation, these keratins are only produced in the nondividing, differentiating populations of proliferating cultures. Moreover, since their expression can be suppressed without a corresponding decrease in proliferation, the expression of these keratins cannot be essential to the nature of the hyperproliferative epidermal cell.

Topics: Blotting, Northern; Carcinoma, Squamous Cell; Cell Division; DNA; Electrophoresis, Gel, Two-Dimensional; Epidermal Cells; Epidermis; Gene Expression Regulation; Humans; Hyperplasia; Keratins; Molecular Weight; Skin Diseases; Tretinoin; Tumor Cells, Cultured

Clear cell metaplasia of the human breast is known to be a benign metaplastic change which has no pre-malignant connotation. Despite its proposed relationship to focal lactational change and to lactating breast, morphological and immunocytochemical features failed to demonstrate a clear relationship between these. Mucin secretion showed a characteristic pattern of granularity, and endocrine differentiation was not present. The mucin and immunocytochemical features suggest a relationship with eccrine sweat glands and a better name would perhaps be 'eccrine metaplasia' to underline the special relationship breast metaplasias have to sweat gland epithelium.

Topics: Alcian Blue; Apolipoproteins; Apolipoproteins D; Breast; Carrier Proteins; Eccrine Glands; Female; Glycoproteins; Humans; Hyperplasia; Immunohistochemistry; Keratins; Lactalbumin; Lactation; Membrane Transport Proteins; Metaplasia; Neoplasm Proteins; Pregnancy; S100 Proteins; Sweat Glands

64 cases of chronic active hepatitis (CAH) and 84 cases of other chronic liver diseases were studied with keratin antibody immunohistochemistry. Proliferation of capillary-like bile ductules (CLBD) was more remarkable in the former cases than that in the latter cases with positive keratin reaction in the cytoplasm. Therefore, proliferation of CLBD was considered to be a characteristic lesion of CAH, which might be used as one of the criteria for differential diagnosis of CAH. This paper also reports the ultrastructural appearance of CLBD in detail and the result of HBV DNA in situ hybridization for CLBD, suggesting that HBV might infect CLBD.

Topics: Animals; Bile Ducts, Intrahepatic; DNA, Viral; Hepatitis B virus; Hepatitis, Chronic; Hyperplasia; Immunohistochemistry; Keratins; Liver; Nucleic Acid Hybridization

In the present study we have isolated and purified fractions of nonparenchymal liver cells were isolated by collagenase-pronase digestion of the biliary and connective hepatic tissue, which remained undissociated after collagenase perfusion of the liver. Fractionation of the nonparenchymal fractions was then achieved by centrifugal elutriation. Both normal rats and rats with proliferated bile duct-like structures, which were induced either by a 14-day bile duct ligation or by feeding 0.1% alpha-naphthylisothiocyanate for 28 days, were used in these studies. Using a normal rat liver, the fraction richest in biliary epithelial cells was that obtained at a pump flow rate of 36-40 ml/min. In this fraction 1.8-3.8 x 10(6) cells per liver were recovered and up to 55% of them were positive for gamma-glutamyl transpeptidase and cytokeratins 7 and 19, all of which were histochemically or immunohistochemically detected solely in the biliary structures in the intact rat liver. When the nonparenchymal cells were isolated from hyperplastic livers, the number of cells recovered in such a fraction ranged from 12 to 19 x 10(6) per liver, and as many as 60%-85% of the cells expressed phenotypes of biliary epithelial cells. These results indicate that (a) by centrifugal elutriation a fraction of nonparenchymal cells enriched in cells with biliary epithelial phenotypes can be obtained from rat liver and (b) the hepatic hyperplasia induced by biliary obstruction or alpha- naphthylisothiocyanate feeding is a useful and valid strategy for improving both the yield and the purity of the isolated biliary epithelial cells.

Topics: Animals; Bile Ducts, Intrahepatic; Cell Separation; Cholestasis; Epithelial Cells; gamma-Glutamyltransferase; Hyperplasia; Immunohistochemistry; Keratins; Liver; Male; Microscopy, Electron; Phenotype; Rats; Rats, Inbred Strains

As the distribution pattern of cytokeratin (CK), filaggrin and involucrin has recently been suggested to discriminate between benign and malignant epithelial growths, biopsies of healthy oral mucosa, leukoplakias without and with dysplasia and squamous cell carcinomas were examined immunohistochemically using a panel of 4 monoclonal antibodies (AB) against different cytokeratin polypeptides (34 beta E12, KL1 and Pkk1) and filaggrin as well as a polyclonal AB to involucrin. Major and statistically significant differences were observed in the profiles of CKs (except Pkk1), filaggrin and involucrin between leukoplakias without and with epithelial dysplasia. However, the alteration in the expression of CKs, filaggrin and involucrin proved to be not a constant feature in leukoplakias with dysplasia as a considerable portion (20-25%) of them revealed the profiles of CKs, filaggrin and involucrin similar to those of benign leukoplakias, and vice versa. Immunostaining of these antigens did not define the diagnosis of dysplasia in leukoplakias more precisely than grading in conventional histology can do so far. However, immunohistochemical sensitivity in detecting a broad range of variation in the abnormal maturation patterns of keratinocytes in leukoplakias with dysplasia can be used to divide these lesions into subgroups to elucidate their prognosis in follow-up studies.

Topics: Carcinoma, Squamous Cell; Epithelium; Female; Filaggrin Proteins; Humans; Hyperplasia; Immunoenzyme Techniques; Intermediate Filament Proteins; Keratins; Leukoplakia, Oral; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Phosphoproteins; Protein Precursors

Immature female Wistar rats were treated with 1 mg of estradiol benzoate for 6 days. The injections were started on the 20th day of age; the animals were autopsied every 3 days after the last injection until the age of 45 days. Islets of hyperplastic cells and metaplasia area were seen in the endocervix in the majority of the animals autopsied. We have the expression of cytokeratin polypeptides in reserve cells, in areas exhibiting reserve cell hyperplasia and squamous metaplasia, using a panel of monoclonal cytokeratin antibodies. The reserve cells were positive for antibodies directed against stratified squamous epithelia, type cytokeratins No. 5, 13 and 17. In addition, hyperplastic cells revealed the presence of cytokeratins No. 7, 8, 18 and 19, specific for simple epithelia, but in a variable manner. The Squamous metaplasia cells exhibited cytokeratins No. 13, 18 and 19, but only weakly reactive. Our observations indicate that estrogen-induced endocervix metaplasia results from a transformation of reserve cells towards an epidermoid type epithelium. Hyperplasia would be the intermediate step in the mechanism of induced cervical metaplasia. This transformation is accompanied by the loss of cytoplasmic keratin proteins and the acquisition of new high molecular weight keratin proteins, specific for stratified squamous epithelia. The basal or reserve cells of the cervix can proliferate to produce regions of squamous cell metaplasia. It appears to be a direct effect of estrogen stimulation. Immunohistochemical staining for different molecular weight keratin proteins may be helpful in the evaluation of reserve cell differentiation.

Topics: Animals; Antibodies, Monoclonal; Estradiol; Female; Hyperplasia; Immunohistochemistry; Keratins; Metaplasia; Rats; Rats, Inbred Strains; Uterine Cervical Diseases

It has been suggested that cytokeratin 13 is a useful marker of malignancy. We examined normal squamous cell epithelia, hyperplasia, dysplasias of various grades, intraepithelial neoplasia and invasive squamous cell carcinomas of the pyriform fossa using K13 and KL1. Positive staining for K13 was seen in all normal or hyperplastic benign epithelia, was inconstant in dysplasia, and intraepithelial neoplasia and carcinoma was negative. KL1 expression is constant and non significant. These results suggest that tumour cells are unable to synthesize keratin 13 a finding which may be valuable in surgical pathology.

Topics: Biomarkers, Tumor; Carcinoma; Carcinoma, Squamous Cell; Epithelium; Gene Expression; Head and Neck Neoplasms; Humans; Hyperplasia; Immunohistochemistry; Keratins; Larynx; Pharynx

This study was to identify histologic tissue changes in the oral mucosa and to compare them in specimens from users of loose can-packed and portion-bag-packed moist snuff. The material consisted of biopsies from 252 regular snuff users. 184 using exclusively loose and 68 portion-bag snuff. An array of structural changes appearing in different combinations were identified among the 252 specimens. Two major patterns were recognized based on changes in the surface layer. Type 1 was characterized by an increased epithelial thickness with vacuolated cells and frequent chevron type changes. Type 2 showed a variably thickened surface layer with evidence of keratinization. Based on these findings, 14 carefully matched pairs of loose and portion-bag users were analyzed and compared. Loose snuff users showed predominantly histologic Type 1 changes while portion-bag users showed more histologic Type 2 or only very discrete changes.

Topics: Adult; Aged; Aged, 80 and over; Atrophy; Case-Control Studies; Cell Membrane; Epithelium; Humans; Hyperplasia; Keratins; Male; Middle Aged; Mouth Mucosa; Nicotiana; Plants, Toxic; Regression Analysis; Sweden; Tobacco, Smokeless

A cytokeratin-immunohistochemical study was performed on eight specimens of focal nodular hyperplasia of the liver in order to determine whether hepatocytes in this lesion can express "bile duct type" cytokeratins. Serially cut cryostat sections were reacted with a panel of six monoclonal antibodies specifically reactive with cytokeratin polypeptides nr. 7, 8, 18 and 19, using a 3-step immunoperoxidase procedure. Hepatocytes were positive for cytokeratins nr. 8 and nr. 18, whereas ductules contained in addition to cytokeratins nr. 8 and nr. 18 also polypeptides nr. 7 and nr. 19. In all cases, a variable number of hepatocytes close to fibrous septa or inside the nodules expressed cytokeratin nr. 7. In four cases, a small number of hepatocytes were also immunoreactive for cytokeratin nr. 19. Our data demonstrate that hepatocytes in focal nodular hyperplasia can express one or even two "bile duct type" cytokeratins, supporting the concept that ductular metaplasia of hepatocytes contributes to the ductular "proliferation" observed in this tumor-like lesion.

Topics: Adult; Female; Humans; Hyperplasia; Immunoenzyme Techniques; Immunohistochemistry; Keratins; Liver; Liver Diseases; Male

Expression of cytokeratin polypeptides characteristic of squamous epithelium was studied in reserve cells of cervical canal obtained from 8 women by the immunofluorescence method with the help of monoclonal antibodies EE21-06d (MAB). MAB EE21-06d were shown to detect individual reserve cells as well as their hyperplasia foci without staining columnar cells.

Topics: Adult; Antibodies, Monoclonal; Cervix Uteri; Epithelial Cells; Female; Fluorescent Antibody Technique; Humans; Hyperplasia; Immunohistochemistry; Keratins; Middle Aged

We characterized the subclass-specific keratins in the epithelium of normal, benign, and malignant breast tissue. Monoclonal antibody 34BE12 stained luminal as well as basal epithelium in normal and benign specimens and all tumor cells in malignant specimens. Antibody 312CS-1 reacted only with basal cells, and antibody LE61 reacted only with luminal cells in the normal and benign specimens. In 34 of 36 breast carcinomas examined, the basal and luminal cell-specific antibodies showed complementary patterns of reactivity, while in the remaining 2 specimens, neither antibody was reactive. The findings reported in this study demonstrate that expression of subclass-specific keratins is mutually exclusive not only in normal and benign mammary specimens but also in breast carcinoma. These findings suggest a role for epithelial subclass-specific antibodies in the histogenetic and prognostic subclassifications of breast carcinoma.

Topics: Antibodies, Monoclonal; Breast; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Epithelium; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins

Two monoclonal antibodies respectively recognizing cytokeratins (CK) 18 and 19 were applied to the human thymic epithelium (in vivo and in vitro) in normal and pathological conditions, including 12 thymomas. We observed that in both normal and hyperplastic thymuses (from patients with myasthenia gravis) virtually the entire epithelial network was CK19-positive as were the majority of cells growing in culture. In four thymomas, however, the expression of cytokeratin 19 was not detected by immunofluorescence. On the other hand, CK18 was expressed by a discrete subset of medullary thymic epithelial cells in normal and in hyperplastic thymuses. Among the thymomas a large majority was either negative or contained few isolated CK18-positive cells scattered within the tumour. Conversely, in the two undifferentiated epithelial thymomas, virtually all the tumoral network was strongly labeled with the anti-CK18 monoclonal antibody. The present investigation thus not only defines the human thymic epithelial cell subset on the basis of differential cytokeratin expression but also indicates that anti-CK antibodies with single cytokeratin specificities can be regarded as useful tools to study the heterogeneity of thymomas.

Topics: Antibodies, Monoclonal; Child, Preschool; Epithelial Cells; Epithelium; Fetus; Humans; Hyperplasia; Immunoblotting; Immunohistochemistry; Infant; Keratins; Thymoma; Thymus Gland; Thymus Neoplasms

Topics: Antibodies; Antibodies, Monoclonal; Biomarkers; Humans; Hyperplasia; Immunohistochemistry; Keratins; Leukoplakia, Oral; Mouth Mucosa; Mouth Neoplasms; Precancerous Conditions

An immunohistochemical study was performed to identify the histogenesis of solid cell nests (SCN) found in 30 of 202 thyroids obtained at autopsy. Immunoperoxidase staining was used to detect the presence of calcitonin, thyroglobulin, thyroxin, low and high molecular weight keratins, and carcinoembryonic antigen (CEA). Results showed that cells forming solid nests had immunoreactivity for calcitonin, low molecular weight keratin, and CEA, but not for thyroglobulin, thyroxin and high molecular weight keratin. Thus, SCN do not result from tangentially cut thyroid follicles (absence of staining for thyroglobulin and thyroxin), nor from a squamous metaplastic process (absence of staining for high molecular weight keratin), but instead they are formed by C-cells because they showed calcitonin immunoreactivity, and neurosecretory granules.

Topics: Aged; Autopsy; Calcitonin; Female; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Middle Aged; Thyroglobulin; Thyroid Gland; Thyroxine

A mild irritant reaction was induced by application of sodium lauryl sulphate to the skin of guinea-pigs. The response was analysed at 24 and 48 h after application using light microscopy, transmission electron microscopy and energy dispersive X-ray microanalysis (EDX). It was found that the sodium lauryl sulphate induced a hyperplastic response in the epidermis with an increased number of keratinocytes. This response was associated with significantly increased levels of intracellular sodium and chloride. The elemental changes were most marked at 24 h, whereas the number of keratinocytes was highest at 48 h. The pattern of the elemental changes and the ultrastructural alterations are compatible with initial membrane damage followed by a transient increase in proliferative activity. The present results demonstrate that EDX is a useful tool for the analysis of functional alterations in epidermal keratinocytes under pathological conditions.

Topics: Animals; Chlorides; Electron Probe Microanalysis; Epidermis; Female; Guinea Pigs; Hyperplasia; Keratins; Microscopy, Electron; Sodium; Sodium Dodecyl Sulfate

We obtained immunohistochemical profiles of several keratin proteins during experimentally induced carcinogenesis in hamster cheek-pouch mucosa using a polyclonal antibody (TK; detecting keratins with molecular masses of 41-65 kilodalton) and two monoclonal antibodies (KL1, 55- to 57-kilodalton keratins; PKK1; 40-, 45- and 52.5-kilodalton keratins). The squamous epithelium of normal pouch mucosa exhibited positive TK staining in all layers, KL1 staining in the spinous layer and PKK1 staining in the basal layer, thus indicating a regional or zonal distribution pattern. Epithelia undergoing basal hyperplasia showed irregular localization of PKK1 binding, while hyperkeratinized lesions exhibited the binding pattern found in normal epithelium. In case of epithelial dysplasia, there was reduced KL1 staining in spinous cells and decreased PKK1 staining in the basal and parabasal layers. Papillomas exhibited a rather zonal distribution of keratin staining. All squamous-cell carcinomas, irrespective of their degree of keratinization and infiltration pattern, showed slight or no PKK1 staining. Such lesions were only positive for KL1-detectable keratins in keratinizing tumour cells and exhibited an irregular distribution of TK binding. The expression of keratin proteins during carcinogenesis in hamster cheek-pouch mucosa may parallel that of keratins in human squamous-cell carcinomas originating in the oral mucosa.

Topics: Animals; Antibodies; Antibodies, Monoclonal; Carcinoma, Squamous Cell; Cricetinae; Histocytochemistry; Hyperplasia; Keratins; Male; Mesocricetus; Methods; Neoplasms, Experimental; Papilloma

Fifty cases (20 cases of benign hyperplasia, 30 cases of adenocarcinoma) of prostatic tissues were studied for expression of keratin. The basal cells were strongly and continuously positive in normal prostatic glands and in benign prostatic hyperplasia. The secretory cells and carcinoma cells were negative. The basal cells remained partially in intra-ductal carcinoma, revealing keratin positive cells in a spotty pattern. These findings may be useful in differential diagnosis between benign prostatic hyperplasia and carcinoma of the prostate.

Topics: Adenocarcinoma; Carcinoma, Intraductal, Noninfiltrating; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Prostate; Prostatic Neoplasms

The potent toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes chloracne and acts as a tumor promoter in the hairless HRS/J mouse model. In the present study we characterized changes in mouse epidermal keratin expression following a single topical application of TCDD to the skin of hairless (hr/hr) and haired (hr/+) HRS/J mice. Morphologic changes and alterations in keratin biosynthesis following TCDD treatment were compared with those induced by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Both TPA and TCDD induced dose-dependent epidermal hyperplasia in hr/hr and hr/+ mice and this was associated with altered keratin subunit expression. In hr/hr mice TCDD caused a pattern of keratin expression that was similar to TPA, characterized by a marked decrease in the synthesis of the Mr 67,000 (basic) and 59,000 (acidic) keratins that are specific markers for suprabasal differentiation in the epidermis. In addition, the synthesis of an acidic keratin of Mr 48,000 and a basic keratin of Mr 62,000 was also decreased. Concomitantly, TCDD caused an increase in the synthesis of a basic keratin of Mr 60,000 and acidic keratins of Mr 54,000, 52,000 and 49,000 that are normally observed in proliferating basal cells and primary epidermal cell cultures. In contrast, while TPA induced similar changes in keratinization in both the hr/+ and hr/hr mice, TCDD-induced hyperplasia in hr/+ mice was only associated with changes in keratin synthesis reflecting increased basal cell proliferation. These results demonstrate that a single application of TCDD to the skin alters the normal pattern of epidermal differentiation in the hr/hr mouse. Molecular events influencing the expression of the keratin genes associated with this process may be linked to the strain- and/or species-specific toxicity of TCDD.

Topics: Administration, Topical; Animals; Dioxins; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Epidermis; Hyperplasia; Keratins; Mice; Mice, Hairless; Molecular Weight; Polychlorinated Dibenzodioxins; Tetradecanoylphorbol Acetate

Langerhans cells vary in their morphology and distribution in the vaginal epithelium of ovariectomized mice stimulated to hyperplasia and keratinization by oestrogen. When the stratum corneum was removed by topical vitamin A application, the shape and distribution of Langerhans cells were unaffected. It was concluded that Langerhans cell morphology and distribution depend on the configuration of the lower strata of the epithelium and not on the presence of a stratum corneum.

Topics: Administration, Topical; Animals; Epithelial Cells; Estrogens; Female; Hyperplasia; Keratins; Langerhans Cells; Mice; Ovariectomy; Vagina; Vitamin A

For six patients with partial or total laryngectomies with extensive mucosal hyperplasias, we generated DNA histograms from multiple mucosal sites using Feulgen-stained tissue sections and microspectrophotometric microscopy. Aneuploid DNA histograms were identified in the mucosa of all six specimens, indicating that neoplastic transformation had occurred. The histologic characteristics of neoplastic change included thickened or hyperplastic epithelium, surface maturation or keratinization, often a proliferation of small, immature basallike cells in the depths of the epithelium, and evidence of abnormal epithelial maturation as evidenced by focal areas of cytoplasmic keratinization in the lower portions of the mucosa. We think this histologic expression of intraepithelial neoplasia is more common than the "classic" form of carcinoma in situ with full mucosal replacement by proliferating immature basallike cells. Keratin is a common reaction in laryngeal mucosa, and its presence on the surface or in the depths of the epithelium does not militate against the diagnosis of severe intraepithelial neoplastic transformation.

Topics: Aged; Carcinoma; Carcinoma in Situ; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; DNA, Neoplasm; Epithelium; Humans; Hyperplasia; Keratins; Laryngeal Mucosa; Laryngeal Neoplasms; Male; Middle Aged

Four cases of focal epithelial hyperplasia (FEH) were studied immunohistochemically, using monoclonal antibodies against the M1 subunit of ribonucleotide reductase and different cytokeratin polypeptides. The FEH lesions showed, compared to normal oral mucosa, extensive alterations in their staining patterns. This included ectopic suprabasal M1 staining and the novel expression of cytokeratin polypeptides differing from those previously reported for other HPV infections. The results are discussed in relation to the causative agent, human papillomavirus, and its expression in focal epithelial hyperplasia.

Topics: Epithelium; Fluorescent Antibody Technique; Humans; Hyperplasia; Keratins; Mouth Mucosa; Papillomaviridae; Ribonucleotide Reductases; Staining and Labeling; Tumor Virus Infections

Extensive squamous metaplasia is described in a case of gynecomastia. Numerous ducts in all sections of breast tissue revealed multiple foci of squamous metaplasia, many of which included large, papillary excrescences of keratinizing squamous cells into duct lumens, with foci of dyskeratosis. Review of four years of gynecomastia cases from our surgical pathology files revealed a total incidence of squamous metaplasia equaling six of 40 cases of gynecomastia, including the case reported here. The other five cases included only one or two small foci of squamous metaplasia. These findings demonstrate that squamous metaplasia in gynecomastia is not rare, but is usually very limited. However, an unusual case, such as that reported here, may show extensive, florid squamous metaplasia, without associated inflammation or neoplasm.

Topics: Adult; Breast; Epithelium; Gynecomastia; Histocytochemistry; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Metaplasia; Retrospective Studies

Cells of the normal colonic mucosa express several types of cytokeratins, the characteristic intermediate filament proteins of epithelial cells. An immunohistochemical study was designed to examine the expression of two distinct groups of cytokeratins, recognized by monoclonal antibodies AE1 and AE3, in the colonic mucosa and to compare the findings with those obtained with a large number of polypoid lesions (adenomatous and hyperplastic) and carcinomas of the colon. AE1 and AE3 immunostaining was found in the surface epithelium and upper portions of the crypts of Lieberkühn (functional zone) of normal colonic mucosa, whereas the lower portions of the crypts (proliferative compartment) were unreactive with both AE1 and AE3. Polypoid lesions of the colonic mucosa can be placed into two categories based on their patterns of cytokeratin expression. Solitary tubular adenomas and hyperplastic polyps are composed of AE1 and AE3 nonexpressing cells with only few, patchy areas of AE1 and AE3 expressing cells present within glands and in the surface epithelium. In contrast, villous adenomas show strong AE1 and AE3 reactivity throughout the glands. Furthermore, tubular and villous adenomas, and even histologically normal mucosa in patients with familial polyposis, show AE1/AE3 expression throughout the glands and surface epithelium. Colonic carcinomas show a predominance of AE1/AE3 expressing cells. Thus, cytokeratins recognized by monoclonal antibodies AE1 and AE3 represent molecular markers of cellular maturation in the normal colonic mucosa, that are expressed in colonic carcinomas and, in addition, serve as markers that distinguish colonic mucosa and adenomas with a high risk for development of cancers from those with a lower risk.

Topics: Adenocarcinoma; Adenoma; Adenomatous Polyposis Coli; Antibodies, Monoclonal; Cell Differentiation; Cell Transformation, Neoplastic; Colon; Colonic Neoplasms; Epithelium; Humans; Hyperplasia; Intestinal Mucosa; Keratins

Epidermal changes, Ia expression on keratinocytes, Langerhans cell hyperplasia and lymphocyte infiltration were sought in skin lesions of leprosy: 15 borderline tuberculoid (BT), six borderline lepromatous (BL), 17 lepromatous (LL), 13 erythema nodosum leprosum (ENL), six Lucio reactions and nine reversal reactions. All three changes were well developed in BT and reversal reactions. ENL showed well developed keratinocyte Ia and Langerhans cell hyperplasia, but little lymphocytic infiltration. LL and Lucio tissues had some Langerhans cell hyperplasia but little or no keratinocyte Ia or lymphocytic infiltration. BL tissues were so diverse as to suggest two distinct subgroups. These findings are consistent with the hypothesis that keratinocyte Ia expression is an immunohistological sign of a cell-mediated immune (CMI) response. However, the Ia keratinocyte expression found in BL and ENL tissues appears contrary to the undifferentiated macrophages and numerous bacilli found in the lesions. Thus, if a sign of CMI, keratinocyte Ia expression is not a measure of the effectiveness of the response.

Topics: Cell Movement; Epidermis; HLA-D Antigens; HLA-DR Antigens; Humans; Hyperplasia; Keratins; Langerhans Cells; Leprosy; Lymphocytes; Skin

Topics: Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Mouth Mucosa; Mouth Neoplasms; Pharyngeal Neoplasms

Topics: Cell Nucleus; Dose-Response Relationship, Radiation; Epidermis; Humans; Hyperplasia; Keratins; Lentigo; Melanocytes; Melanosis; Photochemotherapy; Psoriasis; PUVA Therapy; Skin Neoplasms

The morphology and numbers of Langerhans' cells vary in epithelia with different patterns of hyperplasia and keratinization. Langerhans' cells stained for ATPase were compared at five phases of the estrous cycle in murine vaginal epithelium. The cells were more dendritic and sparsely distributed with hyperplasia and were less dendritic and more densely distributed with atrophy. Greater numbers of the cells did not accompany keratinization at estrus. Ultrastructurally, three types of Langerhans' cells were discriminated. The first type, active in protein synthesis and phagocytosis, was commonest in sloughing and atrophic epithelium. The second type, containing accumulated and dispersed, electron-dense bodies presumed to be lysosomes, predominated in hyperplastic epithelium. The third, a mature resting cell, was found only after keratinization was complete. This study shows that Langerhans' cells in murine vaginal epithelium vary in morphology and numbers with the epithelial changes of the estrous cycle which may relate to their immunological role, but does not support the contention that their distribution is important for keratinization.

Topics: Adenosine Triphosphatases; Animals; Atrophy; Basement Membrane; Epithelial Cells; Estrus; Female; Hyperplasia; Keratins; Langerhans Cells; Mice; Phagocytosis; Vagina

30 surgically removed prostates were selected out of 200 for comparative histological, immunohistochemical and morphometric studies. The presence or the absence of keratin and the mean nuclear area of nuclear profiles are the main differential criteria in distinguishing atypical hyperplasia (cambial zone) from benign prostatic hyperplasia, microcarcinoma and other prostatic cancers.

Topics: Cell Nucleus; Histocytochemistry; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms

As compared with the adult state, neonatal mouse skin (strain NMRI) has a hyperplastic appearance which gradually changes into the mature type between postnatal day 3 and 10. Concomitantly, the late fetal and neonatal keratin polypeptide pattern is replaced by the mature pattern. As long as the adult type of epidermal differentiation is not sufficiently developed (i.e., prior to postnatal day 5), topical application of the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) causes neither morphological alterations nor a measurable induction of cellular proliferation and ornithine decarboxylase activity. TPA application at day 7 evokes, however, (i) a hyperplastic reaction followed by a massive 'psoriasis-like' hyperkeratosis, (ii) an increase of ornithine decarboxylase activity and (iii) a restoration of the neonatal keratin polypeptide pattern. Multistage tumorigenesis experiments carried out with prenatally initiated mice show that during the early period of development (prior to postnatal day 5) mouse skin is also resistant to the effects of TPA as a stage I tumor promoter. Since both the hyperplastic response and the sensitivity to tumor promotion develops in a strictly parallel manner, reactions involved in the induction of epidermal hyperplasia are assumed to provide an important condition of stage I skin tumor promotion.

Topics: Animals; DNA; Female; Hyperplasia; Keratins; Mice; Mice, Inbred Strains; Mitosis; Ornithine Decarboxylase; Phorbols; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate

Seventeen cases of verrucous carcinoma of the oral cavity were reviewed. It was found that cytologic features generally associated with viral modification were observed in 15 of these cases. This finding suggests that viruses may play some role in the pathogenesis of verrucous carcinoma. The hypothesis that an opportunistic, persistent virus may act in concert with frank carcinogens to promote the development of verrucous carcinoma is discussed.

Topics: Adult; Aged; Animals; Carcinoma, Papillary; Cell Nucleus; Cell Transformation, Neoplastic; Cell Transformation, Viral; Epithelium; Female; Humans; Hyperplasia; Keratins; Male; Middle Aged; Mouth Neoplasms; Tumor Virus Infections

The distribution of intracellular keratin proteins was examined in a variety of urinary bladder lesions of the rat using the immunoperoxidase staining technique. In ethanol-fixed sections, the normal epithelium was strongly positive for keratin staining. Focal regenerative hyperplasia of the bladder epithelium induced by freezing exhibited relatively weak staining. However, diffuse regenerative hyperplasia induced by a single intraperitoneal injection of cyclophosphamide (CP) showed an intensely positive reaction throughout the epithelium. Of the sections fixed with Bouin's solution, the staining reaction was drastically reduced in the normal bladder and the staining was totally negative in the regenerative hyperplasia caused by freezing. Simple hyperplasia induced by a 4-week feeding of N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) as 0.2% of the diet exhibited strong reactivity, and nodular and papillarly hyperplasia induced by a 10-week feeding of FANFT was also positive for keratin throughout the lesions. In contrast to the preneoplastic lesions, FANFT-induced transitional cell carcinoma showed differential staining within the tumors. These results suggest that different keratin expression is involved in the proliferative bladder lesions induced mechanically by freezing and chemically by CP or by the carcinogen FANFT.

Topics: Animals; Cyclophosphamide; Epithelium; FANFT; Freezing; Histocytochemistry; Hyperplasia; Immunoenzyme Techniques; Keratins; Male; Rats; Rats, Inbred F344; Thiazoles; Ulcer; Urinary Bladder

The keratins and other cytoskeletal proteins expressed by normal, preneoplastic, and malignant mammary tissues in BALB/c mice and by cells in primary cultures established from these tissues were analyzed and compared. The preneoplastic lesions were hyperplastic alveolar nodules (HAN) derived originally from mice treated by hormonal stimulation (D2), exposed to a chemical carcinogen (C4), or spontaneously expressing mouse mammary tumor virus (CV2) and maintained by serial transplantation. All tumors were mammary adenocarcinomas which developed as primary neoplasms from the HAN outgrowth lines. Cytoskeletal extracts were prepared from the tissues and cultured cells and subjected to two-dimensional polyacrylamide gel electrophoresis. Comparison of the major polypeptides in the normal and abnormal tissue extracts revealed considerable similarities in the cytoskeletal profiles. Three basic and seven acidic polypeptides ranging in molecular weight from 40,000 to 90,000 were regularly identified. However, notable differences were also found. A Mr 55,000 keratin (IEF 55) was prominent in one HAN, the D2, and all tumor tissues but not in normal gland. Likewise, a Mr 46,000 polypeptide (IEF 46), which has been tentatively identified previously as a keratin, was absent in normal epithelium but present in all abnormal tissues except the C4 and CV2 HAN. A Mr 58,000 polypeptide (NEPHGE 58) was not detected in normal gland or the C4 lesions but was found in all other abnormal tissues. The overall pattern of polypeptides in cytoskeletal extracts from normal and abnormal mammary cells in primary culture resembled that of the corresponding tissue but also had important differences. In all cell cultures, IEF 46 and IEF 55 were major species, while the larger and more basic components were markedly reduced. A Mr 56,000 polypeptide (NEPHGE 56) was detected only in C4 HAN and C4 and CV2 tumor cells. Trace or small, variable amounts of a Mr 57,000 basic keratin (NEPHGE 57) were present in normal and D2 tissues and cultured cells. NEPHGE 57 was dramatically increased in C4 and CV2 tissues and cultured cells and may be related to expression of squamous metaplasia and keratinization which are characteristic of these lesions. Although production of IEF 46 and IEF 55 may be associated with neoplastic progression of mammary epithelium, particularly in vivo, the association is not exclusive since normal cells express these polypeptides when grown in primary culture. In addition, corre

Topics: Adenocarcinoma; Animals; Cytoskeleton; Electrophoresis, Polyacrylamide Gel; Female; Hyperplasia; Keratins; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Molecular Weight

Twenty specimens of focal nodular hyperplasia were studied with special attention to the histological features of chronic cholestasis (grouped under the headings of cholestasis, cholate-stasis and signs of ductular reabsorption). In all specimens, evidence was found for one or more features of cholestasis and cholate-stasis. Signs of ductular reabsorption were less constant, and apparently varied according to the developmental stage of the lesion. The cholestatic features emphasize the bile secretory capacity of the lesional parenchyma, and are apparently due to the lack of real bile ducts in the portal tract equivalents of the lesional tissue. Evidence is presented that the "ductular component" in FNH is not due to proliferation of pre-existing ductules, but rather derives from ductular metaplasia of liver cell plates in zone 1 equivalents. This metaplastic development of a ductular network may serve the function of reabsorbing the biliary constituents produced by the lesional parenchyma, leading to periductular inflammation and progressive fibrosis, thus producing an equivalent of biliary fibrosis and biliary cirrhosis.

Topics: Adult; Aged; Bile Ducts, Intrahepatic; Cholestasis, Intrahepatic; Female; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Liver; Male; Middle Aged

We have studied the effects of the potent tumour promoter phorbol, 12-myristate, 13-acetate (PMA) and two non-promoting hyperplasiogenic compounds ethyl phenylpropriolate (EPP) and the divalent cation ionophore A23187 on the terminal differentiation of normal and transformed human keratinocytes using the loss of cloning efficiency and the formation of cornified envelopes as markers of the differentiated state. PMA induced terminal differentiation in a far greater proportion of normal keratinocytes than it did in the squamous cell carcinoma line SCC-27 but EPP and the calcium ionophores A23187 and Br-X537A had no such differential effect, possibly explaining the poor promoting ability of the last three compounds.

Topics: Alkynes; Calcimycin; Carcinoma, Squamous Cell; Cell Differentiation; Cell Line; Cell Transformation, Neoplastic; Cells, Cultured; Clone Cells; Humans; Hyperplasia; Keratins; Phorbols; Skin; Tetradecanoylphorbol Acetate

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the prototype for a group of halogenated aromatic hydrocarbons which can be potent modulators of growth and differentiation of epithelial tissues. TCDD causes chloracne and can act as a skin tumor promoter, but these actions have been demonstrated only in animals in which TCDD causes epidermal hyperplasia. Study of the hyperplastic response to TCDD has been hampered by lack of an in vitro model; all previous investigations indicated that TCDD had no in vitro effect on cell growth. We show here that nanomolar concentrations of TCDD cause hyperplasia in confluent cultures of human keratinocytes and suggest that this model system will be useful for analyzing mechanisms of TCDD-induced epithelial hyperplasia and genetic differences in responsiveness to TCDD.

Topics: Cells, Cultured; Dioxins; Dose-Response Relationship, Drug; Epidermis; Epithelium; Humans; Hyperplasia; Infant, Newborn; Keratins; Male; Polychlorinated Dibenzodioxins; Time Factors

Topics: Animals; Back; Ear; Hyperplasia; Keratins; Mice; Neoplasms, Experimental; Phorbol Esters; Phorbols; Skin; Skin Neoplasms; Tail

Long-term treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) of dorsal skin of 7,12-dimethylbenz(a)anthracene-initiated Syrian golden hamsters does not lead to the formation of epithelial tumors and leaves the epidermis essentially unchanged. However, previous histological studies by others have shown that hamster epidermis can be hyperplastically transformed by a single application of TPA but that the tissue is capable of gradually adapting to the drug after extended TPA exposure. We have investigated the response of hamster back epidermis to single and multiple treatments with increasing doses of TPA with regard to histological, proliferative, and biochemical alterations, and we show that in our animal strain the dorsal epidermis is resistant to even a single exposure to TPA, although the clearance rate of TPA is comparable to that in mouse epidermis and the metabolism of the substance is negligible. In contrast, the epidermis could be moderately stimulated by a single application of the nonpromoting calcium ionophore A 23187 and exhibited a strong proliferate and hyperplastic response following the simultaneous exposure to the calcium ionophore and TPA. Both types of hyperproliferation did not reveal an initial depression of the proliferative activity and were accompanied by typical alterations of the keratin polypeptide pattern, which was not detectable after treatment with TPA alone.

Topics: Adaptation, Physiological; Administration, Topical; Animals; Anti-Bacterial Agents; Calcimycin; Cell Division; Cricetinae; Drug Resistance; Hyperplasia; Keratins; Male; Mesocricetus; Phorbols; Skin; Tetradecanoylphorbol Acetate; Time Factors

Topics: Alkynes; Anthralin; Calcimycin; Carcinogens; Diterpenes; Epidermal Cells; Epidermis; Hyperplasia; Keratins; Phorbol Esters; Terpenes; Tetradecanoylphorbol Acetate

Topics: Animals; Autoradiography; Cell Division; Cells, Cultured; Cytoplasmic Granules; Epidermal Cells; Epidermis; Epithelial Cells; Hyperplasia; Keratins; Melanocytes; Mice; Mice, Inbred C3H; Tetradecanoylphorbol Acetate

Two-dimensional gel electrophoresis was used to compare the changes in mouse epidermal proteins induced by the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), by the moderate promoter mechanical abrasion, and by the weakly promoting hyperplasiogenic agents mezerein and ethylphenylpropiolate. Evidence is presented which indicates that TPA caused many changes in the epidermal protein profiles especially related to the keratins which are the major differentiation product of the epidermis. The keratin modification progresses with time after TPA treatment, resulting in a keratin pattern which resembles that of newborn mouse epidermis. The criteria used for the identification of the keratins were extractability, isoelectric points, molecular weights, filament formation in vitro, immunological cross-reactivity, amino acid composition, and peptide mapping. Several other protein changes were evident in the more soluble epidermal proteins which were also prominent in the newborn epidermis. These protein alterations are observed not only early during the TPA induction of hyperplasia and inflammation at 48 and 72 hr but also in 1- and 2-week samples in which the morphology of the epidermis has returned to normal. Mezerein and abrasion produced protein changes similar to those induced by TPA. Ethylphenylpropiolate-induced protein modifications not only occurred at later times compared with either mezerein or TPA but also were less in magnitude. However, although many of the protein modifications induced by TPA appear to be associated with the hyperplasiogenic properties of TPA, the major difference between a potent promoter like TPA and a weak promoter like ethylphenylpropiolate appeared to be related to the magnitude of the response and the time of appearance of the protein changes.

Topics: Amino Acids; Animals; Female; Hyperplasia; Keratins; Mice; Mice, Inbred Strains; Peptide Fragments; Phorbols; Proteins; Skin; Tetradecanoylphorbol Acetate

Topics: Bronchi; Humans; Hyperplasia; Immune Sera; Keratins; Mucins; Mucous Membrane; Staining and Labeling

Topics: Child; Collagen; Female; Humans; Hyperplasia; Keratins; Mandibular Diseases; Radiography

Specific pathogen free F-344 rats were kept on a vitamin A deficient diet for 3-5 months. After 3 months on this diet the forestomach epithelium showed a mild atrophy. Stereological cytology showed a marked increase in the volume density of cytoplasmic filament bundles and decrease in the volume density of non-bundled cytoplasmic filaments. The volume fraction of keratohyalin granules increased whereas the volume fraction of membrane coating granules decreased. Some animals maintained for 4-5 months on the hypovitaminic diet exhibited the same mild atrophic forestomach epithelium accompanied by hyperkeratinization. Others showed a marked epithelial atrophy and 4 out of 12 animals revealed a marked hyperplasia with increased 3H thymidine labeling index and several papillomatous proliferations. Although many of these alterations reflect a decrease in proliferation as well as hyperkeratinization, the latter changes were not unlike those produced by known carcinogens, and support the putative important role of vitamin A in both carcinogenesis and chemoprevention.

Topics: Animals; Epithelium; Female; Hyperplasia; Keratins; Microscopy, Electron; Rats; Rats, Inbred F344; Stomach; Vitamin A Deficiency

In order to investigate the role that hyperplasia plays in the induction of the keratin modifications by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), the effects of several inhibitors of tumor promotion and cycloheximide on the TPA-induced protein changes were studied. The antiinflammatory steroid fluocinolone acetonide and cycloheximide, which prevent the induction of hyperplasia, were found to prevent the appearance of the TPA-induced keratin modifications. Retinoic acid and tosylphenylalanylchloromethyl ketone, which have minor influence on hyperplasia, were found to have essentially no effect on these protein changes. These results provided further evidence that the TPA-induced epidermal keratin changes were associated with the induction of hyperplasia by TPA and not necessarily related to promoting ability.

Topics: Animals; Carcinogens; Cycloheximide; Electrophoresis, Polyacrylamide Gel; Epidermis; Female; Fluocinolone Acetonide; Hyperplasia; Keratins; Mice; Molecular Weight; Phorbols; Skin; Tetradecanoylphorbol Acetate; Tosylphenylalanyl Chloromethyl Ketone; Tretinoin

Autopsy specimens of normal human thymus, from cases of accidental involution, follicular hyperplasia, thymomas and a teratoma were investigated by immunocytochemistry using specific immune sera to small and large keratins. Keratin antisera represent a "marker" of both Hassall's corpuscles (HC) and so-called epithelial reticular cells. There were no apparent differences in keratin polypeptides distribution between cortical and medullary thymic epithelial cells. In accidental involution, the epithelial framework became prominent: epithelial cortical borders and epithelial perivascular sheaths appeared often to be discontinuous structure. The central and occasionally cystic spaces of HC did not react with keratin antisera. In follicular hyperplasia, almost solid epithelial aggregates were seen which were located around germinal centers. In thymic tumours, neoplastic epithelial cells displayed a marked immunoreactivity with keratin antisera. Immune sera against keratin filaments represent an interesting tool in thymus research and in the diagnostic pathology of thymic tumours.

Topics: Aged; Autopsy; Child; Child, Preschool; Epithelium; Female; Histocytochemistry; Humans; Hyperplasia; Immunoenzyme Techniques; Infant; Infant, Newborn; Keratins; Male; Middle Aged; Teratoma; Thymoma; Thymus Gland; Thymus Neoplasms

Topics: Animals; Diterpenes; Electrophoresis, Polyacrylamide Gel; Epidermis; Fluocinolone Acetonide; Hyperplasia; Keratins; Mice; Molecular Weight; Phorbol Esters; Phorbols; Protein Biosynthesis; Proteins; Terpenes; Tetradecanoylphorbol Acetate

A clinical and histopathologic analysis of 464 oral squamous cell papillomas is presented. Data on age, sex, race, location, clinical appearance, duration, recurrence, and clinical diagnosis are reviewed. One hundred seventy-six of the 464 specimens were examined for hyperkeratosis, character and amount of inflammatory infiltrate, and evidence of cellular atypia. The trends seen in this study support claims made by previous authors regarding incidence and inflammatory involvement. The data support a slightly higher occurrence rate in males than in females and in white as opposed to black patients. Papillomas were most abundant on the palatal complex, dorsum and lateral tongue borders, and lower lips, respectively. Confusion of papilloma for fibroma in the clinical diagnosis was less common than expected. Recurrence rate and incidence of multiple papillomas were low. Histologic study revealed a tendency for hyperkeratotic lesions to arise from nonkeratinized oral sites. Cellular atypia was found, but it is still unclear whether these changes are preneoplastic or due to an increased growth rate.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Female; Humans; Hyperplasia; Inflammation; Keratins; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Neoplasm Recurrence, Local; Papilloma; Time Factors

Effects of cyproterone acetate, a synthetic steroidal compound, on the reproductive organs of female rats have been investigated. This agent caused reduction of ovarian weights indicative of suppression of pituitary gonadotrophins. Oestrogenic nature of cyproterone acetate was investigated in intact and ovariectomized rats taking uterine weight and vaginal keratinization as an index of oestrogenicity. Cyproterone acetate in ovariectomized animals induced vaginal keratinization and increased the uterine weights. These effects were parallel to the effect of oestradiol dipropionate in ovariectomized animals, thus indicating oestrogenic activity of cyproterone acetate. We may conclude that the above compound caused antifertility effects due to its oestrogenic nature at the dose level of 2 mg/alternate day in rats when the compound was administered subcutaneously.

Topics: Animals; Atrophy; Body Weight; Castration; Cyproterone; Estradiol; Female; Fertility; Genitalia, Female; Hyperplasia; Hypertrophy; Keratins; Organ Size; Ovary; Rats; Reproduction; Uterus; Vagina

We report 34 cases of bowenoid papulosis of the genitalia. In each case, the patient had numerous reddish brown or violaceous papular lesions, some distinctly verrucoid, situated on the genitalia. Although clinically the lesions invariably appeared benign, histologic examination of specimens from the genital lesions in each patient showed changes of squamous cell carcinoma in situ. Many of the patients gave a history of preceding viral lesions on the genitalia. Therapy in all cases was conservative but thoroughly ablative. We view bowenoid papulosis as a new entity whose biologic behavior if untreated is as yet unknown.

Topics: Adolescent; Adult; Carcinoma in Situ; Carcinoma, Squamous Cell; Cell Nucleus; Epidermis; Female; Humans; Hyperplasia; Keratins; Male; Penile Neoplasms; Perineum; Vulvar Neoplasms

Reported is a rare case of multiple fibroepithelial hyperplasias of the oral cavity, and the suggestion is made that several previous authors may have confused this lesion with focal epithelial hyperplasia (Heck's disease). The differential diagnosis of multiple fibroepithelial hyperplasias is discussed in order to elucidate some of the confusions in the diagnosis of cases of multiple papules and nodules of the oral mucosa.

Topics: Connective Tissue; Diagnosis, Differential; Epithelium; Humans; Hyperplasia; Keratins; Male; Middle Aged; Mouth Diseases; Mouth Mucosa

Topics: Aspirin; Candidiasis; Cheilitis; Denture, Complete; Diagnosis, Oral; Foreign Bodies; Hyperplasia; Keratins; Leukoplakia; Lichen Planus; Palatal Neoplasms; Phenols; Salivary Duct Calculi; Stomatitis; Stomatitis, Aphthous; Stomatitis, Denture

Hamster cheek pouches were painted thrice weekly with 50% v/v turpentine in liquid paraffin over periods ranging from 1 day to 16 weeks. Pouch mucosa was examined histologically for changes and measurements of epithelial thickness were made with a calibrated eyepiece micrometer. An increase in epithelial thickness was first observed 48 hrs. after a single painting and was accompanied by inflammatory changes in both epithelium and connective tissue. Maximal epithelial thickening occurred after 9 weeks of thrice weekly painting. Cheek pouches of animals left without further treatment for up to 1 year following 9 weeks painting were indistinguishable from controls. The epithelial response to treatment with turpentine is that of a reversible benign epithelial hyperplasia with hyperkeratosis.

Topics: Animals; Connective Tissue; Cricetinae; Epithelium; Hyperplasia; Keratins; Keratosis; Male; Models, Biological; Mouth Mucosa; Stomatitis; Time Factors; Turpentine

"Keratin pools," previously characterized clinically and histochemically in the superficial epithelium of chronic hyperplastic oral mucosa, were studied by light and electron microscopy. These occured as small beaded and larger coalescent masses which varied in metachromasia. Ultrastructurally, the "keratin pools" consisted of electron-dense, amorphous or finely-granular material developing and coalescing, chiefly as extracellular deposits. The "pools" frequently possessed a layered arrangement alternating with cells having distinct tonofilaments, desmosomes, and definite cell membranes. Occasional bands of filamentous-like material, possibly representing tonofilament bundles, were observed in some "pools."

Topics: Aged; Cell Nucleus; Chronic Disease; Desmosomes; Epithelium; Female; Humans; Hyperplasia; Inclusion Bodies; Keratins; Microscopy, Electron; Mouth Diseases; Mouth Mucosa

Topics: Biopsy; Burns; Collagen; Cysts; Elastic Tissue; Epithelium; Granulation Tissue; Humans; Hyperplasia; Keratins; Sebaceous Glands; Skin; Skin Transplantation; Staining and Labeling; Sweat Glands; Transplantation, Autologous; Wound Healing

Topics: Animals; Cell Transformation, Neoplastic; Endometrium; Epithelium; Female; Hyperplasia; Hypertrophy; Intrauterine Devices; Keratins; Metaplasia; Ovarian Diseases; Ovary; Polyps; Rats; Time Factors; Uterine Diseases; Uterus

The smoking habits of 345 Danish and 184 Hungarian leukoplakia patients were analysed against the histopathology of the leukoplakias, i.e. type of keratinization, epithelial thickness, epithelial dysplasia and inflammation. In spite of the reasonable size of the numbers forming the basis for the analysis, no statistically significant differences were found between smokers and non-smokers. However, it was found that the frequency of epithelial dysplasia is not higher among smokers than among non-smokers.

Topics: Atrophy; Denmark; Epithelium; Female; Humans; Hungary; Hyperplasia; Inflammation; Keratins; Keratosis; Leukoplakia, Oral; Male; Smoking

Topics: Abscess; Aluminum; Animals; Hydrogen-Ion Concentration; Hyperplasia; Inflammation; Keratins; Mice; Permeability; Phospholipids; Protein Binding; Protein Denaturation; Skin; Skin Diseases; Skin Ulcer; Sulfhydryl Compounds; Swine

Topics: Adult; Aged; Autopsy; Child; Cholesteatoma; Chronic Disease; Connective Tissue; Ear, Middle; Epithelial Cells; Epithelium; Granulation Tissue; Humans; Hyperplasia; Hypertrophy; Keratins; Male; Metaplasia; Microtomy; Middle Aged; Mucous Membrane; Otitis Media; Staining and Labeling; Temporal Bone; Tympanic Membrane

Topics: Animals; Culture Techniques; Gestational Age; Hair; Hyperplasia; Keratins; Methods; Mice; Skin; Skin Transplantation; Transplantation, Homologous

Topics: Animals; Cell Differentiation; Chick Embryo; Collagen; Epithelium; Hyperplasia; In Vitro Techniques; Keratins; Microscopy, Electron; Mitochondria; Skin

Topics: Animals; Coloring Agents; Epithelium; Hyalin; Hyperplasia; Keratins; Mouth Mucosa; Rats; Skin; Staining and Labeling; Urinary Bladder; Vitamin A Deficiency

Topics: Acne Vulgaris; Cysts; Edema; Folliculitis; Hair; Humans; Hyperplasia; Keratins; Male; Rupture; Sebaceous Glands; Skin

Topics: Autopsy; Dermatitis, Seborrheic; Humans; Hyperplasia; Keratins; Keratosis; Pigmentation Disorders

Topics: Animals; Epithelial Cells; Epithelium; Hyperplasia; Keratins; Keratosis; Microscopy, Electron; Rats; Urinary Bladder; Vitamin A Deficiency

Topics: Alkanes; Body Weight; Guinea Pigs; Hydrocarbons; Hyperplasia; Keratins; Keratosis; Keratosis, Actinic; Metabolism; Pharmacology; Research; Skin; Toxicology; Water