bromochloroacetic-acid and Metaplasia

Keratinising squamous metaplasia of the bladder is a very rare entity that carries a risk of progression to malignancy. We present a case of a 62-year-old man found to have the condition and discuss the management dilemma with a review of the literature.

Topics: Biopsy; Cystoscopy; Disease Progression; Humans; Keratins; Male; Metaplasia; Middle Aged; Precancerous Conditions; Tomography, X-Ray Computed; Urinary Bladder

Keratocystoma is a rare benign tumour of the salivary glands. We report a patient who presented with a mass in the left parotid gland that was treated by subtotal parotidectomy and he was free of recurrence seven years later. After histological and immunohistochemical examinations we identified a keratocystoma.

Topics: Adult; Epithelial Cells; Fibrosis; Humans; Keratins; Ki-67 Antigen; Male; Metaplasia; Parotid Neoplasms; Transcription Factors; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

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

Our objective was to systematically review the existing literature regarding the use of cytokeratin (CK) stain in differentiating Barrett's esophagus (BE) from tissues of the gastric cardia, corpus, or antrum, with or without intestinal metaplasia (IM). Pubmed was searched for full publications in English (1983-2005) addressing the use of CK for differentiation of BE from contiguous tissues. Information was collected on the study sample, blinding, the methods used for CK staining, and for defining and applying the gold standard tests. Test characteristics were obtained or calculated. Sixteen studies (containing 46 comparisons) met the inclusion and exclusion criteria. Immunostaining for CK 7 and 20 was generally highly specific in distinguishing long-segment BE from antrum IM, fundus IM, or noncardiac gastric IM; 27 comparisons showed statistically significant differences. However, only 8 of 15 comparisons (6 of 12 studies) reported significant differences in CK staining patterns between BE and gastric cardia IM with a high sensitivity (89%-100%) and specificity (83%-100%) for long-segment BE and lower estimates for short-segment BE, while the other seven comparisons showed no significant differences and a very low sensitivity. Examination by a blinded pathologist was reported in five of six positive studies and in only one of six of the negative studies. In addition, variation in the patient populations, use of surgical resection versus endoscopic biopsies, and biopsy sampling technique in endoscopic studies may have accounted for these differences. Finally, two studies did not find significant differences in CK staining patterns between BE and normal cardiac mucosa. In conclusions, CK immunostaining has not performed well in differentiating BE, especially short-segment BE, from cardia IM. There seems to be a spectrum bias where the accuracy varies with different tested populations. CK immunostaining distinguished well between BE and IM in noncardiac segments of the stomach; however, these comparisons are not clinically relevant.

Topics: Barrett Esophagus; Biomarkers; Cardia; Diagnosis, Differential; Gastric Fundus; Humans; Immunohistochemistry; Keratin-20; Keratin-7; Keratins; Metaplasia; Predictive Value of Tests; Pyloric Antrum; Sensitivity and Specificity; Stomach; Stomach Diseases

The importance of distinguishing between Barrett metaplasia and intestinal metaplasia of the gastric cardia is now accepted, and the management of each entity is quite different. Patients with Barrett metaplasia are enrolled in surveillance programs, consisting of periodic endoscopy and biopsy, because of the known risk of developing adenocarcinoma of the esophagus. Patients with intestinal metaplasia of the gastric cardia, however, are not currently enrolled in such programs, because this condition carries a low risk of developing adenocarcinoma of the gastric cardia. The distinction between both conditions by morphologic examination of routine histologic sections of endoscopic biopsies is extremely difficult if at all possible. A group of investigators proposed the use of immunostains for cytokeratin (CK) 7 and CK20 to overcome such difficulty. They concluded that the Barrett CK7/CK20 pattern was a highly sensitive and specific marker for Barrett metaplasia. Their observations, however, were not confirmed by other investigators. However, because it may be associated with premalignant lesions elsewhere in the gastric mucosa, we propose that intestinal metaplasia of the gastric cardia may have the same clinical implication as Barrett metaplasia.

Topics: Barrett Esophagus; Biomarkers; Cardia; Humans; Keratins; Metaplasia; Population Surveillance; Stomach Diseases

We reviewed the definition of the esophagogastric junction and the biopsy sites and histologic findings of biopsy specimens from Barrett's esophagus. The borderline between the esophagus and stomach has been defined as the distal limit of the longitudinal vessels by the Japan Esophageal Society, because the longitudinal vessels are always located within the esophagus. As squamous islands in Barrett's mucosa are usually the orifices of esophageal glands proper, biopsy specimens from the squamous islands show esophageal glands proper or their ducts. The identification of esophageal glands proper is a definite histological indicator that a piece of biopsy tissue is of esophageal origin. Therefore, a diagnosis of Barrett's esophagus can be made purely on the basis of the histologic findings in these biopsy specimens of squamous islands. Since columnar mucosa is usually recognizable at endoscopy, a diagnosis of Barrett's esophagus can be made solely on the basis of endoscopic examination, without any need for histologic confirmation, if squamous islands are recognized in columnar-lined mucosa.

Topics: Barrett Esophagus; Biomarkers; Biopsy; Diagnosis, Differential; Esophagogastric Junction; Esophagoscopy; Esophagus; Humans; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Metaplasia; Mucous Membrane; Staining and Labeling

Malignant breast neoplasms consisting of mixtures of epithelial and mesenchymal elements, are a rarity. Pathogenesis of such diverse elements within obviously infiltrating carcinomas has been the subject of much controversy. After the advent of immunohistochemistry, it is now generally accepted that metaplasia of the epithelial elements of a carcinoma gives these lesions their pseudosarcomatous appearance. Hence the name metaplastic carcinoma is given to malignant breast neoplasms which show Cytokeratin positivity in both epithelial and mesenchymal elements. We recently encountered such a case, which is being presented here along with relevant review of literature.

Topics: Adult; Breast Neoplasms; Carcinoma, Ductal, Breast; Female; Humans; Keratins; Metaplasia; Sarcoma

In Okinawa, a subtropical island in southern Japan, squamous cell carcinoma (SCC), especially the well-differentiated form, is prevalent, while this form is relatively rare in both the mainland and other countries (e.g. United States of America). More patients with SCC from Okinawa, moreover, were positive for human papillomavirus (HPV) DNA by polymerase chain reaction (PCR) (79%), and harbored HPV types 6, 16 and 18, in combination. On the other hand, less than 30% of the mainland patients were positive for HPV DNA by PCR. Those patients who were positive all harbored only one HPV type. Furthermore, in Okinawa, there were a significant number of cases with adenosquamous carcinoma, and they too were positive for HPV DNA. The SCC and the adenocarcinoma cells adjacent to the SCC component in these cases were also positive for HPV DNA, and such adenocarcinoma cells were enlarged in size with relatively wide cytoplasm. The authors postulate that HPV infects adenocarcinoma cells and changes them to enlarged cells, followed by squamous metaplasia. In this report, HPV DNA was transfected to adenocarcinoma cells (cultured cell lines) and this showed that HPV causes squamous metaplasia. In addition, aberrant expression of p53 was demonstrated in a large number of the SCC cases in Okinawa. The enlarged adenocarcinoma cells adjacent to the SCC components in adenosquamous carcinomas also showed aberrant expression of p53. The recent advances in the studies of anti-oncogenes, p53, etc. and oncogenes are outlined. It is to be noted that the molecular mechanisms of carcinogenesis in the lung have been studied in general, classifying lung tumors into two groups, namely, small cell carcinoma (SCLC) and non-small cell carcinoma (NSCLC). However, because human lung cancer is represented by a wide variety of histologic types, molecular genetic studies according to a more detailed histological subclassification is needed.

Topics: Adult; Aged; Aged, 80 and over; Animals; Blotting, Southern; Blotting, Western; Carcinoma, Adenosquamous; Carcinoma, Squamous Cell; Female; Humans; In Situ Hybridization; Japan; Keratins; Lung Neoplasms; Male; Metaplasia; Mice; Mice, SCID; Middle Aged; Mutation; Papillomaviridae; Transfection; Tumor Cells, Cultured; Tumor Suppressor Protein p53

We report a case of adenocarcinoma of the rectum with foci of metaplastic shadow cells. The patient was a 65 year old man with anemia. Macroscopically the tumor was an ordinary rectal cancer. Microscopically, in addition to the features of moderately differentiated adenocarcinoma invading the subserosa, islands of shadow cells in tumor nests were detected in both primary and one of three pericolic metastatic lymph node lesions. Neoplastic glandular cells showed gradual transition to shadow cells. An antibody specific for high-molecular-weight cytokeratins reacted with the shadow cells and intermediate zone epithelial cells surrounding them, but no CEA, low-molecular-weight cytokeratins or cyclin D1 was detectable in them. Cytokeratin 14 was expressed only in the transitional zone epithelial cells. The intermediate zone epithelial cells were regarded as metaplastic squamous cells, from which the shadow cells were derived. The patient died of multiple liver metastases nine and a half months after surgery. To our knowledge, this is the first report of an immunohistochemical study of rectal adenocarcinoma containing shadow cells not only in the primary lesion but also in a metastatic lymph node.

Topics: Adenocarcinoma; Aged; Carcinoembryonic Antigen; Cyclin D1; Epithelial Cells; Humans; Immunohistochemistry; Keratins; Lymph Nodes; Lymphatic Metastasis; Male; Metaplasia; Rectal Neoplasms; Rectum; Tumor Suppressor Protein p53

Topics: Animals; Carcinoma, Squamous Cell; Cell Differentiation; Cervix Uteri; Female; Intestinal Mucosa; Keratins; Metaplasia; Phenotype; Precancerous Conditions; Rats; Rats, Wistar; Urodela; Uterine Cervical 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

To review basic and clinical aspects of cytoskeletal keratin expression in normal cervical epithelia as well as in preneoplastic and malignant epithelia of the uterine cervix.. The results of extensive studies from our group and other groups on keratin phenotyping in normal premalignant and malignant cervical epithelia were summarized.. All studies involving keratin expression in the cervix were reviewed, as were general studies on keratin expression in which the cervix was mentioned and studies relevant to understanding cervical cancer etiology (36 studies).. From these studies, keratin phenotypes of the various epithelia were derived. The phenotypes were correlated to existing theories on the development of cervical carcinoma.. It is possible to distinguish the various epithelial types in the normal cervix based on their keratin expression patterns. Reserve cells display a bidirectional keratin pattern, comprising keratins typical of both squamous and simple types of differentiation, reflecting the bipotential nature of these cells. Cervical intraepithelial neoplasia can be divided into two subpopulations, one characterized by the reserve cell keratin phenotype and the other by a keratin phenotype typical of nonkeratinizing squamous epithelia. The first population also contains the simple keratins, the relative percentage of which increases with increasing degree of dysplasia. We therefore suggest that these lesions are progressive in nature. Carcinomas show a differentiation-related keratin expression pattern in addition to the basic reserve cell keratin phenotype. Adenocarcinomas also have been shown to express most of the reserve cell keratins. The latter observation indicates a common progenitor for both carcinoma types.

Topics: Carcinoma in Situ; Cervix Uteri; Epithelium; Female; Forecasting; Humans; Keratins; Metaplasia; Precancerous Conditions; Research; Uterine Cervical Neoplasms

We report a case of keratinizing desquamative squamous metaplasia (KDSM) of the kidney pelvis. The etiopathogenic and diagnostic aspects of this rare pathology are discussed. Absence of relationship between KDSM and the carcinoma of Upper Urinary Tract, allows to suggest a conservative management.

Topics: Humans; Keratins; Kidney Diseases; Kidney Pelvis; Male; Metaplasia; Middle Aged

Squamous cell metaplasia (SCM) is a frequent epithelial alteration of the human tracheobronchial mucosa. This review pays particular attention to the fact that SCM can mimic esophageal, and in some instances even skin-type differentiation, showing striking similarities not only in morphology but also in terms of gene expression. Therefore, characterization of this dynamic process lends insight into the process of stratification, squamous cell formation, and "keratinization" in a pathologically relevant in vivo situation in man. First, the concept of metaplasia is presented with certain historical viewpoints on histogenesis. Then, the morphological characteristics of normal bronchial epithelium are compared with the altered phenotype of cells in SCM. These changes are described as a disturbance of the finely tuned balance of differentiation and proliferation through the action of a variety of extrinsic and intrinsic factors. Molecular aspects of altered cell/cell and cell/extracellular matrix interactions in stratified compared with single-layered epithelia are discussed with reference to SCM in the lung. Intracellular organizational and compositional changes are then summarized with special emphasis on the differential distribution of the cytokeratin (CK) polypeptides. Finally, the still unresolved problems of the histogenetic relationships between normal bronchial mucosa, SCM, and pulmonary neoplasms are addressed. As these questions remain open, examples for detection of well defined "markers" are provided that may be employed as objective criteria for determining clinically important cellular differentiation features.

Topics: Cell Differentiation; Desmosomes; Epithelium; Keratins; Lung; Metaplasia; Microscopy, Fluorescence

An unusual case of pleomorphic adenoma displaying numerous horny pearls is described. The tumour arose in the right lateral lingual border of a 33-year-old man. In many pearls the cores were organized in two separate portions with distinct structural and histochemical features. The narrow peripheral portion had a compact structure and was rich in keratin since it contained cystine and was coloured with acid dyes of intermediate molecular size. The central portion was characterized by a loose texture and its histochemical profile (affinity for acid dyes of large molecular size, weak alcianophilia, vivid binding of colloidal iron) resulted from the existence of acidic mucosubstances in the cell coating of the neoplastic keratinized cells. These observations suggest that certain similarities exist between the processes of normal keratinization and squamous metaplasia in pleomorphic adenoma.

Topics: Adenoma, Pleomorphic; Adult; Histocytochemistry; Humans; Keratins; Male; Metaplasia; Salivary Gland Neoplasms

This diagnostic seminar discusses the current status of the principles and problems of cytology as it is applied to the diagnosis of lung cancer. This discussion is divided into four major parts. Part I presents a discussion of cytopreparatory techniques and cytology of the lung in the absence of cancer. The cytology of benign proliferations which may mimic cancer is emphasized. The role of cytology in the diagnosis of pulmonary infectious organisms is noted. Part II discusses lung cancer as manifested in specimens of sputum, bronchial washings, and bronchial brushings. Part III presents some data on the validity of cytology with respect to role of specimen number and type in lung cancer diagnosis and cell typing in lung cancer. The continued usefulness and importance of multiple specimens of sputum for lung cancer diagnosis are documented. Part IV presents a brief synopsis of fine needle aspiration biopsy of lung cancer.

Topics: Adenocarcinoma; Aspergillus; Biopsy, Needle; Blastomyces; Bronchi; Carcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Nucleus; Coccidioides; Cryptococcus neoformans; Cytodiagnosis; Cytological Techniques; Cytoplasm; Epithelium; Histoplasma; Humans; Keratins; Lung Diseases; Lung Diseases, Fungal; Lung Diseases, Parasitic; Lung Neoplasms; Macrophages; Metaplasia; Pneumocystis; Sputum; Strongyloides; Suction; Virus Diseases

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

Vitamin A deficiency or benzo(a)pyrene instillation into tracheas of Syrian golden hamsters causes squamous metaplasia of tracheobronchial epithelium, normally a mucous secretory tissue. In the present studies, we have employed a tracheal organ culture system and have reproduced the in vivo phenomenon of squamous metaplasia during culturing under vitamin A free conditions as well as after carcinogen treatment. The squamous metaplasia induced by vitamin A deficiency, both in vivo and in vitro, was accompanied by an overall increase in keratin synthesis. Vitamin A deficient tracheas were shown to contain keratins of 50, 48, 46.5 Kd detected with the antibody AE1, and 58, 56 and 52 Kd detected with AE3. These proteins were either absent or present in much less quantity in control tracheas. In deficient tracheas 60 kd keratin was found to be located specifically in squamous suprabasal cells, and 55 and 50 Kd keratin proteins were found in a greatly expanded basal cell compartment. Following carcinogen exposure, the appearance of 60 kd keratin and the enhanced expression of 50 and 55 Kd keratins preceded the squamoid metaplastic response as detected morphologically. Both the keratin changes and the morphological changes were prevented by retinoid treatment.

Topics: Animals; Carcinoma, Squamous Cell; Cell Differentiation; Cricetinae; Epithelial Cells; Epithelium; Keratins; Mesocricetus; Metaplasia; Organ Culture Techniques; Trachea; Vitamin A; Vitamin A Deficiency

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: 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

The transition zones of the squamous and columnar epithelia constitute hotspots for the emergence of cancer, often preceded by metaplasia, in which one epithelial type is replaced by another. It remains unclear how the epithelial spatial organization is maintained and how the transition zone niche is remodelled during metaplasia. Here we used single-cell RNA sequencing to characterize epithelial subpopulations and the underlying stromal compartment of endo- and ectocervix, encompassing the transition zone. Mouse lineage tracing, organoid culture and single-molecule RNA in situ hybridizations revealed that the two epithelia derive from separate cervix-resident lineage-specific stem cell populations regulated by opposing Wnt signals from the stroma. Using a mouse model of cervical metaplasia, we further show that the endocervical stroma undergoes remodelling and increases expression of the Wnt inhibitor Dickkopf-2 (DKK2), promoting the outgrowth of ectocervical stem cells. Our data indicate that homeostasis at the transition zone results from divergent stromal signals, driving the differential proliferation of resident epithelial lineages.

Topics: Adenocarcinoma; Animals; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Differentiation; Cell Lineage; Cellular Microenvironment; Cervix Uteri; Epithelium; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Homeostasis; Humans; Keratins; Metaplasia; Mice, Inbred C57BL; Organoids; Receptors, Notch; Stem Cells; Stromal Cells; Transcription, Genetic; Uterine Cervical Neoplasms; Wnt Signaling Pathway

The nature of endometrial morular metaplasia (MorM) is still unknown. The nuclear β-catenin accumulation and the not rare ghost cell keratinization suggest a similarity with hard keratin-producing odontogenic and hair matrix tumors rather than with squamous differentiation. We aimed to compare MorM to hard keratin-producing tumors. Forty-one hard keratin-producing tumors, including 26 hair matrix tumors (20 pilomatrixomas and 6 pilomatrix carcinomas) and 15 odontogenic tumors (adamantinomatous craniopharyngiomas), were compared to 15 endometrioid carcinomas with MorM with or without squamous/keratinizing features. Immunohistochemistry for β-catenin, CD10, CDX2, ki67, p63, CK5/6, CK7, CK8/18, CK19, and pan-hard keratin was performed; 10 cases of endometrioid carcinomas with conventional squamous differentiation were used as controls. In adamantinomatous craniopharyngiomas, the β-catenin-accumulating cell clusters (whorl-like structures) were morphologically similar to MorM (round syncytial aggregates of bland cells with round-to-spindled nuclei and profuse cytoplasm), with overlapping squamous/keratinizing features (clear cells with prominent membrane, rounded squamous formations, ghost cells). Both MorM and whorl-like structures consistently showed positivity for CD10 and CDX2, with low ki67; cytokeratins pattern was also overlapping, although more variable. Hard keratin was focally/multifocally positive in 8 MorM cases and focally in one conventional squamous differentiation case. Hair matrix tumors showed no morphological or immunophenotypical overlap with MorM. MorM shows wide morphological and immunophenotypical overlap with the whorl-like structures of adamantinomatous craniopharyngiomas, which are analogous to enamel knots of tooth development. This suggests that MorM might be an aberrant mimic of odontogenic differentiation.

Topics: beta Catenin; Biomarkers, Tumor; Carcinoma; Case-Control Studies; Cell Differentiation; Craniopharyngioma; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Odontogenesis; Pilomatrixoma; Pituitary Neoplasms

Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for 'mixed' MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Topics: Antigens, CD; Biomarkers, Tumor; Breast Neoplasms; Cadherins; Class I Phosphatidylinositol 3-Kinases; Cross-Sectional Studies; Epithelial-Mesenchymal Transition; ErbB Receptors; Female; Genetic Predisposition to Disease; Humans; Keratins; Metaplasia; Middle Aged; Mutation; Neoplasm Grading; Neoplasms, Complex and Mixed; Neurofibromin 1; Phenotype; PTEN Phosphohydrolase; Tumor Burden; Tumor Suppressor Protein p53

Differentiating between malignant phyllodes tumors and metaplastic spindle cell carcinomas could be problematic, especially on core biopsies. Immunohistochemical staining for cytokeratin cocktail and p63 has been utilized to differentiate between these tumor types. Forty-three phyllodes tumors (27 benign, 6 borderline, and 10 malignant) and 22 metaplastic carcinomas, consisting at least 80% of spindle cells, were identified. At least 4 tissue blocks from each phyllodes tumor were subjected to immunohistochemical staining for cytokeratin cocktail and p63. The immunohistochemical profiles for the spindle cells in metaplastic carcinoma were reviewed. Phyllodes tumor was diagnosed in the younger age group (mean age 41 y) with a larger tumor size (mean size 6.6 cm), compared with metaplastic spindle cell carcinoma (mean age 62.7 y, mean size 3.4 cm). Focal expression (5% of the tumor cells) of cytokeratin cocktail and p63 was identified in the stroma of 2 of 10 malignant phyllodes tumors in a scattered/patchy pattern. The stroma of benign and borderline phyllodes tumors was negative for these markers. In metaplastic spindle cell carcinomas, cytokeratin cocktail was negative in 2 of 15 cases and very focally positive in another 3 cases, whereas p63 was negative in one case and focally positive in another case. There can be anomalous, focal expression of cytokeratin and p63 in the stroma of malignant phyllodes tumors, whereas metaplastic spindle cell carcinoma can occasionally have cytokeratin and/or p63-negative staining or have very focal positivity. Caution should be exercised when relying on these markers for confirming a diagnosis, especially on core biopsies.

Topics: Adolescent; Adult; Aged, 80 and over; Carcinoma; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Limit of Detection; Membrane Proteins; Metaplasia; Middle Aged; Phyllodes Tumor

Keratinising squamous cell metaplasia (KSCM) is an uncommon diagnosis in the West. Patients typically present with lower urinary tract symptoms: haematuria (visible and non-visible), dysuria, urgency and frequency. Investigation is rigid cystoscopy. Abnormal bladder wall tissue should be resected and biopsies sent for histopathology to confirm KSCM. This is a preneoplastic condition with strong associations with squamous cell carcinoma. Due to a significant lag time, annual cystoscopy with multiple biopsies is recommended.

Topics: Aged, 80 and over; Biopsy; Carcinoma, Squamous Cell; Cystoscopy; Early Detection of Cancer; Humans; Keratins; Male; Metaplasia; Time Factors; Urinary Bladder; Urinary Bladder Neoplasms

Metaplastic breast carcinoma (MBC) is a rare type of invasive breast carcinoma, and chondroid differentiation is even rarer. Here we report a case of MBC with extensive chondroid differentiation in a 38-year-old woman who presented with a lump in her left breast. Ultrasound findings were most compatible with those of giant fibroadenoma. A histopathological examination revealed a malignant lesion comprising neoplastic epithelial cells arranged in solid nests, with large areas of chondroid differentiation. Neoplastic chondroid cells exhibited a positive reaction for S-100, patchy positive reaction for pan-cytokeratin (AE1/AE3) and negative reaction for epithelial membrane antigen. Both carcinomatous and chondroid cells exhibited p53 overexpression. Sentinel lymph node biopsy revealed no tumorous involvement.

Topics: Adult; Breast Neoplasms; Carcinoma; Cell Differentiation; Diagnosis, Differential; Female; Fibroadenoma; Humans; Keratins; Metaplasia; Neoplasm Invasiveness; Treatment Outcome; Tumor Suppressor Protein p53; Ultrasonography, Mammary

Metaplastic breast carcinomas are ductal carcinomas that undergo metaplasia into non-glandular growth patterns. They are very rare and account for less than 1% of all invasive breast carcinomas. Matrix-producing carcinoma is an extremely rare and aggressive subtype of metaplastic breast carcinoma that is characterized by a ductal carcinomatous component with direct transition to areas with cartilaginous/osseous differentiation without an intervening spindle cell element. It has a better prognosis than metaplastic carcinoma. Even though these tumors are composed of a mixture of infiltrating ductal carcinomas and areas of heterologous stroma, each of which behaves aggressively individually, these composite tumors have a better 5-year survival rate with rare nodal metastasis. Immunohistochemically, they are positive for keratin, epithelial membrane antigen and S100. The tumor, which is matrix-producing, is S100-reactive and nonreactive for cytokeratin. They are usually hormone receptor-negative. The average age of these patients is approximately 58 years. Since these tumors are usually triple-negative, chemotherapy after surgery is the mainstay of therapy, using either mastectomy or local excision. Our report highlights this rare entity in a 55-year-old female patient with matrix-producing metaplastic breast carcinoma. Its distinctive histological features and peculiar clinical behavior warrants clear knowledge about this unique entity.. Metaplastische Mammakarzinome sind duktale Karzinome, die Metaplasie zu nicht-glandulären Wachstumsmustern durchlaufen. Sie sind sehr selten und machen weniger als 1% aller invasiven Mammakarzinome aus. Das Matrix-produzierende Karzinom ist ein extrem seltener und aggressiver Subtyp eines metaplastischen Mammakarzinoms, das durch eine duktale karzinomatöse Komponente mit direktem Übergang in Bereiche mit knorpeliger/knöcherner Differenzierung ohne dazwischenliegendes Spindelzellelement gekennzeichnet ist. Es hat eine bessere Prognose als das metaplastische Karzinom. Obwohl diese Tumore aus einer Mischung von infiltrierenden duktalen Karzinomen und Bereichen von heterologem Stroma bestehen, von denen jedes sich einzeln aggressiv verhält, haben diese zusammengesetzten Tumore eine bessere 5-Jahres-Überlebensrate mit seltener Lymphknotenmetastase.Immunhistochemisch sind sie positiv für Keratin, epitheliales Membranantigen und S-100. Matrix-produzierende Tumore sind S-100-reaktiv und nicht reaktiv für Cytokeratin. Sie sind normalerweise Hormonrezeptor-negativ. Das Durchschnittsalter der Patientinnen beträgt ca. 58 Jahre. Da diese Tumoren in der Regel dreifach negativ sind, ist die Chemotherapie nach der Operation das Hauptelement der Therapie, entweder mit Mastektomie oder lokaler Exzision.Unser Bericht beschreibt den Fall einer 55-jährigen Patientin mit Matrix-produzierendem metaplastischen Brustkarzinom, die charakteristischen histologischen Merkmalen und das besondere klinische Verhalten dieses seltenen Krankheitsbildes.

Topics: Breast; Breast Neoplasms; Carcinoma, Ductal, Breast; Female; Humans; Keratins; Metaplasia; Middle Aged; Mucin-1; S100 Proteins

Keratinizing desquamative squamous metaplasia (KDSM) in the renal pelvis is a rare condition with unclear malignant potential. Recent reports suggest it is likely benign and favor endoscopic treatment approaches. Medical record review was completed on two cases at our center to obtain history, physical examination, radiographic findings, and management. A literature review was completed to identify all published cases of KDSM. Both patients at our center suffered recurrent urolithiasis, hypothesized to be secondary to KDSM. Both were managed with a percutaneous approach to ensure complete stone and KDSM plaque removal. Our cases highlight that percutaneous surgery is an excellent management option for stone and KDSM eradication from the collecting system. This approach also allows adequate oncologic surveillance of the underlying urothelium.

Topics: Biopsy; Female; Humans; Keratins; Kidney Pelvis; Lithotripsy; Male; Metaplasia; Middle Aged; Nephrolithiasis; Recurrence; Tomography, X-Ray Computed; Treatment Outcome; Urothelium

To characterize the immunophenotypic relationship between the squamous and the glandular compartments in the oesophagus of patients with columnar-lined oesophagus (CLO).. Eight tissue blocks from three oesophageal resection specimens from patients who underwent oesophagectomy for adenocarcinoma of the oesophagus were selected for immunohistochemical analysis. The markers of intestinal differentiation [CK20, CDX2 and MUC2] were all expressed in the expected pattern, solely in the glandular compartment of the resection specimens. CK4, CK17 and lysozyme were expressed in both the glandular and the squamous compartments. In addition, CK17 expression was found on both the squamous and glandular margins of the squamocolumnar transformation zones and in the submucosal gland (SMG) intraglandular and excretory ducts.. There is an immunophenotypic relationship between the squamous and the glandular compartments of the CLO, with expression of lysozyme, CK4 and CK17 in both squamous and columnar cells. These overlapping immunophenotypes indicate similar differentiation paths, and link the SMG unit with the columnar metaplasia and the neosquamous islands in CLO. Our findings support the theory of a cellular origin of CLO and neosquamous islands from the SMG unit.

Topics: Adenocarcinoma; CDX2 Transcription Factor; Esophageal Neoplasms; Esophagus; Homeodomain Proteins; Humans; Immunohistochemistry; Keratins; Metaplasia; Mucin-2; Mucous Membrane

Metaplastic carcinomas arising in association with benign sclerosing lesions (BSLs) are rare malignancies in which a neoplastic spindle cell proliferation can be recognized extending beyond the boundaries of the complex sclerosing lesion or papilloma. However, in cases in which the metaplastic carcinoma is of the low-grade fibromatosis-like type or is a low-grade adenosquamous carcinoma, distinction from the background BSL can be a significant challenge. Cytokeratin (CK) and/or p63 immunostains are helpful in confirming the diagnosis of metaplastic carcinoma, but the expression patterns of these markers in the stromal cells of BSLs have not been well characterized.. To characterize the expression patterns of CKs and p63 in BSLs.. We evaluated the spindle cell component of 55 BSLs using CK 5/6, CK 903, CK MNF116, and p63.. A total of 45 cases (81%) showed no staining for CKs or p63 in benign stromal cells. CK 5/6, CK 903, and p63 were positive in one case each. CK MNF116 stained spindle cells within 10 BSLs. No cases showed spindle cell reactivity for all 4 markers. Positive cases demonstrated very focal, weak staining of spindle cells; only 1 case showed focal, moderate CK staining. Spindle cell positivity was not associated with lesion type, growth pattern, spindle cell atypia, or mitoses.. These findings suggest that although the presence or absence of expression of CK 5/6, CK 903, and p63 may be useful to distinguish BSL from metaplastic carcinomas arising in this setting, CK MNF116 positivity may be a diagnostic pitfall.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast; Breast Neoplasms; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Middle Aged; Papilloma; Sclerosis; Stromal Cells; Transcription Factors; Tumor Suppressor Proteins; Young Adult

A 60-year-old female with an extensive history of stone disease and shock wave lithotripsy presents with recurrent and increasingly severe renal colic. Work-up reveals obstruction with translucent debris that is found to be composed of keratin. Her history of chronic irritation of the collecting system has resulted in keratinizing squamous metaplasia (KSM) with hyperkeratosis that has sloughed from the upper urinary tract and has become lodged in the ureter. Because of the worsening of her symptoms on conservative management, the patient elected for a nephrectomy and her symptoms have since resolved. KSM of the renal pelvis is a relatively rare phenomenon and most often presents with irritative symptoms. It is thought to result from chronic irritation of the urothelium. KSM has been found to be coincident with squamous cell cancers of the urinary tract, though clear data implicating KSM as a premalignant lesion is lacking. We present a case of recurrent renal colic secondary to sloughing keratin debris from KSM.

Topics: Female; Humans; Keratins; Kidney Pelvis; Metaplasia; Middle Aged; Renal Colic; Ureter

Primary small bowel adenocarcinoma is rare. Although generally similar to colonic adenocarcinoma, some small bowel adenocarcinomas exhibit unique morphologic features, particularly those arising in association with Crohn disease. In this study, 15 sporadic small bowel adenocarcinomas and 11 Crohn enteritis-associated small bowel adenocarcinomas were examined for histology and immunohistochemical profile including cytokeratins (CK) 7 and 20, intestinal markers CDX2 and MUC2, and gastric epithelial markers MUC5AC and MUC6. We found that Crohn enteritis-associated small bowel adenocarcinomas frequently resemble gastric tubular adenocarcinoma histologically. In addition, when compared to sporadic small bowel adenocarcinoma, the former expressed MUC5AC and MUC6 with much higher frequency (82% vs. 7% and 73% vs. 0%, respectively). Ten of 11 Crohn enteritis-associated small bowel adenocarcinomas (91%) were positive for at least one gastric-type marker (MUC5AC or MUC6). Expression of CK7 was also more frequent in Crohn enteritis-associated small bowel adenocarcinoma (73% versus 27%) while expression of CK20 was less frequent (64% vs. 100%). There was no difference between sporadic and Crohn enteritis-associated small bowel adenocarcinoma in expression of CDX2 (100% vs. 91%) and MUC2 (93% vs. 73%). These observations suggest that there is a difference in the morphologic and immunohistochemical characteristics of sporadic versus Crohn enteritis-associated small bowel adenocarcinoma, particularly in their expression of gastric-type mucin. The findings also suggest that gastric differentiation in Crohn enteritis-associated small bowel adenocarcinoma is related to gastric metaplasia, a common phenomenon in Crohn disease.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Crohn Disease; Duodenal Neoplasms; Female; Humans; Ileal Neoplasms; Jejunal Neoplasms; Keratins; Male; Metaplasia; Middle Aged; Mucins; Stomach Neoplasms

Barrett's esophagus is characterized by a distinct Th2-predominant cytokine profile (IL-4) from in vivo or ex vivo evidence. The detailed role of cytokines in Barrett's esophagus, particularly whether Th2 cytokines are causative factors driving metaplastic processes, remains unknown. In this study, air-liquid interface-cultured human esophageal epithelial cells were stimulated by a Th2 cytokine, IL-4, and Th1 cytokines, TNF-α and IL-1β, continuously for 10 days. Barrier function was determined by transepithelial electrical resistance. Morphological changes were investigated by hematoxylin and eosin staining. Keratin profile (keratin 7, 8, 13, and 14) and squamous differentiation markers (involucrin) were investigated by RT-quantitative PCR, Western blotting, and immunohistochemical staining. Pharmacological inhibitors were used to identify the underlying cellular signaling. We report that IL-4, TNF-α, and IL-1β decrease barrier function, but only IL-4 significantly increases cell layers and changes cell morphology. IL-4 time dependently downregulates the expression levels of the squamous cell markers involucrin and keratin 13 and upregulates the expression levels of the columnar cell markers keratin 7 and 8. Neither TNF-α nor IL-1β shows any effect on these indexes. JAK inhibitor I and PI3K inhibitors significantly block the IL-4-induced changes in the levels of keratin 8 and 13. In conclusion, IL-4 inhibits squamous differentiation program of esophageal epithelial cells and induces differentiation toward columnar cells through the JAK/PI3K pathway. Thus IL-4 may be involved in the early stages of Barrett's esophagus development.

Topics: Barrett Esophagus; Biomarkers; Cell Differentiation; Cells, Cultured; Epithelial Cells; Esophagus; Humans; Immunohistochemistry; Interleukin-1beta; Interleukin-4; Keratins; Metaplasia; Protein Precursors; Signal Transduction; Tumor Necrosis Factor-alpha

Barrett's esophagus (BE) is defined as an incomplete intestinal metaplasia characterized generally by the presence of columnar and goblet cells in the formerly stratified squamous epithelium of the esophagus. BE is known as a precursor for esophageal adenocarcinoma. Currently, the cell of origin for human BE has yet to be clearly identified. Therefore, we investigated the role of Notch signaling in the initiation of BE metaplasia. Affymetrix gene expression microarray revealed that BE samples express decreased levels of Notch receptors (NOTCH2 and NOTCH3) and one of the the ligands (JAG1). Furthermore, BE tissue microarray showed decreased expression of NOTCH1 and its downstream target HES1. Therefore, Notch signaling was inhibited in human esophageal epithelial cells by expression of dominant-negative-Mastermind-like (dnMAML), in concert with MYC and CDX1 overexpression. Cell transdifferentiation was then assessed by 3D organotypic culture and evaluation of BE-lineage specific gene expression. Notch inhibition promoted transdifferentiation of esophageal epithelial cells toward columnar-like cells as demonstrated by increased expression of columnar keratins (K8, K18, K19, K20) and glandular mucins (MUC2, MUC3B, MUC5B, MUC17) and decreased expression of squamous keratins (K5, K13, K14). In 3D culture, elongated cells were observed in the basal layer of the epithelium with Notch inhibition. Furthermore, we observed increased expression of KLF4, a potential driver of the changes observed by Notch inhibition. Interestingly, knockdown of KLF4 reversed the effects of Notch inhibition on BE-like metaplasia. Overall, Notch signaling inhibition promotes transdifferentiation of esophageal cells toward BE-like metaplasia in part via upregulation of KLF4. These results support a novel mechanism through which esophageal epithelial transdifferentiation promotes the evolution of BE.

Topics: Barrett Esophagus; Calcium-Binding Proteins; Cell Culture Techniques; Cell Line; Cell Transdifferentiation; DNA-Binding Proteins; Epithelial Cells; Esophagus; Gene Expression Regulation; Homeodomain Proteins; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Keratins; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Membrane Proteins; Metaplasia; Mucins; Proto-Oncogene Proteins c-myc; Receptors, Notch; RNA Interference; Serrate-Jagged Proteins; Signal Transduction; Tissue Array Analysis; Transcription Factors

Topics: Adult; Biomarkers; Endometrium; Female; Humans; Keratins; Metaplasia; Uterine Diseases

Immature squamous metaplasia of the pancreatic duct (ISMPD) can be difficult to differentiate from an intraductal carcinoma of the pancreas (ICP), and little is known about the pathological nature of ISMPD. The aim of this study was to analyse 20 ISMPD and 10 ICP tissue samples.. ISMPD shares some characteristics with ICP. Seven of 20 ISMPD samples were covered by a layer of pancreatic duct epithelium, whereas this was not seen in the ICP samples. Immunohistochemistry of ISMPD revealed positivity for p63 (100%), cytokeratin 5/6 (95%), cytokeratin 7 (95%), cytokeratin 20 (10%), and MUC-1 (95%), and the samples were negative for p53, carcinoembryonic antigen (CEA), and bcl-2. In contrast, ICP was positive for p63 (40%), p53 (10%), cytokeratin 7 (90%), cytokeratin 20 (20%), CEA (30%), and MUC-1 (80%), and negative for cytokeratin 5/6. However, in 84% (16) of the ISMPD samples, cytokeratin 7 was expressed only by an epithelial layer at the apical surface; this expression pattern was not found in any of the 10 ICP samples. The mean Ki67 labelling index was 1.0% in ISMPD and 18.5% in ICP.. Our study suggests that immunohistochemical staining for cytokeratin 5/6 and Ki67 constitutes the best combination for differentiating ISMPD from ICP.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Ki-67 Antigen; Male; Metaplasia; Middle Aged; Mucin-1; Pancreatic Ducts; Pancreatic Neoplasms; Transcription Factors; Tumor Suppressor Proteins

Rathke's cleft cyst (RCC) with significant squamous and/or stratified epithelium including smooth transition from single cuboidal to squamous epithelium (tRCC) is rare and possibly represents an intermediate form to craniopharyngioma.. Twelve patients with histologically confirmed tRCC were retrospectively investigated from a series of 167 cases of RCC and 96 cases of craniopharyngiomas. Clinical data were reviewed, and immunohistochemistry findings for cytokeratins and β-catenin were examined.. All lesions were located in the sella turcica with marked extension to suprasellar cistern. Six of the 12 patients had suffered postoperative re-enlargement, and three of these six patients required more than two additional operations and irradiation. CAM5.2 was positive in the glandular epithelium in all tRCCs and focally positive in the squamous epithelium of all these tRCCs. 34βE12 was positive in the squamous epithelium in all tRCCs and focally positive in the glandular epithelium in all but one tRCC. The findings of cytokeratin expression of tRCCs were very similar to those of craniopharyngioma. β-Catenin showed nuclear translocation in five cases. All patients with nuclear translocation of β-catenin suffered postoperative re-enlargement.. tRCC carries an extremely high risk of re-enlargement. Cytokeratin expression resembles that in craniopharyngioma, which might indicate a very close origin of these pathologies. Nuclear translocation of β-catenin may be related to the aggressive clinical course.

Topics: Adolescent; Adult; Aged; beta Catenin; Central Nervous System Cysts; Child; Craniopharyngioma; Female; Humans; Keratins; Male; Metaplasia; Middle Aged; Pituitary Neoplasms; Postoperative Period; Retrospective Studies; Risk Factors; Young Adult

Sarcomatoid basal cell carcinoma (BCC) is rare. In the literature, data on the prognosis of such a variant is somewhat contradictory. D2-40 immunoexpression has been shown to have prognostic connotations in carcinomas of organs other than the skin. However, although D2-40 immunoexpression has been investigated in "common" (nonsarcomatoid) BCC, it has not yet been studied in the spindle cell component of a sarcomatoid BCC. We present a sarcomatoid BCC on the neck of an 87-year-old man that has grown rapidly over the last few months. The sarcomatoid component of the tumor expressed several types of cytokeratins, such as AE1/AE3, CK 5/6, 34betaE12, and CAM 5.2. It was also positive for p63 and for D2-40 in a diffuse pattern.

Topics: Aged, 80 and over; Antibodies, Monoclonal, Murine-Derived; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma, Basal Cell; Gene Expression; Head and Neck Neoplasms; Humans; Immunohistochemistry; Keratins; Male; Metaplasia

Many epidemiological studies show the benefit of fruits and vegetables on reducing risk of lung cancer, the leading cause of cancer death in the United States. Previously, we demonstrated that cigarette smoke exposure (SM)-induced lung lesions in ferrets were prevented by a combination of low dose of β-carotene, α-tocopherol (AT), and ascorbic acid (AA). However, the role of a combination of AT and AA alone in the protective effect on lung carcinogenesis remains to be examined. In the present study, we investigated whether the combined AT (equivalent to ∼100 mg/day in the human) and AA (equivalent to ∼210 mg/day) supplementation prevents against SM (equivalent to 1.5 packs of cigarettes/day) induced lung squamous metaplasia in ferrets. Ferrets were treated for 6 weeks in the following three groups (9 ferrets/group): (i) Control (no SM, no AT+AA), (ii) SM alone, and (iii) SM+AT+AA. Results showed that SM significantly decreased concentrations of retinoic acid, AT, and reduced form of AA, not total AA, retinol and retinyl palmitate, in the lungs of ferrets. Combined AT+AA treatment partially restored the lowered concentrations of AT, reduced AA and retinoic acid in the lungs of SM-exposed ferrets to the levels in the control group. Furthermore, the combined AT+AA supplementation prevented SM-induced squamous metaplasia [0 positive/9 total ferrets (0%) vs. 5/8 (62%); p<0.05] and cyclin D1 expression (p<0.05) in the ferret lungs, in which both were positively correlated with expression of c-Jun expression. Although there were no significant differences in lung microsomal malondialdehyde (MDA) levels among the three groups, we found a positive correlation between MDA levels and cyclin D1, as well as c-Jun expressions in the lungs of ferrets. These data indicate that the combination of antioxidant AT+AA alone exerts protective effects against SM-induced lung lesions through inhibiting cyclin D1 expression and partially restoring retinoic acid levels to normal.

Topics: alpha-Tocopherol; Animals; Antioxidants; Ascorbic Acid; Cyclin D1; Dietary Supplements; Ferrets; Genes, jun; Keratins; Lung; Malondialdehyde; Metaplasia; Microsomes; Proliferating Cell Nuclear Antigen; Respiratory Mucosa; Retinoids; Smoke; Smoking

Understanding the molecular and cellular processes underlying the development, maintenance, and progression of Barrett's esophagus (BE) presents an empirical challenge because there are no simple animal models and standard 2D cell culture can distort cellular processes. Here we describe a three-dimensional (3D) cell culture system to study BE. BE cell lines (CP-A, CP-B, CP-C, and CP-D) and esophageal squamous keratinocytes (EPC2) were cultured on a matrix consisting of esophageal fibroblasts and collagen. Comparison of growth and cytokeratin expression in the presence of all-trans retinoic acid or hydrochloric acid was made by immunohistochemistry and Alcian Blue staining to determine which treatments produced a BE phenotype of columnar cytokeratin expression in 3D culture. All-trans retinoic acid differentially affected the growth of BE cell lines in 3D culture. Notably, the non-dyplastic metaplasia-derived cell line (CP-A) expressed reduced squamous cytokeratins and enhanced columnar cytokeratins upon ATRA treatment. ATRA altered the EPC2 squamous cytokeratin profile towards a more columnar expression pattern. Cell lines derived from patients with high-grade dysplasia already expressed columnar cytokeratins and therefore did not show a systematic shift toward a more columnar phenotype with ATRA treatment. ATRA treatment, however, did reduce the squamoid-like multilayer stratification observed in all cell lines. As the first study to demonstrate long-term 3D growth of BE cell lines, we have determined that BE cells can be cultured for at least 3 weeks on a fibroblast/collagen matrix and that the use of ATRA causes a general reduction in squamous-like multilayered growth and an increase in columnar phenotype with the specific effects cell-line dependent.

Topics: Barrett Esophagus; Cell Line, Transformed; Coculture Techniques; Collagen; Epithelial Cells; Esophagus; Fibroblasts; Humans; Hydrochloric Acid; Hydrogen-Ion Concentration; Keratinocytes; Keratins; Metaplasia; Phenotype; Telomerase; Time Factors; Transfection; Tretinoin

Squamous metaplasia is a proliferative lesion characterized by the replacement of the transitional epithelium with stratified squamous cells. In the urinary system, it is mostly seen in the bladder. It can be nonkeratinized or keratinized. We report the cases of 2 adolescent girls with keratinizing metaplasia, 1 of whom presented with difficulty with indwelling catheterization and 1 with final terminal hematuria. The predisposing factors were recurrent urinary tract infection and additional catheterization in 1 of the patients. The diagnosis was confirmed by histologic examination in both patients. We report on these cases to draw attention to this rare entity in children.

Topics: Adolescent; Female; Humans; Keratins; Metaplasia; Urinary Bladder; Urinary Bladder Diseases

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

Toxic injury can induce squamous metaplasia of respiratory epithelium, which normally is pseudostratified. Terminally differentiated squamous epithelial cells have a flattened, elongated appearance. During differentiation, they have an intermediate phenotype that is difficult to identify and distinguish from tangentially cut columnar cells in tissue sections from endobronchial biopsies, whose small size makes orientation difficult. The aim of our study was to develop a panel of antibodies that could be employed to distinguish normal epithelium from metaplastic epithelium and would be suitable for use on endobronchial biopsies. Nasal polyp tissue and tonsil tissue, which have pseudostratified and squamous epithelia, respectively, were collected from surgical cases and embedded in glycol methacrylate resin. Cut sections were stained immunohistochemically with a panel of antibodies to cytokeratins (CK), whose expression varies with epithelial type and stage of differentiation, and involucrin, a marker of terminal squamous differentiation. Squamous epithelium stained positively for CK5/6, CK13 and involucrin. In the pseudostratified epithelium, basal cells exhibited weak staining for CK13 and strong staining for CK5/6, and columnar cells exhibited strong immunoreactivity for CK7, CK8 and CK18. Application of this panel to endobronchial biopsies from smokers enabled areas of squamous metaplasia to be distinguished from tangentially sectioned epithelium.

Topics: Antibodies; Biopsy; Bronchi; Epithelial Cells; Epithelium; Humans; Immunohistochemistry; Keratins; Metaplasia; Smoking

Pleomorphic adenoma (PA), the most common salivary gland tumor, accounts for 54 to 65% of all salivary gland neoplasias and 80% of the benign salivary gland tumors. It most frequently affects the parotid gland, followed by the submandibular and the minor salivary glands. Microscopically, mucous, sebaceous, oncocytic and squamous metaplasia, sometimes with the formation of keratin pearls, may be present, but the latter rarely results in the formation of extensive keratin-filled cysts lined by squamous epithelium. Extensive squamous metaplasia can be mistaken for malignancy, including mucoepidermoid carcinoma and squamous cell carcinoma. Here, we present an unusual case of PA with extensive squamous metaplasia and keratin cyst formations in a minor salivary gland, and discuss its microscopic features, including the immunohistochemical characteristics, and differential diagnosis of this uncommon presentation.

Topics: Adenoma, Pleomorphic; Adult; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Salivary Gland Neoplasms; Salivary Glands, Minor

Ligand-dependent activation of the Hedgehog (Hh) signaling pathway has been implicated in both tumor initiation and metastasis of pancreatic ductal adenocarcinoma (PDAC). Prior studies in genetically engineered mouse models (GEMMs) have assessed the role of Hh signaling by cell autonomous expression of a constitutively active Gli2 within epithelial cells. On the contrary, aberrant pathway reactivation in the human exocrine pancreas occurs principally as a consequence of Sonic Hh ligand (Shh) overexpression from epithelial cells. To recapitulate the cognate pathophysiology of Hh signaling observed in the human pancreas, we examined GEMM where Hh ligand is conditionally overexpressed within the mature exocrine pancreas using a tamoxifen-inducible Elastase-Cre promoter (Ela-CreERT2;LSL-mShh). We also facilitated potential cell autonomous epithelial responsiveness to secreted Hh ligand by generating compound transgenic mice with concomitant expression of the Hh receptor Smoothened (Ela-CreERT2;LSL-mShh;LSL-mSmo). Of interest, none of these mice developed intraductal precursor lesions or PDAC during the follow-up period of up to 12 months after tamoxifen induction. Instead, all animals demonstrated marked expansion of stromal cells, consistent with the previously described epithelial-to-stromal paracrine Hh signaling. Hh responsiveness was mirrored by the expression of primary cilia within the expanded mesenchymal compartment and the absence within mature acinar cells. In the absence of cooperating mutations, Hh ligand overexpression in the mature exocrine pancreas is insufficient to induce neoplasia, even when epithelial cells coexpress the Smo receptor. This autochthonous model serves as a platform for studying epithelial stromal interactions in pancreatic carcinogenesis.

Topics: Acinar Cells; Animals; Cell Proliferation; Estrogen Antagonists; Female; Genetic Engineering; Hedgehog Proteins; Humans; Immunoblotting; Immunohistochemistry; Insulin; Keratins; Male; Metaplasia; Mice; Mice, Transgenic; Microscopy, Confocal; Pancreas; Receptors, G-Protein-Coupled; Smoothened Receptor; Stromal Cells; Tamoxifen; Tubulin

Purpose. To investigate the specific role of Pinin (Pnn) in the development of anterior eye segment in mice. Methods. Conditional inactivation of Pnn in the developing surface eye ectoderm and lens was achieved by creating mice carrying a Pnn null and a floxed Pnn allele as well as a Pax6-Cre-GFP (Le-Cre) transgene. The resultant Pnn conditional knockout mice were examined by histologic and immunohistologic approaches. Results. Pax6-Cre-mediated deletion of Pnn resulted in severe malformation of lens placode-derived tissues including cornea and lens. Pnn mutant corneal epithelium displayed the loss of corneal epithelial identity and appeared epidermis-like, downregulating corneal keratins (K12) and ectopically expressing epidermal keratins (K10 and K14). This squamous metaplasia of Pnn mutant corneal epithelium closely correlated with significantly elevated beta-catenin activity and Tcf4 level. In addition, Pnn inactivation also led to misregulated level of p68 RNA helicase in mutant corneal epithelium. Conclusions. These data indicate that Pnn plays an essential role in modulating and/or orchestrating the activities of major developmental factors of anterior eye segments.

Topics: Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; beta Catenin; Cell Adhesion Molecules; Cell Death; Cell Differentiation; Cell Proliferation; DEAD-box RNA Helicases; DNA-Binding Proteins; Epithelium, Corneal; Eye Proteins; Female; Gene Silencing; Green Fluorescent Proteins; Homeodomain Proteins; Immunoenzyme Techniques; In Situ Nick-End Labeling; Integrases; Keratins; Male; Metaplasia; Mice; Mice, Knockout; Nuclear Proteins; Paired Box Transcription Factors; PAX6 Transcription Factor; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factor 4

The molecular mechanism underlying epithelial metaplasia in Barrett's esophagus remains unknown. Recognizing that Hedgehog signaling is required for early esophageal development, we sought to determine if the Hedgehog pathway is reactivated in Barrett's esophagus, and if genes downstream of the pathway could promote columnar differentiation of esophageal epithelium.. Immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction were used to analyze clinical specimens, human esophageal cell lines, and mouse esophagi. Human esophageal squamous epithelial (HET-1A) and adenocarcinoma (OE33) cells were subjected to acid treatment and used in transfection experiments. Swiss Webster mice were used in a surgical model of bile reflux injury. An in vivo transplant culture system was created using esophageal epithelium from Sonic hedgehog transgenic mice.. Marked up-regulation of Hedgehog ligand expression, which can be induced by acid or bile exposure, occurs frequently in Barrett's epithelium and is associated with stromal expression of the Hedgehog target genes PTCH1 and BMP4. BMP4 signaling induces expression of SOX9, an intestinal crypt transcription factor, which is highly expressed in Barrett's epithelium. We further show that expression of Deleted in Malignant Brain Tumors 1, the human homologue of the columnar cell factor Hensin, occurs in Barrett's epithelium and is induced by SOX9. Finally, transgenic expression of Sonic hedgehog in mouse esophageal epithelium induces expression of stromal Bmp4, epithelial Sox9, and columnar cytokeratins.. Epithelial Hedgehog ligand expression may contribute to the initiation of Barrett's esophagus through induction of stromal BMP4, which triggers reprogramming of esophageal epithelium in favor of a columnar phenotype.

Topics: Adenocarcinoma; Animals; Barrett Esophagus; Bile; Bile Reflux; Bone Morphogenetic Protein 4; Calcium-Binding Proteins; Cell Communication; Cell Differentiation; Cell Line; Disease Models, Animal; DNA-Binding Proteins; Epithelial Cells; Esophageal Neoplasms; Esophagus; Gastroesophageal Reflux; Hedgehog Proteins; Humans; Hydrogen-Ion Concentration; Keratins; Mesoderm; Metaplasia; Mice; Mice, Transgenic; Patched Receptors; Patched-1 Receptor; Phenotype; Precancerous Conditions; Receptors, Cell Surface; RNA Interference; Signal Transduction; SOX9 Transcription Factor; Transfection; Tumor Suppressor Proteins

To report the clinical and histologic findings of a new subset of idiopathic corneal edema: zipper cell endotheliopathy.. Observational case report.. A 55-year-old woman with unilateral bullous keratopathy.. Clinical observation consisted of slit-lamp examination and in vivo confocal microscopy (IVCM). Aqueous humor samples and the excised corneal button were analyzed for the presence of herpes viruses. The excised cornea was subjected to detailed immunohistochemistry (IHC) and scanning and transmission electron microscopy.. Clinical and pathologic characteristics of zipper cell endotheliopathy.. In vivo confocal microscopy revealed unique morphologic alterations of the corneal endothelial layer. Focal areas of denudation were surrounded by endothelial cells with zipper-like cell borders and intercellular structures. Besides central corneal edema, no other signs of corneal inflammation were detected. A herpes virus origin for the bullous keratopathy was excluded. The IHC analysis disclosed positive staining for cytokeratin (CK) 7, CK8/18, and CK19, suggesting epithelial metaplasia of the endothelial cells. Ultrastructural examination confirmed the IVCM findings by showing large areas of endothelial denudation and vacuolated endothelial cells with large, broad-based extensions that partially overlapped neighboring cells. Despite extensive complementary research and review of the literature, the endothelial alterations could not be attributed to any known corneal disorder.. To the authors' knowledge, zipper cell endotheliopathy is a new subset of idiopathic corneal edema. The case report presented illustrates the potential use of IVCM to differentiate the spectrum of corneal disorders and to discover new corneal diseases.

Topics: Biomarkers; Corneal Edema; Endothelium, Corneal; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Microscopy, Confocal; Microscopy, Electron, Scanning; Middle Aged; Visual Acuity

Topics: Breast Neoplasms; Carcinoma; Female; Fibroma; Humans; Keloid; Keratin-5; Keratins; Lymphatic Metastasis; Metaplasia; Middle Aged

Metaplastic breast carcinoma (MBC) is a rare subtype of breast cancer characterized by coexistence of carcinomatous and sarcomatous components. Snail is a nuclear transcription factor incriminated in the transition of epithelial to mesenchymal differentiation of breast cancer. Aberrant Snail expression results in lost expression of the cell adhesion molecule E-cadherin, an event associated with changes in epithelial architecture and invasive growth. We aimed to identify the utility of Snail, and of traditional immunohistochemical markers, in accurate MBC classification and to evaluate clinicopathologic characteristics and outcome.We retrospectively reviewed 34 MBC cases from January 1997 to September 2007. The control group contained 26 spindle cell lesions. Immunohistochemistry used Snail, p63, epidermal growth factor receptor (EGFR), OSCAR, and wide spectrum cytokeratin (WS-KER). Negative was a score less than 1%. We found that Snail and EGFR are sensitive (100%) markers with low specificity (3.8% and 19.2%) for detecting MBC. p63 and WS-KER are specific (100%), with moderate sensitivity (67.6% and 76.5%); OSCAR is sensitive (85.3%) and specific (92.3%). A combination of any 2 of the p63, OSCAR, and WS-KER markers increased sensitivity and specificity. MBCs tended to be high-grade (77%), triple negative (negative for estrogen receptor, progesterone receptor, and HER2) [27/33; 81.8%], and carcinomas with low incidence of axillary lymph node involvement (15%), and decreased disease-free [71% (95%CI: 54%, 94%) at 3 yrs.) and overall survival. A combination of p63, OSCAR and WS-KER are useful in its work-up. On the other hand, Snail is neither a diagnostic nor a prognostic marker for MBC.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast Neoplasms; Carcinoma; Case-Control Studies; Disease-Free Survival; ErbB Receptors; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Keratins; Male; Metaplasia; Middle Aged; Minnesota; Neoplasm Staging; Predictive Value of Tests; Receptor, ErbB-2; Receptors, Cell Surface; Receptors, Estrogen; Receptors, Progesterone; Retrospective Studies; Sensitivity and Specificity; Snail Family Transcription Factors; Time Factors; Transcription Factors; Treatment Outcome; Young Adult

Topics: Actins; Aged; Biomarkers, Tumor; Breast Neoplasms; Carcinoma; Carcinosarcoma; Diagnosis, Differential; ErbB Receptors; Female; Hemangiosarcoma; Humans; Keratins; Membrane Proteins; Metaplasia; Neoplasm Proteins; Phyllodes Tumor; Stromal Cells; Syringoma

Concordance between sinusitis and otitis media with effusion (OME) has been reported in 5-60% of patients. Since nasal diseases induce edema and lymphoid tissue hyperplasia in the nasopharyngeal mucosa, especially the adenoids, chronic infection of the adenoids has been reported to induce otitis media. In addition, deterioration in the mucosal barrier of the adenoids makes the latter vulnerable to bacterial infections, resulting in OME or sinusitis. We therefore evaluated adenoid local immunity and Eustachian tube function by sinusitis and the concordance between sinusitis and OME.. We examined PNS series and tympanometry of 520 patients who had undergone adenotonsillectomies. In addition, local adenoidal immunity was evaluated in 10 children with OME and sinusitis, 11 with only sinusitis, 10 with only OME and 12 with no history of OME or sinusitis. Adenoid size, squamous metaplasia, IgA, BCL-6, and mucosal barrier were also determined.. Of 520 patients, 80 (15.4%) had both OME and sinusitis. The incidence of Eustachian tube dysfunction differed significantly between patients with and without sinusitis (p=0.03). The incidence of squamous metaplasia differed significantly between patients with sinusitis plus OME and patients with sinusitis alone (p=0.01), and between patients with OME alone and those without both conditions (p=0.005). Patients with both sinusitis and OME differed significantly in IgA secretion (p=0.01) and Bcl-6 expression (p=0.02) from those with sinusitis alone, as did patients with OME alone and those without both conditions (p=0.02 and p=0.03, respectively).. Sinusitis plus OME were present in 15.4% of patients. Eustachian tube dysfunction was present in 37.9% of sinusitis patients and in 28.4% of those without sinusitis. IgA, BCL-6 and squamous metaplasia were important in local adenoidal immunity.

Topics: Acoustic Impedance Tests; Adenoidectomy; Adenoids; Adolescent; Child; Child, Preschool; DNA-Binding Proteins; Epithelium; Eustachian Tube; Female; Humans; Immunoglobulin A; Infant; Keratins; Male; Metaplasia; Otitis Media with Effusion; Proto-Oncogene Proteins c-bcl-6; Sinusitis

Pax6 is the universal master control gene for eye morphogenesis. Other than retina and lens, Pax6 also expressed in the ocular surface epithelium from early gestation until the postnatal stage, in which little is known about the function of Pax6. In this study, corneal pannus tissues from patients with ocular surface diseases such as Stevens-Johnson syndrome (SJS), chemical burn, aniridia and recurrent pterygium were investigated. Our results showed that normal ocular surface epithelial cells expressed Pax6. However, corneal pannus epithelial cells from the above patients showed a decline or absence of Pax6 expression, accompanied by a decline or absence of K12 keratin but an increase of K10 keratin and filaggrin expression. Pannus basal epithelial cells maintained nuclear p63 expression and showed activated proliferation, evidenced by positive Ki67 and K16 keratin staining. On 3T3 fibroblast feeder layers, Pax6 immunostaining was negative in clones generated from epithelial cells harvested from corneal pannus from SJS or aniridia, but positive in those from the normal limbal epithelium; whereas western blots showed that some epithelial clones expanded from pannus retained Pax6 expression. Transient transfection of an adenoviral vector carrying EGFP-Pax6 transgenes into these Pax6(-) clones increased both Pax6 and K12 keratin expression. These results indicate that Pax6 helps to maintain the normal corneal epithelial phenotype postnatally, and that down-regulation of Pax6 is associated with abnormal epidermal differentiation in severe ocular surface diseases. Reintroduction of activation of the Pax6 gene might be useful in treating squamous metaplasia of the ocular surface epithelium.

Topics: Adolescent; Adult; Aged; Cell Differentiation; Cells, Cultured; Child; Corneal Diseases; Down-Regulation; Epithelial Cells; Epithelium, Corneal; Eye Proteins; Female; Filaggrin Proteins; Homeodomain Proteins; Humans; Keratin-12; Keratins; Male; Metaplasia; Middle Aged; Paired Box Transcription Factors; PAX6 Transcription Factor; Repressor Proteins; Stem Cells; Transfection; Up-Regulation

An 81-year-old man presented with epigastric pain and weight loss for one month. He had a past history of pulmonary tuberculosis, 10 years ago. We performed a gastroscopy, which showed a linear depressed whitish gastric ulcer scar (0.8 cm in length) in the posterior wall of the prepyloric antrum. The result of biopsy was reported as squamous epithelium. Immunohistochemical staining using an antibody to high molecular weight cytokeratin (HMC) revealed positive staining in the squamous epithelium. Two years later, the lesion was followed up. The lesion remained at same site endoscopically, but no squamous epithelium could be seen microscopically.

Topics: Abdominal Pain; Aged, 80 and over; Biopsy; Epithelium; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Molecular Weight; Stomach Ulcer; Treatment Outcome; Ulcer

Barrett's esophagus (BE) is a metaplastic condition in which normal squamous esophageal epithelium is replaced by columnar epithelium. It is proposed that one of the possible mechanisms is dedifferentiation of squamous epithelium into columnar epithelium. The pathophysiology through which this metaplasia occurs is unknown. A recent study by serial analysis of gene expression showed that bone morphogenetic protein 4 (BMP-4) is uniquely expressed in BE. In this study, the role of the BMP pathway in the metaplastic transformation of normal squamous cells into columnar cells was examined.. Tissues from patients with esophagitis and BE and in an esophagitis-BE rat model were examined for the activation of the BMP pathway. Short-term cultures of primary normal squamous esophageal cells were treated with BMP-4, and cell biological changes were examined by Western blot analysis, immunohistochemistry, and microarrays.. In both human and rat tissues, the BMP pathway proved to be activated in esophagitis and BE. Upon incubation of squamous cell cultures with BMP-4, the cytokeratin expression pattern showed a shift that was consistent with columnar epithelium. Involvement of the BMP pathway was suggested by up-regulation of Phosphorylated-Smad 1/5/8 (P-Smad 1/5/8) that was effectively blocked by Noggin, a BMP antagonist. Comparison of the gene expression profiles of squamous cells, BMP-4-treated squamous cells, and BE cells showed a significant shift in the profile of the BMP-4-treated squamous cells toward that of the cultured BE cells.. These results suggest that the BMP pathway could play a role in the transformation of normal esophageal squamous cells into columnar cells.

Topics: Adult; Aged; Aged, 80 and over; Animals; Barrett Esophagus; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Cells, Cultured; Esophagitis; Esophagus; Female; Genome, Human; Humans; Keratins; Male; Metaplasia; Microarray Analysis; Middle Aged; Phenotype; Rats; Rats, Sprague-Dawley

Deterioration of local immunity in the adenoids may make them vulnerable to infection by microorganisms, resulting in otitis media with effusion. To determine the factors associated with this condition, we evaluated adenoid size, mucosal barrier, squamous changes of ciliated epithelium, IgA secretion, and BCL-6 expression in adenoids.. Seventeen children diagnosed with otitis media with effusion (OME group) and 20 children without any history of OME (control group) were enrolled. Their adenoids were sized by lateral view X-ray and stained with hematoxylin and eosin to detect squamous metaplasia. The adenoids were also stained with cytokeratin to evaluate mucosal barriers, and with anti- IgA antibody and anti- BCL-6 antibody to determine expression of IgA and BCL-6.. The OME group showed greater incidence of squamous metaplasia, fewer ciliated cells, and lower expression of BCL-6 (p < 0.05 each). Deterioration of the mucosal barrier was detected in the OME group (p > 0.05). IgA secretion and adenoid size were the same for the OME and the control groups.. These results suggest that increased squamous metaplasia and lower BCL-6 expression in adenoids may be associated with increased susceptibility to OME.

Topics: Adenoids; Child; Child, Preschool; Female; Humans; Immunoglobulin A; Immunohistochemistry; Keratins; Male; Metaplasia; Mucous Membrane; Otitis Media with Effusion; Proto-Oncogene Proteins c-bcl-6

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

The histological distinction between Barrett's esophagus involving the distal esophagus and intestinal metaplasia of the stomach has important clinical implications and can be difficult even with the use of histochemical stains. Cytokeratin (CK) 7 and 20 are cytoplastic structural proteins that show restricted expression in normal and malignant epithelia of the gastrointestinal tract. CK7 and 20 immunostaining were performed on a 67-year-old male with cardiac cancer with reflux esophagitis due to sliding hernia. The CK7/20 immunoreactivity pattern of cancer and reflux esophagitis in this case showed superficial CK20 staining and strong CK7 staining of both superficial and deep glands. In intestinal metaplasia of the stomach, strong CK20 immunostaining in superficial and deep glands and absent CK7 immunoreactivity were noted. Neither CK7 nor CK20 immunoreactivity was noted in squamous cell epithelium. Therefore, we concluded that in this patient intestinal metaplasia of the esophagus was BE. The CK7/20 reactivity pattern is useful for identifying the intestinal metaplasia of the esophagus from the stomach using histological materials from biopsy and surgically resected specimens.

Topics: Aged; Barrett Esophagus; Diagnosis, Differential; Endoscopy; Gene Expression Regulation; Humans; Immunohistochemistry; Keratin-20; Keratin-7; Keratins; Lymph Nodes; Male; Metaplasia; Stomach; Stomach Diseases

Metaplastic breast carcinoma is very rare, and metaplastic carcinoma with chondroid differentiation is even rarer. Here, we report a case of metaplastic carcinoma with extensive chondroid differentiation mimicking chondrosarcoma that was challenging to diagnose. The tumor was characterized by an abundant chondromyxoid matrix. The definitive area of classic invasive ductal carcinoma was minimal. The peripheral portion of the tumor showed increased cellularity with pleomorphism and definitive invasive growth. Tumor cells in the chondrosarcomatous areas were diffusely immunoreactive for S-100 protein, patchy positive for cytokeratin, but negative for epithelial membrane antigen (EMA). Tumor cells in carcinomatous areas were diffusely positive for cytokeratin, S-100 protein, and patchy positive for EMA. In both areas, tumor cells were negative for smooth muscle actin (SMA) and CD34, while oncoprotein p53 was overexpressed. When pathologists encounter breast tumors with chondroid differentiation, careful sampling and immunohistochemistry for cytokeratin and SMA are most helpful to differentiate metaplastic carcinoma from malignant phyllodes tumor and malignant adenomyoepithelioma.

Topics: Actins; Antigens, CD34; Breast Neoplasms; Carcinoma; Cell Differentiation; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Middle Aged; Mucin-1; Muscle, Smooth; Neoplasm Metastasis; S100 Proteins

Recently, an immunohistochemical panel comprising antibodies against HER2, oestrogen receptor (ER), epidermal growth factor receptor (EGFR) and cytokeratin (CK) 5/6 was reported to identify basal-like breast carcinomas, as defined by cDNA microarrays. Our aim was to analyse a series of metaplastic breast carcinomas (MBCs) using this panel plus two other basal markers (CK14 and p63) and progesterone receptor (PR), to define how frequently MBCs show a basal-like immunophenotype.. Sixty-five cases were retrieved from the pathology archives of the authors' institutions and reviewed by three of the authors. Immunohistochemistry with antibodies for HER2, ER, EGFR, CK5/6, CK14 and p63 was performed according to standard methods. All but six cases (91%) showed the typical immunoprofile of basal-like tumours (ER- and HER2-, EGFR+ and/or CK5/6+). When CK14 and p63 were added to the panel, two additional cases could be classified as basal-like. The majority of MBCs lacked PR, except 4/19 (21%) carcinomas with squamous metaplasia.. Our results demonstrate that MBCs show a basal-like phenotype, regardless of the type of metaplastic elements. Moreover, as these neoplasms frequently overexpress EGFR (57%), patients with MBC may benefit from treatment with anti-EGFR drugs.

Topics: Biomarkers, Tumor; Breast Neoplasms; ErbB Receptors; Female; Humans; Immunohistochemistry; Keratins; Membrane Proteins; Metaplasia; Neoplasms, Basal Cell; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone

To evaluate the immunohistochemical characteristics of human corneas with the diagnosis of Fuchs endothelial dystrophy (FED).. Formalin-fixed, paraffin-embedded sections of corneas with the diagnosis of FED (15 patients) and 10 control corneas were stained with hematoxylin-eosin and periodic acid-Schiff (PAS). Adjacent histologic sections were stained with monoclonal antibodies that react with epithelial antigens: pancytokeratin, cytokeratins (CK) 7 and 20 CAM 5.2, epithelial membrane antigen (EMA), and Ber EP4. Eight corneas were stained with antibodies to vimentin, smooth-muscle actin (SMA), and CD 68.. The endothelial cells in FED were attenuated and atrophic; some contained pigment consistent with melanin. The endothelial cells stained for pancytokeratin, CK 7, and vimentin in all corneas of FED, whereas variable staining was noted with CAM 5.2. No staining of endothelium was noted with CK 20, EMA, BerEP4, SMA, or CD 68.. Some cytokeratins that are normally restricted to true epithelium are present in the endothelium of FED. Epithelial metaplasia of endothelium in FED may represent a nonspecific response of distressed endothelial cells, as previously reported in posterior polymorphous dystrophy, congenital hereditary endothelial dystrophy, and iridocorneal endothelial syndrome.

Topics: Actins; Aged; Biomarkers; Endothelium, Corneal; Epithelium, Corneal; Female; Fuchs' Endothelial Dystrophy; Humans; Keratin-20; Keratin-7; Keratins; Male; Metaplasia; Middle Aged; Mucin-1; Periodic Acid-Schiff Reaction; Vimentin

The authors present a case of pseudoglandular schwannoma with immunohistochemical findings consistent with epithelial metaplasia. Pseudoglandular schwannoma is a rare morphological variant of benign schwannoma characterized by the presence of glandlike structures lined with Schwann cells. To the best of the authors' knowledge, this is only the fifth case of pseudoglandular schwannoma reported in the literature. Clinical, imaging, and pathological findings are described. The pathological findings were consistent with a pseudoglandular schwannoma composed of typical Schwann cells arranged in an Antoni B pattern, with numerous large pseudocystic spaces. Serial immunohistochemical studies of tissue sections revealed that the cells lining the pseudoglandular spaces were not only diffusely reactive for S100 protein, but also demonstrated focal positivity for epithelial membrane antigen and cytokeratins AE and AE3. The particular immunohistochemical features of incompletely differentiated Schwann cells in the present case give support to the metaplastic theory of the origin of glandlike structures in benign peripheral nerve sheath tumors.

Topics: Adult; Cauda Equina; Epithelium; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Neurilemmoma; Peripheral Nervous System Neoplasms; S100 Proteins; Schwann Cells

The formation of a simple columnar epithelium in the uterus is essential for implantation. Perturbation of this developmental process by exogenous estrogen, such as diethylstilbestrol (DES), results in uterine metaplasia that contributes to infertility. The cellular and molecular mechanism underlying this transformation event is not well understood. Here we use a combination of global gene expression analysis and a knockout mouse model to delineate genetic pathways affected by DES. Global gene expression profiling experiment revealed that neonatal DES treatment alters uterine cell fate, particularly in the luminal epithelium by inducing abnormal differentiation, characterized by the induction of stratified epithelial markers including members of the small proline-rich protein family and epidermal keratins. We show that Msx2, a homeodomain transcription factor, functions downstream of DES and is required for the proper expression of several genes in the uterine epithelium including Wnt7a, PLAP, and K2.16. Finally, Msx2-/- uteri were found to exhibit abnormal water trafficking upon DES exposure, demonstrating the importance of Msx2 in tissue responsiveness to estrogen exposure. Together, these results indicate that developmental exposure to DES can perturb normal uterine development by affecting genetic pathways governing uterine differentiation.

Topics: Alkaline Phosphatase; Animals; Apoptosis; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell Transformation, Neoplastic; Diethylstilbestrol; DNA Primers; DNA-Binding Proteins; DNA, Complementary; Epithelium; Estrogens, Non-Steroidal; Female; Homeodomain Proteins; In Situ Hybridization; Infertility; Keratins; Metaplasia; Mice; Mice, Knockout; Mice, Transgenic; Models, Biological; Mutation; Oligonucleotide Array Sequence Analysis; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Proto-Oncogene Proteins; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleases; Time Factors; Transcription, Genetic; Up-Regulation; Uterus; Wnt Proteins; Wnt-5a Protein

A unique pattern of cytokeratin (CK) 7/20 immunostaining (diffuse staining with CK7 and surface and superficial crypt staining with CK20) has been reported to be useful in differentiating Barrett esophagus (BE) from intestinal metaplasia of the stomach. However, there are conflicting results regarding the prevalence of a BE CK7/20 staining pattern in BE between different studies. Therefore, this study was performed to determine the degree of variability in interpretation of a BE CK7/20 pattern and to determine the reasons for variability when present. Esophageal and gastric mucosal biopsies from 67 patients with BE and antral intestinal metaplasia at 2 institutions were immunostained for CK7/20. All cases were evaluated for the presence of a BE CK7/20 pattern by 2 gastrointestinal pathologists from each institution, and the degree of agreement between institutions was determined. To determine the effect of tissue fixation and staining methods on the pattern of CK7/20 staining, unstained slides were exchanged between institutions, stained separately by each institution, and reexamined by all pathologists. There was excellent agreement on the presence of a BE CK7/20 staining pattern between pathologists at the same institution but only moderate agreement between pathologists at different institutions (71% overall, kappa = 0.58). Among BE cases, a BE CK7/20 staining pattern was identified in 50 (96%) of 52 cases by Cleveland Clinic Foundation pathologists but only 35 (67%) of 52 cases by Brigham and Women's Hospital pathologists. The major source of disagreement related to the interpretation of weak or variable CK7 staining of deep intestinalized mucosa in BE biopsies that were fixed in Hollande, but not those that were fixed in formalin. After the creation of a new set of criteria for a positive BE CK7/20 staining pattern, which took into account the effects of Hollande's fixative, the degree of agreement between pathologists at each of the 2 institutions was excellent (100%, kappa value = 1.0). Therefore, the CK7/20 staining pattern is influenced by the type of fixative used. Only a moderate level of interobserver agreement among pathologists regarding a BE CK7/20 pattern can be achieved if one is not aware of these effects. Nevertheless, specific criteria for interpretation of CK7/20 staining can be successfully applied between institutions and need to be developed before use of this technique in clinical practice.

Topics: Barrett Esophagus; Diagnosis, Differential; Gastric Mucosa; Humans; Immunohistochemistry; Intermediate Filament Proteins; Intestinal Mucosa; Keratin-20; Keratin-7; Keratins; Metaplasia; Reproducibility of Results; Tissue Fixation

Barrett's esophagus is a recognized risk factor for the development of esophageal dysplasia and carcinoma. Unfortunately, gastric incomplete intestinal metaplasia arising in Short Segment Barrett's esophagus can be indistinguishable histologically on hematoxylin/eosin stains. Distinct patterns of CK 7 and CK 20 immunohistochemical expression have been demonstrated to be both highly sensitive and specific for Barrett's esophagus, but have not been found in gastric metaplasia. The aim of our study was to test whether immunostaining with CK 7/20 helps to distinguish between Barrett's epithelium and gastric incomplete metaplasia. Cases of long segment Barrett's esophagus, short segment Barrett's esophagus, and cases with a normal gastroesophageal junction, as well as specimens with gastric antral intestninal metaplasia, were examined: three patterns were defined. Barrett's pattern (superficial CK 20 staining; superficial and crypt CK 7 staining); gastric pattern (superficial and crypt staining of both markers); other patterns (different from Barrett and gastric types). Seventy-five patients were enrolled in this study, 26 with long segment Barrett's esophagus, 21 with short segment esophagus, 13 with intestinal metaplasia of the cardia, and 18 with antral intestinal metaplasia. The Barrett pattern showed a high specificity of 97%, but a sensitivity of only 30% in patients with short segment Barrett esophagus. Our results do not confirm the hypothesis that CK 7/20 immunostaining can be used for a reliable differentiation between incomplete intestinal metaplasia and Barrett's epithelium.

Topics: Adult; Barrett Esophagus; Biomarkers, Tumor; Cardia; Diagnosis, Differential; Female; Humans; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Male; Metaplasia; Middle Aged; Predictive Value of Tests; Prospective Studies; Pyloric Antrum

Cytokeratin 7/20 staining has been reported to be helpful in diagnosing Barrett's oesophagus and gastric intestinal metaplasia. However, this is still a matter of some controversy.. To determine the diagnostic usefulness of cytokeratin 7/20 immunostaining for short-segment Barrett's oesophagus in Korea.. In patients with Barrett's oesophagus, diagnosed endoscopically, at least two biopsy specimens were taken from just below the squamocolumnar junction. If goblet cells were found histologically with alcian blue staining, cytokeratin 7/20 immunohistochemical stains were performed. Intestinal metaplasia at the cardia was diagnosed whenever biopsy specimens taken from within 2 cm below the oesophagogastric junction revealed intestinal metaplasia. Barrett's cytokeratin 7/20 pattern was defined as cytokeratin 20 positivity in only the superficial gland, combined with cytokeratin 7 positivity in both the superficial and deep glands.. Barrett's cytokeratin 7/20 pattern was observed in 28 out of 36 cases (77.8%) with short-segment Barrett's oesophagus, 11 out of 28 cases (39.3%) with intestinal metaplasia at the cardia, and nine out of 61 cases (14.8%) with gastric intestinal metaplasia. The sensitivity and specificity of Barrett's cytokeratin 7/20 pattern were 77.8 and 77.5%, respectively.. Barrett's cytokeratin 7/20 pattern can be a useful marker for the diagnosis of short-segment Barrett's oesophagus, although the false positive or false negative rate is approximately 25%.

Topics: Adult; Aged; Barrett Esophagus; Biomarkers; Biopsy; Cardia; Esophagoscopy; Female; Humans; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Male; Metaplasia; Middle Aged; Sensitivity and Specificity; Stomach

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

Topics: Adenocarcinoma, Mucinous; Adult; Breast; Breast Neoplasms; Carcinoma; Female; Humans; Keratins; Metaplasia; Mucin-1; S100 Proteins

Intestinal metaplasia and gastro-oesophageal reflux disease typify classical Barrett's oesophagus. Cytokeratin (CK) 7 and 20 phenotypes differentiate intestinal metaplasia in long segment Barrett's oesophagus from gastric intestinal metaplasia. This study examines the relationship between CK7/20 phenotypes and reflux disease in intestinal metaplasia of the distal oesophagus.. Eighty patients with oesophageal pH studies included 30 with long segment Barrett's, 16 with short segment Barrett's and 34 with intestinal meatplasia of the gastro-oesophageal junction. Representative biopsy specimens were immunostained for CK7 and CK20. All 30 long segment patients demonstrated a Barrett's CK7/20 phenotype. All nine short segment patients with gastro-oesophageal reflux had a Barrett's CK7/20 phenotype, while four of seven short segment patients without reflux had a gastric CK7/20 phenotype (P = 0.019). Of 14 patients with intestinal metaplasia of the gastro-oesophageal junction and reflux, 10 (71%) had a Barrett's CK7/20 phenotype, compared with 11 (55%) of the 20 non-reflux patients.. CK7/20 immunoreactivity for patients with intestinal metaplasia of the distal oesophagus without long segment Barrett's oesophagus suggests a heterogeneous group, with an association between Barrett's CK7/20 pattern and gastro-oesophageal reflux disease in both short segment Barrett's and intestinal metaplasia of the gastro-oesophageal junction.

Topics: Barrett Esophagus; Esophagus; Female; Gastric Mucosa; Gastroesophageal Reflux; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Male; Metaplasia; Middle Aged

Although the epithelial lining of much of the mammalian urinary tract is known simply as the urothelium, this epithelium can be divided into at least three lineages of renal pelvis/ureter, bladder/trigone, and proximal urethra based on their embryonic origin, uroplakin content, keratin expression pattern, in vitro growth potential, and propensity to keratinize during vitamin A deficiency. Moreover, these cells remain phenotypically distinct even after they have been serially passaged under identical culture conditions, thus ruling out local mesenchymal influence as the sole cause of their in vivo differences. During vitamin A deficiency, mouse urothelium form multiple keratinized foci in proximal urethra probably originating from scattered K14-positive basal cells, and the keratinized epithelium expands horizontally to replace the surrounding normal urothelium. These data suggest that the urothelium consists of multiple cell lineages, that trigone urothelium is closely related to the urothelium covering the rest of the bladder, and that lineage heterogeneity coupled with cell migration/replacement form the cellular basis for urothelial squamous metaplasia.

Topics: Animals; Biomarkers; Cattle; Cell Lineage; Cell Movement; Cells, Cultured; Epithelial Cells; Female; Keratins; Male; Metaplasia; Mice; Ureter; Urinary Bladder; Urothelium; Vitamin A

To investigate the roles of mucin histochemistry, cytokeratin 7/20 (CK7/20) immunoreactivity, clinical characteristics and endoscopy to distinguish short-segment Barrett's esophageal (SSBE) from cardiac intestinal metaplasia (CIM).. High iron diamine/Alcian blue (HID/AB) mucin-histochemical staining and immunohistochemical staining were used to classify intestinal metaplasia (IM) and to determine CK7/20 immunoreactivity pattern in SSBE and CIM, respectively, and these results were compared with endoscopical diagnosis and the positive rate of gastroesophageal reflux disease (GERD) symptoms and H pylori infection. Long-segment Barrett's esophageal and IM of gastric antrum were designed as control.. The prevalence of type III IM was significantly higher in SSBE than in CIM (63.33% vs 23.08%, P< 0.005). The CK7/20 immunoreactivity in SSBE showed mainly Barrett's pattern (76.66%), and the GERD symptoms in most cases which showed Barrett's pattern were positive, whereas H pylori infection was negative. However, the CK7/20 immunoreactivity in CIM was gastric pattern preponderantly (61.54%), but there were 23.08% cases that showed Barrett's pattern. H pylori infection in all cases which showed gastric pattern was significantly higher than those which showed Barrett's pattern (63.83% vs 19.30%, P< 0.005), whereas the GERD symptoms in gastric pattern were significantly lower than that in Barrett's pattern (21.28% vs 85.96%, P< 0.005).. Distinction of SSBE from CIM should not be based on a single method; however, the combination of clinical characteristics, histology, mucin histochemistry, CK7/20 immunoreactivity, and endoscopic biopsy should be applied. Type III IM, presence of GERD symptoms, and Barrett's CK7/20 immunoreactivity pattern may support the diagnosis of SSBE, whereas non-type III IM, positive H pylori infection, and gastric CK7/20 immunoreactivity pattern may imply CIM.

Topics: Barrett Esophagus; Cardia; Diagnosis, Differential; Esophageal Diseases; Esophagogastric Junction; Gastroesophageal Reflux; Gastrointestinal Diseases; Gastroscopy; Helicobacter Infections; Humans; Intestines; Keratin-20; Keratin-7; Keratins; Metaplasia; Mucins

Topics: Adenolymphoma; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Humans; Keratins; Ki-67 Antigen; Male; Metaplasia; Middle Aged; Parotid Neoplasms

Intestinal metaplasia in Barrett's esophagus (BIM) is a precancerous condition, whereas the carcinogenic potential of intestinal metaplasia of the cardia (CIM) is uncertain. Although clinically important, histological distinction between both conditions by endoscopic biopsies is considered problematic. In the present study, 4-mm samples of BIM (n=31) and CIM (n=9) were selected from esophagectomy specimens that had been resected for esophageal cancer. Slides were coded and stained with hematoxylin and eosin (H&E), Alcian blue-periodic acid-Schiff (PAS), cytokeratins (CK) 7 and 20, and CD10, which labels the intestinal brush border. The predictive value of these stains for the recognition of BIM and CIM was evaluated independently by two senior pathologists. With the use of H&E-stained slides exclusively, BIM samples were categorized correctly in 93.5% and 83.9% of cases (pathologists 1 and 2, respectively), and CIM samples, in 100% and 88.9% of cases. Alcian blue-PAS-positive goblet cells were identified by both investigators in all BIM and CIM samples. BIM-typical CK 7 and 20 immunostaining pattern was identified in 90.3%/83.9% of BIM but only in 11.1%/11.1% of CIM. CD10-positive brush border was present in 32.3%/25.8% of BIM and in 88.9%/88.9% of CIM. When HE-stained slides and immunohistologically stained slides were used together for tissue recognition, BIM were categorized correctly in 90.3%/80.6% of cases, and CIM, in 88.9%/88.9% of cases. In conclusion, BIM and CIM can be usually distinguished on the basis of HE sections. CK 7 and CK 20 expression pattern analysis discriminates correctly between BIM and CIM in the majority of cases. CD10-positive intestinal brush border is present in the majority of CIM but only in a minority of BIM. However, immunohistochemical investigations could not improve the diagnostic accuracy of HE histology alone.

Topics: Adult; Aged; Aged, 80 and over; Barrett Esophagus; Biomarkers; Cardia; Diagnosis, Differential; Esophagectomy; Female; Humans; Immunoenzyme Techniques; Intermediate Filament Proteins; Intestinal Mucosa; Intestines; Keratin-20; Keratin-7; Keratins; Male; Metaplasia; Middle Aged; Neprilysin; Precancerous Conditions; Reproducibility of Results

We observed that in urothelium, both cornifying and noncornifying forms of squamous metaplasia are accompanied by changes in the localization of the nuclear hormone receptors, peroxisome proliferator activated receptor gamma (PPAR-gamma) and retinoid X receptor (RXR-alpha). To obtain objective evidence for a role for PPAR-gamma-mediated signaling in urothelial differentiation, we examined expression of the cytokeratin isotypes CK13, CK20, and CK14 as indicators of transitional, terminal transitional, and squamous differentiation, respectively, in cultures of normal human urothelial cells. In control culture conditions, normal human urothelial cells showed evidence of squamous differentiation (CK14+, CK13-, CK20-). Treatment with the high-affinity PPAR-gamma agonist, troglitazone (TZ), resulted in gain of CK13 and loss of CK14 protein expression. The effect of TZ was significantly augmented when the autocrine-stimulated epidermal growth factor receptor pathway was inhibited and this resulted in induction of CK20 expression. The RXR-specific inhibitors PA452, HX531, and HX603 inhibited the TZ-induced CK13 expression, supporting a role for RXR in the induction of CK13 expression. Thus, signaling through PPAR-gamma can mediate transitional differentiation of urothelial cells and this is modulated by growth regulatory programs.

Topics: Cell Differentiation; Chromans; Cloning, Molecular; DNA, Complementary; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Humans; Immunoblotting; Immunohistochemistry; Keratins; Metaplasia; Microscopy, Fluorescence; Quinazolines; Receptors, Cytoplasmic and Nuclear; Ribonucleases; RNA, Messenger; Signal Transduction; Thiazolidinediones; Transcription Factors; Troglitazone; Urothelium

Intestinal-type sinonasal adenocarcinoma (ITAC) is an uncommon neoplasm, which resembles adenocarcinoma of the gastrointestinal tract. ITAC occurs sporadically or in association with occupational exposure to hardwood dust and other agents.. To investigate the phenotype and possible pathogenetic mechanisms of primary sinonasal and nasopharyngeal adenocarcinomas by staining for cytokeratin 7 (CK7), CK20, CDX-2, and villin.. Twelve sporadic sinonasal and nasopharyngeal adenocarcinomas were stained with monoclonal antibodies to CK7, CK20, CDX-2, and villin. The ITACs were classified as papillary, colonic, solid, mixed, or mucinous types.. The diagnosis of ITAC was confirmed in 10 cases: five were colonic type and five were papillary. One was a sinonasal papillary low grade adenocarcinoma, and one a papillary nasopharyngeal adenocarcinoma, and these tumours were CK7 positive, but CK20, CDX-2, and villin negative. All ITACs were positive for CK20, CDX-2, and villin, and six were CK7 positive. One ITAC had a focus of intestinal metaplasia away from the invasive carcinoma.. Sinonasal ITACs have a distinctive phenotype, with all cases expressing CK20, CDX-2, and villin. Most ITACs also express CK7, although a proportion of tumours are CK7 negative. ITAC seems to be preceded by intestinal metaplasia of the respiratory mucosa, which is accompanied by a switch to an intestinal phenotype. Although ITACs are morphologically similar, differences in cytokeratin expression patterns suggest two distinct types. The expression pattern of CK7, CK20, CDX-2, and villin positive may be useful in separating these tumours from other non-ITAC adenocarcinomas of the sinonasal tract and nasopharynx.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carrier Proteins; CDX2 Transcription Factor; Female; Homeodomain Proteins; Humans; Immunohistochemistry; Industry; Intermediate Filament Proteins; Intestinal Mucosa; Intestinal Neoplasms; Keratin-20; Keratin-7; Keratins; Male; Metaplasia; Microfilament Proteins; Middle Aged; Nose Neoplasms; Occupational Diseases; Paranasal Sinus Neoplasms; Trans-Activators; Wood

A 10-year-old Knabstrupper stallion was euthanatized because of severe dyspnea and exercise intolerance. Postmortem examination revealed diffuse severe alveolar emphysema and chronic fibrosing pleuritis of the caudal lung. Parts of both caudal lung lobes were covered with multiple raised firm gray to yellow plaques. Histologically, these areas consisted of circumscribed pleural fibroses and cysts of metaplastic keratinizing squamous epithelium. Immunohistochemistry revealed intense labeling for cytokeratins 5/6 and 10. In addition, caudal lung lobes were severely affected by a chronic partially obliterative bronchiolitis and peribronchiolitis with multifocal pleural involvement.

Topics: Animals; Bronchopneumonia; Fatal Outcome; Horse Diseases; Horses; Immunohistochemistry; Keratins; Male; Metaplasia; Pleura

Intestinal metaplasia (IM) in endoscopic biopsies obtained from close to the gastroesophageal junction may represent IM of the cardia (CIM) or Barrett's esophagus (BE), which have different malignant potentials despite similar morphology. This study compared cytokeratin (CK) 7/20 and mucin (MUC1, 2, 5AC, and 6) immunopatterns in biopsies from BE (n = 41), CIM (n = 35), and antral gastric IM (AIM, n = 37) to evaluate their roles as diagnostic aids. CK7 and CK20 expression was described as absent, patchy (superficial and deep), continuous superficial only, continuous deep only, and diffuse. Eleven different combinations of CK7/20 expression were seen. Since CK20 staining was positive in all cases, four main patterns were defined on the basis of the observed CK7 staining as 1, absent; 2, patchy (superficial and/or deep); 3, diffuse; and 4, continuous superficial only. Overall CK7 positivity (regardless of pattern) was higher in BE and CIM than in AIM. CK patterns 3 and 4 were also higher in BE and CIM than in AIM. For either pattern 3 or 4, the positive and negative predictive values for BE versus AIM were 95% and 67%, respectively. MUC1 was rarely expressed in BE and CIM compared with AIM, whereas the opposite was noted for MUC5AC expression. MUC2 and MUC6 expression was similar in all locations. In conclusion, diffuse or continuous superficial CK7 staining is highly characteristic of BE and CIM and contrasts with AIM. It is, however, not very sensitive. CK20 profiles have no added value. Mucin expression also differs between BE and CIM versus AIM, but the specificity of any pattern is insufficient for distinction in individual cases. Importantly, CK and MUC expression patterns in BE and CIM are virtually indistinguishable, limiting their use in this differential and raising the question of whether they are biologically related.

Topics: Barrett Esophagus; Biomarkers; Diagnosis, Differential; Gene Expression Profiling; Humans; Intermediate Filament Proteins; Intestines; Keratin-20; Keratin-7; Keratins; Metaplasia; Mucin 5AC; Mucin-1; Mucin-2; Mucin-6; Mucins; Retrospective Studies; Stomach

Epithelial cancers are believed to originate from transformation of tissue stem cells. However, bone marrow-derived cells (BMDCs), which are frequently recruited to sites of tissue injury and inflammation, might also represent a potential source of malignancy. We show that although acute injury, acute inflammation, or transient parietal cell loss within the stomach do not lead to BMDC recruitment, chronic infection of C57BL/6 mice with Helicobacter, a known carcinogen, induces repopulation of the stomach with BMDCs. Subsequently, these cells progress through metaplasia and dysplasia to intraepithelial cancer. These findings suggest that epithelial cancers can originate from marrow-derived sources and thus have broad implications for the multistep model of cancer progression.

Topics: Animals; Apoptosis; Bone Marrow Cells; Bone Marrow Transplantation; Carcinoma in Situ; Cell Differentiation; Cell Fusion; Disease Progression; Female; Gastric Mucosa; Gastritis; Helicobacter felis; Helicobacter Infections; Keratins; Male; Mesenchymal Stem Cells; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mucins; Muscle Proteins; Parietal Cells, Gastric; Peptides; Phenotype; Stem Cells; Stomach Neoplasms; Trefoil Factor-2

Intestinal metaplasia occurs in the esophagus as a consequence of gastroesophageal reflux disease and in the stomach secondary to H. pylori infection. The etiology of intestinal metaplasia limited to the gastroesophageal junction or cardia (CIM) is disputed. We hypothesized that CIM has dual etiologies: gastroesophageal reflux in some, H. pylori infection in others, and that cytokeratin immunostaining can help to differentiate between these two etiologies.. We defined CIM as the presence of intestinal metaplasia within cardiac mucosa on biopsy from an endoscopically normal-appearing gastroesophageal junction. Thirty patients with CIM who had multiple biopsy specimens taken from the esophagus, gastroesophageal junction, and stomach were identified. Tissue blocks from biopsy specimens taken at the gastroesophageal junction were sectioned and immunostained for cytokeratins 7 and 20. The cytokeratin 7/20 staining of the CIM in each patient was determined to be either a Barrett's or non-Barrett's pattern. H. pylori infection was assessed by Giemsa staining of antral biopsy specimens.. H. pylori infection was present in 16 patients. A Barrett's cytokeratin 7/20 staining pattern in the CIM was present in only 46% of the H. pylori-positive patients, as compared to 86% in the 14 patients with CIM and no H. pylori (p = 0.025). Objective evidence of reflux disease was present in 71% of patients with CIM and no H. pylori, as compared to 31% of patients with H. pylori.. The two different patterns of cytokeratin 7/20 staining found in patients with CIM support the concept of dual etiologies for CIM. A Barrett's staining pattern was associated with objective evidence of gastroesophageal reflux and the absence of H. pylori, suggesting that cytokeratin 7/20 immunostaining is useful to determine the likely etiology of CIM.

Topics: Biopsy; Esophagitis; Esophagus; Gastric Mucosa; Gastroesophageal Reflux; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Metaplasia

It has been reported previously in cases of adenosquamous carcinoma of the lung in Okinawa, a subtropical island 2000 km south of mainland Japan, that the squamous cell carcinoma components were positive for human papillomavirus (HPV) by non-isotopic in situ hybridisation (NISH). The adenocarcinoma cells adjacent to the squamous cell carcinoma components were enlarged and also positive for HPV. This is thought to indicate that after adenocarcinoma cells are infected with HPV, they undergo morphological changes, and that "squamous metaplasia" follows. In this present study, the effects of HPV transfection into adenocarcinoma cells were examined. The relation between the region expressing the HPV gene and squamous metaplasia was also studied.. Plasmid pBR322 containing HPV type 16 (HPV-16) was transfected into cultured colonic adenocarcinoma (DLD-1) and lung adenocarcinoma (PC-14) cells using the calcium phosphate method. Neomycin was used as a selection marker. The presence of HPV E1, E2, E4, E5, E6, E7, L1, and L2 mRNAs and also transglutaminase 1, involucrin, cyclin dependent kinases (CDKs), cyclins, caspases, apoptosis inducing factor, DNase gamma, Fas, and Fas ligand mRNAs in HPV transfected cells was investigated by means of reverse transcription polymerase chain reaction (RT-PCR). The G0-G1 cell population was analysed by flow cytometry. Morphological examination under light and electron microscopes was also carried out.. The virus transfected cells showed squamous metaplasia when they were injected into severe combined immunodeficient mice, expressing the high molecular weight keratin (Moll's number 1 keratin) and involucrin molecules immunohistochemically, and involucrin and transglutaminase I mRNAs by RT-PCR. The squamous metaplasia was most conspicuous in the HPV transfected DLD-1 cell when compared with HPV transfected PC-14 cells. Squamous metaplasia was most clearly demonstrated in one HPV transfected DLD-1 cell clone, which expressed not only E2 but also E6-E7 fusion gene mRNA. Viral L1 mRNA expression was absent in HPV transfected cell clones, and was not related to squamous metaplasia. The growth rate of HPV transfected cells was reduced. Transfection of the virus into the cultured adenocarcinoma cells increased the G0-G1 cell population greatly, as assessed by flow cytometer analysis. Furthermore, in the virus transfected cells, apoptosis was also observed by means of the terminal deoxynucleotidyl transferase mediated dUTP biotin nick end labelling method.. HPV transfection into adenocarcinoma cells induced clear squamous metaplasia. One of the HPV transfected cell clones that expressed E2 and E6-E7 fusion gene mRNA showed the squamous metaplasia particularly clearly, and apoptosis was also demonstrated.

Topics: Adenocarcinoma; Animals; Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Cycle; Cell Differentiation; DNA, Viral; Humans; Keratins; Lung Neoplasms; Metaplasia; Mice; Mice, SCID; Neoplasm Proteins; Neoplasm Transplantation; Papillomaviridae; Protein Precursors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Viral; Transfection; Tumor Cells, Cultured

Intestinal metaplasia is a histologic hallmark of Barrett's esophagus and chronic gastritis. Intestinal metaplasia may progress to dysplasia or carcinomas without proper treatment. Most cases of intestinal metaplasia are easily recognized on hematoxylin and eosin-stained sections. However, some cases of intestinal metaplasia may be hard to recognize if they lack the characteristic mucin-producing cells and Paneth cells, or if they are small in size. Recently, keratin 7, keratin 20, and MUC2 expression patterns were reported to be useful in confirming the diagnosis of intestinal metaplasia. We studied hepatocyte (Hep) antigen (a hepatocellular antigen mainly expressing in normal and neoplastic hepatic tissues) in 33 cases of Barrett's esophagus (9 cases associated with esophageal adenocarcinoma) and 13 cases of chronic gastritis associated with intestinal metaplasia and gastric adenocarcinoma. Hep monoclonal antibody recognizes intestinal metaplasia in all cases. We also compared expression of Hep with that of keratin 7, keratin 20, and MUC2 in intestinal metaplasia. The specificity and sensitivity of Hep for intestinal metaplasia were higher than that of keratin 7 and keratin 20, or MUC2. We conclude that Hep may be used as a single diagnostic marker for intestinal metaplasia.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Barrett Esophagus; Biomarkers, Tumor; Chronic Disease; Esophageal Neoplasms; Gastritis; Hepatocytes; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Metaplasia; Mucin-2; Mucins; Precancerous Conditions; Sensitivity and Specificity; Stomach Diseases

Adenocarcinomas of the distal oesophagus and especially the oesophago-gastric junction have shown an increasing incidence during the last decade. Definition of subgroups according to different sites of development, histogenesis or aetiology may prove to be valuable for clinical diagnosis and treatment. Previous studies have shown differences in cytokeratin patterns between Barrett's metaplasia of the oesophagus and intestinal metaplasia in the stomach. The aim of our study was to investigate whether the expression of certain cytokeratins (CK7, CK20) and mucins (MUC1, MUC2, MUC5AC) exhibit clear-cut patterns, thus allowing a subclassification of adenocarcinomas of the oesophago-gastric junction. The possibility of a relationship between antigen expression and the presence or absence of Barrett's metaplastic epithelium was also studied.. CK7, CK20, MUC1, MUC2 and MUC5AC were visualized in six adenocarcinomas of the distal oesophagus, 29 adenocarcinomas of the oesophago-gastric junction and eight adenocarcinomas of the proximal stomach. CK7, CK20 and MUC1 were strongly expressed in the great majority of all neoplasms under study, whereas MUC2 and MUC5AC were absent or only faintly detectable. CK20 exhibited a significantly stronger expression in poorly differentiated tumours (G3) and MUC1 immunoreactivity correlated with tubular and papillary versus signet-ring cell histopathology. Other statistically significant correlations between antigens and histopathological features (pTNM stage, grading, histopathological subtype, presence/absence of Barrett's epithelium) were not observed.. According to our results, most adenocarcinomas of the oesophago-gastric junction show a CK7+, CK20+, MUC1+ phenotype irrespective of the presence or absence of Barrett's epithelium. The immunohistochemical data suggest a similar histogenesis of these tumours.

Topics: Adenocarcinoma; Barrett Esophagus; Biomarkers, Tumor; Cardia; Esophageal Neoplasms; Esophagogastric Junction; Humans; Immunohistochemistry; Keratins; Metaplasia; Mucins; Neoplasm Staging; Stomach Neoplasms

A prospective, immunohistochemical study of bladder biopsies taken from spinal cord injury (SCI) patients.. To investigate whether cytokeratin 14 immunostaining may be useful to detect early squamous metaplasia in bladder biopsies from patients with SCI.. Southport, United Kingdom.. Biopsy of bladder mucosa was taken from adults with SCI, while they underwent an elective therapeutic procedure in the urinary tract. A total of, 54 biopsies, which showed transitional epithelium only with no evidence of squamous metaplasia on routine H&E staining, formed the study group. In all, 22 biopsies, which showed squamous metaplasia on routine H&E staining, acted as controls. All biopsies were benign with no evidence of dysplasia or malignancy. Immunohistochemical staining for cytokeratin 14 was performed on all biopsies in a single batch, using a standard avidin-biotin complex method.. All control biopsies showed positive immunostaining for cytokeratin 14 in basal and parabasal cells in areas of squamous metaplasia. Of the 54 biopsies, which showed only transitional epithelium on H&E staining, immunohistochemistry for cytokeratin 14 showed no staining in 47 biopsies. The remaining seven biopsies showed positive immunostaining for cytokeratin 14 in the epithelium, in individual cells or clusters of basal cells, revealing unexpected early squamous metaplasia in these biopsies.. Immunostaining for cytokeratin 14 identifies an early phenotypic switch from transitional to squamous epithelium in bladder mucosa. Cytokeratin 14 staining is sufficiently sensitive to identify early squamous metaplasia, which is not yet evident on examination of routine H&E stained sections. This early identification may be of use in alerting physicians to change bladder management regimens to prevent predisposition to recurrent urinary infection and progression of squamous metaplasia. A cost/benefit analysis should be performed to assess the feasibility of routine cytokeratin 14 immunostaining of bladder biopsies from SCI patients.

Topics: Animals; Biopsy; Humans; Keratin-14; Keratins; Metaplasia; Mice; Prospective Studies; Spinal Cord Injuries; Urinary Bladder

A histopathological and immunohistochemical study of a case of nephrogenic adenoma of the bladder associated to glandular cystitis is presented with a very similar immunostaining to adenomatoid tumors in other organs and probably of a mesothelial origin. Its pathogenesis seems to correspond to a metaplastic change of the bladder's urothelium through anomalous differentiation of the reserve cells faced with different irritating agents. Because of its benign characteristics, we think that treatment can be confined to endoscopic observation and conservative technique.

Topics: Adenoma; Aged; Biomarkers, Tumor; Carcinoma; Cystitis; Diagnosis, Differential; Humans; Immunoenzyme Techniques; Keratins; Male; Metaplasia; Mucin-1; Neoplasm Proteins; Urinary Bladder Neoplasms; Urography; Urothelium; Vimentin; von Willebrand Factor

The normal histology at the gastroesophageal junction, and in particular the nature of cardiac mucosa, remains in dispute. Likewise, the relationship of intestinal metaplasia at the gastroesophageal junction (CIM) to Barrett's and intestinal metaplasia of the stomach (GIM) is unclear. The aim of this study was to assess the immunostaining characteristics of cardiac mucosa and CIM and compare their staining pattern with that of other foregut mucosal types. We hypothesized that the immunostaining patterns of these foregut tissues would provide insight into the nature and etiology of cardiac mucosa and CIM.. Paraffin-embedded biopsy specimens from 50 patients with normal antral or fundic mucosa, cardiac mucosa, squamous mucosa, CIM, GIM, or Barrett's were obtained and immunostained with a panel of monoclonal antibodies including those for cytokeratins 7 and 20 (CK7/CK20) and DAS-1.. Biopsies from normal gastric antral and fundic mucosa and squamous esophageal mucosa all showed a non-Barrett's type CK7/CK20 immunostaining pattern, whereas in 85% of patients, cardiac mucosa had a Barrett's type CK7/CK20 pattern (p < 0.001). A Barrett's type CK7/ CK20 staining pattern was seen in 100% of Barrett's, 78% of CIM, and 0% of GIM patients. Likewise, DAS-1 staining was similar in patients with CIM and Barrett's and significantly different in patients with GIM.. Cytokeratin immunostaining of cardiac mucosa demonstrates significant differences from recognized normal gastric and esophageal mucosa but a similarity to Barrett's. This suggests that cardiac mucosa, like Barrett's, may be acquired. Likewise, immunostaining similarities between CIM and Barrett's biopsies point to the possibility of a reflux etiology for CIM in some patients.

Topics: Antibodies; Barrett Esophagus; Biopsy; Cardia; Esophagogastric Junction; Gastric Fundus; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Metaplasia; Mucous Membrane; Pyloric Antrum

Topics: Barrett Esophagus; Humans; Immunophenotyping; Intestinal Mucosa; Keratins; Metaplasia; Stomach

We report a case of early adenocarcinoma arising in foci of intestinal metaplasia (IM) at a normal-appearing gastroesophageal junction (GEJ). The tumor infiltrated the submucosa without nodal involvement (T1N0). Non-neoplastic mucosa adjacent to neoplasia had foci of incomplete IM with a band-like CK20 positivity of the surface epithelium and a diffuse CK7 staining of both superficial and deep glands. There were histological features of reflux esophagitis as well as chronic non-atrophic, Helicobacter pylori-related pangastritis, without IM, at the extensively assessed gastric mucosa. In this case, the CK7/20 pattern of IM adjacent to neoplasia, the demonstration of reflux esophagitis, and the absence of IM in the stomach favor the theory that the pathogenesis of IM and associated adenocarcinoma of the GEJ is related to gastroesophageal reflux rather than H. pylori infection.

Topics: Adenocarcinoma; Aged; Cardia; Chronic Disease; Esophagogastric Junction; Gastrectomy; Gastric Mucosa; Gastritis; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Stomach Neoplasms

Topics: Conjunctiva; Conjunctival Diseases; Humans; Immunohistochemistry; Keratins; Membrane Proteins; Metaplasia; Mucous Membrane; Protein Precursors; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transglutaminases

Cytokeratin (CK) expression patterns have been studied in numerous intact and diseased oral tissues. However, CK expression in metaplastic squamous cells has not been explored in depth and the origin of metaplastic epithelial linings of the jaw cysts has not been sufficiently investigated.. We examined CK expression in 46 postoperative maxillary cysts (POMCs) which were lined with pseudostratified columnar cells only, columnar and squamous cells, and squamous cells only, in 13, 30 and 3 cases, respectively.. The expression of CK8, CK13 and CK18 were observed in 39, 9 and all 43 of the columnar epithelial linings, respectively. Metaplastic squamous epithelia expressed more CK13, and less CK18 and CK8. Of the 33 metaplastic linings, 24 expressed CK8, 23 CK13 and 26 linings expressed CK18. The patterns of expression of CK13 and CK18 observed were CK18(+)-CK13(-) in 10 metaplastic linings, CK18(+)-CK13(+) in 16, and CK18(-)-CK13(+) in 7. The expression of CK13- and CK18-mRNA was generally correlated with level of protein expressed. CK18-mRNA expression was observed by in situ hybridization, not only in the 26 metaplastic linings which were positive for CK18 protein, but also in five of the seven metaplastic linings which did not express CK18 protein. In addition, RT-PCR revealed an expression of CK18-mRNA in all metaplastic squamous linings, although the expression level was weaker than that in the columnar epithelial linings. The CK13-mRNA was expressed inversely to the CK18-mRNA.. These results indicate that CK18-mRNA is preserved through metaplasia, although the protein expression decreased. Metaplastic squamous cells differentiate with a decrease of CK18 and an increase of CK13 expression.

Topics: Cell Differentiation; Epithelial Cells; Gene Expression; Humans; Immunohistochemistry; In Situ Hybridization; Isoelectric Focusing; Keratins; Maxillary Diseases; Metaplasia; Nonodontogenic Cysts; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

To analyse the clinical and pathological features with long-term follow-up of a series of 12 cases of sarcomatoid carcinoma of the breast. methods and results: The cases were selected from the surgical files of the Department of Pathology, University of Edinburgh, between 1977 and 1988. The following clinical parameters were recorded: the age of the patients, size of tumour, presence or absence of lymph node or distant metastases, and patient survival. Pathological assessment included: the type of epithelial and mesenchymal components, the proportion of monophasic to biphasic tumours and the presence of adjacent in-situ carcinoma/atypical epithelial proliferation. The mean age of the patients was 61 years with a median of 64 and range 46-82 years. The mean size of the tumour was 52 mm (range 22-100 mm). None of the patients had distant metastasis at presentation and only one case had local lymph node metastasis which had a carcinomatous appearance. Five women were still alive after a minimum 12-year follow-up period. Four patients died of their disease (three with lung metastasis only and one with lung and bone metastases), one died of carcinoma of the cervix and two patients were lost to follow-up. Pathologically, four cases (33.3%) had no or almost undetectable epithelial structures by light microscopy, i.e. "monophasic sarcomatoid carcinoma". The remaining cases revealed varying proportions of both epithelial and mesenchymal elements, i.e. "biphasic sarcomatoid carcinoma". Of the epithelial component, six (50%) tumours had predominantly carcinoma of no special type, one lobular and one tubular carcinoma. The mesenchymal component was fibromatosis/nodular fasciitis-like, malignant fibrous histiocytoma-like (MFH), osteosarcoma-like and fibrosarcoma-like in five (42%), four (33%), two (17%) and one (8%) tumours, respectively. In 3/4 monophasic tumours, the mesenchymal component was of a low-grade fibromatosis/nodular fasciitis type. In 6/12 (50%) of the cases there was associated in-situ atypical epithelial proliferation (five ductal carcinoma in situ (DCIS) and one atypical ductal hyperplasia).. From this small series it appears that sarcomatoid carcinoma is an uncommon tumour, which is large in size and tends to lack local or distant metastasis at presentation. Pathologists should be alert to the presence of the bland monophasic sarcomatoid carcinoma which has a pure mesenchymal appearance on light microscopy, but epithelial components demonstrated by cytokeratin immunohistochemistry. These showed metastases on long-term follow-up, similar to other histological patterns of sarcomatoid carcinoma.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Breast Neoplasms; Carcinosarcoma; Female; Follow-Up Studies; Humans; Immunohistochemistry; Keratins; Metaplasia; Middle Aged; Survival Rate

Although androgens have long been implicated in the development, regulation, and pathophysiology of the prostate, evidence suggests that estrogens may also affect these processes. Specifically, estrogens have been shown to influence the development of the fetal and neonatal rodent prostate and to induce a pathognomonic change, termed squamous metaplasia, in the developing and adult prostate. Studies have been inconclusive, however, as to whether estrogens enhance or restrain the growth of the gland. Although the fetal rodent prostate has been reported to contain both estrogen receptor alpha (ER-alpha) and beta (ER-beta), there have been no reports as to whether either of the ER subtypes is expressed in the developing human prostate.. In the present study, we used a novel antibody, directed against a unique sequence in the F domain of ER-beta, and laser capture microdissection/reverse transcriptase-polymerase chain reaction to study the expression of the receptor in the fetal, neonatal, and prepubertal human prostate. Results were compared with the expression of ER-alpha, androgen receptor (AR), prostatic acid phosphatase (PAP), prostate specific antigen (PSA), high molecular weight cytokeratin (HMCK), and the proliferative marker Ki67.. For the first time, we report that ER-beta is the only estrogen receptor detected at the protein level in the morphologically normal developing human fetal prostate. By midgestation, strong immunostaining for ER-beta was detected in the nuclei of nearly 100% of epithelial and in the majority of stromal cells. This pattern of expression was evident in the fetal, neonatal, and early prepubertal prostate. However, by 11 years postnatal, staining for the receptor became restricted primarily to the basal epithelial and stromal compartments, a pattern analogous to that observed in the normal adult gland. ER-alpha mRNA was present in microdissected stroma of the fetal gland. Although ER-alpha was not immunodetected in any morphologically normal fetal epithelial or stromal cells, weak staining for the receptor, however, was found in some examples of squamous metaplasia, suggesting the role of alpha-subtype in this lesion. ER-alpha was clearly visualized immunohistochemically at 1 month of postnatal development where it was then localized exclusively in periacinar stromal nuclei, which suggests that it may exert paracrine influences on further prostatic glandular development. Interestingly, the expression of ER-beta early in prostatic development occurred coincident with both the increasing rate of epithelial cell proliferation, observed in the first half of gestation, and the reported high levels of estrogen in the gland from midgestation until term. Paradoxically, however, staining for the receptor remained intense, despite the dramatic decrease in Ki67 labeling observed in the second half of gestation.. Our results indicate that the effects of estrogens on the growth of the human fetal prostate are mediated primarily by ER-beta but that ER-alpha contributes to postnatal glandular development. Furthermore, these results suggest that ER-beta, possibly in concert with androgens, may mediate diverse effects on prostate epithelial proliferation by first promoting cell expansion early in gestation, and then acting to limit growth later in prostatic development.

Topics: Acid Phosphatase; Child; Estrogen Receptor alpha; Estrogen Receptor beta; Fetal Diseases; Gene Expression; Gestational Age; Humans; Immunohistochemistry; Infant; Infant, Newborn; Keratins; Ki-67 Antigen; Male; Metaplasia; Molecular Weight; Prostate; Prostate-Specific Antigen; Protein Tyrosine Phosphatases; Receptors, Androgen; Receptors, Estrogen; Reverse Transcriptase Polymerase Chain Reaction

The exact mechanisms of physiological regeneration and of metaplastic processes of the salivary duct have not been definitely established, although regeneration from a putative uncommitted stem cell population has long been favored. In the present study, double immunohistochemical labeling for Ki 67 and alpha-actin or different cytokeratin subtypes, respectively, made possible an exact localization and quantification of cellular proliferation in the regular salivary duct and in different types of metaplasia. Our data demonstrate a baseline proliferative capacity in all five cell types of the salivary duct. Luminal secretory cells of the acinus and intercalated duct regenerate independently from myoepithelial or basal cells. In contrast, the renewal of oxyphilic cells in the striated and excretory duct is maintained by proliferation and differentiation of basal cells. The great majority of metaplasias develops from uncommitted, Bcl-2 positive basal cells of striated/excretory ducts which possess an enormous capacity for pluridirectional morphogenetic differentiation. Despite this important role of basal cells, our findings demonstrate that all cell types principally have to be considered as potential progenitor cells for salivary gland tumors. The improved insight into regenerative and metaplastic processes of the salivary duct may contribute to a better understanding of the complex formal carcinogenesis.

Topics: Actins; Adult; Aged; Aged, 80 and over; Cell Differentiation; Cell Division; Female; Humans; Immunohistochemistry; Keratins; Ki-67 Antigen; Male; Metaplasia; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Regeneration; Salivary Ducts

Metaplastic spindle cell carcinomas may be difficult to distinguish histologically from other spindle cell lesions in the breast. Variable staining with cytokeratin immunomarkers has been reported for metaplastic carcinomas. We evaluated the diagnostic utility of anti-cytokeratin polyclonal antibody, wide spectrum screening keratin, to assess spindle cell breast lesions.. Twenty-four patients with spindle cell breast carcinoma and 31 patients with benign or malignant spindle cell tumours were studied using a panel of antibodies directed against multiple cytokeratins (AE1/AE3, CAM5.2, wide spectrum screening keratin), epithelial membrane antigen (EMA), and vimentin. Sites of origin for the 31 controls included breast, bone, and soft tissue. All but one (95.8%) metaplastic carcinomas stained positively with wide spectrum screening keratin. Only rare or focal immunoreactivity was observed with AE1/AE3 in four cases; however, sensitivity of AE1/AE3 was improved in 13 cases using steam EDTA as an antigen retrieval technique. Three cases were immunoreactive with CAM5.2 and eight cases were immunoreactive with EMA. All control cases lacked immunoreactivity with the cytokeratin panel and EMA. The spindle cells in the metaplastic breast tumours (88%) and in the controls (97%) stained with vimentin.. Wide spectrum screening keratin may be the most useful and convenient antibody in differentiating metaplastic spindle cell carcinoma from other spindle cell lesions in the breast.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Breast Neoplasms; Carcinoma; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Middle Aged; Mucin-1; Vimentin

Topics: Barrett Esophagus; Diagnosis, Differential; Gastroesophageal Reflux; Humans; Intermediate Filament Proteins; Intestines; Keratin-20; Keratin-7; Keratins; Metaplasia; Staining and Labeling

Long segment Barrett's esophagus (LSBE) is a recognized risk factor for the development of esophageal dysplasia and carcinoma. However, the risk of dysplasia arising within intestinal metaplasia below a normal-appearing Z-line (i.e., in native cardiac mucosa) is unknown. Regular endoscopic surveillance is required in patients with LSBE and is frequently performed in short segment BE (SSBE), but the need for surveillance in cardiac intestinal metaplasia (CIM) is unknown. Unfortunately IM arising in SSBE and immediately below a normal Z-line can be indistinguishable histologically on H&E stains. Previous reports suggest that the appearance of superficial CK20 immunohistochemical staining accompanied by intermediate and deep CK7 positivity is characteristic of BE, whereas CIM specimens show superficial and deep CK20 positivity and weak to absent CK7 staining. We hypothesized that CK7/20 immunostaining of metaplastic biopsies from the esophagus and stomach would allow complete differentiation of these two entities when correlated with the endoscopic appearance. We undertook an evaluation of gastric and esophageal specimens to determine whether these characteristics were valid. Cases of both BE (long and short segment) and CIM, as well as cases of gastric cardiac biopsies lacking IM, were evaluated for CK7 and CK20 and correlated with the endoscopic appearance. We observed that, although the "Barrett's" pattern of CK7/20 was maintained for many cases of BE, the sensitivity and specificity were only moderate (65% and 56%, respectively). The pattern of staining for the CIM was variable, i.e., some cases showed a CK7/20 Barrett's pattern despite a normal appearance at endoscopy. The differences between this and previous studies may be due to inaccurate visualization of SSBE on endoscopy, the development of very early SSBE cases, inter-observer variability, fixation differences, or antibody differences. Whatever the cause of the differences, if results between laboratories are not comparable, CK7/20 immunostaining cannot be used to differentiate reliably between IM present in biopsy specimens taken from above versus below the Z-line. However, further studies should be performed to determine whether the presence or absence of a Barrett's pattern of CK7/20 immunostaining could predict progression to dysplasia or carcinoma.

Topics: Barrett Esophagus; Cardia; Diagnosis, Differential; Female; Gastrointestinal Diseases; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Male; Metaplasia; Predictive Value of Tests; Sensitivity and Specificity

Intraductal papillary neoplasia of the liver (IPN-L) was recently proposed as the name for intraductal papillary proliferation of neoplastic biliary epithelium with a fine fibrovascular stalk resembling intraductal papillary mucinous neoplasm of the pancreas. We histochemically and immunohistochemically examined IPN-L alone or associated with hepatolithiasis, with an emphasis on the gastrointestinal metaplasia, nuclear p53 expression, and histologic progression. A total of 66 cases of IPN-L were divided into 4 groups: group 1, IPN-L with low-grade dysplasia (13 cases); group 2, IPN-L with high-grade dysplasia (20 cases); group 3, IPN-L lined with carcinoma in situ and no or microinvasion (19 cases); and group 4, group 3 with distinct invasive carcinoma (14 cases). It is suggested that IPN-L progresses from group 1 to group 4. As controls, 20 cases of nonneoplastic intrahepatic large bile ducts and 17 cases of nonpapillary invasive intrahepatic cholangiocarcinoma (ICC) were used. Biliary epithelial hypersecretion of sialomucin rather than sulfomucin was prevalent in IPN-L, and this was associated with the progression of INP-L. Immunohistochemically, cytokeratin (CK) 20 and MUC2, a gastrointestinal marker, were expressed more frequently in IPN-L than in nonneoplastic bile ducts and nonpapillary ICC (P <0.01), and their incidence were significantly increased in parallel with the progression of IPN-L (P < 0.01). In contrast, expression of CK 7, a biliary marker, was decreased in IPN-L compared with nonpapillary ICC. Nuclear p53 immunostaining was detected in 30% of IPN-L as a whole and increased in tandem with the progression of IPN-L (P < 0.01). It is suggested that IPN-L forms a spectrum of biliary epithelial neoplasia with frequent gastrointestinal metaplasia, different from the usual nonpapillary ICC, and shows stepwise progression from the perspective of mucin profile, gastrointestinal metaplasia, and p53 nuclear expression.

Topics: Adult; Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Nucleus; Cholangiocarcinoma; Disease Progression; Female; Humans; Immunoenzyme Techniques; Keratin-7; Keratins; Lithiasis; Liver Diseases; Male; Metaplasia; Middle Aged; Mucins; Phenotype; Precancerous Conditions; Tumor Suppressor Protein p53

Metaplastic differentiation, including squamous, mucinous, and tubal (ciliated), is common in both benign and neoplastic endometrium, and the cell of origin for this pathway is poorly understood. In this study, expression of a marker for basal and reserve cells in cervical squamous mucosa, designated p63, was investigated in a spectrum of endometrial alterations.. One hundred ninety different endometria from 132 patients were examined, including fetal (6), premenarchal (3), benign cyclic (29) and noncyclic (54), hyperplastic (14), and neoplastic (93) endometrial glandular epithelia. The latter included conventional endometrioid carcinomas with and without mucinous, ciliated, and squamous metaplasia, and uterine papillary serous carcinoma (UPSC).. p63 expression was identified in basal/subcolumnar cells in the fetal endometrium in a distribution similar to that in basal/reserve cells of the cervix. Staining was confined to individual scattered basal and suprabasal cells in cycling endometrium. In polyps and postmenopausal endometria, focal clusters of p63-positive cells were identified in inactive glands or surface epithelium. Metaplastic (squamous or mucinous) epithelia, either alone or in conjunction with hyperplasias or carcinomas, exhibited the most intense staining, primarily in basal or subcolumnar cells. In some cases, immediately adjacent nonmetaplastic columnar epithelium also stained positive. UPSCs contained only rare scattered p63-positive cells.. Cells with a basal or reserve cell phenotype exist in the endometrium during fetal life, are not conspicuous during the reproductive years, but may emerge during shifts in differentiation. Whether these cells signify specialized multipotential endometrial cells is not clear, but the similarity of these cells to basal/reserve cells of the cervix and their association with neoplasia merit further study.

Topics: Animals; Biomarkers, Tumor; Cell Differentiation; DNA-Binding Proteins; Endometrial Neoplasms; Endometrium; Epithelial Cells; Female; Genes, Tumor Suppressor; Humans; Immunophenotyping; Keratin-14; Keratins; Membrane Proteins; Menstrual Cycle; Metaplasia; Mice; Phosphoproteins; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins

The pathogenesis of short segment Barrett's esophagus (SSBE) and intestinal metaplasia (IM) of the gastroesophageal junction (IMGEJ) are poorly understood. Also, these conditions are difficult to distinguish from one another based solely on endoscopic and pathologic criteria. Therefore, the aim of this study was to evaluate the immunophenotypic features of SSBE and IMGEJ and to compare the results with lesions of known etiologies: long segment BE (LSBE) caused by reflux disease and Helicobacter pylori-induced IM of the gastric antrum (IMGA). Routinely processed mucosal biopsy specimens from 11 patients with LSBE, 17 with SSBE, 10 with IMGEJ, 16 with IMGA, 17 with a normal nonmetaplastic GEJ, and 7 patients with a normal gastric antrum were immunohistochemically stained with monoclonal antibodies to: Das1, an antibody shown to react specifically with colonic goblet cells; 45M1, an antibody that recognizes the M1 gastric mucin antigen; and cytokeratin (CK) 7 and 20, antibodies that have previously been reported to show specific staining patterns in BE versus IMGA. Also evaluated was nonintestinalized mucinous epithelium from LSBE, SSBE, and also the normal GEJ and gastric antrum. LSBE, SSBE, and IMGEJ showed similar prevalences of Das1 (91% versus 88% versus 100%) and 45M1 reactivity (100% versus 100% versus 100%), and a similar pattern of CK7/20 reactivity (diffuse strong CK7 staining of the surface and crypt epithelium, and strong surface and superficial crypt CK20 staining) (91% versus 94% versus 90%). In contrast, although 45M1 reactivity in IMGA (93%) was similar to that of the other three groups, IMGA showed a significantly lower prevalence of Das positivity (13%, p < 0.001), and only a 14% prevalence of the CK7/20 staining pattern that was predominant in the other three groups (p < 0.001). Das1, 45M1, and CK7/20 staining were similar in nonintestinalized "cardia-type" mucinous epithelium from LSBE, SSBE, and the GEJ, but all were distinct from the normal gastric antrum. In summary, the immunophenotypic features of SSBE and IMGEJ are similar and closely resemble those seen in classic LSBE, but are distinct from IMGA. This may indicate that IM in LSBE, SSBE and at the GEJ have similar biologic properties. Based on our data, SSBE and IMGEJ cannot be distinguished on the basis of their immunophenotype.

Topics: Antibodies; Barrett Esophagus; Biomarkers; Esophagogastric Junction; Gastroesophageal Reflux; Humans; Immunophenotyping; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Metaplasia; Retrospective Studies

In combination with androgens, estrogens can induce aberrant growth and malignancy of the prostate gland. Estrogen action is mediated through two receptor subtypes: estrogen receptors alpha (ERalpha) and beta (ERbeta). Wild-type (wt) and transgenic mice lacking a functional ERalpha (alphaERKO) or ERbeta (betaERKO) were treated with the synthetic estrogen diethylstilbestrol (DES). DES induced prostatic squamous metaplasia (SQM) in wt and betaERKO but not in alphaERKO mice, indicating an essential role for ERalpha, but not ERbeta, in the induction of SQM of prostatic epithelium. In order to determine the respective roles of epithelial and stromal ERalpha in this response, the following tissue recombinants were constructed with prostatic epithelia (E) and stroma (S) from wt and ERKO mice: wt-S+wt-E, alphaERKO-S+alphaERKO-E, wt-S+alphaERKO-E, and alphaERKO-S+wt-E. A metaplastic response to DES was observed in wt-S+wt-E tissue recombinants. This response to DES involved multilayering of basal epithelial cells, expression of cytokeratin 10, and up-regulation of the progesterone receptor. Tissue recombinants containing alphaERKO-E and/or -S (alphaERKO-S+alphaERKO-E, wt-S+alphaERKO-E, and alphaERKO-S+wt-E) failed to respond to DES. Therefore, full and uniform epithelial SQM requires ERalpha in the epithelium and stroma. These results provide a novel insight into the cell-cell interactions mediating estrogen action in the prostate via ERalpha.

Topics: Animals; Animals, Newborn; Diethylstilbestrol; Epithelial Cells; Estrogen Receptor alpha; Estrogen Receptor beta; Keratins; Male; Mesoderm; Metaplasia; Mice; Mice, Knockout; Mice, Transgenic; Prostate; Receptors, Estrogen; Receptors, Progesterone; Stromal Cells; Up-Regulation

Accurate tumour classification is critical for meaningful epidemiological studies in the assessment of cancer incidence rates and trends. Differentiating primary gastric carcinoma from oesophageal carcinoma can be difficult, especially when tumours are large and involve both the oesophagus and stomach. Furthermore, adenocarcinomas of both organs typically are of intestinal histological type and arise in a background of intestinal metaplasia. Consequently, histological markers that reliably distinguish Barrett's-related oesophageal adenocarcinoma from gastric adenocarcinoma would be useful. Cytokeratins (CK)7 and 20 are cytoplasmic structural proteins with restricted expression that help to determine the origin of many epithelial tumours including those of the gastrointestinal tract. The aim of this study was to determine the utility of co-ordinate CK7 and 20 expression in the distinction of Barrett's-related oesophageal adenocarcinoma from gastric adenocarcinoma arising in a background of intestinal metaplasia.. CK7 and 20 immunostaining was performed on randomly selected surgical resection specimens from patients with Barrett's-related oesophageal adenocarcinoma (n = 30) and intestinal type gastric adenocarcinoma (n = 14) arising in a background of intestinal metaplasia. A CK7+ CK20- immunophenotype was demonstrated in 27 of 30 (90%) patients with Barrett's-related oesophageal adenocarcinoma and only three of 14 (21%) gastric adenocarcinomas. The sensitivity, specificity and positive predictive value of a CK7+/20- immunophenotype for a diagnosis of Barrett's-related oesophageal adenocarcinoma was 90%, 79%, and 90%, respectively.. A CK7+/20- tumour immunophenotype is associated with Barrett's-related oesophageal adenocarcinoma and may be useful in accurate tumour classification, thus facilitating improving epidemiological evaluation of tumours at the oesophagogastric junction.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Barrett Esophagus; Biomarkers, Tumor; Esophageal Neoplasms; Female; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Male; Metaplasia; Middle Aged; Observer Variation; Predictive Value of Tests; Sensitivity and Specificity; Stomach Neoplasms

A distinctive type of multilayered epithelium (ME) has been described at the neo-squamocolumnar junction and within columnar mucosa in patients with Barrett's esophagus (BE). This epithelium has morphologic and ultrastructural features of both squamous and columnar epithelium. Multilayered epithelium may represent an early or intermediate stage of columnar metaplasia; therefore, we performed this study to determine the morphologic and biologic characteristics of this epithelium and to gain insight into its derivation. Esophageal mucosal biopsies containing ME from 17 patients with BE were evaluated morphologically, stained with a variety of mucin histochemical stains; and also immunostained with antibodies against cytokeratins (CK) 13 (squamous epithelium marker); 14 (basal squamous epithelium marker) 7, 8/18, 19, and 20 (columnar epithelium markers), MIB-1 (proliferation marker); villin (intestinal brush border protein); and TGFalpha, EGFR, pS2, and hSP (enteric proliferation/differentiation regulatory peptides). The results were compared with normal esophageal squamous epithelium, normal gastric cardia epithelium, specialized-type intestinal epithelium (BE), and esophageal mucosal and submucosal gland duct epithelium. Multilayered epithelium expressed a pattern of mucin production (neutral mucin, sialomucin, and sulfomucin in 88%, 100%, and 71% of cases, respectively) and cytokeratin expression (CK 13 and 19 in the basal "squamoid" cells, CK 7, 8/18, 19, and 20 in the superficial "columnar" cells) similar to that of columnar epithelium in BE, and showed a high capacity for cellular proliferation (Ki-67-positive in 88% of cases) and differentiation (TGFalpha, EGFR, pS2 and villin-positive in 100%, 100%, 93%, and 66% of cases, respectively). The mucosal gland duct epithelium showed a similar phenotypic pattern and, in one case, was seen to give rise to ME at the surface of the mucosa. These data provide evidence in support of the hypothesis that ME represents an early or intermediate stage in the development of esophageal columnar metaplasia (BE). The mucosal gland duct epithelium may contain progenitor cells that can give rise to ME.

Topics: Adult; Aged; Aged, 80 and over; Barrett Esophagus; Biomarkers; Biopsy; Epithelium; Esophagogastric Junction; Female; Fluorescent Antibody Technique, Indirect; Gastric Mucosa; Gastroesophageal Reflux; Humans; Keratins; Male; Metaplasia; Middle Aged; Mucins; Retrospective Studies

It has been suggested that Barrett's epithelium and intestinal metaplasia in the gastric cardia have different cyotokeratin (CK) staining patterns and that Barrett's epithelium can be distinguished by CK staining pattern. The aim of this study was to test the utility of CK staining for distinguishing Barrett's esophagus from gastric intestinal metaplasia.. Topographically mapped gastric biopsy specimens were obtained from patients without Barrett's esophagus, and esophageal biopsies were obtained from patients with long-segment Barrett's esophagus (>3 cm). Serial sections were stained with Genta or El-Zimaity triple stain, and biopsies with intestinal metaplasia were stained with antibodies against CK 4, 13, 7, and 20.. Sections from 33 biopsies with Barrett's esophagus, 23 with intestinal metaplasia of the gastric cardia, 27 with intestinal metaplasia of the gastric body, and 33 with intestinal metaplasia of the antrum were examined. CK 4 and CK 13 stained squamous epithelium only. The proposed "diagnostic" CK Barrett's 7/20 pattern was found in only 39% of long-segment Barrett's compared to 35%, 4%, and 24% in intestinal metaplasia from the gastric cardia, body, and antrum, respectively. The criteria proposed had a sensitivity of 45% and a specificity of 65%.. These results do not support keratin phenotyping as a tool for differentiating intestinal metaplasia originating in the cardia from intestinal metaplasia of Barrett's.

Topics: Barrett Esophagus; Biopsy; Cardia; Diagnosis, Differential; Endoscopy; Esophagus; Humans; Intestinal Mucosa; Intestines; Keratins; Metaplasia; Pyloric Antrum; Stomach

We report here the first case of sebaceous gland metaplasia arising within an intraductal papilloma of the breast of a 70-year-old female. Several lobules and nests composed of clear cells closely resembling sebaceous glands of the skin were discovered within an intraductal papilloma of the breast. Squamous metaplasia was also noted in certain areas of the tumor. Immunohistochemically, the cells of the lobules and nests stained positively for monoclonal antibodies anti-cytokeratin 14 and epithelial membrane antigen. This study confirms a novel type of metaplasia of the breast.

Topics: Aged; Apolipoproteins; Apolipoproteins D; Biomarkers, Tumor; Breast Neoplasms; Carrier Proteins; Female; Glycoproteins; Humans; Immunohistochemistry; Keratins; Membrane Transport Proteins; Metaplasia; Mucin-1; Papilloma, Intraductal; Sebaceous Glands

Two novel series of all-trans-beta-retinoic acid derivatives were synthesized and found to possess anticancer activity. The first series, cephalosporin 3'-retinoic esters 6 and 7 were, respectively, obtained by the condensation of all-trans-beta-retinoic acid (2) with cephalosporins 4 and 5. The second series, 7-(retinamido)cephalosporins 11 and 12, were synthesized, respectively, by the condensation of 2 with cephalosporins 9 and 10. These four heretofore undescribed compounds 6, 7, 11, and 12 showed inhibitory activity against murine leukemias (L1210 and P388), sarcoma 180, breast carcinoma (MCF7), and human T-lymphocytes (Molt4/C8 and CEM/0). They also inhibited squamous metaplasia and keratinization in tracheal organ cultures derived from vitamin-A-deficient hamsters. Moreover, cephalosporin 3'-retinoic ester 7 exhibited enhanced activity against keratinization with ED(50)=3.91 x 10(-11) M in the presence of a beta-lactamase from Staphylococcus aureus 95. A tumor targeting fusion protein (dsFv3-beta-lactamase) was also used in conjunction with cephem-based retinoid 7 and the potency of 7 toward L1210, P388, and MCF7 was found to approach that of the free retinoic acid (2). In the presence of dsFv3-beta-lactamase, tumor cells were found to be much more susceptible to retinoid 7 than normal human embryonic lung cells. These notions provide a new approach to the use of beta-retinoic acid for antitumor therapy.

Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; beta-Lactamases; Cell Survival; Cephalosporins; Drug Design; Drug Stability; Esters; Humans; Hydrolysis; Keratins; Kinetics; Magnetic Resonance Spectroscopy; Metaplasia; Mice; Prodrugs; Rats; Solubility; Tretinoin; Tritium; Tumor Cells, Cultured; Water

A peripheral ameloblastoma with atypical features occurring on the left maxillary alveolar ridge of 40-year-old man is described, along with an immunohistochemical profile of its cytokeratin (CK). The lesion apparently originated from the surface gingival epithelium. The tumor nests or strands were highly cellular with a variable degree of squamous differentiation and microcyst formation. Occasional mitotic figures and dystrophic calcification, both of which are not seen in conventional ameloblastomas, were also observed. The tumor infiltrated deep into the alveolar mucosa, including the periodontal ligament, and showed histological and topographical evidence of atypism, resulting in resorption of the underlying alveolar bone. On the CK immunohistochemistry, CK19 was demonstrated in all the types of neoplastic epithelia, including microcyst-forming cells, densely packed round or spindle cells within the tumor nests, cells with squamous metaplasia, and peripheral tall columnar cells. The CK immunohistochemical findings suggest the lesion's cell of odontogenic origin; they may reflect an immature phenotypic expression of cell differentiation in the odontogenic epithelia during the tumor growth in the gingival mucosa.

Topics: Adult; Alveolar Bone Loss; Ameloblastoma; Calcinosis; Cell Differentiation; Epithelium; Gingival Neoplasms; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Mitosis; Mouth Mucosa; Periodontal Ligament; Phenotype

Warthin's tumour is characterized by a bilayered columnar epithelium. Transformation into metaplastic (infarcted) Warthin's tumour includes squamous metaplasia of the epithelium along with regressive changes in the stroma. Misinterpretation of metaplastic Warthin's tumour for malignancy is a serious diagnostic pitfall. This study assesses the utility of cytokeratin expression in Warthin's tumour and its metaplastic variant.. Twenty-six cases of Warthin's tumour, among them eight metaplastic Warthin's tumours, were investigated employing immunohistochemistry. Both Warthin's tumour and its metaplastic variant regularly expressed cytokeratins (CK) 7, 8, 18, and 19. Staining results with antibodies to CK10, 10/13, 1/2/10/11, and 20 were negative in all specimens. Immunoreactivity for CK 5/14 and 17 was restricted to basal cells in Warthin's tumour, but involved basal as well as surface cells in metaplastic Warthin's tumour.. Warthin's tumour and its metaplastic (infarcted) variant both express CK 7, 8, 18, and 19, which are typical for columnar differentiation. Cytokeratins typical of squamous differentiation are absent from Warthin's tumour and its metaplastic variant, irrespective of the squamous morphology of the epithelium in metaplastic Warthin's tumour. The expression of CK 5/14 and 17, which are typical of regenerative cells, is restricted to basal cells in Warthin's tumour, but is expressed also in surface cells in metaplastic Warthin's tumour.

Topics: Adenolymphoma; Aged; Aged, 80 and over; Cell Differentiation; Epithelium; Female; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Middle Aged; Parotid Neoplasms

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

Cytokeratin (CK) 7 and 20 patterns are specific for long and short segments of Barrett's oesophagus but their use has not been assessed in intestinal metaplasia arising in macroscopically normal gastro-oesophageal junction (GOJ).. This study was carried out in a large prospective series of 254 patients who underwent upper endoscopy, had normal gastro-oesophageal anatomy, and who had biopsies of the antrum, fundus, cardia, GOJ, and lower oesophagus. Intestinal metaplasia of the GOJ was typed by histochemistry with high iron diamine-alcian blue staining and by immunohistochemistry using CK7 and CK20 antibodies. Results were correlated with clinical, endoscopic, and pathological data.. Sixty (23.6%) of our patients presenting with a normal GOJ had intestinal metaplasia. The CK7/CK20 pattern identified two groups of patients: one highly correlated with Barrett's and the other with characteristics of Helicobacter pylori gastritis. The Barrett's type CK7/CK20 pattern was related to a high frequency of gastro-oesophageal reflux symptoms (p<0.02) and normal endoscopic appearance of the stomach (p<0.03). In contrast, the gastric type CK7/CK20 pattern was linked to atrophic (p<0.02) or erythematous (p<0.05) appearance of the stomach (p<0.03), high frequency of H pylori infection (p<0.04), antral inflammation (p<0.006) with atrophy (p<0.02), and intestinal metaplasia (p<0.02).. In patients presenting with intestinal metaplasia in normal appearing GOJ, the cytokeratin pattern identifies two groups of patients, one with features identical to those of long segment Barrett's oesophagus and one with features seen in H pylori gastritis. These data may be used by clinicians and should result in improved endoscopic surveillance strategies targeted specifically at patients at increased risk of Barrett's oesophagus and thus cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Barrett Esophagus; Biomarkers; Esophagogastric Junction; Female; Gastritis; Gastroesophageal Reflux; Helicobacter Infections; Helicobacter pylori; Histocytochemistry; Humans; Immunohistochemistry; Intermediate Filament Proteins; Intestines; Keratin-20; Keratin-7; Keratins; Male; Metaplasia; Middle Aged; Prospective Studies; Statistics, Nonparametric

Cancer presumably arises from stem cells, preserved in an undifferentiated status since fetal development, or from a dedifferentiation of mature cells that return into a fetal phenotype with the potential for proliferation and renewal. Dedifferentiation in this context could represent a transient phase, passed through by cells, before they switch to redifferentiation, metaplasia or neoplasia. Cytokeratin-7 (CK7) is present in fetal, largely absent in normal adult, and transiently neoexpressed in metaplastic and neoplastic epithelial cells of the stomach according to previous observations. CK7 neoexpression in the stomach could, hence, define a fetal-like, dedifferentiated, cellular phenotype during the development of metaplasia and neoplasia. To test this hypothesis, we investigated CK7 expressions in fetal stomachs, non-neoplastic control stomachs, and neoplastic stomachs exhibiting metaplasia, intraepithelial neoplasia, and early cancer. Proliferation and beta-catenin expression of CK7-positive cells were also evaluated. The chronology of CK7 expression was studied during the experimental gastritis-cancer sequence in Mongolian gerbils. Our results show that metaplastic and neoplastic changes in the gastritis-cancer sequence are related to dedifferentiated epithelial cells which are defined by CK7 expression and can phenotypically be linked to fetal cells at the start of gastric pit development. The dedifferentiated cells exhibit a low proliferation and beta-catenin accumulation, similar to stem cells. Thus, the "stem cell" and "dedifferentiation" hypotheses for cancer origin could complement one another, and dedifferentiation-redifferentiation processes might be decisive for carcinogenesis in the stomach.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Animals; Carcinoma in Situ; Cell Transformation, Neoplastic; Child; Disease Models, Animal; Epithelial Cells; Female; Fetus; Gastric Mucosa; Gastritis; Gerbillinae; Gestational Age; Helicobacter Infections; Helicobacter pylori; Humans; Keratin-7; Keratins; Male; Metaplasia; Middle Aged; Stomach; Stomach Neoplasms

p63 is a p53-related DNA-binding protein that helps regulate differentiation and proliferation in epithelial progenitor cells. Its expression has never been evaluated in the human gastrointestinal tract. The aim of this study was to evaluate the expression of p63 in the esophagus and related metaplastic and neoplastic disorders to gain insight into the pathogenesis of these processes. Of particular interest was the expression of p63 in Barrett esophagus (BE) and in BE-associated multilayered epithelium. Multilayered epithelium has been postulated to represent an early precursor to the development of BE primarily because it shares morphologic and immunophenotypic features of both squamous and columnar epithelium, and has been shown prospectively to be highly associated with BE. Routinely processed mucosal biopsy or resection specimens that contained normal esophageal squamous epithelium (n = 20), squamous dysplasia (n = 4), squamous cell carcinoma (n = 7), BE (n = 10), BE-associated multilayered epithelium (n = 13), esophageal mucosal gland ducts (n = 10), BE-associated dysplasia (n = 12), and BE-associated adenocarcinoma (n = 7) were immunostained for p63 to determine the extent and location of staining. p63 staining was compared with the staining patterns observed for p53, Ki 67 (proliferation marker), and cytokeratins (CKs) 13 (squamous marker), 14 (basal squamous marker), 8/18 (columnar marker), and 19 (basal/columnar marker). Expression of p63 messenger RNA (mRNA) isoforms was also analyzed by reverse-transcription polymerase chain reaction of freshly isolated tissues. In the normal esophagus, p63 was expressed in the basal and suprabasal layers of the squamous epithelium and in basal cells that line the mucosal gland ducts but was negative in all other epithelia of the gastrointestinal tract, including the stomach, small intestine, and colon. Similarly, p63 was not expressed in BE, but it, was present in the basal layer of multilayered epithelium in 9 of 13 cases (69%). p63-positive cells in multilayered epithelium and in the mucosal gland duct epithelium were positive for CK8/18 (100%) and CK13 (67% and 30%, respectively) and negative for CK14 (0%), in contrast to p63-positive cells in squamous epithelium, which were positive for CK14 and CK13 (100%) but negative for CK8/18. In neoplastic tissues, p63 was diffusely expressed in all cases of esophageal squamous cell dysplasia and carcinoma but was negative in all cases of esophageal and colorectal ad

Topics: Adenocarcinoma; Barrett Esophagus; Carcinoma, Squamous Cell; Digestive System; DNA-Binding Proteins; Epithelium; Esophageal Diseases; Esophageal Neoplasms; Esophagus; Genes, Tumor Suppressor; Humans; Immunohistochemistry; Keratins; Ki-67 Antigen; Membrane Proteins; Metaplasia; Phosphoproteins; Protein Isoforms; Retrospective Studies; RNA, Messenger; Trans-Activators; Transcription Factors; Transcription, Genetic; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Metaplastic carcinoma is a very rare breast neoplasm that is often confused with benign and others malignant entities on both clinical and conventional histopathologic basis. Three cases of metaplastic carcinoma of breast are presented. The difficulties found on fine needle aspiration cytology and the limitations of this procedure are discussed as well the main features of this tumor.

Topics: Adult; Aged; Biopsy, Needle; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Squamous Cell; Cell Differentiation; Diagnosis, Differential; Female; Humans; Keratins; Metaplasia; Middle Aged

Nephrogenic metaplasia with cytologic atypia (atypical nephrogenic metaplasia) is occasionally encountered and its biologic potential is uncertain.. The authors describe 18 cases of atypical nephrogenic metaplasia characterized by the presence of prominent cytologic atypia, including nuclear enlargement, nuclear hyperchromasia, and enlarged nucleoli. DNA ploidy analysis by digital image analysis and immunostaining for high-molecular-weight cytokeratin (34betaE12), cytokeratin 7, cytokeratin 20, carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), p53, and MIB-1 were performed in 9 cases.. The mean patient age was 62 years (median, 65 years; range, 39-84 years). The male-to-female ratio was 2.6:1. Two patients had a history of noninvasive papillary urothelial carcinoma. The typical clinical presentation was hematuria (8 patients) and voiding symptoms (5 patients). Cystoscopic findings were suspicious for neoplasm in 7 of 13 cases. The neoplastic cells were positive for high-molecular-weight cytokeratin, cytokeratin 7, and EMA, and were usually negative for cytokeratin 20 and CEA. p53 nuclear accumulation and increased MIB-1 labeling index were seen in 4 cases. DNA ploidy analysis showed aneuploid pattern in 2 of 9 cases. The mean patient follow-up was 3.5 years (range, 0.5-10.6 years); 2 patients had recurrent nephrogenic metaplasia, and the remainder were alive without recurrence or urothelial carcinoma.. Atypical nephrogenic metaplasia is benign; it occasionally displays substantial cytologic abnormalities of no apparent clinical significance. Awareness of the spectrum of cytologic changes within this entity is critical to prevent overdiagnosis of cancer and avoid unnecessary treatment. There is no direct evidence that links atypical nephrogenic metaplasia to cancer.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoembryonic Antigen; Diagnosis, Differential; DNA; Female; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Middle Aged; Mucin-1; Ploidies; Precancerous Conditions; Tumor Suppressor Protein p53; Urinary Tract; Urologic Neoplasms

A model of rabbit tracheal epithelial (RTE) cells in primary culture was used to characterize specific and repair responses of airway epithelial cells to oxidative stress. Two well-known reactive oxygen species (ROS) generating systems were used: H(2)O(2) alone or in combination with Fe(2+) to produce the hydroxyl radical. RTE cells exhibited lipid peroxidation when exposed to H(2)O(2) + Fe(2+). Moreover, catalase (CAT) activity decreased after a 1-hour treatment in 3-day-old cultures but increased in 7-day-old cultures which have higher antioxidant enzyme activities. Superoxide dismutase (SOD) activity was never affected. In addition, RTE cells displayed a repair response leading to squamous metaplasia. H(2)O(2) + Fe(2+) treatment resulted in a time-dependent increase in the steady-state level of c-myc mRNA while c-jun and c-fos were not activated. Moreover, a chronic exposure induced the expression of the squamous phenotype characterized by the expression of the cytokeratin 13 confirmed both at the message and protein levels. RTE cells in primary culture react early to H(2)O(2) + Fe(2+) exposure by an increase in c-myc expression and by modifications in CAT activity. Further, a lipid peroxidation occurs and the tracheal epithelium evolves to squamous metaplasia.

Topics: Animals; Blotting, Western; Catalase; Cell Survival; Epithelium; Hydrogen Peroxide; Keratins; L-Lactate Dehydrogenase; Lipid Peroxidation; Malondialdehyde; Metaplasia; Oncogene Proteins; Oxidants; Oxidative Stress; Phenotype; Rabbits; RNA; Superoxide Dismutase; Trachea

The roles of the different retinoid receptors on the differentiation of rabbit tracheal epithelial (RbTE) cells in primary culture were analysed using selective agonists for the retinoid acid receptor subtypes RARalpha (CD336), RARbeta (CD2019), RARgamma (CD437), an RAR panagonist (CD367), a retinoid X receptor RXR panagonist (CD2624) and an antagonist for RARbeta/gamma (CD2665). Squamous differentiation was assessed via expression of cytokeratins CK13/CK4 and transglutaminase I (TGI), specific markers of metaplasia. Treatment with RARalpha and beta agonists or RAR panagonist, but not the RARgamma agonist or RXR agonist, is required for the inhibition of squamous metaplasia, evidenced by inhibition of CK13/CK4 and TGI expression. The expression of CK10 cytokeratin of keratinizing epithelia, CK14/CK5 basal cell cytokeratins, and CK6 marker of cell proliferation decreases upon exposure of the RARaalpha/beta and RXR agonists. The RARgamma agonist CD437, inactive in the decrease in CK13/CK4, CK10 and CK14, reduces CK5/CK6 amounts. CD437 is responsible for a dose-dependent apoptotic response. Nuclear labelling with propidium iodide (PI) and electron microscopy revealed chromatin condensation and nuclear fragmentation. DNA cleavage and cell fragmentation were confirmed by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. The RARbetagamma antagonist was also slightly active. The results indicate that CD437 causes growth arrest in the early S-phase of the cell cycle and prevents the transition G1-S-phase. CD437 was demonstrated to induce apoptosis in the S-phase cells identified by bromodeoxyuridine (BrdU) incorporation. In conclusion, RARalpha/beta ligands are effective inhibitors of squamous differentiation. On the contrary, RARgamma ligand appears to be inefficient in metaplasia inhibition, but the selective RARgamma agonist CD437 induces growth arrest and apoptosis of basal proliferative cells.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzoates; Cell Differentiation; Cells, Cultured; DNA Fragmentation; Epithelial Cells; Keratins; Ligands; Metaplasia; Microscopy, Electron; Naphthalenes; Necrosis; Rabbits; Receptors, Retinoic Acid; Retinoids; S Phase; Teratogens; Tetrahydronaphthalenes; Trachea

The origin of intestinal metaplasia in short segments of columnar mucosa at the esophagogastric junction has clinical importance but can be difficult to determine at endoscopy. Cytokeratin (CK) 7 and 20 patterns are specific for long-segment Barrett's esophagus; however, their utility in short-segment Barrett's esophagus has not been assessed.. Endoscopic biopsy specimens from patients with long-segment Barrett's esophagus (n = 49), suspected short-segment Barrett's esophagus (n = 43), and gastric intestinal metaplasia (n = 26) were immunostained for CK7 and CK20. Comprehensive clinical data were obtained, including age, gender, and hiatal hernia and Helicobacter pylori status.. A Barrett's CK7/20 pattern was present in 48 (98%) of 49 patients with long-segment Barrett's esophagus, 35 (82%) of 43 with suspected short-segment Barrett's esophagus, and 0 (0%) of 26 patients with gastric intestinal metaplasia. Patients with suspected short-segment Barrett's esophagus with a Barrett's CK7/20 pattern were clinically similar to those with long-segment Barrett's esophagus. In contrast, patients with suspected short-segment Barrett's esophagus with no Barrett's CK7/20 pattern were clinically similar to those with gastric intestinal metaplasia.. A Barrett's CK7/20 pattern identifies a subset of patients with suspected short-segment Barrett's esophagus who have a patient profile similar to that seen in long-segment Barrett's esophagus. A Barrett's CK7/20 pattern is an objective marker of Barrett's mucosa that in conjunction with appropriate clinical and endoscopic data can be used by clinicians to better define patients with short-segment Barrett's esophagus.

Topics: Aged; Barrett Esophagus; Cohort Studies; Esophagoscopy; Esophagus; Female; Gastric Mucosa; Humans; Immunologic Techniques; Intermediate Filament Proteins; Intestinal Mucosa; Intestines; Keratin-20; Keratin-7; Keratins; Male; Metaplasia; Middle Aged; Mucous Membrane; Observer Variation; Stomach

The purpose of this study was to study the morphology and cytokeratin expression in the epithelia of pterygia. Impression cytology and immunohistochemical staining with antikeratin antibodies were performed in 32 eyes of 16 patients with pterygia. TUNEL stain and electron microscopy were also performed in surgical specimens ofpterygium. Squamous metaplasia-like epithelial cells were found in all specimens of impression cytology, especially in the head part. These specimens had positive immunostaining by antipancytokeratin antibodies, but not by anti-K12 AK2 mAb. Goblet cells were found around the area of these abnormal epithelial cells. TUNEL-positive cells were found in the epithelia of the pterygial head, but not in the body of pterygia and normal conjunctiva. The expressional patterns of keratin by these epithelial cells ofpterygia are consistent with the notion that they are derived from conjunctival epithelium and mimic the process of squamous metaplasia.

Topics: Aged; Aged, 80 and over; Epithelium; Female; Fluorescent Antibody Technique, Indirect; Humans; Immunoenzyme Techniques; In Situ Nick-End Labeling; Keratins; Male; Metaplasia; Middle Aged; Pterygium

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

To clarify the correlation between multidirectional differentiation and aggressiveness of endometrial adenocarcinomas, we assessed both proliferative activities (PA) using Ki-67 expression and squamous and/or endocrine differentiation. We divided 51 adenocarcinomas into 22 adenocarcinomas with typical squamous differentiation (>/=10% of tumor cells, typical SQ) classified into 10 adenoacanthomas (AA) and 12 adenosquamous carcinomas (AS), 17 adenocarcinomas with focal squamous differentiation (<10% of tumor cells), and 12 typical adenocarcinomas without morphological squamous differentiation (pure AC), according to the new WHO classification. Paraffin-embedded sections were stained using monoclonal antibodies against high-molecular-weight keratins (HMWK) to recognize squamous cells, chromogranin A to recognize endocrine cells, and Ki-67 antigen to recognize proliferating cells. Both AA and AS exhibited lower PA than pure AC. Typical SQ exhibited lower PA than pure AC. This difference was also significant after selecting only grade 1 or stage I/II cases. AA exhibited lower PA than AS and also after selecting only grade 1 or stage I/II cases. PA of adenocarcinoma with the expression of HMWK in >/=30% of tumor cells was lower than those without HMWK. PA of adenocarcinoma with the expression of chromogranin A in >/=10% of tumor cells was lower than those without chromogranin A. These differences were also significant after selecting only grade 1 or stage I/II cases. Squamous and/or endocrine differentiation is a good marker for a reduction of PA. Endometrial adenocarcinomas with multidirectional differentiation exhibited lower PA and were likely to be more mature than those with monodirectional differentiation.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Carcinoma, Adenosquamous; Cell Transformation, Neoplastic; Chromogranin A; Chromogranins; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Keratins; Ki-67 Antigen; Metaplasia; Middle Aged; Neoplasm Invasiveness

The histological distinction between intestinal metaplasia involving the distal esophagus (Barrett's esophagus [BE]) and intestinal metaplasia of the stomach has important clinical implications and can be difficult even with the use of histochemical mucin stains. Cytokeratin (CK) 7 and 20 are cytoplasmic structural proteins that show restricted expression in normal and malignant epithelia of the gastrointestinal tract. The aim of this study was to determine the use of CK7 and 20 expression in the histological distinction of BE from gastric intestinal metaplasia. CK7 and 20 immunostaining was performed on randomly selected surgical resection (n = 31) and biopsy specimens (n = 34) from patients with long-segment BE and gastric resection specimens (n = 11) and gastric cardia biopsy specimens (n = 13) in patients with histological evidence of intestinal metaplasia. A unique pattern of immunoreactivity designated the Barrett's CK7/20 pattern showed superficial CK20 staining and strong CK7 staining of both superficial and deep glands in 29 of 31 (94%) esophageal resection specimens and 34 of 34 (100%) esophageal biopsy specimens form patients with long-segment BE. A Barrett's CK7/20 pattern was not observed in gastric cardia biopsy specimens (n = 13) or gastric resection specimens (n = 11) in patients with histological evidence of intestinal metaplasia. The sensitivity, specificity, and positive predictive value of a Barrett's CK7/20 pattern for a diagnosis of long-segment BE was 97%, 100%, and 100%, respectively. CK7 and 20 reactivity patterns can reliably identify the location of intestinal metaplasia in the esophagus and stomach using histological material from both routine endoscopic biopsy and surgical resection specimens.

Topics: Barrett Esophagus; Biomarkers; Biopsy; Diagnosis, Differential; Esophagus; Female; Humans; Immunohistochemistry; Intermediate Filament Proteins; Intestines; Keratin-20; Keratin-7; Keratins; Male; Metaplasia; Stomach

Transitional, glandular, and squamous epithelia show distinctive patterns of expression of cytokeratins 13, 17, 18, and 20. Furthermore, some markers, such as cytokeratin (CK) 20 and the asymmetric unit membrane, are related to terminal urothelial differentiation, their expression limited to superficial and occasional intermediate cells. In this study, seven cases fulfilling the morphologic criteria of transitional metaplasia of the uterine cervix were investigated with these markers to determine whether there was evidence of true urothelial-type differentiation in these lesions. Results were consistent and showed clear differences between the squamous, glandular, and metaplastic transitional areas of the cervix. In particular, the expression of CK13, CK17, and CK18 in the metaplastic areas was identical to the pattern observed in normal urothelium. However, full urothelial differentiation was not observed, as CK20 and asymmetric unit membrane were never expressed in the transitional metaplasia. Based on these findings, the term of immature transitional metaplasia would be a more accurate description of this entity.

Topics: Aged; Biomarkers; Cell Differentiation; Cervix Uteri; Female; Humans; Immunohistochemistry; Immunophenotyping; Keratins; Metaplasia; Middle Aged; Urothelium

There are many similarities in the morphology of benign and malignant lesions of the sweat glands and the breasts. The recently described cutaneous mammary-like sweat glands, also known as mixed sweat glands or apoeccrine glands, are also a likely source of selected proliferations that closely mimic those of the breast. We present three cases of breast-like lesions arising in the skin that demonstrate the ways in which the morphologic and pathologic continuum of the mammary glands, cutaneous mammary-like glands, and sweat glands can produce difficulties in precise diagnosis. The examples demonstrate that an anatomic location outside the milk line does not preclude the diagnosis of ectopic mammary tissue, and that lesions closely resembling those of the breast may also arise outside the milk line from conventional sweat glands or mixed sweat glands. The concept of homologous lesions of the breast, breast-like glands and sweat glands, in which morphology is partially mirrored by biochemical similarities, provides a perspective for classification of problematic cases of breast-like cutaneous lesions.

Topics: Adult; Apolipoproteins; Apolipoproteins D; Breast; Carcinoembryonic Antigen; Carrier Proteins; Choristoma; Diagnosis, Differential; Female; Glycoproteins; Humans; Immunohistochemistry; Keratins; Membrane Transport Proteins; Metaplasia; Receptors, Progesterone; S100 Proteins; Skin; Sweat Glands

Ovarian carcinomas are thought to arise in the ovarian surface epithelium (OSE). Although this tissue forms a simple epithelial covering on the ovarian surface, OSE cells exhibit some mesenchymal characteristics and contain little or no E-cadherin. However, E-cadherin is present in metaplastic OSE cells that resemble the more complex epithelia of the oviduct, endometrium and endocervix, and in primary epithelial ovarian carcinomas. To determine whether E-cadherin was a cause or consequence of OSE metaplasia, we expressed this cell-adhesion molecule in simian virus 40-immortalized OSE cells. In these cells the exogenous E-cadherin, all three catenins, and F-actin localized at sites of cell-cell contact, indicating the formation of functional adherens junctions. Unlike the parent OSE cell line, which had undergone a typical mesenchymal transformation in culture, E-cadherin-expressing cells contained cytokeratins and the tight-junction protein occludin. They also formed cobblestone monolayers in two-dimensional culture and simple epithelia in three-dimensional culture that produced CA125 and shed it into the culture medium. CA125 is a normal epithelial-differentiation product of the oviduct, endometrium, and endocervix, but not of normal OSE. It is also a tumor antigen that is produced by ovarian neoplasms and by metaplastic OSE. Thus, E-cadherin restored some normal characteristics of OSE, such as keratin, and it also induced epithelial-differentiation markers associated with weakly preneoplastic, metaplastic OSE and OSE-derived primary carcinomas. The results suggest an unexpected role for E-cadherin in ovarian neoplastic progression.

Topics: Actins; Cadherins; Cell Differentiation; Cell Line, Transformed; Cell Transformation, Neoplastic; Cytoskeletal Proteins; Epithelial Cells; Female; Humans; Keratins; Mesoderm; Metaplasia; Ovary; Simian virus 40

A resected esophagus with numerous heterotopic sebaceous glands was examined in an attempt to determine whether esophageal heterotopic sebaceous glands are the result of a metaplastic process or a congenital anomaly. The present case concerns a 79-year-old Japanese man with numerous esophageal heterotopic sebaceous glands accompanied by superficial esophageal cancer. The resected esophagus possessed numerous heterotopic sebaceous glands, which could be seen clearly as slightly elevated, yellowish lesions. Histological examination of these glands, all of which were located in the lamina propria, revealed lobules of cells that showed characteristic sebaceous differentiation. Bulbous nests of proliferating basal cells showing sebaceous differentiation were occasionally observed in the esophageal epithelium. Of the antibodies against six different keratins used, only anti-keratin 14 labeled both the heterotopic sebaceous glands and the bulbous nests. Acquired metaplastic change of the esophageal epithelium is probably the pathogenetic mechanism involved in these unusual lesions.

Topics: Aged; Carcinoma, Squamous Cell; Choristoma; Esophageal Diseases; Esophageal Neoplasms; Humans; Immunohistochemistry; Keratin-14; Keratins; Male; Metaplasia; Sebaceous Glands

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

Collagenous spherulosis (CS) is a rare lesion which is an incidental finding in breast and salivary glands. It is characterized by fibrillar spherules exhibiting an intrinsic radiating or concentric pattern which are surrounded by myoepithelial cells. This entity can be misdiagnosed as adenoid cystic carcinoma and in-situ ductal carcinoma.. We report here the first case of CS arising in a borderline endometrioid tumour of the ovary where it merged with squamous metaplasia.. This observation illustrates another pitfall of CS which can be misidentified as keratin pearls. The pathogenesis remains unclear but it has been claimed that the accumulation of basement membrane material may be due to the proliferation of pre-existing myoepithelial cells that secrete matrix components. Since ovarian tumours do not contain myoepithelial cells, one should assume that the epithelial cells differentiate towards myoepithelial cells as it has been shown in vitro and ex vivo.

Topics: Adult; Carcinoma, Endometrioid; Collagen; Diagnosis, Differential; Diagnostic Errors; Extracellular Matrix; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Ovarian Cysts; Ovarian Neoplasms; Ovary

Retinoic acid is necessary for the growth and differentiation of organisms and exerts its molecular actions by binding to specific nuclear receptors that belong to the thyroid-steroid hormone receptor superfamily. Steroids and retinoids control the differentiation of the female reproductive epithelia: estrogen maintains the squamous differentiation of vaginal and ectocervical epithelia, whereas retinoic acid maintains the simple columnar endocervical and uterine epithelia. These lining epithelia transform into a squamous metaplastic phenotype in vitamin A-deficient animals. Furthermore, mortality due to vitamin A deficiency is usually attributed to infection resulting in part from dysfunction of the protective epithelia.. Our objective was to test the hypothesis that estrogen depletion might change the squamous metaplastic response to vitamin A deficiency and affect animal survival.. We used female SENCAR mice maintained on a purified vitamin A-deficient diet containing either 0 or 3 microg retinoic acid/g diet. Mice were either ovariectomized or intact. Squamous cells arising in the normally simple columnar epithelium of the endocervix and uterine cavity were monitored by keratin 5 expression with immunohistochemistry.. Ovariectomy did not change the time to onset of vitamin A deficiency. It increased the number of squamous metaplastic cells and prolonged survival in mice consuming a vitamin A-deficient diet by as much as 40%.. Factors other than epithelial differentiation per se control survival outcome of vitamin A-deficient mice. The results also show a significant increase in longevity of vitamin A- deficient mice when ovariectomized.

Topics: Animals; Epithelium; Female; Immunohistochemistry; Keratins; Metaplasia; Mice; Mice, Inbred SENCAR; Ovariectomy; Uterus; Vitamin A Deficiency

Nephrogenic Adenoma (NA) is a rare lesion of the urinary tract, considered a metaplastic response to chronic inflammation, trauma or immunosuppression.. We report two cases of NA arising in the urinary bladder of patients with previous history of recurrent urinary tract infections due to neuropsychiatric disease. Pathological examination of the lesions, resected by transurethral (TUR) management, revealed a papillary proliferation of tubules and cysts lined by cuboidal to low-columnar cells without atypia. Immunohistochemistry showed positivity for Cam 5.2, CK7 and EMA. MIB 1 count demonstrated a positivity in 12/200 cells in case 1 and < 2/200 in case 2. No expression of nuclear p53 was evident.. NA is a benign unusual neoplasm which might be misdiagnosed as clear cell adenocarcinoma of the bladder or prostatic adenocarcinoma. Its recognition is important because it is a benign lesion cured by a conservative resection and no additional therapy is generally required.

Topics: Adenocarcinoma; Adenocarcinoma, Clear Cell; Adenoma; Antigens, Nuclear; Biomarkers, Tumor; Calbindin 2; Carcinoma in Situ; Carcinoma, Transitional Cell; Diagnosis, Differential; Epithelial Cells; Female; Humans; Immunophenotyping; Keratins; Ki-67 Antigen; Male; Metaplasia; Middle Aged; Mucin-1; Neoplasm Proteins; Neoplasms, Multiple Primary; Nuclear Proteins; Prostatic Neoplasms; Protein Isoforms; S100 Calcium Binding Protein G; Urinary Bladder Neoplasms

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

A distinctive variant of a papillary noninvasive transitional cell carcinoma (TCC) of the vagina removed from a postmenopausal woman is described. The neoplasm was evaluated by immunohistochemistry. The designation of this neoplasm as a TCC is supported by its morphological features and its coexpression for cytokeratin (CK) 7 and CK 20. Its main feature is pagetoid infiltration into adjacent vaginal epithelium. This is the second reported case involving a transitional cell metaplasia (TCM) of the vagina, a possible precursor lesion of the TCC.

Topics: Adult; Carcinoma, Transitional Cell; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Postmenopause; Urinary Bladder Neoplasms; Vagina; Vaginal Neoplasms

An autopsied case of an 80-year-old man with spindle cell carcinoma of the gingiva is reported. The tumor was polypoid and mostly composed of a sarcomatous proliferation of spindle cells with a small focus of squamous cell carcinoma at the stalk portion. The carcinoma metastasized to a cervical lymph node, lungs and pleura with extension to the diaphragm. In the metastatic lymph node, the squamous cell component was more prominent than the spindle cell one, while only anaplastic pleomorphic carcinoma cells were found in the lungs. The spindle or anaplastic cells were immunohistochemically positive for vimentin and carcinoembryonic antigen (CEA) but not for other epithelial antigens. We have concluded that the sarcomatoid component arose from the oral squamous cell carcinoma by a metaplastic process. This is the first case report of an oral spindle cell carcinoma examined by autopsy.

Topics: Aged; Aged, 80 and over; Anaplasia; Autopsy; Carcinoembryonic Antigen; Carcinoma; Carcinoma, Squamous Cell; Diaphragm; Gingival Neoplasms; Humans; Keratins; Lung Neoplasms; Lymphatic Metastasis; Male; Metaplasia; Mucin-1; Neoplasms, Multiple Primary; Pleural Neoplasms; Vimentin

The retinal pigment epithelium (RPE) can undergo reactive hyperplasia and metaplasia following a variety of ocular insults. However, true neoplasms of the RPE are rare. We report a case of a papillary adenocarcinoma of the RPE arising in the blind staphylomatous right eye of a 79-year-old woman with a long history of bilateral posterior staphylomas who was seen with increasing pain and exophthalmos of the right eye. Findings from ultrasonography and computed tomography demonstrated linear calcification consistent with osseous metaplasia of the RPE. Progression of the exophthalmos and worsening exposure keratitis led to enucleation of the eye. Gross pathology showed a 79-mm-long globe. Histopathologic findings revealed a largely amelanotic papillary adenocarcinoma arising from the RPE. Positive immunoreactivity for cytokeratin supported the epithelial origin of the tumor. Adenocarcinoma of the RPE is rare but may develop in a blind eye.

Topics: Adenocarcinoma, Papillary; Aged; Biomarkers, Tumor; Blindness; Calcinosis; Exophthalmos; Eye Enucleation; Female; Humans; Keratins; Magnetic Resonance Imaging; Metaplasia; Pain; Pigment Epithelium of Eye; Retinal Neoplasms; Scleral Diseases; Tomography, X-Ray Computed

Topics: Administration, Topical; Animals; Conjunctiva; Cyclosporine; Dog Diseases; Dogs; Keratins; Keratoconjunctivitis Sicca; Metaplasia

A 54-year-old patient, who had a remote history of radial nephrotomy for nephrolithiasis, presented with a symptomatic renal mass. The lesion was suspicious for malignancy on excretory urography, retrograde pyelogram, and computed tomography. A nephroureterectomy was performed. The histologic sections showed keratinizing squamous metaplasia.

Topics: Carcinoma, Transitional Cell; Diagnosis, Differential; Female; Humans; Keratins; Kidney; Kidney Neoplasms; Metaplasia; Middle Aged

Metaplastic carcinomas of the breast are defined by mesenchymal and/or squamous cell components associated with ductal carcinoma and may raise diagnostic problems in FNA cytology. We reviewed FNA smears of a series of nine cases; seven were compared with histological sections and two with cell-block sections. The cytological pattern was diagnostic of carcinoma in six cases; in two cases a diagnosis of sarcoma/phyllodes tumour was considered, as cells were predominantly spindle-shaped. One case had a pleomorphic adenoma type pattern. The cytological findings suggesting a diagnosis of metaplastic carcinoma include a liquid aspirate, a proteinaceous or chondromyxoid background and a poorly differentiated tumour with multinucleated giant cells, neoplastic or histiocytic. A definite diagnosis requires the presence of both carcinomatous and metaplastic (squamous/mesenchymal) components.

Topics: Adult; Aged; Biopsy, Needle; Breast Neoplasms; Carcinoma; Carcinoma, Adenosquamous; Carcinoma, Ductal, Breast; Carcinosarcoma; Diagnosis, Differential; Female; Giant Cells; Humans; Immunohistochemistry; Keratins; Metaplasia; Middle Aged; Phyllodes Tumor; Vimentin

The presence of keratin in the middle ear cavity is usually associated with the diagnosis of cholesteatoma or epidermoid metaplasia. Analysis of a series of 18 cases suggests that it may correspond to a specific entity developing in the course of severe or long-lasting opened chronic otitis. This condition, we called mallear epidermosis, is characterized by: i) a perforation of the tympanic membrane lining the handle of the malleus and the umbo; ii) a proliferation of keratin surrounding the handle of the malleus and diffusing into the mesotympanum on the internal side of the tympanic membrane, without matrix; and iii) a mild inflammation of the middle ear epithelium. The process is usually limited to the mesotympanum and does not extend towards the attic and the posterior cavities. Epidemiological, clinical, pathophysiological, and histological features allow this entity to be distinguished from cholesteatoma and epidermoid metaplasia. Management is either medical consisting of local treatment and microaspiration, or surgical including resection of the umbo, removal of the tympanic membrane invaded by the adherent hyperkeratotic layers and repair by conventional underlay myringoplasty. This report emphasizes the need for a clear identification of the various types of chronic otitis media presenting with keratin in the middle ear, as they do not share the same course and do not require the same therapeutic management.

Topics: Adolescent; Adult; Aged; Cholesteatoma, Middle Ear; Chronic Disease; Diagnosis, Differential; Ear, Middle; Epithelium; Female; Humans; Keratins; Male; Malleus; Metaplasia; Middle Aged; Myringoplasty; Otitis Media; Suction; Tympanic Membrane; Tympanic Membrane Perforation

Retinoids are thought to be required for the normal development and maturation of a number of tissues, including most epithelia. The action of retinoids appears to be mediated through the binding to retinoic acid receptors (RARs) in the nucleus. The activity of retinoic acid can be inhibited in cells carrying dominant negative mutations of RAR alpha. We created transgenic mice expressing a dominant negative mutant of RAR alpha driven by the murine mammary tumor virus promoter. Expression of the transgene was evident in the epididymis and vas deferens in transgenic males. These males were either infertile or had reduced fertility, and the epithelium lining the ducts of the epididymis and vas deferens had undergone squamous metaplasia. Sperm developed normally in the testis but degenerated in the epididymis and vas deferens because inspissated ductal fluid blocked the normal passage of the sperm.

Topics: Animals; Epididymis; Female; Genes, Dominant; Genes, myc; Humans; Immunohistochemistry; Infertility, Male; Keratins; Litter Size; Male; Mammary Tumor Virus, Mouse; Metaplasia; Mice; Mice, Inbred C3H; Mice, Transgenic; Mutation; Promoter Regions, Genetic; Receptors, Retinoic Acid; Recombinant Proteins; Retinoic Acid Receptor alpha; Spermatozoa; Vas Deferens

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

To test the hypothesis that the aberrant, cytokeratin-expressing cells that replace endothelium in the iridocorneal endothelial (ICE) syndrome are of endothelial origin.. Corneas from four patients with Chandler's syndrome and three with essential iris atrophy were examined by two-color immunofluorescence for simultaneous expression of cytokeratins and two markers of endothelial lineage: vimentin and the antigen recognized by the antiendothelial monoclonal antibody 2B4.14.1.. In six corneas, unequivocal endothelial staining for cytokeratins was present; in each of these, cells coexpressing cytokeratins and the two endothelial markers were clearly identifiable. In the remaining cornea, weak cytokeratin staining that colocalized with vimentin was present.. These results lend strong support to the hypothesis that the "epithelial-like" endothelial cells in ICE syndrome are cells of endothelial lineage rather than heterotopia of epithelial cells; these cells probably arise via a metaplastic transformation of preexisting endothelium.

Topics: Adult; Aged; Antibodies, Monoclonal; Corneal Diseases; Endothelium, Corneal; Fluorescent Antibody Technique, Indirect; Humans; Iris Diseases; Keratins; Metaplasia; Middle Aged; Syndrome; Vimentin

A case of primary or idiopathic squamous metaplasia of the breast occurring in a 45-year-old woman is presented. Immunohistochemical studies suggested that the metaplasia had arisen in ductular epithelium. No evidence of neoplasia was identified.

Topics: Biomarkers, Tumor; Breast; Epithelium; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Middle Aged; Mucin-1

Topics: Humans; Keratins; Kidney Diseases; Male; Metaplasia; Middle Aged; Ureteral Diseases

Genuine adenocarcinomas of the ureter are rare tumors and have to be distinguished from other gland-forming malignancies arising from the transitional epithelium, due to the poor clinical outcome. The histopathological features of a tumor combined with intestinal metaplasia of the adjacent urothelium are described. The tumor has to be distinguished from transitional cell cancer with glandular metaplasia, muco-urothelial cancer, microcystic transitional cell cancer and transitional cell cancer with mucoid cytoplasmatic inclusions. Immunohistochemical analysis of the cancer shows positivity for carcinoembryonic antigen and a staining pattern characteristic for adenocarcinomas. The expression of keratin types 7 and 13, which is typically found in transitional cell carcinomas, is lost.

Topics: Adenocarcinoma; Aged; Carcinoembryonic Antigen; Carcinoma, Transitional Cell; Diagnosis, Differential; Humans; Immunoenzyme Techniques; Keratins; Male; Metaplasia; Mucin-1; Neoplasm Proteins; Ureteral Neoplasms

The first case of sebaceous gland metaplasia arising in cardiac-type mucosa of the oesophago-gastric junction of 71-year-old man is reported. Within cardiac glands, small nests composed of clear cells closely resembling sebaceous glands of the skin were found. Immunohistochemically, the cell nests stained positively for a monoclonal antibody 115D8 against milk-fat globule membrane (MAM-6). These cells were sometimes covered by cylindrical cells positive for foveolar-type mucin of the stomach (MI), and basal marginal cells of these nests expressed high molecular weight cytokeratins (34BE12). This study documents a new type of metaplasia of the gastric mucosa.

Topics: Aged; Esophagogastric Junction; Gastric Mucosa; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Molecular Weight; Mucin-1; Mucins; Sebaceous Glands

Ep-CAM, an epithelial adhesion molecule, is absent in normal squamous epithelia but can be detected in some squamous carcinomas. Using a panel of monoclonal antibodies to keratinocyte differentiation and proliferation markers, we investigated the association of EP-CAM expression with differentiation-related and/or neoplastic changes in cervical epithelium. Normal endocervical glandular epithelium (Both columnar and reserve cells) appeared strongly positive for EP-CAM, whereas ectocervical squamous epithelial cells did not express this molecule. Expression of Ep-CAM (in basal cells) was sometimes observed in morphologically normal ectocervical tissue but only in areas bordering cervical intraepithelial neoplasia (CIN) lesions. At the early stages of neoplasia the expression of Ep-CAM was regularly present in squamous epithelium, in general consistent with the areas of atypical, undifferentiated cells. Thus, in CIN grades I and II, the basal/suprabasal layers of the epithelia were positive, whereas in CIN grade III lesions, up to 100% of the cells over the whole thickness of the epithelium sometimes excluding the very upper layers, expressed Ep-CAM. A clear increase, not only in number of positive cells but also in levels of Ep-CAM expression (intensity) was observed during progression from CIN I to CIN III. Expression of Ep-CAM in ectocervical lesions did not coincide with a reappearance of the simple epithelium cytokeratins (CK8 and CK18). On the other hand, expression of Ep-CAM in atypical cells of CIN lesions correlated with the disappearance of CK13, which normally marks cells undergoing squamous differentiation. As was shown with Ki-67, a marker for proliferating cell populations, the areas of Ep-CAM expression were also the areas of enhanced proliferation. Cells expressing Ep-CAM did not express involucrin, a marker for cells committed to terminal differentiation. In the majority of both squamous and adenocarcinomas of the cervix a strong expression of Ep-CAM was observed, although some decrease in the expression (both the intensity and the number of positive cells), as compared with CIN III lesions, was observed in the areas of squamous differentiation. This study demonstrates that the expression of Ep-CAM in cervical squamous epithelium is associated with abnormal proliferation of cell populations that are not committed to terminal differentiation.

Topics: Antigens, Neoplasm; Biomarkers; Biomarkers, Tumor; Cell Adhesion Molecules; Cell Differentiation; Cell Division; Cervix Uteri; Epithelial Cell Adhesion Molecule; Epithelium; Female; Humans; Keratins; Metaplasia; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Our previous studies have shown that epidermal mucous metaplasia of chick embryonic skin can be induced by culture in medium containing 20 microM retinol for only 8 hr and then in a chemically defined medium without retinol for 2 days and that retinol primarily affects the dermal cells, which then transform the epithelial cells into mucus-secreting cells.. Tarsometatarsal skin of 13-day-old chick embryo was cultured with 20 microM retinol for 1 day and then without the vitamin but with 0.1 microgram/ml tunicamycin for 5 days. Effect of tunicamycin on epidermal mucous metaplasia was studied biochemically and morphologically.. Tunicamycin, which prevents the formation of N-glycans and inhibits maturation or morphological organization of various epithelial cells, irreversibly inhibited the synthesis of sulfated glycoproteins (O-glycans, mucin) in the epidermis only when applied to retinol-pretreated skin. Microvilli on the surface of the cells were well developed, but mucous granules surrounded by a limiting membrane were not observed in the upper cell layer of the epidermis, and many vesicles without electron-dense materials (mucin) and dilated rough endoplasmic reticulum were seen in the intermediate cell layers of the epidermis. When recombinants of 13-day-old normal epidermis and cultured dermis, which had been treated with retinol for 24 hr and with only tunicamycin for 2 days, were cultured without the antibiotic for 5 days, epidermal mucous metaplasia was induced.. These results suggest that tunicamycin did not prevent morphological changes induced by retinol but inhibited mucin synthesis by a direct action on the epidermis of retinol-pretreated skin. Because in some cell-line mucin precursors contain high mannose N-linked oligosaccharides side chains, tunicamycin may have inhibited mucin synthesis. Interaction between epidermal basal cells and retinol-pretreated dermal fibroblasts is prerequisite for epidermal mucous metaplasia. Thus, the present study suggests that N-linked protein glycosylation is not required for this interaction.

Topics: Animals; Chick Embryo; Cytoplasmic Granules; Electrophoresis; Epidermis; Glycoproteins; Hydrocortisone; Keratins; Metaplasia; Mucins; Mucus; Proteins; Skin; Tunicamycin; Vitamin A

Mucinous syringometaplasia (MS) is an unusual skin lesion of unknown etiology, characterized histologically by epidermal invaginations lined by mucin-laden goblet-like cells and by nonkeratinized squamous cells. The present case study was performed to elucidate further the characteristics of this lesion using immunohistochemistry and electron microscopy. The mucin-laden cells in the MS lesion stained positively for carcinoembryonic antigen, epithelial membrane antigen, and low molecular weight keratins. The ultrastructural examination, which was performed on deparaffined sections, revealed two morphological variants of mucous granules. Electron-dense mucous granules predominated in the mucus-containing cells, which were situated among the keratinocytes adjacent to the epidermal invaginations, mostly in the lower parts of the epidermis. Larger, electron-lucent granules containing flocculent material were found more abundantly in the cells lining the epidermal invaginations. Also, some of the mucus-containing cells showed bundles of tonofilaments; structures that appeared to be isolated short, stubby microvilli; and attachments to adjacent mucus-containing cells and keratinocytes by desmosomes. The ultrastructural and immunohistochemical findings in our case suggest that the mucinous changes occurred as a metaplastic process in the resident epidermal cells and were accompanied by changes in cellular antigen expression resembling those of simple secretory epithelium.

Topics: Adult; Carcinoembryonic Antigen; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Microscopy, Electron; Skin Diseases

To investigate differences in expression of keratin 20, a cytoskeletal protein in gastrointestinal epithelial cells, in completely differentiated intestinal metaplasia (type I) and incomplete metaplasia (types II and III).. Gastric biopsy specimens from 66 patients with intestinal metaplasia were analysed immunohistochemically. Expression of keratin 20 was quantified as the percentage of immunoreactive cells on the tips, the upper, and deep foveolae.. In all specimens keratin 20 was found on the tips and in the upper foveolae of intestinal metaplasia. Keratin 20 was not observed in the deep foveolae. No differences were seen between the antrum and the body. Expression patterns were comparable between types I and III. In type II, however, lower immunoreactivity was found. Both the differences between types I and II as well as between types II and III were significant (p < 0.05).. Keratin 20 is expressed in metaplastic mucosa as a result of intestinal differentiation. Positive staining found exclusively in juxtaluminal cells occurs only in mature cells containing keratin 20. Lowered immunoreactivity in type II compared with types I and III indicates the different nature of type II intestinal metaplasia. Further studies are needed to shed light on the basic fundamental mechanism responsible for this.

Topics: Adult; Aged; Biopsy; Female; Gastritis; Humans; Immunohistochemistry; Intestinal Mucosa; Intestines; Keratins; Male; Metaplasia; Middle Aged

We studied the immunohistochemical phenotype in 13 cases of the nodular hidradenoma (NH), with special emphasis on the expression of different types of keratins (cytokeratins, 7, 10, 6/18, 8/18, and 10/17/18 and their distribution in normal sweat glands. Variable reactions with keratins, alpha-smooth muscle actin, and epithelial membrane antigen (EMA) were found, as these markers were present in different cellular components of the tumors. The most constant finding was almost complete absence of cytokeratins (all but keratin 10/17/18, which was positive in two of 13 cases) in clear cells, which yet were positive for EMA. The tumors expressed mostly cytokeratin 6/18, 7, 8/18, and 10/17/18, which were found in 11, 13, 11, and 12 cases, respectively. The cellular distribution and quantity of stained cells differed, as keratins 6/18, 8/18, and 7 produced the most abundant staining and were predominantly localized in small squamoid cells and the cells lining the tubular and cystic spaces. Cytokeratin 10/17/18 was expressed in smaller or larger clusters of squamoid cells and rarely in clear cells. Cytokeratins 10, 19, and 20 were found sporadically in single cells or small cellular clusters. alpha-Smooth muscle actin was expressed in four cases, whereas we did not find reactivity of S-100 protein. Comparing these results with the pattern of keratin distribution and antigenic reactivity in eccrine sweat glands, we conclude that NH presents cellular heterogeneity of its elements and differentiation toward different parts of the sweat gland.

Topics: Actins; Adenoma, Sweat Gland; Biomarkers, Tumor; Coloring Agents; Eccrine Glands; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Keratins; Metaplasia; Mucin-1; Phenotype; S100 Proteins; Sweat Gland Neoplasms; Sweat Glands

When a subareolar breast abscess (SBA) is incised and drained, an extraordinarily high frequency of recurrence is noted.. To develop a pathogenesis-based treatment plan, 24 women with a total of 84 abscesses were monitored.. In nine women SBA was under the left areola, under the right, in 7 and in eight the SBA occurred either simultaneously or sequentially under both areolae. In 11 of 24 patients a chronic lactiferous duct fistula also existed. In four of 24 patients four SBAs were treated with antibiotics; alone; all recurred. In 16 of 24 patients initial treatment was incision and drainage plus antibiotics; all recurred. When the abscess plus the plugged lactiferous duct was excised, there were no recurrences; however, in four patients a new abscess in a different duct occurred, which was treated by en bloc resection of all subareolar ampullae, without further recurrence. Patients with a fistulous tract had the fistula, its feeding abscess, and its plugged lactiferous duct excised, without recurrence. In first time SBA the organism was usually staphylococcus; in recurrences mixed flora was isolated. Pathologic findings ranged from squamous metaplasia with keratinization of lactiferous ducts to chronic abscess.. The cause of SBA is plugging of lactiferous duct within the nipple by keratin. To prevent recurrence the abscessed ampulla with its plugged proximal duct needs excision.

Topics: Abscess; Adult; Anti-Bacterial Agents; Breast; Combined Modality Therapy; Cutaneous Fistula; Disease Susceptibility; Female; Humans; Keratins; Mastitis; Metaplasia; Middle Aged; Nipples; Recurrence; Smoking; Staphylococcal Infections; Vitamin A Deficiency

The expression of cytokeratin (CK) subclasses was immunohistologically investigated in normal laryngeal epithelia by the ABC technique using monospecific monoclonal antibodies. There are two types of epithelium in the larynx; squamous epithelium of the glottis and ciliated epithelium mainly of the supraglottis. A difference in expression pattern was observed between these two epithelia only in 3 CKs, specifically CK-8, CK-13 and CK-19. In the glottis, CK-8 was negative in all layers, CK-13 was positive in the suprabasal and superficial layers, and CK-19 was strongly positive in the basal layer, but apparently reduced in suprabasal layers and completely negative in the superficial layers. In the supraglottis, on the contrary, CK-8 was positive except in the basal layer, CK-13 was negative in all layers, and CK-19 was positive in all layers. When ciliated epithelia were reduced to squamous metaplasia, the epithelial cells were morphologically similar to the squamous cells, and the CK expression also showed the same pattern. In proximity to this squamous metaplasia, however, there were lesions whose cell type morphologically still resembled that of the ciliated epithelium, but whose pattern of CK expression had already been reduced to that of the squamous cell.

Topics: Carcinoma, Squamous Cell; Epithelium; Humans; Immunohistochemistry; Keratins; Laryngeal Mucosa; Laryngeal Neoplasms; Larynx; Metaplasia

Topics: Aged; Female; Humans; Keratins; Metaplasia; Mucous Membrane; Urinary Bladder

The expression of epidermal growth factor receptor (EGFr) and transforming growth factor alpha (TGF-alpha) was compared with the presence of "squamous differentiation" (SD) visualized in various histotypes of endometrial carcinoma by using a panel of monoclonal antibodies. The results of the current study demonstrate that EGFr and TGF-alpha are present in routinely processed endometrial carcinoma. The highest positive EGFr and TGF-alpha expression was seen in the group of adenocarcinomas with SD. The more intense EGFr and TGF-alpha immunoreactivity was observed in "squamous" foci both in adenoacanthomas (AA) and in adenosquamous carcinomas (AS). These EGFr- and TGF-alpha-positive squamous areas prevalently displayed a "stratification-related" cytokeratin (CK) immunoprofile characterized by the expression of CKs 1, 4, 5, 10, 13, 14, and 16. No correlation was found between EGFr- and TGF-alpha-positive status and depth of myometrial invasion or surgical stage. These results clearly demonstrate that EGFr and TGF-alpha expression is related remarkably to endometrial carcinoma with "squamous" areas both morphologically and immunophenotypically. This specific association leads us to suggest that EGFr and TGF-alpha expression in endometrial carcinoma may be prevalently involved in the equilibrium of cell differentiation of the "squamous" foci commonly observed in this group of neoplasias.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Carcinoma, Adenosquamous; Cell Differentiation; Endometrial Neoplasms; ErbB Receptors; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Middle Aged; Transforming Growth Factor alpha

Topics: Humans; Keratins; Leukoplakia; Male; Metaplasia; Middle Aged; Urinary Bladder Neoplasms

Expression of keratins 1, 6, 15, 16, and 20 was examined in normal cervical epithelia, squamous metaplasia, various grades of cervical intraepithelial neoplasia, and both squamous cell carcinomas and adenocarcinomas of the cervix with monospecific antibodies. Ectocervical epithelium contains all of these keratins except keratin 20. They show a heterogeneous distribution, with a basally restricted detection of keratin 15. Endocervical columnar cells were found to contain significant amounts of keratin 16, whereas the subcolumnar reserve cells expressed considerable amounts of keratin 15 and 16, and frequently keratin 6. These reserve cell keratins were also found in immature and mature squamous metaplastic epithelium. In the cervical intraepithelial neoplastic lesions they were generally found with increasing intensity as the severity of the lesion progressed. In the keratinizing variety of squamous cell carcinoma of the cervix, these three keratins seem to constitute an important part of the intermediate filament cytoskeleton, whereas in nonkeratinizing squamous cell carcinoma, they occur to a much lesser extent. Surprisingly, these keratins were also occasionally found in adenocarcinomas. From these data we conclude that the keratin phenotype of reserve cells and endocervical columnar cells is more complex than previously suggested. In particular, the keratins occurring in reserve cells are also present in most of the premalignant and in a considerable number of the malignant lesions of the cervix. The differentiation features of the various carcinoma types are, however, reflected in their specific keratin filament composition.

Topics: Adenocarcinoma; Carcinoma; Carcinoma, Squamous Cell; Cervix Uteri; Epithelium; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Reference Values; Uterine Cervical Neoplasms

A case of granulosa cell tumor of the ovary associated with hepatocytic differentiation is reported in a 45-year-old patient with a torsioned ovarian tumor. Serum alpha-fetoprotein (AFP) levels were normal 6 days postoperatively. Histopathologically, the granulosa cell tumor was typically trabecular. Its cells had nuclear grooves and were positive only for vimentin. Scattered diffusely throughout the tumor were small groups of regular polygonal cells, the cytoplasm of which secreted bile and was strongly positive for keratin, carcinoembryonic antigen (CEA), alpha-1-antitrypsin (A1AT), and ferritin and moderately positive for fibrinogen and ceruloplasmin. These results unequivocally identified them as hepatic cells. The AFP negativity of the hepatic cells was interpreted as a sign of terminal hepatocytic differentiation. The scattered arrangement of the hepatocytes simulated stromal luteinization. As neither a primary liver tumor nor any associated germ cell tumor was found, the histogenesis of the hepatic cells was thought to be metaplastic.

Topics: alpha 1-Antitrypsin; alpha-Fetoproteins; Carcinoembryonic Antigen; Cell Differentiation; Cell Nucleus; Female; Ferritins; Granulosa Cell Tumor; Humans; Immunohistochemistry; Keratins; Liver; Liver Diseases; Luteal Cells; Metaplasia; Middle Aged; Ovarian Neoplasms; Ovary; Vimentin

The histologic significance of various changes in the bile ductal structures as observed by cytokeratin immunoperoxidase assay was studied in 122 patients with alcoholic liver disease (ALD) as a part of a large Veterans Administration Cooperative Study on alcoholic hepatitis. Four types of morphologic changes in the biliary structures were observed: 1) proliferation of interlobular bile ducts in the portal tracts; 2) marginal bile ductular proliferation at the periphery of the portal tracts; 3) appearance of bile duct type cells ("oval cells") in the liver parenchyma; and 4) metaplasia of bile duct epithelium to cells resembling hepatocytes. These bile ductal changes correlated strongly with liver fibrosis (p = 0.0003; 0.0003; 0.05; 0.0035, for 1, 2, 3, and 4, respectively), cirrhosis (p < 0.0001 for all four parameters), portal inflammation (p < 0.0001 for 1, 2, and 4; p = 0.0024 for "oval cells"), and with overall histologic severity scores (p < 0.0001; p = 0.0001; p = 0.0017; p = 0.0005, respectively). However, these changes did not correlate significantly with fatty change, parenchymal degeneration and necrosis, cellular infiltrate or Kupffer cell hyperplasia, suggesting that they are probably not the direct consequences of liver cell necrosis. Periportal piecemeal necrosis correlated significantly with both portal bile duct (p = 0.0041) and marginal (p = 0.0078) bile ductular proliferation. Among all these changes, only marginal bile ductular proliferation correlated significantly with Mallory bodies present both in the hepatocytes (p = 0.05) and the bile ducts (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Bile Ducts; Bile Ducts, Intrahepatic; Biopsy; Humans; Immunoenzyme Techniques; Keratins; Liver; Liver Diseases, Alcoholic; Metaplasia

Squamous syringometaplasia (SS) is defined as a mature squamous metaplasia of the eccrine ducts. We prospectively evaluated its frequency and clinical and pathological features in a series of 21 patients. SS was found in association with several diseases, chiefly chronic ulcers. The patient' ages ranged between 20 and 80 years and there was no sex predominance. The involved eccrine ducts were usually located in the superficial and mid dermis and displayed inner keratinization. The stimulus required for SS is unknown. Differential diagnosis between SS and well-differentiated squamous cell carcinoma (SCC) depends on the preservation of a lobular configuration and the absence of epithelial dysplasia or invasion.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Diagnosis, Differential; Eccrine Glands; Female; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Middle Aged; Prospective Studies; Reference Values; Skin; Sweat Gland Neoplasms

Topics: Biomarkers, Tumor; Biopsy; Cell Transformation, Neoplastic; Gastric Mucosa; Gastritis; Gastroscopy; Humans; Keratins; Metaplasia; Polyps; Precancerous Conditions; Stomach Neoplasms; Stomach Ulcer

We describe an animal model to induce the histogenesis of squamous metaplasia of the cervical columnar epithelium, a condition usually preceding cervical neoplasia. This model is based on dietary retinoid depletion in female mice. Control sibling mice fed the same diet but with all-trans-retinoic acid (at 3 micrograms/g diet) showed the normal endocervical epithelial and glandular columnar morphology, typical of a simple epithelium without subcolumnar reserve cells. The stratified squamous ectocervical epithelium of these mice fed all-trans retinoic acid showed intense immunohistochemical staining in basal and suprabasal cells with mono-specific antibodies against keratins K5, K14, K6, K13, and, suprabasally, with antibodies specific for K1 and K10. At the squamocolumnar junction, the adjacent columnar epithelium (termed "suprajunctional") did not show staining for K5, K14, K6, K13, K1, and K10 but specifically stained for keratin K8, typical of simple epithelia and absent from the adjacent ectocervical squamous stratified lining (termed "subjunctional"), in striking contrast. Sections of the squamocolumnar junction from mice kept on the vitamin A-deficient diet for 10 weeks showed suprajunctional isolated patches of reserve cells, proximal and distal to the junction. These cells were detected prior to any symptoms of vitamin A deficiency, such as loss of body weight or respiratory discomfort. The subcolumnar reserve cells induced by vitamin A deficiency displayed positive staining for K5 and K14. As deficiency became severe, the reserve cells occupied the entirety of the suprajunctional basement membrane. This epithelium eventually became stratified and squamous metaplastic, the squamocolumnar junction was no longer discernible, and the entire endocervical epithelium and the endometrial glands lost K8 positivity, while acquiring K5, K14, K6, K13, K1, and K10 keratins typical of the ectocervix under normal conditions of vitamin A nutriture. Vitamin A deficiency also altered keratin expression and localization in squamous subjunctional epithelium. In situ hybridization studies for K1 and K5 mRNA showed their major site of expression at the basal (K5) and immediately suprabasal (K1) cell layers. The localization of both K5 and K1 proteins in these same cell layers, and above, is consistent with transcriptional regulation of these keratins. Early vitamin A deficiency caused the appearance of single subcolumnar reserve cells expressing K5 mRNA. After these ce

Topics: Animals; Carcinoma, Squamous Cell; Cervix Uteri; Diet; Disease Models, Animal; Epithelium; Female; Immunohistochemistry; In Situ Hybridization; Keratins; Metaplasia; Mice; Mice, Inbred BALB C; Mice, Nude; Phenotype; Precancerous Conditions; Retinoids; RNA, Messenger; Tretinoin; Uterine Cervical Neoplasms; Vitamin A Deficiency

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

We describe the existence in normal human primary thyroid cultures of a hitherto unrecognised sub-population of epithelial cells. This variant phenotype is characterised by squamoid morphology, absence of thyroglobulin, and an altered profile of intermediate filament expression. We suggest that these cells are derived from scattered foci of squamous metaplasia present in the normal gland. Although they are initially present at a frequency of less than 10(-4), their very high proliferative capacity enables them to outgrow the 'classical' follicular cells and confers a much increased capacity for gene transduction. Recognition of these cells is therefore crucial in the interpretation of long-term thyroid culture experiments and those involving in vitro gene transfer.

Topics: Biomarkers; Cell Differentiation; Cell Division; Cells, Cultured; Epithelial Cells; Genes, ras; Genetic Vectors; Humans; Keratins; Metaplasia; Phenotype; Selection, Genetic; Thyroid Gland; Transfection

Expression of keratins (cytokeratins, CK) known to be suitable markers for different types of epithelial differentiation was analyzed in specimens of feline mammary tissue. A panel of specific anti-CK monoclonal antibodies (MAb) was used to determine CK distribution pattern in normal feline tissues (n = 3), and in benign (n = 18) and malignant (n = 20) feline mammary tumors. In selected tumors, the CK distribution pattern was also determined by biochemical methods. A MAb specific for alpha-smooth muscle actin was used to discriminate between myoepithelial cells and luminal epithelial cells. In normal mammary gland tissues, 6 MAb reacted exclusively, either with myoepithelial cells or with luminal epithelial cells. Luminal epithelial cells reacted with MAb specific for CK typical of simple epithelia, whereas myoepithelial cells reacted with MAb specific for CK in basal cells of stratified epithelia. A similar distribution of CK was detected in specimens from benign tumors, except that CK4 was not detected in normal mammary gland tissues and was detected in some ducts in specimens with adenosis. Almost all tumor cells in specimens from malignant tumors reacted with MAb specific for CK typical of simple epithelia. Concomitant expression of CK typical of stratified epithelia was detected in small or large subpopulations of tumor cells in 70% of carcinomas. Cytokeratins typical of basal cell layers and typical for suprabasal layers of inner stratified epithelia were detected. Cytokeratins typical of stratified epithelia were always found in areas of squamous metaplasia, but also were found in adenocarcinomal cells surrounding these areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenofibroma; Animals; Antibodies, Monoclonal; Biomarkers, Tumor; Carcinoma; Cat Diseases; Cats; Electrophoresis, Gel, Two-Dimensional; Keratins; Mammary Glands, Animal; Mammary Neoplasms, Animal; Metaplasia; Precancerous Conditions

We have previously shown that cultured normal human endocervical cells (HENs) form epithelium resembling squamous metaplasia in vivo. To analyze the cellular origin of squamous metaplasia, the cytokeratin and mucin expression and morphological features of HENs in monolayer cultures and in implants beneath the skin of nude mice were examined. Primary HENs had two distinct morphological phenotypes in vitro pleomorphic epithelial cells and keratinocytelike cells. Using a panel of monoclonal antibodies for various cytokeratins (CKs), we observed that the pleomorphic cells, which were the primary outgrowths, expressed CK7 and CK18 and produced mucin, suggesting their origin to be the mucosecretory columnar cells (CCs) of the endocervix. Keratinocytelike cells were observed in proximity of the CC-like cells after a few days of HEN culture. Interestingly, these cells were homogeneously negative for CK7 expression, as for native reserve cells (RCs), and homogeneously positive for CK13 expression with the antibody that is specific for RCs. During early passages, the culture consisted mostly of the RC-like keratinocytelike cells, and in the late passages, the CC-like cells were predominant. HEN implants in nude mice morphologically formed epithelia similar to immature squamous metaplasia and showed variable CK18 expression. Moreover, they showed homogeneous CK13 expression throughout all layers and expressed mucin and CK7 in the suprabasal cells. The possibility that the HEN culture was originally a mixed population of CCs and RCs, that we failed to detect, cannot be eliminated. Our results support the more likely view that the endocervical simple epithelia, which form squamous metaplasia, are bipotential cells and undergo differentiation readily and reversibly to give rise to CC-like and RC-like cells in culture.

Topics: Adult; Animals; Cell Differentiation; Cell Line; Cells, Cultured; Cervix Uteri; Female; Humans; Keratins; Metaplasia; Mice; Mice, Nude; Middle Aged; Mucins; Muscles; Skin; Surgical Flaps; Tissue Distribution; Tissue Transplantation

We have previously demonstrated that human olfactory epithelia can be classified into five grades according to the degree of degeneration present in patients with various kinds of olfactory disorders. In practice, however, the occurrence of additional types of cell changes in other kinds of olfactory disorders and findings with immunohistochemical techniques have led us to re-evaluate our previous classification. In the present study, changes in olfactory epithelia from ten patients with various kinds of olfactory disorders are discussed and a revised classification is proposed. Microvillar and differentiating cells were also evaluated in the epithelium studied.

Topics: Adult; Aged; Atrophy; Cell Nucleus; Dendrites; Epithelium; Female; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Microvilli; Middle Aged; Olfaction Disorders; Olfactory Mucosa; Phosphopyruvate Hydratase; S100 Proteins; Sensory Receptor Cells; Sensory Thresholds; Smell

Monoclonal antibodies E3 against cytokeratin No. 17 were used for immunohistochemical examination of samples from 19 squamous-cell carcinomas of the uterine cervix and 10 cases of squamous-cell metaplasia of the endocervix. The above antibodies selectively labelled reserve cells of the cervical canal mucosa, basal layer of mature metaplastic epithelium and parabasal and basal cells of immature metaplastic squamous epithelium. In large-cell keratinizing, non-keratinizing and small-cell carcinomas, the expression of cytokeratin No. 17 revealed tendency to basal orientation and was in many respects similar to that in metaplastic squamous epithelium. It was suggested that all the squamous-cell carcinomas studied originated from reserve (metaplastic) cells.

Topics: Adult; Antibodies, Monoclonal; Carcinoma, Squamous Cell; Cervix Uteri; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Middle Aged; Molecular Weight; Uterine Cervical Neoplasms

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

Expression of keratins 5, 14 and 17 in endocervical subcolumnar reserve cells was detected by means of immunohistochemical studies using polypeptide specific monoclonal antibodies. These particular keratins that were found among others in basal cells could also be detected to a variable extent in metaplastic and dysplastic cervical lesions. In some cases of immature squamous metaplasia all three keratin subtypes were expressed throughout the full thickness of the epithelium. In contrast, in mature squamous metaplasia a compartmentalization of these keratins was observed. Mature squamous metaplastic epithelium showed a keratin distribution pattern comparable to ectocervical squamous epithelium, with the exception of keratin 17, which was only sporadically found in the basal layer of ectocervical epithelium and was always present in the basal cells of mature squamous metaplastic epithelium. During progression of cervical intraepithelial neoplasia a clear increase in the expression of keratin 17 was observed. However, also keratins 5 and 14 were expressed. Our results demonstrate that a considerable number of premalignant lesions of the uterine cervix express the same keratins as found in the progenitor reserve cells. Lesions that lack expression of keratin 17 may form a distinct group, which are regressive in nature and do not progress into cervical cancer.

Topics: Cervix Uteri; Epithelium; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Neoplasm Staging; Uterine Cervical 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

The importance of cervical squamous metaplasia and human papillomavirus 16 (HPV 16) infection for cervical carcinoma has been well established. Nearly 87% of the intraepithelial neoplasia of the cervix occur in the transformation zone, which is composed of squamous metaplastic cells with unclear origin. HPV DNA, mostly HPV 16, has been found in 90% of cervical carcinomas, but only limited experimental data are available to discern the role of HPV 16 in this tissue specific oncogenesis. We have initiated in vivo studies of cultured endocervical cells as an experimental model system for development of cervical neoplasia. Using a modified in vivo implantation system, cultured normal endocervical epithelial cells formed epithelium resembling squamous metaplasia, whereas those immortalized by HPV 16 developed into lesions resembling carcinoma in situ. In contrast, their ectocervical counterparts formed well differentiated stratified squamous epithelium and a lesion with mild dysplastic change, respectively. The HPV 16-immortalized cells showed in vivo cytokeratin expression patterns similar to their respective normal counterparts, confirming their different origins. Thus, this study provides direct experimental evidence for the transformation of simple epithelial cells of endocervical origin into stratified squamous metaplasia and indicates the differential susceptibility of endo- and ectocervical epithelial cells for conversion to cancer by HPV 16.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Transformed; Cell Transformation, Neoplastic; Cells, Cultured; Cervix Uteri; Epithelium; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Mice; Mice, Nude; Microscopy, Electron; Mucins; Papillomaviridae; Transplantation, Heterologous; Uterine Cervical Neoplasms

In a retrospective study of 28 women and eight men with squamous cell metaplasia in different parts of the bladder, including the trigone, no histopathological differences were observed among the regions. All the five (female) patients with parakeratosis had a concomitant invasive bladder tumour. Thirty-eight% of all the patients had a simultaneous neoplastic tumour. The metaplastic lesions were investigated for keratin in 13 patients, and all were positive. In seven out of eight patients, the urothelium adjacent to the squamous cell metaplasia was also positive for keratin, indicating a direct transformation of the urothelium to squamous cell epithelium. The metaplastic cells were investigated for oestrogen receptors in five men and five women, and all were negative, suggesting no relationship between estrogens and squamous cell metaplasia of the bladder. Squamous cell metaplasia in the bladder is not considered a premalignant condition. However, metaplasia and neoplastic tumours are often associated with chronic tissue damage, and the presence of metaplasia may give a warning of conditions that can also cause cancer.

Topics: Adult; Aged; Epithelium; Female; Humans; Keratins; Male; Metaplasia; Middle Aged; Receptors, Estrogen; Retrospective Studies; Urinary Bladder

Normal epithelial cell differentiation is characterized by the production of distinct cytokeratin proteins. It is well known that epithelia of several organs show squamous metaplasia in a vitamin A-deficient status. It is not yet known whether these histological changes are concomitant with a change in cytokeratin expression. Therefore, 3-week-old female rats (BN/BiRij) were fed a vitamin A-deficient diet for 8 weeks. The cytokeratin expression in epithelia of various organs was monitored immunohistochemically during the induction of vitamin A deficiency. Therefore, monoclonal antibodies specific for human cytokeratin 4, 5, 5 + 8, 7, 10, 14, 18 and 19 were used. In a normal vitamin A status, the distributional pattern for the different cytokeratins in rats was similar to that reported for human tissue. No change in cytokeratin expression was seen in trachea, skin, liver and colon at any time point studied. Squamous metaplasia in urinary bladder and salivary glands was observed after six weeks on the vitamin A-deficient diet. This was concomitant with a substitution of cytokeratins 4, 5 + 8, 7, 18 and 19 by cytokeratin 10. The latter cytokeratin is specific for keratinized squamous epithelium. A change in cytokeratin expression was observed in bladder, ureter, kidney, salivary glands, uterus and conjunctiva before histological alterations appeared. In conclusion, the changes in cytokeratin expression observed under vitamin A deficiency in epithelia in vivo are in agreement with those described in other studies for epithelial cells in vitro. The changes in cytokeratin expression and the subsequent differentiation into squamous cells occurs in basal cells of the bladder but not in transitional cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cell Differentiation; Epithelium; Female; Gene Expression Regulation; Keratins; Metaplasia; Organ Specificity; Rats; Rats, Inbred BN; Vitamin A; Vitamin A Deficiency

To determine the characteristics of metaplastic changes of the nasal respiratory epithelium, the distribution of individual cytokeratins (CKs) was studied immunohistochemically and by two-dimensional gel electrophoresis. The authors define four types of changes of the normal pseudostratified columnar epithelium: (1) transitional pseudostratified epithelium (first unusual CK.: no. 13); (2) stratified columnar epithelium (increased expression of CKs 4 and 13; CKs 7, 8, 18 and 19 reduced); (3) stratified squamous epithelium, nonkeratinized (appearance of CK 16); and (4) stratified squamous epithelium, keratinized (expression of CKs 1 and 10, variable CK5 and 14 patterns in basal cells). These phenotypes were found simultaneously within single specimens, resulting in apparent overall variability in the immunohistochemical staining patterns. Spatially, changes in CK expression towards "normal" parts were not abrupt but rather gradual. Biochemical data confirmed the immunohistochemical findings and added CK 6 to the pattern of altered nasal mucosa. The findings of this study suggest a stem cell metaplasia in the nasal epithelium which is based on its inherent bimodal developmental programme. A gradual loss of normal respiratory epithelial differentiation, as seen by the loss of CKs 7, 8, and 18, was paralleled by the appearance of squamous epithelial type CKs, e.g. the expression of CKs 1, 10 and 13. Basal cell types CKs 5, 14, 17 and 19 were maintained during this process. Implications of these results for general concepts of CK expression in the metaplastic process are discussed.

Topics: Adolescent; Adult; Child; Epithelium; Female; Humans; Keratins; Male; Metaplasia; Middle Aged; Nasal Mucosa

We induced vitamin A depletion to define early and late changes during the histogenesis of squamous metaplasia of hamster tracheal epithelium. An early change is the "minimal morphological change" (MMC), in which the mucociliary epithelium is separated from the basement membrane by a continuous layer of basal cells. Immunohistochemistry showed an exclusive localization of the keratins K5 and K14 in basal cells of normal and MMC epithelia. At the MMC stage no staining was observed above the basal layer with antibodies to K5, but upon progression of the lesion to a squamous focus all cells from basal to terminally differentiated were positive for K5 and K14. In contrast, when we used antibodies to the keratins K6 or K13 all cells were negative in the normal epithelium and in the MMC epithelium. Successive layers of suprabasal squamous cells found in squamous metaplasia failed to express normal epidermal differentiation marker keratins K1 and K10 but expressed the proliferation marker keratin K6 and the internal stratified epithelium keratin K13, not normally found in the epidermis or in the trachea. Hamster tracheal epithelial cells could be maintained in culture in serum-free medium for at least 4 weeks in the presence of retinoic acid (RA). In non-RA-containing medium, cells from vitamin A-deficient hamsters showed markedly reduced growth and an increase in the expression of keratins K5, K6, K13, and K14. Since our previous work had implicated retinoids in the control of cell adhesiveness, we were interested to find out whether changes in cell adhesion occur in vitamin A-deficient hamster tracheal epithelial cells, compared to normal cells. Functional assays demonstrated that hamster tracheal epithelial cells, obtained from non-RA-treated tracheas or maintained in culture, displayed reduced attachment to laminin, compared to RA-treated cells. Immunofluorescence studies did not show a decrease either in the alpha 6 integrin subunit, which was localized in the basal aspect of basal cells, or in basement membrane laminin. However, the expression of laminin-binding protein 37 decreased as the epithelium changed from pseudostratified to stratified. Therefore, a coordinated pattern of changes in keratin gene expression, as well as in the expression of laminin-binding protein 37, the precursor to the cell surface laminin receptor 67LR, and in adhesive properties takes place in tracheal epithelium when its phenotype changes from mucociliary to the preneoplastic s

Topics: Amino Acid Sequence; Animals; Antibodies; Blotting, Western; Cell Adhesion; Cell Adhesion Molecules; Cells, Cultured; Cricetinae; Epithelium; Fibroblasts; Immunohistochemistry; Keratins; Laminin; Male; Mesocricetus; Metaplasia; Molecular Sequence Data; Protein Binding; Trachea; Tretinoin; Vitamin A Deficiency

The distribution of the 52 kDa keratin 13 was evaluated immunohistochemically, using the AE8 monoclonal antibody. Various squamous and transitional cell epithelial lesions and representative control tissues were studied. This antibody performed adequately in formalin-fixed and paraffin-embedded tissue, but like keratin immunohistochemistry in general, required protease pretreatment. Keratin 13 was found consistently in the suprabasal layers of squamous epithelia of oral cavity, tonsils, larynx, esophagus, lower female genital tract, and transitional urothelium, but it was absent in the epidermis. Generally, various forms of squamous metaplasia were AE8-positive. In dysplasia, AE8 reactivity was considerably decreased or even absent despite the presence of apparent suprabasal maturation. In differentiated squamous cell carcinomas, AE8 immunoreactivity was usually limited to a few cells in the center of the keratinized foci. However, in 10% of squamous cell carcinomas, a significant number of tumor cells was positive. Only well-differentiated urothelial carcinomas showed AE8 immunoreactivity, while poorly differentiated tumors were negative. Interestingly, a Brenner's tumor showed a high number of AE8-positive epithelial cells. Our results show that the expression of keratin 13, as immunohistochemically determined by AE8 antibody, is significantly down-regulated in squamous cell malignancies. Its possible value as an adjunct to diagnosis of dysplasia should be investigated further.

Topics: Antibodies, Monoclonal; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Cervix Uteri; Female; Humans; Immunohistochemistry; Keratins; Larynx; Metaplasia

The capacity of the peritoneal serosa to undergo metaplasia to müllerian-type epithelium is well recognized. We report a case of squamous metaplasia of the peritoneum that was studied by light microscopy. Immunohistochemical techniques, and electron microscopy. The pathogenesis of peritoneal squamous metaplasia is obscure, but may be a response to chronic irritation.

Topics: Adult; Carcinoembryonic Antigen; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Microscopy, Electron; Peritoneum; Serous Membrane

Three cases of tubular adenoma of the gallbladder with squamoid spindle cell metaplasia are reported. Two of the three patients, who were middle-aged Japanese, had a solitary polyp in the gallbladder, and the other had three polyps. All the lesions were detected incidentally by ultrasonography. The polyps were pedunculated with a fine or frail stalk, and ranged from 0.5 to 3.9 cm in diameter. Histologically, they were tubular adenomas accompanied by scattered foci composed of a compact collection of short-spindle or oval cells with mild atypia. These cells did not retain intercellular bridges, and lacked intracellular keratinization. Immunohistochemically, the spindle cells stained positively for high-molecular-weight cytokeratin (EAB 903, a marker of squamous cell differentiation), whereas adenoma cells lining the tubules were negative for this antigen. Therefore, the spindle cell component is considered to represent squamoid metaplasia of adenoma cells.

Topics: Adenoma; Adult; Female; Gallbladder Neoplasms; Histocytochemistry; Humans; Immunohistochemistry; Keratins; Male; Metaplasia; Middle Aged; Molecular Weight

The L1 antigen was investigated as a marker of squamous differentiation in urothelium using a monoclonal antibody Mac387, and the results were compared with the expression of high molecular weight cytokeratins. L1 antigen was consistently demonstrated in all instances of partial and complete squamous metaplasia and in squamous carcinomas. In contrast, pure transitional cell carcinomas (except one with minor focal staining), adenocarcinomas and normal and hyperplastic urothelium did not label. In a few squamous carcinomas in situ, the pattern of labelling obtained with Mac387 was different from that seen in invasive squamous carcinomas and metaplasias. Compared with high molecular weight cytokeratins, the expression of L1 was more intense in areas of squamous differentiation. L1 expression, as identified by antibody Mac387, may therefore serve as a useful marker of squamous differentiation in urothelial lesions.

Topics: Antibodies, Monoclonal; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Cell Adhesion Molecules, Neuronal; Cell Transformation, Neoplastic; Humans; Keratins; Leukocyte L1 Antigen Complex; Metaplasia; Urinary Bladder; Urinary Bladder Neoplasms

The present study aimed to examine possible changes in keratin expression during neoplastic transformation of the uterine mucosa and possible differences in keratin expression between endocervical and endometrial adenocarcinomas. Routinely processed specimens with normal morphology or neoplastic changes were stained immunohistochemically using 5 commercial antibodies to keratin-filaments of molecular weight 39-58 kD: CAM 5.2, RCK 102, MCA 144, PKE and PRE. We generally found a change in keratin expression during the neoplastic transformation, consisting of pronounced heterogeneity compared with normal epithelia. In distinguishing koilocytic atypia from CIN, RCK 102 (52.5, 58 Kd) may prove helpful as it stains neoplastic cells strongly and shows no reaction in koilocytic. Staining with the antibody CAM 5.2 (reactive with 39, 43, 50 kD filaments) may aid in distinguishing between cervical and endometrial adenocarcinomas. The former is stained uniformly; the latter shows a more variable staining.

Topics: Adenocarcinoma; Cervix Uteri; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Mucous Membrane; Neoplasm Invasiveness; Pregnancy; Staining and Labeling; Uterine Cervical Neoplasms; Uterine Neoplasms; Uterus

Topics: Adolescent; Adult; Aged; Anemia, Pernicious; Antibodies, Monoclonal; Female; Gastric Mucosa; Gastritis; Gastritis, Atrophic; Humans; Immunoenzyme Techniques; Keratins; Male; Metaplasia; Middle Aged

Immunohistochemical study of the exo- and endocervix in squamous metaplasia is performed using EE21-06d monoclonal antibodies revealing simultaneously five cytokeratinous polypeptides characteristic of squamous epithelium, and f-12-19h revealing simultaneously wide spectrum of cytokeratinous polypeptides characteristic of the epithelium various types. PAP method and the reaction of immunofluorescence were used. Monoclonal antibodies 12-19d label cells of all layers of normal exocervix, endocervix and metaplastic squamous epithelium, both immature and differentiated. Monoclonal antibodies EE21-06d react in the exocervix with suprabasal and higher located cells and in the endocervix with reserve cells only. Positive reaction with EE21-06d in the metaplastic foci increases in proportion with the squamous cell differentiation, thus this antibody being the marker of reserve cells and the degree of the squamous metaplasia maturity.

Topics: Adult; Antibodies, Monoclonal; Antibody Specificity; Biopsy; Cervix Uteri; Epithelium; Female; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Immunohistochemistry; Keratins; Metaplasia; Middle Aged

Subdermal metastatic nodules in a 62-year old male patient with esophageal carcinoma contained both carcinomatous and chondroid areas. The carcinomatous areas showed the histology of poorly differentiated squamous cell carcinoma, and light microscopically an apparent transition could be traced from carcinomatous cells to chondroid cells. In the chondroid cells, the characteristics of chondrocytes were demonstrated by light microscopic, electron microscopic, histochemical and immunohistochemical studies, although nuclear atypism was evident, suggesting their malignancy. Furthermore, immunohistochemical studies showed that some chondroid cells contained both keratin proteins and squamous cell carcinoma antigen, which were also found in the carcinomatous cells. These findings together with the light microscopic observations suggest that chondroid cells are derived from squamous cell carcinoma cells.

Topics: Carcinoma, Squamous Cell; Cartilage; Collagen; Esophageal Neoplasms; Extracellular Matrix; Humans; Immunoenzyme Techniques; Keratins; Male; Metaplasia; Microscopy, Electron; Middle Aged

Keratins and secretory component (SC) were immunohistochemically examined in fresh tissue samples from 45 odontogenic and 35 non-odontogenic cysts. Lining epithelia of almost all cases contained keratins which reacted with polyclonal antibodies (Dako, Bio-Science), and no difference could be found between the two groups of lesions. By staining with two monoclonal antibodies against keratins, i.e., RGE53 (Bio-Science) and RKSE60 (Bio-Science), it was revealed that the epithelia of non-odontogenic cysts, which were columnar epithelium in most cases, had fully and positively reacted with RGE53, while none of the cases was positive for RKSE60. In contrast, the squamous linings of odontogenic cysts except for two cases did not react with RGE53, and few cases possessed RKSE60-reactive keratin. SC was also contradictory. All non-odontogenic cysts exhibited SC. Regarding each pair of non-odontogenic and odontogenic cysts covered with RGE53 and SC-positive, and RKSE60-negative squamous epithelium, it seemed reasonable from the staining results to conclude that the squamous linings were metaplastic from the columnar epithelium. Based on the results, concomitant examinations of SC with keratins will be helpful in deciding the epithelial derivation of jaw cysts.

Topics: Dentigerous Cyst; Epithelium; Humans; Immunohistochemistry; Jaw Cysts; Keratins; Metaplasia; Molecular Weight; Nonodontogenic Cysts; Odontogenic Cysts; Radicular Cyst; Secretory Component

The cellular phenotype of 34 primary adenoid liver tumours induced in rats with N-nitrosomorpholine was studied by immunocytochemical and electron microscopical methods in order to elucidate the histo- and cytogenesis of these tumours. Three types of ducts were distinguished in the adenoid liver tumours at the ultrastructural level being characterized as of hepatocellular, transitional and cholangiocellular phenotype. The transitional cells took an intermediate position between the hepatocellular and the cholangiocellular phenotype. Frequent features of the hepatocyte-like differentiation were large round nuclei with a dispersed chromatin, glycogen-associated ER complexes, peroxisomes and the formation of bile canaliculi. Evidence for the relationship to bile ductular cells was provided by the regular association with a basement membrane, the (inconstant) positive immunohistochemical reaction for cytokeratin polypeptide KA-4, a poorly developed ER and small mitochondria. An additional finding in the ducts with a transitional cellular phenotype was the selective accumulation of mast cells integrated into the epithelium. Intimate associations between cells of the hepatocellular, transitional and cholangiocellular phenotype were observed at the light and electron microscopic level. The results suggest that a transdifferentiation (metaplasia) from cells with a hepatocellular to those with a transitional or cholangiocellular phenotype takes place in many liver tumours.

Topics: Adenoma; Animals; Immunohistochemistry; Inclusion Bodies; Keratins; Liver Neoplasms, Experimental; Male; Metaplasia; Microscopy, Electron; Morpholines; Phenotype; Rats; Rats, Inbred Strains

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

A cytokeratin immunohistochemical study was performed on 38 liver biopsies from cases of primary biliary cirrhosis, primary sclerosing cholangitis, extrahepatic biliary obstruction or drug-induced liver disease in order to analyse the cytoskeletal changes in detail. On paraffin sections of 27 cases, a variable number of hepatocytes were reactive with a polyclonal anti-cytokeratin antiserum that, in the normal liver, stains bile duct cells only. On cryostat sections of 23 cases, a variable number of hepatocytes were immunoreactive with a monoclonal antibody specifically directed against cytokeratin no. 7 and were most numerous in cases of long-standing cholestasis irrespective of the aetiology. In three cases of primary sclerosing cholangitis and two cases of primary biliary cirrhosis a few hepatocytes were also weakly positive with a monoclonal antibody specific for cytokeratin no. 19. Since cytokeratins no. 7 and no. 19 are, in the normal liver, restricted to bile duct cells, these results further support the concept of 'ductular metaplasia' of hepatocytes, the mechanism of which remains unclear.

Topics: Antibodies, Monoclonal; Autopsy; Biopsy; Chemical and Drug Induced Liver Injury; Cholangitis, Sclerosing; Cholestasis, Intrahepatic; Cytoskeleton; Frozen Sections; Humans; Keratins; Liver; Liver Cirrhosis, Biliary; Liver Diseases; Metaplasia; Paraffin

We present a case of tubular adenomatous metaplasia (nephrogenic adenoma) arising within a urethral diverticulum in a woman complaining of a vaginal mass with dyspareunia. This lesion, which uncommonly affects the urethra, may clinically manifest as a gynecologic condition and mimic a low-grade adenocarcinoma on pathologic assessment. Criteria for diagnosis and current concepts of pathogenesis are discussed. Our findings, including an immunocytochemical work-up, support the concept of a reactive metaplastic response rather than nephrogenic differentiation.

Topics: Adenoma; Adult; Female; Humans; Immunohistochemistry; Keratins; Metaplasia; Pregnancy; Pregnancy Complications, Neoplastic; Urethral Neoplasms

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

Sequential histologic, ultrastructural, immunohistochemical and morphometric studies were made of the evolutional changes of metaplastic and regenerating alveolar epithelial cells in monkeys from 3 days to 8 weeks after paraquat administration. In the early proliferative phase, many alveoli were lined by single-layered and stratified squamous epithelium and bronchiolized epithelium (i.e., presumably derived from bronchi and bronchioles). The regenerating epithelial cells had well developed bundles of actin-like filaments, which were arranged parallel to the basal surfaces of the cells and were associated with zonulae adherentes; these cells also had intermediate filaments and some desmosomes, but lacked basement membranes, hemidesmosomes and anchoring fibrils. They covered either denuded, wavy and disrupted original epithelial basement membranes or areas of developing intraalveolar fibrosis. In zones of squamous epithelial cell metaplasia associated with intraalveolar fibrosis, fibronexus-like structures appeared to be responsible for the initial adhesion of the cells to the underlying connective tissue. In later phases, single-layered and stratified squamous epithelial cells disappeared, and only bronchiolized epithelial cells, with hemidesmosomes and anchoring fibrils on their basal surfaces, were found in fibrotic alveoli. Although bronchiolized and squamous metaplastic epithelial cells are generally thought to be formed as late events in pulmonary damage, such cells play an important role in early, temporary repair of damaged alveoli.

Topics: Animals; Epithelium; Immunohistochemistry; Keratins; Macaca fascicularis; Metaplasia; Microscopy, Electron; Paraquat; Pulmonary Alveoli; Pulmonary Fibrosis; Time Factors

Normal bladder urothelium and large spectrum bladder lesions have been investigated by immunohistochemistry with monoclonal antibodies of variable specificity (SK 56-23, a large spectrum antibody; SK 60-61, which reacts with cytokeratin polypeptides no. 8 and 18 of Moll's catalogue; SK 2-27, specific for polypeptides no. 14, 16 and 17). The normal urothelial pattern is in agreement with previous reports. In pathological conditions, modified immunostaining has been demonstrated in almost all cases. In detail, the cytoskeletal pattern detected in transitional cell papilloma seems to discriminate between types which are otherwise histologically similar. We also observed a correlation between higher degrees of malignancy and loss of specialization, as demonstrated by the increasing positivity for SK 60-61, which as a rule specifically stains "umbrella" cells, and SK 2-27, an antibody exclusively detected in cells of the basal layer. These findings indicate that the cytokeratin pattern may constitute a modern new tool for the pathologist in the diagnosis of urothelial proliferative disorders.

Topics: Antibodies, Monoclonal; Carcinoma, Transitional Cell; Cystitis; Epithelium; Histocytochemistry; Humans; Immunohistochemistry; Keratins; Metaplasia; Papilloma; Urinary Bladder; Urinary Bladder Diseases; Urinary Bladder Neoplasms

The immunocompetent cell population of the cervical transformation zone of 18 uteri removed for noncervical disease, has been investigated with monoclonal antibodies. The panel included Leu 2a, 3a, 4, 14, and IL II receptor for lymphocytes and T cell subsets, Leu 7 for NK cells, Leu M5, Leu 10, HLA-DR, DRC 1 for dendritic cells, and Leu 6 for Langerhans' cells (LC). In ectocervical epithelium HLA-DR, Leu 6 and Leu 10 antibodies identified subpopulations of dendritic cells which differed in number and in topographic distribution. Furthermore, a strong HLA-DR epithelial positivity was constantly observed in endocervical columnar cells as well as in keratinocytes of squamous metaplasia. Leu 2a+ cells (T suppressor/cytotoxic) prevailed in the stromal and epithelial compartments of ecto/endocervix; in 6 cases, however, Leu 3a+ cells (T helper/inducer) represented the main T cell subset in the ectocervical stroma. B lymphocytes were occasionally noticed in the subepithelial stroma while NK and DRC-1 cells were never observed. Finally, only few lymphocytes displayed a positivity for IL II receptor. This study suggests that several phenotypes of intraepithelial dendritic cells are present in the transformation zone and that endocervical columnar cells and keratinocytes of squamous metaplasia express HLA-DR products; the latter finding may be related to the presence of intraepithelial and stromal T lymphocytes.

Topics: Adult; Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; Cervix Uteri; Dendritic Cells; Epidermis; Epithelium; Female; HLA-DR Antigens; Humans; Immunohistochemistry; Keratins; Langerhans Cells; Metaplasia; Middle Aged; Phenotype; Receptors, Antigen, T-Cell; Receptors, Immunologic; Receptors, Interleukin-2; T-Lymphocytes; Uterine Cervicitis

We report four cases of corneoconjunctival keratinization that were successfully treated with topical retinoic acid ointment. In two cases keratinization was due to squamous metaplasia and in two others it was secondary to intraepithelial corneoconjunctival neoplasia. Treatment reversed severe keratinization in a case of drug-induced pseudopemphigoid and stabilized the disease in one of the two affected eyes without additional treatment. In a case of ocular cicatricial pemphigoid, retinoic acid was useful as an adjuvant therapy to immunosuppression, by reversing keratinization of the conjunctiva. In two cases of corneoconjunctival neoplasia, lesions regressed markedly. Long-term treatment was well tolerated in three patients. Our findings suggest that retinoic acid ointment is effective in treating severe squamous metaplasia in cicatrizing diseases of the conjunctiva. Our findings indicate further that retinoic acid seems to inhibit growth of corneoconjunctival neoplasias and thus might be useful complementary therapy in this situation.

Topics: Administration, Topical; Aged; Aged, 80 and over; Conjunctiva; Conjunctival Diseases; Conjunctival Neoplasms; Conjunctivitis; Cornea; Corneal Diseases; Epithelium; Female; Humans; Keratins; Male; Metaplasia; Tretinoin

In a defined culture system for hamster tracheal explants, the activity of 12 different retinoids was evaluated for reversal of keratinization induced by exposure to the carcinogen, benzo[alpha]pyrene (BP-HTOC assay). The effects of retinoids in this system were compared to those in a defined culture system for tracheal explants from vitamin A-deficient hamsters (standard-HTOC assay). In both assays, all-trans-retinoic acid (RA) and 13-cis-RA were the most active retinoids. For RA and 13-cis-RA, the values of ED50 determined in the BP-HTOC bioassay were 4 x 10(-12) and 1 x 10(-11) M, respectively, whereas the corresponding values in the standard HTOC assay were 2 x 10(-11) and 3.3 x 10(-10) M. For all 12 retinoids, the ED50 values from the BP-HTOC were lower than those from the standard-HTOC assay, and there was also a statistically significant correlation between the rank-ordering of ED50 values from the 2 assays. Among 3 N-(retinoyl)amino acids examined in both assays, N-(retinoyl)leucine was the most active, N-(retinoyl)phenylalanine the least active, and N-(retinoyl)alanine intermediate. Among a novel series of bifunctional retinoic acid analogues, the dicarboxyl derivative was the most active. On the basis of these results, the BP-HTOC assay appears to be one of the most sensitive assays for retinoids yet developed. This assay is an appropriate model for evaluating the chemopreventive potential of new retinoids in vitro.

Topics: Animals; Benzo(a)pyrene; Cricetinae; Culture Techniques; Epithelium; Keratins; Mesocricetus; Metaplasia; Retinoids; Trachea; Vitamin A Deficiency

A case of superficially invasive well-differentiated cutaneous squamous cell carcinoma containing numerous mucin-producing cells both within the epidermal and dermal components is reported. Histological, histochemical and immunohistochemical overlap exists between these cells and those of extramammary Paget's disease. The presence of mucinous metaplasia within this tumor supports an intraepidermal origin for extramammary Paget's disease.

Topics: Biopsy; Carcinoma, Squamous Cell; Epidermis; Facial Neoplasms; Humans; Keratins; Male; Metaplasia; Middle Aged; Mucins; Staining and Labeling

Gastric carcinomas have been assayed for the presence of villin and for the small intestinal hydrolases aminopeptidase N and sucrase isomaltase. These proteins seem not to be present in normal stomach epithelium. However intestinal metaplasia in stomach, and tumour cells in the glandular patterns of gastric carcinoma were positive for all three markers, showing characteristic apical positivity. In contrast, in diffuse gastric carcinomas the percentage of signet ring cells positive for these markers varied from 10-100% with each marker showing a similar percentage of positive cells. Testing of gastric carcinomas with antibodies specific for different keratin polypeptides showed that while all 7 tumours were positive for keratins 8 and 18.2 were also positive for keratin 7. In the keratin 7 positive tumours all tumour cells were keratin 7 positive. The keratin 8 antibody also reacted on routinely fixed specimens. Thus gastric carcinomas reveal different degrees of gastric and intestinal differentiation.

Topics: Adenocarcinoma, Mucinous; Alkaline Phosphatase; Aminopeptidases; Calcium-Binding Proteins; Carrier Proteins; CD13 Antigens; Fluorescent Antibody Technique; Frozen Sections; Humans; Hydrolases; Immunohistochemistry; Intestine, Small; Keratins; Metaplasia; Microfilament Proteins; Microvilli; Stomach Neoplasms; Sucrase-Isomaltase Complex

The aim of the present study was to explore the histogenesis of metaplastic cells in the human uterine cervix. In a previous study we demonstrated that squamous cervical metaplasia expresses a unique set of cytokeratin polypeptides different from that expressed by the various normal epithelial elements of both the exo- and endocervix. It was thus proposed that the formation of squamous metaplasia represented a new route of differentiation. In the present study we further investigated this aspect by expanding the battery of monoclonal antibodies directed against specific cytokeratin epitopes used for immunohistochemical labelling. The antibodies used were: KS-1 A3, which specifically stains cytokeratin polypeptide no. 13; antibody KS-2.1, which is an anti-cytokeratin reacting with pseudostratified transitional and some simple epithelia; and antibody KS-B17.2 reacting with cytokeratin polypeptide no. 18. Examination of the staining patterns obtained with these antibodies revealed specific staining of ciliated cells with antibody KS-2.1 and of endocervical reserve cells with antibody KS-1A3. In 6 out of 19 cases tested reserve cells were also stained with antibody KS-2.1. These results enabled us to distinguish between at least four types of cells residing within the simple epithelium of the endocervix, namely columnar nonciliated cells, ciliated cells, and two subpopulations of reserve cells. Since metaplasia was positively stained by antibodies KS-1A3 and KS-2.1, we propose that the endocervical reserve cells that express cytokeratin polypeptide no. 13 are most probably the cells from which endocervical metaplasia is derived.

Topics: Antibodies, Monoclonal; Cervix Uteri; Electrophoresis, Gel, Two-Dimensional; Epithelial Cells; Epithelium; Female; Fluorescent Antibody Technique; Humans; Keratins; Metaplasia; Reference Values

The keratins expressed in cultured rat cervical epithelial cells were analyzed by using two-dimensional gel electrophoresis and monoclonal antikeratin antibodies and were compared with those expressed in the rat cervix in vivo in the presence and absence of estrogen stimulation. The cervical epithelium in vivo responds to estrogen stimulation with alterations in keratin composition. In response to estrogen, the epithelium undergoes proliferation and stratification and begins expressing increased amounts of two basic Mr 57,000 and 58,000 keratins and two acidic Mr 51,000 and 52,000 keratins. Cultured rat cervical epithelial cells were found to express only small amounts of the basic Mr 57,000 and 58,000 keratins and the two acidic Mr 51,000 and 52,000 keratins characteristic of the estrogen-stimulated cervix. In addition to the keratins found in the cervical epithelium in vivo, rat cervical epithelial cells in vitro begin expressing two Mr 55,000 and 56,000 keratins of the basic keratin family (type II) and an acidic component with a molecular weight of 40,000. Although these components are not detected in the rat cervix in vivo, they migrate similarly on two-dimensional electrophoretic gels to proteins expressed by the rat endometrial epithelium in vivo. These findings indicate that alterations in keratin expression could serve as markers for studying the effects of steroid hormones on the differentiation of rat cervical epithelial cells in vitro and during the development of squamous metaplasia.

Topics: Animals; Carcinoma, Squamous Cell; Cells, Cultured; Cervix Uteri; Cytoskeletal Proteins; Epithelium; Female; Fluorescent Antibody Technique; Keratins; Metaplasia; Molecular Weight; Rats; Rats, Inbred Strains

The monoclonal antibody CAM 5.2 was used to investigate the expression of lower molecular weight cytokeratin proteins immunocytochemically in conventionally processed samples of schistosoma-associated squamous metaplasias and carcinomas of the urinary bladder. The antibody did not differentiate between squamous metaplasias and well differentiated squamous carcinomas, though it did focally label moderate to poorly differentiated tumours. The results suggest that squamous carcinomas of the bladder in this setting differ fundamentally from such tumours at other sites in their patterns of cytokeratin protein expression.

Topics: Antibodies, Monoclonal; Carcinoma, Squamous Cell; Humans; Keratins; Metaplasia; Molecular Weight; Schistosomiasis haematobia; Urinary Bladder; Urinary Bladder Neoplasms

Immunofluorescent and immunoperoxidase labelling of normal and metaplastic human submandibular salivary glands with a battery of cytokeratin-specific monoclonal antibodies was carried out. Labelling with a broad spectrum cytokeratin antibody (KG 8.13), as well as with antibody to cytokeratin polypeptide No. 18 (Ks 18.18) was observed in all the epithelial elements of the gland. Polypeptide No. 19, however, was present in ductal cells only, sparing the acini and the associated myoepithelium. Antibody KS 8.58, specific for cytokeratins Nos. 13 and 16, selectively labelled basal cells along the large ducts. Examination of squamous metaplasia associated with chronic suppurative sialadenitis indicated that the metaplastic cells display the same cytokeratin profile as the normal ductal cells and are not labelled with antibodies KS 8.58 and KK 8.60 which usually stain normal and pathological stratified epithelia. The significance of these observations for the histogenesis of normal salivary glands, as well as for the development of the metaplastic process, is discussed.

Topics: Antibodies, Monoclonal; Child; Epithelium; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Keratins; Metaplasia; Microscopy, Fluorescence; Peptides; Salivary Gland Diseases; Sialadenitis; Submandibular Gland; Submandibular Gland Diseases

An immunohistochemical survey of the distribution of keratin was studied in chemically induced carcinomas of the submandibular glands of mice. Initial signs of premalignant changes were degranulation of granular convoluted tubule cells and deposition of keratin protein in small limited areas of the degranulated cells. There was a gradual increase in the area showing keratin staining in altered tubule cells. Duct-like and cystic structures stained intensely for keratin, as did squamous metaplastic epithelial cells. Induced carcinomas were variably keratinized. Basal layers of cells of squamous-cell carcinomas displayed weak keratin staining, and spinous tumor cells and parakeratotic tumor cells showed somewhat increased levels of keratin staining. Some desquamated keratotic tumor cells stained intensely for keratin. Just as the localization of epidermal and nerve growth factors and lectin-binding histochemistry have been used in studying tumorigenesis in the mouse submandibular gland, immunohistochemically detected keratin proved to be a useful marker of tumor cells of ductal segment origin.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Epithelium; Histocytochemistry; Immunoenzyme Techniques; Keratins; Male; Metaplasia; Mice; Mice, Inbred Strains; Precancerous Conditions; Salivary Gland Neoplasms; Submandibular Gland; Submandibular Gland Neoplasms

CAM 5.2 is a monoclonal antibody which identifies lower molecular weight cytokeratin proteins (50, 43 and 38 kD). It is an antibody which works reliably on formalin-fixed, paraffin-embedded tissues. In this study, using CAM 5.2 in the indirect immunoperoxidase method we have examined ectocervical epithelium ranging from normal, through metaplasia and cervical intraepithelial neoplasia to invasive squamous carcinoma. CAM 5.2 is demonstrated to be a useful indicator of changes associated with malignant transformation in the ectocervix.

Topics: Antibodies, Monoclonal; Carcinoma, Squamous Cell; Cervix Uteri; Female; Humans; Immunoenzyme Techniques; Keratins; Metaplasia; Molecular Weight; Uterine Cervical Neoplasms

Tracheas from vitamin A-deficient hamsters in organ culture in vitamin A-free medium developed squamous metaplasia. Addition of retinyl acetate to the medium prevented squamous metaplasia and a mucociliary epithelium was maintained. Indirect immunofluorescent staining with antikeratin antibodies AE1 and AE3 indicated positive reactions with epithelium of tracheas either cultured in vitamin A-free or retinyl acetate (RAc)-containing medium. The "stratum corneum"-like squames in metaplastic tracheas were strongly stained by AE3. Immunoprecipitation of cytoskeletal extracts from [35S]methionine labeled tracheas with a multivalent keratin antiserum indicated that the concentration of keratins synthesized in tracheas cultured in vitamin A-free medium was greater than that observed in tracheas cultured in the presence of RAc. In addition, new species of keratin were expressed in tracheas cultured in RAc-free medium. Alterations in the program of keratin synthesis were clearly detectable after 1 d in vitamin A-free medium, even though squamous metaplasia was not yet obvious. Squamous tracheas were shown by immunoblot analysis to contain keratins of 50, 48, 46.5, and 45 kilodalton (kd) detected with AE1; and 58, 56, and 52 kd detected with AE3. Immunoblot analysis with monospecific antimouse keratin sera also demonstrated the presence of 60, 55, and 50 kd keratins in the metaplastic tracheas. All these various species of keratins were either absent or present in much reduced quantity in mucociliary tracheas in RAc-containing medium. Interestingly, the induction of squamous metaplasia in tracheal epithelium did not result in the expression of the 59 and 67 kd keratins which are characteristically expressed in the differentiated layers of the epidermis. Therefore, this study shows that squamous metaplasia of tracheas due to vitamin A-free cultivation is accompanied by an increase in keratin synthesis as well as by the appearance of keratin species not normally present in mucociliary tracheal epithelium.

Topics: Animals; Cricetinae; Cytoskeleton; Diterpenes; Electrophoresis, Polyacrylamide Gel; Epithelium; Fluorescent Antibody Technique; Immunologic Techniques; Immunosorbent Techniques; Keratins; Mesocricetus; Metaplasia; Organ Culture Techniques; Retinyl Esters; Trachea; Vitamin A; Vitamin A Deficiency

Repopulation of rat tracheas of human tracheobronchial epithelial cells obtained from intermediate autopsies was achieved by introducing into de-epithelialized rat tracheas either pieces of donor tissue containing respiratory mucosa or epithelial cells produced by an in vitro amplification of these cells. After tracheas were sealed, and transplanted into the subcutaneous tissues of nude mice, a newly formed epithelium migrated over the denuded luminal surface. During this process, regenerative epidermoid metaplasias, consisting of the growth of thin stratified epithelium with keratinization but without atypia was observed. Four weeks after xenotransplantation, most of the luminal surface was covered by columnar epithelium with occasional patches of epidermoid metaplasia. When this epithelium was exposed to 7,12-dimethylbenzo[a]anthracene (DMBA) a thick epidermoid metaplasia with mild to moderate atypia was observed. This type of epithelium is seen one to three months after insertion of the DMBA-containing pellets into the tracheal lumen. Immunohistochemical staining with antikeratin monoclonal antibodies AE1 and AE3 revealed increased immunostaining in both regenerative and DMBA-induced metaplasias compared with that of untreated normal mucociliary epithelium. Although no differences between the two types of metaplasias were detected with AE1 and AE3, the use of involucrin immunostain showed important differences. Normal respiratory epithelium did not contain involucrin, but this protein was seen in the surface layer of regenerative epidermoid metaplasias. In DMBA-induced metaplasias, involucrin was found not only in the superficial cells but was also present in numerous suprabasal cells. The hyperplastic nature of these carcinogen-induced lesions, together with the presence of cellular atypia and an altered involucrin distribution pattern, suggest a preneoplastic state.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Epidermis; Epithelium; Humans; Keratins; Metaplasia; Mice; Mice, Nude; Precancerous Conditions; Rats; Trachea; Tracheal Neoplasms; Transplantation, Heterologous

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

The expression of cytokeratin polypeptides in squamous metaplasia of the human uterine cervix was investigated by immunocytochemical labeling with polypeptide-specific antibodies against cytokeratins. Immunofluorescence microscopic examination of cervical tissues using various monoclonal antibodies indicated that squamous cervical metaplasia expresses a unique set of cytokeratin polypeptides, this being distinctively different from that expressed by all of the normal epithelial elements of the exo- and endocervix. The development of metaplastic foci was accompanied by the expression of cytokeratin polypeptide no. 13, which is commonly detected in stratified epithelia, and by a reduction in the level of polypeptide no. 18, which is typical of simple epithelia. The 40-kilodalton cytokeratin (no. 19) described by Moll et al., which is abundant in the columnar and reserve cells of the endocervix, was found throughout the metaplastic lesions. Only in 'well-differentiated' metaplasias did we detect polarity of cytokeratin expression reminiscent of the staining patterns in the exocervix. This was manifested by the exclusive labeling of the basal cell layer(s) with antibodies KB 8.37 and KM 4.62, which stain the basal cells of the exocervix. Furthermore, a comparison of cervical metaplasia with squamous areas occurring within endometrial adenocarcinomas pointed to a close similarity in the cytokeratin expression of the two. We discuss the use of cytokeratins as specific markers of squamous differentiation, the relationships between squamous metaplasia and cervical neoplasia, and the involvement of reserve cells in the metaplastic process.

Topics: Adult; Aged; Antibodies, Monoclonal; Cervix Uteri; Collodion; Electrophoresis, Polyacrylamide Gel; Epithelium; Female; Fluorescent Antibody Technique; Humans; Keratins; Metaplasia; Microscopy, Fluorescence; Middle Aged; Peptides; Uterine Cervical Neoplasms

The behaviour of keratins in the human prostate is investigated immunohistochemically by polyclonal rabbit antibodies against keratins from human stratum corneum (kit from ORTHO/Heidelberg) and compared to the behaviour of prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA). In normal glands and cribriform as well as adenomatous hyperplasia only basal cells contain keratin. The secretory epithelium is keratin-negative and in contrast to the basal cells PAP- as well as PSA-positive. In prostatic ducts and utriculus prostaticus keratin is demonstrable in basal cells and urothelium. As in normal glands, the light cylindric epithelium is keratin-negative and PAP- as well as PSA-positive. The cells in atrophic glands and postatrophic hyperplasia may contain keratin as well as PAP and PSA. Urothelial and squamous metaplasia are strongly keratin-positive. PAP and PSA are not found. The cylindric epithelium of the ejaculatory ducts contains keratin at many places. PAP and PSA are not demonstrable. The utriculus does not differ from normal prostatic glands immunohistochemically. This supports the view that the epithelium of the sinus urogenitalis is involved in the embryogenesis of normal prostatic glands and the utriculus as well. Urothelial and squamous metaplasia obviously arise from basal cells which share the same immunohistochemical features. Whether the cells in atrophic glands and postatrophic hyperplasia derive from basal cells or secretory epithelium cannot be decided. The keratin composition of the prostate should be further analyzed by keratin-specific monoclonal antibodies.

Topics: Acid Phosphatase; Antigens; Histocytochemistry; Humans; Immunochemistry; Keratins; Male; Metaplasia; Prostate; Prostate-Specific Antigen; Prostatic Hyperplasia

Keratin immunoreactivity in the benign and neoplastic human prostate was examined immunohistochemically using two monoclonal antibodies with differing specificities. One of these antibodies stained only the basal cells of the normal and hyperplastic prostatic epithelium, with no reactivity in tumor cells of prostatic adenocarcinoma. The other monoclonal antibody recognized a keratin protein present in all normal and hyperplastic columnar (secretory) epithelial cells, as well as in all cancer cells regardless of degree of tumor differentiation. In addition, the second antibody stained acinar and ductal epithelial cells exhibiting premalignant changes. Our findings indicate that keratin immunoreactivity differs among the epithelial cell populations of the human prostate, probably reflecting expression of different keratin proteins. The distinctive patterns of staining obtained with these two antibodies may assist in distinguishing hyperplastic from neoplastic prostatic epithelium, as well as in the recognition of basal cell hyperplasia, transitional cell metaplasia, and premalignant changes.

Topics: Antibodies, Monoclonal; Humans; Keratins; Male; Metaplasia; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms

Squamous metaplasia is not an uncommon feature of a number of salivary gland lesions. Arterial ligation of rat submandibular and sublingual salivary glands was used for study of the processes and cell types involved in the development of the squamous metaplasia that occurs in ischemic and infarcted portions of gland parenchyma 6 to 8 days following vessel ligation. Light and electron micrographs show that the principal portion of salivary gland tissue undergoing squamous metaplasia is the acinar-intercalated duct cell complex. Early stages of this process involve a gradual dedifferentiation of acinar cells and hyperplasia of acinar, duct luminal cells, and myoepithelium. Subsequently, both luminal and myoepithelial cells have increasing accumulation of tonofilaments and formation of desmosomes, and centrally located cells may undergo keratinization. Immunohistochemical staining of ischemic salivary gland tissue with developing squamous metaplasia was performed with the use of rabbit antisera to human epidermal and Mallory body cytokeratins. The two antisera gave complementary patterns in normal acini and ducts, with antibody to epidermal cytokeratin (ECK) staining only myoepithelial cells and antibody to Mallory body cytokeratin (MBCK) staining mainly luminal epithelial cells. In early phases of squamous metaplasia (6 days after ligation), antibody to ECK stained central and peripheral (myoepithelial) cells, but by 8 days after ligation only central cells were stained. At 6 days after ligation, a proportion of central cells in squamoid clusters stained with antibody to MBCK, and myoepithelial cells were unstained. By 8 days after arterial ligation, cell clusters exhibiting squamous metaplasia were completely unstained with antibody to MBCK, despite the presence ultrastructurally of numerous tonofilament bundles in both types of cells forming these clusters. The propensity for squamous alteration of acinar-intercalated duct complexes has important connotations for salivary gland tumors such as pleomorphic adenoma and mucoepidermoid carcinoma.

Topics: Animals; Humans; Immunoenzyme Techniques; Keratins; Metaplasia; Mice; Rats; Rats, Inbred Strains; Salivary Gland Neoplasms; Salivary Glands; Submandibular Gland

We report on a biphasic synovial sarcoma showing slight squamous cell differentiation of their epithelioid component under the light microscope. The electron microscopical examination revealed numerous tonofilaments arranged in dense bundles, which could be characterized as tonofibrils with keratohyalin granules in the same cells. The presence of such structures indicates the possibility of squamous metaplasia in biphasic synovial sarcoma.

Topics: Cell Differentiation; Cytoplasmic Granules; Cytoskeleton; Female; Forearm; Humans; Keratins; Metaplasia; Microscopy, Electron; Middle Aged; Organoids; Sarcoma, Synovial

Five thousand seven hundred seventy-eight adenomas or adenomas containing carcinoma from 3215 patients were examined by routine histologic methods for the presence of epithelial metaplasias. Three forms of epithelial metaplasia were encountered: squamous cell metaplasia (0.44%), Paneth cell metaplasia (0.20%), and melanocytic metaplasia (0.017%). In several instances multiple forms of metaplasia were encountered in the same polyp. In those cases in which the paraffin blocks were available, a Grimelius stain was performed. Grimelius-positive cells were present in 63% of the adenomas containing a metaplastic cell type. All cases with Paneth cell differentiation were immunoreactive for lysozyme; all lesions containing areas of squamous differentiation were immunoreactive for keratin except 2. The histopathologic features of these cases are discussed, and it is concluded that rather than representing a true metaplastic process, Paneth cell, squamous cell, and melanocyte differentiation represent the full range of cellular differentiation that endodermally derived tissues can exhibit, particularly when they undergo neoplastic alterations.

Topics: Adenoma; Adult; Age Factors; Aged; Cell Differentiation; Colonic Neoplasms; Female; Histocytochemistry; Humans; Intestinal Polyps; Intestine, Large; Keratins; Male; Melanocytes; Metaplasia; Middle Aged; Muramidase; Rectal Neoplasms; Retrospective Studies; Sex Factors

Strata cornea of normal human gingival and palatal epithelia and of metaplastic lesions (leukoplakia simplex) in the mucosa of the cheek and floor of the mouth were examined by light- and electronmicroscopy. The overall thickness of the stratum corneum, individual corneocyte thickness, number of corneocyte layers, and the type of keratin pattern expressed by individual corneocytes were determined. The data demonstrated that (1) the oral gingival and hard palate epithelia produce similar strata cornea with corneocytes ranging from 0.9 to 1.3 micron in thickness and displaying a high degree of conformity with respect to the keratin pattern, (2) the normal keratin pattern expressed in oral corneocytes differs from that reported for epidermal corneocytes, (3) under conditions of metaplastic keratosis, the strata cornea of lesions developing in the mucosa of the cheek and floor of the mouth are of variable thickness with 15 to 30 layers of corneocytes displaying either the oral or, more often, the epidermal keratin pattern. It is suggested that (1) the expression of a particular keratin pattern is independent of the presence or absence of nuclei and (2) the mechanism generating and alteration in cell differentiation from normal, non-keratinizing cheek epithelium to an epidermal one possibly operates through an intermediary step usually encountered as an expression of the oral keratin pattern of normal gingiva and hard palate.

Topics: Adolescent; Adult; Aged; Child; Epithelial Cells; Female; Gingiva; Humans; Keratins; Leukoplakia, Oral; Male; Metaplasia; Middle Aged; Mouth Diseases; Mouth Mucosa; Palate

Topics: Adult; Breast; Bucladesine; Cell Differentiation; Cells, Cultured; Cyclic AMP; Epithelial Cells; Female; Humans; Keratins; Menstruation; Metaplasia; Middle Aged; Prostaglandins

Cytokinetic and ultrastructural studies were carried out to elucidate mechanisms involved in the reversal of squamous metaplasia (SM) by beta-retinoic acid in organ cultures of tracheas derived from vitamin A-deficient hamsters. Tracheal cultures exhibiting focal areas of SM were treated with the retinoid for up to 7 days. The retinoid significantly inhibited [3H]-thymidine labeling indices in the basal cells and stimulated the labeling indices in mucous cells. At the ultrastructural level the retinoid induced marked remodeling alterations in the metaplastic epithelium that included: (a) disruption of desmosomes and widening of intercellular spaces; (b) extensive vacuolation and degeneration of the metaplastic cells; (c) extrusion of the degenerated cells; (d) aggregation of keratin filaments; and (e) differentiation of certain basal cells into secretory cells. Consequently most degenerated metaplastic cells were extruded and the epithelium repopulated as a result of differentiation of basal cells into mucous cells and hyperplasia of the pre-existing mucous cells. The degenerative effects of the retinoid were limited to the metaplastic foci since the uninvolved epithelium adjoining metaplastic foci were not significantly altered. The results suggest that the restoration of normal tracheal epithelium following the retinoid treatment of explants exhibiting focal areas of squamous metaplasia is associated with the enhanced proliferation of the mucous cells. The inhibition of proliferation of basal cells further prevented hyperplasia and restored cell replication within the normal range.

Topics: Animals; Cell Differentiation; Cell Division; Cricetinae; Epithelium; Keratins; Metaplasia; Microscopy, Electron; Organ Culture Techniques; Trachea; Tretinoin; Vitamin A Deficiency

All stages of regeneration in hamster tracheal epithelium were studied following a denuding mechanical injury. At 1 h all the cells had sloughed from the wound site leaving a bare and sometimes disrupted basal lamina. Viable cells at the wound margins rapidly changed shape, flattened and migrated to cover the denuded lesion by 12 h. In addition, epithelial cells that remained viable demonstrated sublethal changes that included the rapid discharge of mucous granules from secretory cells, internalization of cilia by ciliated cells and evidence of heterophagy in both cell types. By 24 h a wave of epithelial cell divisions occurred, primarily by secretory cells. This produced a multilayered epidermoid metaplasia that was best developed at 48 h. The metaplastic epithelium was largely composed of cells with both secretory (mucous granules) and epidermoid (tonofilament bundles and numerous desmosomes) characteristics. The peroxidase-antiperoxidase (PAP) method demonstrated a few keratin-positive cells in the wound as early as 12 h post-wounding and keratin was demonstrated in more cells by 24 h. All cells in the metaplastic wound epithelium were keratin-positive by 48 h. Following 48 h some of the most superficial keratinized cells sloughed from the epithelium and the keratin content of the remaining cells began to decline. At 72 h pre-ciliated and pre-secretory cells were seen in the wound. Pre-ciliated cells were characterized by an abundant electron-lucent cytoplasm, large pale nucleus, filiform apical microvilli and evidence of ciliogenesis, similar to that seen during fetal development. Pre-ciliated cells often contained apical mucous granules, apparently carried over from the parent secretory cells. With the appearance of these columnar cells the normal mucociliary morphology was restored in small wounds by 120 h, but some persistent epidermoid metaplasia remained in the large wounds through 168 h post-wounding. These data provide further evidence for the important role of secretory cells in the histogenesis of epidermoid metaplasia and the regeneration of normal morphology following injury. The implications of these findings in understanding the histogenesis of other lesions in the tracheo-bronchial epithelium are discussed.

Topics: Animals; Cricetinae; Cytoskeleton; Desmosomes; Epithelium; Female; Keratins; Male; Mesocricetus; Metaplasia; Microscopy, Electron; Microvilli; Regeneration; Time Factors; Trachea; Wound Healing

Epithelial cell differentiation is accompanied by biochemical and immunological changes of cytoplasmic components. Antibodies against filamentous and nonfilamentous substances of epithelial cells are helpful for the visualization of the gradual maturation processes in different epithelia. The present study is concerned with differentiation characteristics of the normal cervical mucosa and, in particular, the squamocolumnar junction. Antibodies against tissue polypeptide antigen (TPA), large keratins (67K), and all keratin fractions were applied in this investigation. Antibody binding was revealed by indirect immunofluorescence. TPA was found to be characteristic for basal layer cells and undifferentiated reserve cells of the transformation zone. In contrast, 67K represent an indication of squamous differentiation and were only found in suprabasal cells of the ectocervical epithelium and in keratinizing cells of the transformation zone. Antibodies against all keratin fractions were seen to label all epithelial cells. The immunomorphological definition of epithelial compartments of the normal cervical mucosa supports earlier concepts of the physiological processes at the squamocolumnar junction and represents an interesting tool for studies of cervical neoplasias of various differentiations.

Topics: Adult; Antigens; Binding Sites, Antibody; Cervix Uteri; Female; Fluorescent Antibody Technique; Humans; Keratins; Metaplasia; Middle Aged; Mucous Membrane; Peptides

The histologic similarities between the craniopharyngioma and the ameloblastoma are well recognized and supported by their common embryologic origin from oral ectoderm. Differences in these lesions include a greater tendency for craniopharyngiomas to be cystic and form ghost cells and calcifications. The keratinizing and calcifying odontogenic cyst (KCOC), a lesion that features proliferating ameloblastic epithelium, ghost keratin, calcification, and cyst formation, may more precisely mimic the craniopharyngioma. The histologic features of twenty-seven craniopharyngiomas were studied. Twenty cases resembled KCOC microscopically. Two examples duplicated the histologic features of infiltrative ameloblastoma, while five showed characteristics of both lesions. This study shows that the range of histologic features in craniopharyngioma includes and spans both odontogenic lesions but more often simulates KCOC. The results suggest that the KCOC and the ameloblastoma may be closely related developmentally.

Topics: Ameloblastoma; Craniopharyngioma; Diagnosis, Differential; Epithelium; Humans; Keratins; Metaplasia; Odontogenic Tumors; Pituitary Neoplasms

The distribution of intracellular keratins was investigated in normal bronchial epithelium and in several morphologically distinct forms of respiratory tract carcinomas. This study was performed with two different experimentally produced antisera against normal human stratum corneum keratin and against keratin protein of MW 67,000 dalton, using indirect immunofluorescence and immunoperoxidase methods on tissue sections and cell suspensions. In normal bronchial epithelium, the basal cells were strongly labelled by both antisera. The ciliated columnar cells appeared devoid of cytokeratins in tissue sections but were strongly labelled with both antisera in cell suspensions. The goblet cells remained negative in every case. In squamous metaplasia of the bronchus, all epithelial cells were unevenly stained with both antisera. Among tumours, only the squamous cell carcinomas were strongly labelled by both antisera. Primary lung adenocarcinoma appeared weakly positive, whereas metastatic lung carcinomas, undifferentiated lung carcinomas, oat cell tumours, carcinoid tumours were negative. The immunocytochemical determination of keratins appeared to be of value in the study of normal and abnormal epithelial differentiation, in the diagnosis of poorly differentiated carcinomas and in their distinction from metastatic tumours of the lung.

Topics: Adenocarcinoma; Bronchi; Bronchial Neoplasms; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Epithelium; Humans; Keratins; Lung Neoplasms; Metaplasia

Topics: Animals; Bucladesine; Culture Techniques; Drug Synergism; Epithelium; Keratins; Male; Metaplasia; Methylcholanthrene; Mice; Mice, Inbred BALB C; Papaverine; Phorbol Esters; Prostaglandins; Prostate; Retinoids; Vitamin A

The use of the synchronous induction method enables both assessment of the sequence and reliability of the appearance of morphologic signs of vitamin A deficiency, and their accurate correlation with biochemical and physiologic abnormalities. In the trachea, hyperplasia of basal epithelial cells was observed by Day 4 (T4) following the withdrawal of retinoic acid from retinoate-cycled, stringently deficient rats. Keratinization was observed by Day 6, the upper part of the trachea showing the highest incidence of keratinization. All such metaplastic changes originated in the narrow strip of tissue directly cojoining the esophagus. In the submaxillary glands, atrophy of the acini, an increase in interlobular spaces, and fibrosis and dilatation of the ducts was observed by Day 10. In more advanced stages of deficiency (T14-T18), cyst formation associated with suppuration and extensive cell atrophy was observed. Morphologic changes were less marked in the sublingual glands, although mucin levels were noticeably depressed by Day 12 of deficiency. Following the oral dosing of deficient animals (T12) with 350 micrograms retinyl palmitate, all such changes were reversed within 6 days in the trachea and within 10 days in the submaxillary and sublingual glands. Similar patterns were observed whether animals were force-fed or were fed ad libitum. Apart, therefore, from cause-effect considerations per se, morphologic changes are also potentially valuable reference indicators of deficiency, particularly in time course studies, or where force-feeding attenuates other signs of deficiency.

Topics: Animals; Atrophy; Keratins; Male; Metaplasia; Rats; Salivary Glands; Sublingual Gland; Submandibular Gland; Trachea; Vitamin A Deficiency

Topics: Animals; Bucladesine; Cell Differentiation; Epidermis; Female; Keratins; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Metaplasia; Mice; Organ Culture Techniques; Papaverine; Prostaglandins; Retinaldehyde

An attic cholesteatoma is defined as an epidermoid cyst found in the attic. This is differentiated from an infected retraction pocket of the pars tensa or a retraction pocket cholesteatoma. Stratified squamous epithelium may also be present in the middle ear as other clinical or pathological entities, such as metaplastic islands of the mucosa in chronic ears with central perforations. Histological examination of 22 temporal bones with attic cholesteatomas has shown them to reside mainly medial to the ossicular chain. This explains the difficulty they have in self-cleansing, as well as the ensuing secondary infection. When a similar process occurs lateral to the ossicles, a self-cleansing nature's atticotomy may be formed. The aetiology of an attic epidermoid cyst, i.e., an attic cholesteatoma, is usually considered to be an invasive retraction from the external ear. However, it is difficult to accept invasion of external canal skin into the upper medial attic. This is especially so in the face of such biological phenomena as epithelial contact inhibition, or the invariable outward migration of stratified squamous epithelium from the edges of retraction pockets as well as from cholesteatoma perforations. Also, large cholesteatomas usually present themselves from the "beginning" simultaneously with their perforations; no documentation of an evolving process from a pre-existing perforation exists at present. Marginal perforations, which have later evolved into attic cholesteatomas have so far not been documented. On the other hand, retraction pockets of the pars tensa or pars flaccida associated with some middle ear negative pressure do occur, however, it is yet to be shown that such retractions can reach the medial part of the ossicular chain and form epidermoid-like cysts there. Therefore, the possibility that an attic cholesteatoma often arises primarily in the attic and presents itself secondarily in the external canal as a "perforated" epidermoid cyst, is to be considered. The possibility that a congenital rest is responsible for such an epidermoid cyst has often been put forward, but evidence that such rests actually exist has not yet been presented. The frequency with which cholesteatoma sacs found in the attic show mucosal cells as part of their lining, suggests a metaplastic phenomenon. This means that the epithelial cells of the middle ear lining may have changed from mucosal into keratinizing cells (or even vice versa). Metaplastic changes of muco

Topics: Cholesteatoma; Ear Diseases; Epidermal Cyst; Epithelium; Eustachian Tube; Humans; Keratins; Metaplasia; Mucus; Temporal Bone; Tympanic Membrane

Keratinization of the tarsal conjunctiva in an eye with adequate tears occurs following a number of conditions, including irritation and sensitivity to topical medications, Stevens-Johnson syndrome, radiation to the lid, and occasionally from unknown causes. The keratinized cells produce an epithelial keratitis with subsequent vascularization of the cornea. The morphogenesis of this condition is discussed, along with therapy including mucous membrane grafts and freezing of the tissue.

Topics: Animals; Conjunctiva; Cornea; Epidermis; Eye Diseases; Eyelid Neoplasms; Humans; In Vitro Techniques; Keratins; Keratitis; Metaplasia; Stevens-Johnson Syndrome; Vitamin A Deficiency

Twelve retinoids were evaluated in organ culture for activity in modulating epithelial differentiation of metatarsal skin explants from 13-day chick embryos. The epithelium differentiated into a squamous, keratinizing epidermis; but, in the presence of active retinoids, keratinization was inhibited, and a mucous metaplasia developed. The methyl-keto and 1-methoxyethyl cyclopentenyl analogs of retinoic acid were about tenfold more effective than retinoic acid in altering epithelial differentiation. The dichlorophenyl analog exhibited about the same activity as retinoic acid. The following analogs were one-half to one-third as effective as retinoic acid in inhibiting keratinization: the chlorotrimethylphenyl analog of retinoic acid and the 13-cis, 10-fluoro analog of trimethylmethoxyphenyl methyl retinoate. The other 7 retinoids were essentially not active at the concentration tested (1.4--2.0 x 10(-5) M). The activity of synthetic retinoids in altering epithelial differentiation may be related to their ability to affect or treat epithelial lesions provided that modification of the retinoid molecule can enhance its activity and decrease toxicity.

Topics: Animals; Cell Differentiation; Chick Embryo; Epidermal Cells; Epidermis; Epithelial Cells; Epithelium; Keratins; Metaplasia; Organ Culture Techniques; Skin; Tretinoin; Vitamin A

Epithelial cells from hamster small intestine, in short term culture, incorporated [carbinol-14C]retinol into a compound that is identical to synthetic retinyl phosphate, as judged by chromatography on DEAE-cellulose, silicic acid, and thin layers of silica gel. The biological compound displays the same absorption spectrum as does synthetic retinyl phosphate with a maximum at 325 nm. Hydrolysis with mild alkali yields anhydroretinol, as it does for synthetic retinyl phosphate, with absorption maxima at 388, 368, and 346 nm. Enzymic hydrolysis by alkaline phosphatase releases 9% of the radioactivity as [14C]retinol. Under the same conditions, 9% of synthetic retinyl phosphate is hydrolyzed to retinol. The biological compound was tested for biological activity. At a concentration of 5.5 x 10-8 M it was as active as retinol and retinyl phosphate in reversing keratinization induced in hamster tracheal epithelium by vitamin A deficiency. It is concluded that hamster intestinal cells synthesize retinyl phosphate.

Topics: Alkaline Phosphatase; Animals; Cricetinae; Diterpenes; Dolichols; Epithelial Cells; Epithelium; Intestine, Small; Keratins; Male; Metaplasia; Organ Culture Techniques; Organophosphorus Compounds; Phosphates; Tracheal Diseases; Vitamin A; Vitamin A Deficiency

Topics: Acid Phosphatase; Animals; Cell Differentiation; Cricetinae; Diterpenes; Drug Interactions; Female; Hydrocortisone; Keratins; Metaplasia; Organ Culture Techniques; Retinyl Esters; Trachea; Vitamin A

Topics: Abdominal Muscles; Animals; Bladder Exstrophy; Cystitis; Disease Models, Animal; Epithelial Cells; Female; Inflammation; Keratins; Metaplasia; Methods; Rats; Urinary Bladder

Topics: Animals; Cattle; Cattle Diseases; Extraembryonic Membranes; Female; Keratins; Metaplasia; Pregnancy

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

Topics: Adolescent; Adult; Age Factors; Aged; Child; Dentigerous Cyst; Epithelial Cells; Epithelium; Female; Humans; Hyalin; Keratins; Male; Mandible; Maxilla; Metaplasia; Middle Aged; Mucus; Odontogenic Cysts; Periodontal Cyst; Staining and Labeling

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: Adult; Aged; Child; Cholesteatoma; Diagnosis, Differential; Female; Humans; Keratins; Kidney Diseases; Kidney Pelvis; Male; Metaplasia; Middle Aged; Nephrectomy; Radiography; Tuberculosis, Renal; Urinary Tract Infections

Topics: Animals; Cell Differentiation; Chick Embryo; Culture Techniques; Epithelium; Feathers; Head; Hot Temperature; Keratins; Mesoderm; Metaplasia; Skin

Topics: Animals; Basement Membrane; Castration; Cell Division; Cell Nucleus; Cytoplasmic Granules; Desmosomes; Diethylstilbestrol; Epithelium; Keratins; Male; Metaplasia; Mice; Microscopy, Electron; Prostate; Prostatic Hyperplasia; Testis

Topics: Adult; Breast Neoplasms; Diagnosis, Differential; Female; Granuloma; Humans; Keratins; Male; Mastitis; Metaplasia; Pregnancy

Topics: Cell Differentiation; Cell Division; Culture Techniques; Epithelium; Histocytochemistry; Humans; Keratins; Keratosis; Leukoplakia; Leukoplakia, Oral; Lichen Planus; Metaplasia; Mouth Mucosa; Mouth Neoplasms; Organ Culture Techniques

Topics: Acid Phosphatase; Animals; Chick Embryo; Esterases; Extraembryonic Membranes; Histocytochemistry; Keratins; Metaplasia; Naphthaleneacetic Acids

Topics: Animals; Carcinoma; Goats; Keratins; Lung Neoplasms; Metaplasia; Microscopy; Mucins; Retrospective Studies

Topics: Animals; Cheek; Cricetinae; Epithelium; Glycols; Histocytochemistry; Keratins; Male; Metaplasia; Mouth Mucosa; Mucins; Neuraminic Acids; Proteins; Sulfates; Vitamin A

Topics: Animals; Chickens; Keratins; Metaplasia; Nasal Mucosa; Newcastle Disease; Turbinates; Vitamin A Deficiency

Topics: Animals; Cytoplasmic Granules; Epithelium; Estradiol; Keratins; Metaplasia; Methylcholanthrene; Microscopy, Electron; Rats; Urinary Bladder; Urinary Bladder Diseases; Vitamin A Deficiency

Topics: Animals; Culture Media; Culture Techniques; Embryo, Mammalian; Hair; Keratins; Metaplasia; Rabbits; Rats; Skin; Vitamin A

Topics: Adenoma; Breast; Breast Neoplasms; Epidermal Cyst; Humans; Keratins; Medical Records; Metaplasia

Topics: Estrogens; Female; Humans; Keratins; Male; Metaplasia; Prostate; Vagina; Vitamin A Deficiency