bromochloroacetic-acid and Carcinoma--Small-Cell

Ovarian pulmonary-type small cell carcinoma is a rare and extremely aggressive neoplasm. We report the occurrence of an ovarian small cell carcinoma of pulmonary type in a 54-year-old woman. She underwent a total abdominal hysterectomy with a bilateral salpingo-oophorectomy and infracolic omentectomy. A diagnosis of stage IIIA pulmonary-type small cell carcinoma was rendered. The tumor appeared to be composed of a solid growth of small cells arranged in sheets and closely packed nests with insular arrangements separated by a fibrous stroma. The tumor cells had hyperchromatic nuclei with inconspicuous nucleoli and scanty cytoplasm. Rosette and rosette-like structures were scattered. Immunohistochemical staining showed positivity for synaptophysin, neural cell adhesion molecule (NCAM), and focally for chromogranin. Cytokeratin and neuron-specific enolase (NSE) were also positive. Over 80% of the tumor cells showed strong reactivity for MIB-1. Electron microscopy showed neuroendocrine granules. She was effectively treated with paclitaxel plus carboplatin after the surgery.

Topics: Antineoplastic Agents; Carboplatin; Carcinoma, Neuroendocrine; Carcinoma, Ovarian Epithelial; Carcinoma, Small Cell; Carrier Proteins; Female; Humans; Keratins; Lung; Middle Aged; Neoplasms, Glandular and Epithelial; Neural Cell Adhesion Molecules; Ovarian Neoplasms; Paclitaxel; Tomography, X-Ray Computed; Ubiquitin-Protein Ligases

Small cell carcinoma of the urinary bladder is a rare, often fatal, disease. Its presenting symptoms and gross morphology are similar to those of conventional urothelial carcinoma, whereas its prognosis is much poorer with frequent metastasis. Small cell carcinoma of the urinary bladder shares similar histology with its counterparts in other organs; however, its immunoreactivity to conventional neuroendocrine markers is low. Its diagnosis is thus considered permissible on morphologic grounds alone. Multimodal treatments are often employed, although no definite treatment algorithm has been established. For this extremely aggressive malignancy with an as-yet inconclusive etiology, further studies are needed to clarify its molecular pathogenesis to serve as a basis for diagnostic markers and therapeutic targets. The clinical, morphologic, immunoreactive, molecular, and therapeutic features of bladder small cell carcinoma are reviewed, including a detailed discussion on the utility of immunohistochemical markers.

Topics: Biomarkers, Tumor; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Cyclin-Dependent Kinase Inhibitor p16; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Male; Molecular Biology; Nuclear Proteins; Prognosis; Thyroid Nuclear Factor 1; Transcription Factors; Urinary Bladder Neoplasms

Topics: Adenocarcinoma; Biomarkers, Tumor; Brain Neoplasms; Breast Neoplasms; Carcinoma, Hepatocellular; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Differentiation; Cytogenetic Analysis; Head and Neck Neoplasms; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Lymphatic Metastasis; Magnetic Resonance Imaging; Mesothelioma; Neoplasm Metastasis; Neoplasms, Unknown Primary; Peritoneal Neoplasms; Positron-Emission Tomography; Prognosis; Rhabdomyosarcoma; Tomography, X-Ray Computed; Urinary Bladder Neoplasms

Topics: Adenocarcinoma; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Electrochemistry; Humans; Immunoenzyme Techniques; Keratin-19; Keratins; Luminescent Measurements; Lung Neoplasms; Radioimmunoassay; Reference Values; Specimen Handling

Primary small cell neuroendocrine carcinoma of the vagina is extremely rare, and its clinical behavior is aggressive. To our knowledge, 22 patients with this tumor have been reported in the English literature to date.. To investigate 3 patients with this tumor clinically and pathologically.. The pathology database at the University of Texas Medical Branch at Galveston was searched, and 3 cases of primary small cell neuroendocrine carcinoma of the vagina were found. The histologic, immunohistochemical, and ultrastructural profiles of the tumors were investigated. The medical charts of the patients were reviewed, and the patients were followed up.. Women with the diagnosis of primary small cell neuroendocrine carcinoma of vagina.. All 3 patients presented with advanced disease, and 2 patients died within 4 months of the initial diagnosis. One 38-year-old patient was newly diagnosed, and her clinical outcome had not yet been determined. The histologic features of all 3 tumors were similar to those of their pulmonary counterpart. All cases were positive for cytokeratin, chromogranin A, and synaptophysin. The expression pattern of thyroid transcription factor 1 was examined in all 3 patients, of whom 2 were negative and 1 was positive with negative clinical and radiologic thyroid or pulmonary findings. Ultrastructural evaluation showed scattered intracytoplasmic electron-dense neurosecretory granules.. Primary small cell neuroendocrine carcinoma of the vagina has histologic, immunohistochemical, and ultrastructural features similar to those of its pulmonary counterpart. Because thyroid transcription factor 1 can be positive, it should not be used to differentiate primary from metastatic disease. The current therapies have usually resulted in poor outcomes, and new therapeutic modalities should be explored.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brachytherapy; Carcinoma, Small Cell; Chromogranin A; Chromogranins; Cisplatin; Combined Modality Therapy; Etoposide; Fatal Outcome; Female; Hemorrhage; Humans; Keratins; Middle Aged; Neoplasm Proteins; Nuclear Proteins; Radioisotope Teletherapy; Synaptophysin; Thyroid Nuclear Factor 1; Transcription Factors; Vaginal Diseases; Vaginal Neoplasms

A primary small cell undifferentiated carcinoma of the submandibular gland is reported. Histological studies revealed that the major part of this tumor was composed of cells slightly larger (10-14 microm) than lymphocytes. These tumor cells showed myoepithelial-cell differentiation, which was confirmed by the immunohistochemical and ultrastructural findings. Furthermore, some of them showed luminal-cell and basal-cell differentiation immunohistochemically. However, there was no evidence of neuroendocrine differentiation. These findings demonstrated that the tumor had the features of all the salivary ductal components (myoepithelial, basal, and luminal cells) and supported that the tumor might arise from the salivary duct. Furthermore, it supports the hypothesis of multipotential stem cells as the origin for small cell undifferentiated carcinomas in salivary glands.

Topics: Actins; Carcinoma, Small Cell; Cell Nucleus; Humans; Immunoenzyme Techniques; Immunohistochemistry; Keratins; Male; Microscopy, Electron; Middle Aged; Mucin-1; Salivary Ducts; Submandibular Gland Neoplasms; Vimentin

One case of breast neuroendocrine primary small cell carcinoma with light microscopic and immunohistochemical findings is reported. The patient died of unrelated disease 21 months after diagnosis and treatment by modified radical mastectomy, radiotherapy and subsequent chemotherapy. Immunohistochemical studies revealed cytokeratin and neuroendocrine markers (chromogranin, neuron-specific enolase) immunostaining on tumoral cells. Expression for neuropeptides (met-enkephalin, leu-enkephalin, beta-endorphin) and CALLA antigen was found. Based on this case report and six other previously reported cases, breast neuroendocrine primary small cell carcinoma appears to be a very aggressive tumor for which no firm conclusions regarding treatment can be drawn.

Topics: Aged; beta-Endorphin; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Small Cell; Chromogranins; Cytoplasm; Enkephalin, Leucine; Female; Humans; Immunohistochemistry; Keratins; Mammography; Mastectomy, Modified Radical; Phosphopyruvate Hydratase; Radiotherapy, Adjuvant

Within the past few years, the measurement of serum and tissue markers has had an increasing influence on clinical decisions about initial treatment and follow-up. Lung cancer illustrates the types and importance of these various markers. This review presents data concerning the most studied and interesting markers in non-small cell (NSCLC) and small cell lung cancer (SCLC). CEA, TPA, SCC-Ag, CYFRA 21-1, ferritin, CA19-9, CA50, CA242, H-K-N-ras mutations and p53 mutation seem to be the most prolific in NSCLC, while NSE, BN/GRP, CK-BB, NCAM, IL-2R, IGF-I, transferrin, ANP, mAb (cluster 5), Le-y and c-N-L-myc mutation are markers in SCLC patients. Some of these serum markers might be useful adjuncts for monitoring response to therapy, including early detection of tumour reactivation to allow curative therapy and rapid detection of treatment failure to allow change of the regimen. The study of these markers also may lead to a better understanding of the biological characteristics of lung cancer. The information derived from these biological studies represents the most promising avenue towards new treatment strategies, as well as attempts at secondary prevention.

Topics: Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Genes, p53; Genes, ras; Humans; Keratins; Lung Neoplasms; Peptides; Phosphopyruvate Hydratase; Tissue Polypeptide Antigen

Sixteen cases of small-cell carcinoma of the endometrium were encountered in patients who ranged in age from 30 to 78 (mean, 57.4) years. Of the 12 patients whose presenting features are known, eight had abnormal vaginal bleeding, three had pain related to metastatic tumor, and one patient had both symptoms. On pelvic examination, adnexal masses were palpable in three patients, and vaginal involvement was evident in two; one patient had a large palpable periumbilical mass. Thirteen patients underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Extrauterine spread was documented intraoperatively in eight cases, including widespread intraabdominal and ovarian metastases in four cases, vaginal involvement in the two cases noted previously, paraaortic lymph node involvement in one case, and tubal involvement in one case. Three tumors were International Federation of Gynecology and Obstetrics (FIGO) stage I, four were stage II, two were stage III, and six were stage IV; in one case, there was insufficient information to allow staging. On gross examination, the tumors were usually described as bulky, ill-defined, and invasive of the myometrium; four were polypoid. Microscopic examination revealed sheets, cords, and nests of small or intermediate-sized cells with scanty cytoplasm, hyperchromatic nuclei, and a high mitotic rate. Single-cell and zonal necrosis and vascular invasion were typically present. Synchronous grade 1 or grade 2 endometrial endometrioid adenocarcinoma was present in eight cases, and complex atypical endometrial hyperplasia, in two others. In three cases, the adenocarcinoma merged almost imperceptibly with the small-cell component. None of the tumors contained argyrophil or argentaffin cells, although nine of 11 tumors were immunoreactive for neuron-specific enolase (one of these was also Leu-7 positive), and another was chromogranin positive. Of the 11 cases with follow-up information, seven patients died of disease (at least four with distant metastases) with a median survival of 12 months, and another patient was alive with distant metastases at 18 months. The remaining patients were clinically free of disease at postoperative intervals of < or = 1 year (two cases) and 4.5 years (one case). This study confirms that small-cell carcinomas of the endometrium are a histologically distinctive subtype of endometrial carcinoma, which, like their counterparts in the uterine cervix, are aggressive tumors with a propensity for

Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Small Cell; Endometrial Neoplasms; Female; Histocytochemistry; Humans; Immunohistochemistry; Keratins; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms, Multiple Primary; Phosphopyruvate Hydratase

Small cell carcinoma of the ovary is a rare histological form which is highly malignant. We have decided to consider this as an epithelial tumour after studying it with the optical and the electron microscope. It is however difficult to put it in to a definite type because it is highly undifferentiated. On the clinical level small cell carcinoma is different from other ovarian cancers in several respects. Whereas ovarian tumours usually tend to occur in menopausal women in the fifth or sixth decade of life, small cell carcinomas of the ovary occur mainly in younger women of ages between 10 and 38 years. Furthermore, women who are attacked by this kind of a carcinoma tend to die very soon after the diagnosis has been made without receiving any benefit from the many therapies that have been tried to improve the prognosis. We have studied the condition after seeing two cases of small cell carcinoma in the University Gynaecological Department of Tours, and we have made a study of the literature. We have studied the therapeutic angle for these tumours and we have tried to find out what the best technique will be to cope with this awful prognosis. We discuss whether it might be worthwhile in future to intensify therapy in combination with bone marrow autotransplantation.

Topics: Adult; Antigens, Neoplasm; Carcinoma, Small Cell; Combined Modality Therapy; Female; Humans; Keratins; Membrane Glycoproteins; Mucin-1; Neoplasm Staging; Ovarian Neoplasms; Prognosis

This is an immunohistochemical and ultrastructural study of two small cell carcinomas of the ovary with a review of the literature. These cases showed a dimorphic population of small and large cells sharply demarcated from each other. Cytokeratin 18 and vimentin were mainly expressed in the large tumour cells, some of which also stained for alpha-smooth muscle actin. Periodic-acid-Schiff-positive, alpha-1-antitrypsin-positive hyaline globules were present in one case. Ultrastructural findings included filamentous nucleolonema as well as evidence of smooth muscle differentiation. Some of these observations have not been previously reported. Certain of the above features seem to support a germ cell origin of small cell carcinoma, but they cannot be considered specific for germ cell neoplasms. Thus, small cell carcinoma of the ovary cannot be classified into one of the known categories of ovarian tumours at the present time.

Topics: Actins; Adult; alpha 1-Antitrypsin; Carcinoma, Small Cell; Female; Humans; Immunohistochemistry; Keratins; Ovarian Neoplasms; Vimentin

Small cell carcinomas of the major salivary glands are rare tumors, accounting for less than 1% of malignant neoplasms at these sites. To date, approximately 41 such tumors have been described. They recently have been classified into two groups, based on the ultrastructural presence or absence of intracytoplasmic neuroendocrine (NE) granules, "small cell neuroendocrine carcinoma" and "small cell ductal carcinoma". This study concerns 11 primary small cell carcinomas that had been previously studied ultrastructurally; it was undertaken to determine whether these lesions possessed a neuroendocrine phenotype, using a battery of immunohistochemical stains. Antibodies to epithelial membrane antigen (EMA), cytokeratin (CK), Leu 7, vimentin (VIM), synaptophysin (SYN), chromogranin (CHR), and neuron-specific enolase (NSE) were employed, with the avidin-biotin-peroxidase complex technique and paraffin sections. All tumors in this study expressed at least one neuroendocrine marker. In eight tumors EMA was found; CK was present in all 11 cases, seven of which demonstrated focal paranuclear staining. Leu 7 was seen in eight tumors, VIM was expressed in two cases, SYN was found in three tumors, and CHR was detected in three neoplasms. Anti-neuron-specific enolase labeled eight tumors. From the preceding data one may conclude that all small cell salivary gland carcinomas have neuroendocrine characteristics, even though dense core granules cannot be demonstrated in some of them ultrastructurally.

Topics: Animals; Carcinoma, Small Cell; Humans; Immunohistochemistry; Keratins; Meta-Analysis as Topic; Rabbits; Salivary Gland Neoplasms; Staining and Labeling

Merkel cell carcinomas (MCC) were compared to small cell carcinomas of the lung (SCCL) and oesophagus (SCCO). Most MCC were of the intermediate cell type while SCCL and SCCO were usually of the small cell type. Only MCC of trabecular type could be separated from SCCL and SCCO by means of histopathological examination alone. All MCC (25) stained with cytokeratin CAM 5.2, 20 of which in a "paranuclear globular" or combined "paranuclear globular"/diffuse pattern while 17 MCC stained with cytokeratin AE1/AE3. Cytokeratin CAM 5.2 reacted with 60 percent of the SCCL and 86 percent of the SCCO, and cytokeratin AE1/AE3 with 33 and 28 percent respectively. Neurofilament stained 17 MCC in a "paranuclear globular" pattern but none of the SCCL and SCCO. All MCC with a diffuse staining pattern for cytokeratin CAM 5.2 were negative for neurofilament. The results of this study and review of the literature indicate that in most instances Merkel cell carcinoma can be separated from other SCC, pulmonary as well as extrapulmonary, by means of histopathological and, above all, immunohistochemical examinations.

Topics: Antigens, CD; Antigens, Differentiation; Carcinoma, Merkel Cell; Carcinoma, Small Cell; Esophageal Neoplasms; Histocompatibility Antigens; Humans; Intermediate Filament Proteins; Keratins; Leukocyte Common Antigens; Lung Neoplasms; Membrane Glycoproteins; Mucin-1; Neurofilament Proteins; Phosphopyruvate Hydratase; S100 Proteins

Topics: Adenocarcinoma; Adenoma, Islet Cell; Animals; Antibodies, Monoclonal; Breast Neoplasms; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cytoskeletal Proteins; Desmoplakins; Desmosomes; Electrophoresis, Polyacrylamide Gel; Granulosa Cell Tumor; Humans; Immunosorbent Techniques; Intermediate Filament Proteins; Intermediate Filaments; Keratins; Kidney Neoplasms; Lung Neoplasms; Melanoma; Membrane Proteins; Meningioma; Mesothelioma; Microscopy, Electron; Microscopy, Fluorescence; Neoplasms; Neurosecretory Systems; Skin 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

Topics: Antibodies, Monoclonal; Carcinoma, Small Cell; Cell Line; Desmosomes; Humans; Intermediate Filament Proteins; Keratins; Lung Neoplasms; Neoplasms; Neuroectodermal Tumors, Primitive, Peripheral; Rhabdomyosarcoma

A wide variety of human neoplasms were examined by immunocytochemical and ultrastructural techniques. In most, one intermediate filament (IF) type was expressed reflecting the tissue of origin. However, multiple classes of intermediate filaments were regularly found in a subgroup of these tumors. We chose to subdivide them into those with a complex or mixed growth pattern, and those which showed a more "monomorphic" histologic growth pattern. This latter group is the subject of this paper. Regular coexpression of cytokeratin and vimentin was observed in tumors of endometrial, thyroid, ovarian and renal origin, and coexpression of cytokeratin and neurofilament was observed in a subgroup of neuroendocrine tumors. Immunocytochemical/ultrastructural correlation demonstrated few, if any, observable intermediate filaments in tumors expressing only low molecular weight cytokeratin, whereas vimentin and neural filament characteristically were randomly dispersed or formed whorled bundles of cytoplasmic filaments. The potential diagnostic usefulness of these observations in surgical pathology is discussed.

Topics: Carcinoid Tumor; Carcinoma; Carcinoma, Small Cell; Cytoskeleton; Endocrine System Diseases; Female; Humans; Intermediate Filaments; Keratins; Kidney Neoplasms; Lung Neoplasms; Ovarian Neoplasms; Thyroid Neoplasms; Uterine Neoplasms; Vimentin

Cytokeratins, the intermediate filaments, are expressed by many epithelial cells. Immunohistochemistry revealed the presence of cytokeratin-19 both in bronchial epithelium and in lung cancer cells. The aim of our study was to establish the value of serum cytokeratin-19 estimation by immunoenzymatic assay (Enzymun Cyfra 21-1, Boehringer Mannheim) in the patients (pts) with lung cancer (Ic). 153 pts (104 men, 49 women, median age 50 years) entered this study. The group consisted of 37 pts with benign lung diseases (control group), 56 pts with squamous cell Ic, 37 pts with small cell Ic and 23 with adenocarcinoma. Cut off value was determined at 4 ng/ml, with 96% of specificity. Elevated cytokeratin-19 values were found in 41% of pts with lung cancer (45% of squamous cell Ic, 39% of adenocarcinoma and 35% of small cell Ic). Median cytokeratin-19 values were 2.2 ng/ml in the control group, 3.4 ng/ml in squamous cell Ic, 3.3 ng/ml adenocarcinoma and 2.9 in small cell Ic. Cytokeratin-19 elevation was observed more often in non small cell Ic pts with advanced disease, stage III--46%, stage IV--50% than in early stages (I + II)--34%. In small cell Ic pts the frequency of cytokeratin-19 elevation was 20% in limited disease versus 45% in extensive disease. We conclude that cytokeratin estimation is not valuable in the recognition of histologic type of lung cancer, although elevated levels are seen more often in squamous cell Ic. Cytokeratin-19 estimation may be also helpful in lung cancer staging.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Biomarkers, Tumor; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Keratins; Lung Neoplasms; Male; Middle Aged; Peptide Fragments

Topics: Biomarkers, Tumor; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Diagnosis, Differential; Female; Gene Expression; Humans; Keratins; Membrane Proteins; Middle Aged; Nuclear Proteins; Oropharyngeal Neoplasms; Synaptophysin; Thyroid Nuclear Factor 1; Transcription Factors

Small-cell lung cancer (SCLC) has a very aggressive clinical course with early metastasis. This study investigated how the distinctive neuroendocrine characteristics contribute to disease progression and invasion in human SCLC.. The neuroendocrine phenotype (pro-opiomelanocortin (POMC)) was quantified by ELISA in blood samples from 43 SCLC patients. The neuroendocrine (POMC, chromogranin A, neuron-specific enolase, NCAM) and epithelial (cytokeratin and E-cadherin) phenotypes were investigated, using ELISA and immunocytochemistry/immunohistochemistry.. In SCLC patients, 16% had elevated circulating POMC, which was associated with significantly worse survival (P=0.02) and liver metastases (P=0.004). In addition, POMC correlated with epithelial-positive circulating tumour cells (P=0.0002). In a panel of SCLC cell lines, all POMC-secreting cell lines expressed cytokeratin (40% of total). Even after cloning, DMS 79 cells expressed both neuroendocrine and epithelial markers. DMS 79 xenografts secreted POMC into the blood, which mirrored the tumour volume. These xenografts expressed both neuroendocrine and epithelial phenotypes in all tumours, with both phenotypes prevalent in cells invading the surrounding tissue.. Both neuroendocrine and epithelial phenotypes coexist in human SCLC tumours in vitro and in vivo and this persists in invading tumour cells. In patients, POMC secretion predicts poor survival and liver metastases, suggesting a crucial role of the neuroendocrine phenotype.

Topics: Animals; Cadherins; Carcinoma, Small Cell; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; Keratins; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Neoplastic Cells, Circulating; Neuroendocrine Cells; Phenotype; Pro-Opiomelanocortin; Survival Rate; Transplantation, Heterologous

Topics: Calbindin 2; Carcinoma, Small Cell; Female; Humans; Hypercalcemia; Keratins; Ovarian Neoplasms; S100 Calcium Binding Protein G; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biopsy; Bone Neoplasms; Carcinoma, Small Cell; Chromogranin A; Fatal Outcome; Head and Neck Neoplasms; Humans; Keratins; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Scalp; Skin Neoplasms; Tomography, X-Ray Computed

The cytopathologic diagnosis of basaloid squamous cell carcinoma can be problematic as there are several components of the differential diagnosis that share common cytomorphologic features. In this study, we report the fine-needle aspiration (FNA) findings of 16 basaloid squamous cell carcinoma cases and compare those cases to 16 cases of small cell carcinoma. To our knowledge, this is the largest series of basaloid squamous cell carcinoma FNA cases ever reported. The following cytomorphologic features were compared for both tumors: cohesive tissue fragments, single cells, adenoid cystic-like features (cribriform pseudoglandular lumina with hyaline materials), necrosis, nuclear size, nuclear molding, nucleoli, cytoplasm, and the presence of single keratinized cells. Adenoid cystic-like features and the presence of single keratinized cells were specific for basaloid squamous cell carcinoma (P < 0.05).

Topics: Aged; Biopsy, Fine-Needle; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Nucleus; Cytoplasm; Female; Gastrointestinal Neoplasms; Humans; Keratins; Male; Middle Aged; Necrosis; Respiratory Tract Neoplasms

Topics: alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carcinoma, Small Cell; CD57 Antigens; CDX2 Transcription Factor; Chromogranins; Diagnosis, Differential; Homeodomain Proteins; Humans; Immunohistochemistry; Keratins; Liver; Liver Neoplasms; Male; Middle Aged; Synaptophysin

To study the clinicopathologic features and histologic differential diagnosis of small cell neuroendocrine carcinoma (SmCC) of kidney.. The clinicopathologic features of 12 cases of SmCC of kidney encountered during the period from 1999 to 2010 were retrospectively reviewed.. Six cases of primary and 6 cases of metastatic SmCC involving kidney were identified. Amongst the primary renal SmCC, 2 were located in renal parenchyma and 4 in renal pelvis. Chest X-ray showed negative findings. Five of them underwent radical nephrectomy. On gross examination, the tumor was located centrally around the renal pelvis in 4 cases and peripherally in renal parenchyma in 1 case. On the other hand, 4 of the 6 cases of metastatic SmCC were discovered during therapy for pulmonary SmCC. Two of these patients presented with abdominal pain and gross hematuria, with lung and renal tumor masses identified simultaneously. The diagnosis of all the 6 cases of metastatic SmCC was confirmed by fine needle aspiration biopsy. Microscopically, pure SmCC was demonstrated in the 2 cases of primary renal parenchymal SmCC and 6 cases of metastatic SmCC. The 4 primary renal pelvic SmCC coexisted with urothelial carcinoma component. On immunohistochemical study, all cases were positive for cytokeratin, synaptophysin and CD56. All metastatic cases and 4 primary cases were also positive for TTF-1. Of six patients with primary SmCC two died 4 and 9 months after operation, and two were alive with a follow-up of 25 and 138 months, respectively. Five of six cases with metastatic SmCC died 3 - 8 months after diagnosis. The other 3 cases were failed to follow-up.. Both primary and metastatic SmCC can be found in the kidney. Although rare, primary SmCC is located either in renal parenchyma or in pelvis. The diagnosis of SmCC relies on morphologic examination and immunohistochemical study. TTF-1 immunostaining cannot reliably distinguish primary from metastatic SmCC in kidney. Correlation with clinicoradiologic findings and demonstration of coexisting urothelial carcinoma component (if any) is helpful in delineation of the tumor origin.

Topics: Adult; Aged; Carcinoma, Neuroendocrine; Carcinoma, Renal Cell; Carcinoma, Small Cell; CD56 Antigen; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Keratins; Kidney Neoplasms; Lung Neoplasms; Lymphoma; Male; Middle Aged; Nephrectomy; Nuclear Proteins; Retrospective Studies; Sarcoma, Ewing; Synaptophysin; Thyroid Nuclear Factor 1; Transcription Factors; Treatment Outcome; Wilms Tumor

To study the clinical and pathologic characteristics of small cell neuroendocrine carcinoma of urinary tract.. All cases of urinary tract carcinoma encountered in the General Hospital of People Liberation Army during the period from 1999 to 2010 were retrospectively reviewed. The clinicopathologic data of small cell neuroendocrine carcinomas were further analyzed, with literature review.. A total of 16 cases of small cell neuroendocrine carcinoma were identified, including 10 from urinary bladder, 2 from ureter, 3 from renal pelvis, and 1 multifocal tumor involving renal pelvis and ureter. There were altogether 8 males and 8 females. The median age of the patients was 63 years (range = 24 to 79 years). Gross hematuria (11 cases) represented the main presenting symptom. Four patients had flank pain and 4 had urinary irritation symptoms. Seven patients underwent radical cystectomy. Six other patients underwent radical nephroureterectomy, 1 partial cystectomy, 1 TURBT and the remaining case biopsy only. The size of the tumor ranged from 0.8 to 8.0 cm (median = 4.5 cm). Histologically, 15 cases represented mixed small cell neuroendocrine carcinoma (with 13 mixed with transitional cell carcinoma and 2 with adenocarcinoma). Immunohistochemical study showed positive staining for neuroendocrine markers. On presentation, 1 patient was in stage pT1, 7 in stage pT2, 6 in stage pT3, 2 in stage pT4. Six patients died of the disease after operation. The overall survival was 25 months and the 5-year survival rate was 32.4%.. Small cell neuroendocrine carcinoma of urinary bladder is a highly malignant disease and associated with poor prognosis. The diagnosis relies on detailed histologic examination. Early diagnosis, when coupled with cystectomy or nephroureterectomy and adjuvant chemotherapy, represents the mainstay of management.

Topics: Adult; Aged; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; CD56 Antigen; Chemotherapy, Adjuvant; Cystectomy; Female; Follow-Up Studies; Humans; Keratins; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Nephrectomy; Phosphopyruvate Hydratase; Retrospective Studies; Survival Rate; Synaptophysin; Ureteral Neoplasms; Urinary Bladder Neoplasms; Urologic Neoplasms; Young Adult

Small cell carcinoma of the kidney is distinctively rare. We searched pathology files in 2 institutions and found 14 cases of renal small cell carcinoma. The patients' mean age at diagnosis was 59 years (range, 22-75 years); 8 were women, and 6 were men. Patients usually presented with hematuria (n = 6) and abdominal pain (n = 5). The mean tumor size was 7.1 cm (range, 3.5-14.0 cm). The small cell carcinoma was pure in 9 cases and mixed with high-grade urothelial carcinoma in 5 cases. None was associated with any type of renal cell carcinoma. Tumor necrosis was present in all cases, and lymphovascular invasion was identified in 6 cases. The tumor invaded the perinephric adipose tissue in 13 cases and was confined to the kidney in only 1 case. Lymph node metastases were identified in all patients who underwent lymph node dissection (5/5). On immunostains, the small cell carcinoma cells were positive for pancytokeratin (11/12), chromogranin (6/9), and synaptophysin (8/9). Follow-up data were available for 13 patients, and 11 died of small cell carcinoma at a mean of 15 months (range, 4-31 months) after diagnosis. Of the 2 surviving patients, 1 was alive at 5 months after diagnosis, and the other, whose disease was confined to the kidney, was alive with no evidence of disease at 137 months. In summary, renal small cell carcinoma is a highly aggressive disease that often presents at an advanced stage with widespread metastases. Patients usually have a poor clinical outcome despite multimodal therapy. The frequent coexistence of small cell carcinoma with urothelial carcinoma suggests that renal small cell carcinomas may evolve from a preexisting urothelial carcinoma.

Topics: Adult; Aged; Carcinoma, Small Cell; Carcinoma, Transitional Cell; Chromogranins; Combined Modality Therapy; Female; Humans; Keratins; Kidney; Kidney Neoplasms; Male; Middle Aged; Retrospective Studies; Synaptophysin

Adult rhabdomyosarcoma (RMS) in the urinary bladder is rare, and is the subject of case reports and small series. It consists of sheets of small round blue cells with high nuclear cytoplasmic ratio, brisk mitosis and apoptosis. In this study, we reported one case of pure rhabdomyosarcoma and two cases of urothelial carcinomas with extensive rhabdomyosarcomatous differentiation. In addition, their immunohistochemical profile was compared to that of small cell carcinoma of the bladder. Our study showed that sufficient sampling was critical for the diagnosis of urothelial carcinoma with extensive rhabdomyosarcomatous differentiation. As adult RMS in the bladder and urothelial carcinoma with rhabdomyosarcomatous differentiation shared morphological features with small cell carcinoma of the bladder, appropriate immunohistochemical stains were necessary in the differential diagnosis. We showed both rhabdomyosarcoma and rhabdomyosarcomatous areas of the urothelial carcinoma were positive for myogenin, negative for cytokeratin and chromogranin stains. In contrast, small cell carcinoma was positive for cytokeratin, and 7 out of 9 cases were also positive for chromogranin. Both rhabdomyosarcoma and small cell carcinoma could be positive for synaptophysin, a potential pitfall to avoid. In addition, all of the tumors with rhabdomyosarcomatous differentiation were negative for FKHR rearrangement.

Topics: Biomarkers, Tumor; Carcinoma, Small Cell; Cell Differentiation; Chromogranins; Diagnosis, Differential; Female; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Keratins; Male; Middle Aged; Myogenin; Predictive Value of Tests; Rhabdomyosarcoma; RNA-Binding Protein EWS; Synaptophysin; Translocation, Genetic; Urinary Bladder; Urinary Bladder Neoplasms; Urothelium

Small cell carcinoma (SCC) of the renal pelvis and/or ureter is very rare, with only case reports published in the literature.. To describe the clinicopathologic and immunohistochemical findings in the largest series to date.. A review of a regional cancer registry identified 10 cases diagnosed as SCC from 930 patients with renal pelvic and/or ureteral cancer from 1971 to 1998. The original slides, demographics, treatment, and clinical outcome were reviewed. Representative sections were immunostained for AE1/AE3, cytokeratin 7, cytokeratin 20, CD56, synaptophysin, chromogranin, and thyroid transcription factor 1.. Of the 10 cases, 5 were pure SCC, 2 were mixed (SCC and urothelial carcinoma), 2 were reclassified as poorly differentiated squamous carcinoma, and 1 was reclassified as urothelial carcinoma. The patients with SCC had an age range of 50 to 80 years (median, 72 years) with a female to male ratio of 2.5:1. All patients had non-organ confined disease. Five of 7 patients died of disease; 4 of those 5 had been clinically followed (median survival, 23 months) and 1 was diagnosed at autopsy. The SCC cases revealed positive staining of the SCC component as follows: AE1/AE3 (7 of 7), CD56 (7 of 7), synaptophysin (6 of 7), thyroid transcription factor 1 (5 of 7), chromogranin (4 of 7), and cytokeratin 7 (1 of 7). None were positive for cytokeratin 20 (0 of 7).. SCC of the renal pelvis/ureter is seen in a predominately female population in Sweden, is clinically aggressive, and has poor survival when presenting at an advanced stage in patients only treated by surgery. An immunostain panel serves as a useful adjunct in classifying these tumors.

Topics: Aged; Aged, 80 and over; Carcinoma, Small Cell; Chromogranins; Female; Humans; Immunohistochemistry; Keratins; Kidney Neoplasms; Kidney Pelvis; Male; Middle Aged; Prognosis; Registries; Sweden; Synaptophysin; Ureteral Neoplasms; Vesicular Transport Proteins

Primary esophageal small cell carcinoma (PESCC) is a relatively rare and aggressive tumor with poor prognosis. Systemic spreading and metastasis often occur at diagnosis. Although 5-year survival rate of superficial squamous cell carcinoma of the esophagus can be 86.1%, 5-year survival rate of superficial PESCC is still relatively low. This study mainly retrospectively analyzed clinicopathological and immunohistochemical features of 15 cases of superficial PESCC in our hospital from 1990 to 2004, in order to find suitable diagnostic markers and applicable therapies for this disease. The records mainly included presenting symptoms, demographics, diagnostic method, histopathology, follow-up, and therapy. Immunohistochemical staining of chromogranin A (CgA), neuron-specific enolase (NSE), synaptophysin (Syn), neuronal cell adhesion molecules (CD56), thyroid transcription factor-1 (TTF-1), cytokeration 34betaE12 (CK34betaE12), cytokeratin (AE1/AE3), and cytokeratin 10/13 was performed. Incidence of superficial PESCC accounted for 4.8% of that of superficial carcinoma of the esophagus during the same period. Initial symptoms of all patients were dysphagia or accompanied with retrosternal pain and upper abdominal pain, and duration of these symptoms was 75 days averagely. Mean age of patients was 58.8 years old, and the male-to-female ratio was 2.75 : 1. Lesions were mainly located at middle thoracic esophagus. One, 2, and 5-year survival rates were 66.7, 33.3, and 6.7%, respectively. The median survival time was 19 months and mean survival time was 23.7 months after diagnosis. The percentages of PESCC samples with positive immunoreactivity were NSE 100%, Syn 100%, AE1/AE3 100%, CD56 93.3%, TTF-1 60%, CgA 53.3%, CK34betaE12 6.7%, and cytokeratin 10/13 0%, respectively. Our study suggested that PESCC was a rare and aggressive tumor with high malignancy. Superficial PESCC had rapid progression and poor prognosis compared with superficial squamous cell carcinoma of the esophagus at the same stage. The systemic therapy based on combination of postoperative chemotherapy and radiotherapy might be an effective approach for the treatment of superficial PESCC as a systemic disease. Higher proportion of positive labeling of NSE, Syn, AE1/AE3, CD56, TTF-1, and CgA in PESCC was valuably applied in diagnosis and differential diagnosis.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Small Cell; CD56 Antigen; Chromogranin A; Deglutition Disorders; Esophageal Neoplasms; Esophagectomy; Female; Follow-Up Studies; Humans; Keratin-13; Keratins; Lymph Node Excision; Male; Middle Aged; Neoadjuvant Therapy; Nuclear Proteins; Phosphopyruvate Hydratase; Retrospective Studies; Sex Factors; Survival Rate; Synaptophysin; Thyroid Nuclear Factor 1; Transcription Factors; Treatment Outcome

Topics: Carcinoma, Small Cell; Female; Humans; Immunohistochemistry; Keratins; Middle Aged; Ovarian Neoplasms

A reliable diagnosis of small cell lung cancers (SCLC) is of high clinical relevance. We investigated whether immunocytology substantially improves the diagnostic accuracy of conventional cytology in diagnosing SCLC.. 162 carcinomatous specimens clinically suspected to originate from pulmonary neoplasms were investigated by cytology and immunocytology. Immunocytology was performed on smears using HEA125 and pancytokeratin antibodies as epithelial markers and MOC-1 as SCLC probe.. As histologically clarified, 114 specimens corresponded to pulmonary neoplasms (SCLC = 51; non-small cell lung cancer: NSCLC = 59; mixed SCLC/NSCLC = 2; carcinoid = 2), 48 to nonpulmonary adenocarcinomas. By conventional cytology tumor cells were clearly detected in 93 (57.4%) and suspected in another 43 (26.5%) cases (83.9% overall sensitivity). Considering SCLC samples, tumor cells were diagnosed or suspected in 36 (70.5%), not identified in 10 (19.6%), and misdiagnosed as hematological malignancy in 5 cases. Only 2 specimens were accurately diagnosed as SCLC. Using the epithelial antibodies all samples were identified as carcinomatous. MOC-1 stained all but one SCLC, both SCLC/NSCLC, and both carcinoids. One SCLC brush smear was MOC-1 negative, containing only squamous epithelium. 3 pulmonary adenocarcinomas stained falsely positive, all nonpulmonary carcinomas MOC-1 negative.. Immunocytology substantially improves the diagnostic accuracy of cytology in diagnosing SCLC with a diagnostic sensitivity of 98% and specificity of 97%.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Biomarkers, Tumor; Carcinoid Tumor; Carcinoma, Small Cell; Carcinoma, Squamous Cell; CD56 Antigen; Diagnosis, Differential; Humans; Immunoenzyme Techniques; Keratins; Lung; Lung Neoplasms; Predictive Value of Tests

The purpose of this study is to evaluate the value of cytokeratin (CK) MNF116 and vimentin in the differential diagnosis of malignant pleural effusions. There were evaluated smears from 30 patients with pleural effusions stained with May-Grünwald Giemsa and Papanicolaou techniques for the routine cytological diagnosis. Additional smears were immunostained with CK MNF116 and vimentin using LSAB2 technique. Two independent observers evaluated all smears. Smears were classified first by cytological examination in seven cases (23.33%) as benign, and in 23 cases (76.67%) as malignant pleural effusions. Mesothelial cells expressed CK MNF116 in 96.67% (29/30) of cases and vimentin in 33.33% (10/30) of cases. Malignant cells expressed CK MNF116 in 52.17% (12/23) of cases and vimentin in 30.43% (7/23) of cases. The pattern of immunostaining was diffuse cytoplasmic. In conclusion, CK MNF116 and vimentin may be used as a part of the panel of antibodies for differential diagnosis of malignant pleural effusions with primary unknown.

Topics: Adenocarcinoma; Antibodies; Carcinoma, Small Cell; Diagnosis, Differential; Eosine Yellowish-(YS); Female; Humans; Keratins; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Melanoma; Methylene Blue; Pleural Effusion, Malignant; Pleural Neoplasms; Vimentin

Topics: Biomarkers, Tumor; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chromosome Aberrations; Diagnosis, Differential; Humans; Keratins; Lymphoma; Mucin-1; Urinary Bladder; Urinary Bladder Neoplasms

We assessed the usefulness of several immunohistochemical stains in distinguishing these two neoplasms, including cytokeratin 7, cytokeratin 20 (CK20), neuron-specific enolase, chromogranin, synaptophysin, neurofilaments (NF), thyroid-transcription factor-1 (TTF-1), CD56 antigen, S-100 protein, vimentin, c-erbB-2 oncoprotein, and CD117 antigen. All 13 cases of Merkel cell carcinoma evaluated were positive for CK20, and negative for TTF-1. Twelve of 13 Merkel cell carcinoma cases were positive for NF. Eleven of 13 cases of small cell lung carcinoma were positive for TTF-1. All small cell lung carcinoma cases were negative for NF, and all but one were negative for CK20. In terms of the remaining antigens, there were no differences of significance between the two neoplasms. These findings suggest that a set of three immunohistochemical stains, including CK20, NF, and TTF-1, is useful in affording a distinction between Merkel cell carcinoma and small cell lung carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Merkel Cell; Carcinoma, Small Cell; CD56 Antigen; Chromogranins; Female; Humans; Immunohistochemistry; Keratin-20; Keratin-7; Keratins; Lung Neoplasms; Male; Middle Aged; Neurofilament Proteins; Nuclear Proteins; Phosphopyruvate Hydratase; Proto-Oncogene Proteins c-kit; Receptor, ErbB-2; S100 Proteins; Skin Neoplasms; Synaptophysin; Thyroid Gland; Thyroid Nuclear Factor 1; Transcription Factors; Vimentin

To elucidate additional phenotypic differences between large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), we performed tissue microarray (TMA) analysis of surgically resected LCNEC and SCLC specimens. Immunostaining with 48 antibodies was scored based on staining intensity and the percentage of cells that stained positively. Four proteins were identified as significantly expressed in LCNEC as compared with SCLC: cytokeratin (CK)7, 113 vs 49 (P < .0301); CK18, 171 vs 60 (P < .0008); E-cadherin, 77 vs 9 (P < .0073); and beta-catenin, 191 vs 120 (P < .0286). Immunostaining of cross-sections containing LCNEC and SCLC components revealed significant expression of CK7, CK18 and beta-catenin in the LCNEC component compared with the SCLC component in 2 of 3 cases. Our results indicate that significant expression of CK7, CK18, E-cadherin, and beta-catenin is more characteristic of LCNEC than of SCLC, and these findings provide further support that these tumor types are separate entities morphologically and immunophenotypically, if not biologically.

Topics: beta Catenin; Biomarkers, Tumor; Cadherins; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Diagnosis, Differential; Humans; Immunohistochemistry; Keratin-7; Keratins; Lung Neoplasms; Neoplasm Proteins; Retrospective Studies; Tissue Array Analysis

Primary small cell carcinoma of esophagus (SCC) is a rare disease but has more aggressive behavior than esophageal squamous cell carcinoma (SQC). The distinction of SCC from SQC is very important therapeutically. Few systematic studies of immunohistochemical analysis to differentiate primary esophageal SCC with concomitant SQC, and adjacent normal esophageal epithelium have been reported. The objective of this study is to know the immunohistochemical markers in distinguishing SCC from SQC of esophagus. We studied 6 cases of primary esophageal SCC histologically and immunohistochemically using 15 different antibodies including a cytokeratin (CK) panel and neuroendocrine markers. Pure SCCs were identified in 2 of the 6 cases (33.3%), and the remaining 4 cases (66.7%) were found to exhibit combined SCC with an SQC component. Among the combined types, in situ SQC was observed in all 4 cases (100.0%) and invasive SQC was observed in 3 cases (75.0%). Among the normal esophageal epithelia specimens (n=7), CK14 expression was seen 6 out of 7 (85.7%) specimens and CKAE1/3 in 5 out of 7 (71.4%) specimens. CD56 was more frequently expressed among the SCC specimens (4/6; 66.7%) than among the SQC specimens (0/4; 0%; p = 0.07). The expression of p53 protein in SCC (4/6; 66.7%) and SQC (3/4; 75.0%) specimens was significantly more frequent than in normal esophageal epithelium (0/7; 0%; p = 0.02 each). Neurone-specific enolase (NSE), synaptophysin, and CKAE1/3 were expressed in 83.3%, 66.7%, and 66.7% of the SCC cases (n=6), respectively. NSE expression was significantly more frequent in SCC specimens (5/6; 83.3%) (p = 0.02) than in normal esophageal epithelium (0/7; 0%; p = 0.02). However, the frequencies of NSE expression in SCC (5/6; 83.3%) and SQC (2/4; 50%) were not significantly different. All of the SQC specimens (n=4) expressed CK14 and CKAE1/3. The CK14 expression was significantly more frequent in SQC specimens (4/4; 100.0%) than in (p = 0.04) SCC specimens (1/6; 16.6%; p = 0.04). These findings suggest that the CK14 and CD56 may be useful markers for differentiating SQC from SCC and vice versa. The p53 may also be useful to differentiate normal esophageal epithelium from SCC or SQC tissue.

Topics: Carcinoma, Small Cell; Carcinoma, Squamous Cell; CD56 Antigen; Diagnosis, Differential; Epithelium; Esophageal Neoplasms; Humans; Immunochemistry; Keratins

To evaluate the performance of 18F-FDG three-head tomography with coincidence imaging and serum tumor marker assays in identifying lung lesions in 104 patients with abnormal findings on chest X-ray or computer tomography.. A prospective evaluation of 18F-FDG coincidence imaging and the measurement of 3 serum markers for lung cancer ( carcinoembryonic antigen, CYFRA21-1 and neuron specific enolase) were performed within one week in 104 inpatients with suspected lung malignancy. All images were analyzed visually. It was considered positive for malignancy if the 18F-FDG uptake was increased relative to that in the adjacent lung tissue, and was focal. The serum tumor marker test was considered positive for malignancy if the serum level of at least one marker was elevated.. 66 patients were proven to have lung cancer by pathology, and 38 patients had benign lung diseases. The sensitivity, specificity, accuracy of 18F-FDG coincidence imaging and serum tumor markers in assessing lung cancers were 80. 0% , 77. 2% , 77. 9% and 56. 0% , 60. 9%, 64. 4% , respectively. 18F-FDG coincidence images in assessing lung lesions showed significantly higher sensitivity, specificity and accuracy than serum tumor markers. Four patients with lung cancer had negative findings on 18F-FDG coincidence images but showed positive serum markers.. 18F-FDG coincidence imaging is a powerful tool for evaluating patients with lung lesions suggestive of malignancy. Although the determination of serum marker levels is less accurate than 18F-FDG coincidence imaging, the combination of a positive 18F-FDG coincidence result and positive tumor markers may be helpful in improving the diagnosis of lung cancers.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Fluorodeoxyglucose F18; Humans; Keratin-19; Keratins; Lung Neoplasms; Male; Middle Aged; Phosphopyruvate Hydratase; Plasma Cell Granuloma, Pulmonary; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Sensitivity and Specificity; Tuberculosis, Pulmonary

Accurate morphologic distinction between small cell carcinoma and poorly differentiated squamous cell carcinoma has critical therapeutic significance, but can be limited by crush artifact, tumor necrosis, limited tumor representation, and overlapping morphologic features. We evaluated a panel of antibodies for their efficacy in distinguishing between these neoplasms. Formalin-fixed paraffin-embedded tissue sections of small cell carcinomas and poorly differentiated squamous cell carcinomas underwent immunohistochemical staining with antibodies to thyroid transcription factor-1, p63, high molecular weight keratin, and p16(INK4A). Of 28 small cell carcinomas, 26 (93%) small cell carcinomas showed diffuse moderate or strong staining for thyroid transcription factor-1 with no staining for high molecular weight keratin and p63. In contrast, 27/28 (96%) poorly differentiated squamous cell carcinomas manifested opposite immunoreactivities, with diffuse moderate or strong staining for high molecular weight keratin and p63, and no or minimal staining for thyroid transcription factor-1. In two additional cases originally interpreted as small cell carcinoma, high molecular weight keratin highlighted small numbers of neoplastic large cells, leading to reclassification as combined small cell and non-small cell carcinomas. p16(INK4A) expression varied widely in poorly differentiated squamous cell carcinomas, but was consistently moderate or strong and diffuse in small cell carcinomas, and proved helpful in the two thyroid transcription factor-1-negative small cell carcinomas. This study demonstrates that a panel consisting of antibodies to thyroid transcription factor-1, p63, high molecular weight keratin, and p16(INK4A) is highly effective for distinguishing between small cell carcinoma and poorly differentiated squamous cell carcinoma. This panel also facilitates diagnosis of combined small cell and non-small cell carcinomas.

Topics: Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Differentiation; Cyclin-Dependent Kinase Inhibitor p16; Diagnosis, Differential; DNA-Binding Proteins; Genes, Tumor Suppressor; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Nuclear Proteins; Phosphoproteins; Thyroid Nuclear Factor 1; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins

Large cell neuroendocrine carcinoma (LCNEC) of the lung is a malignant neuroendocrine tumor clinicopathologically similar to and falling in-between atypical carcinoid tumor and small cell lung carcinoma (SCLC). The diagnosis of LCNEC is based mainly on a characteristic neuroendocrine morphology and biological neuroendocrine differentiation. In order to know the discrepancy between morphological and biological neuroendocrine differentiation, LCNEC was immunohistochemically and molecular biologically compared with large cell carcinoma with neuroendocrine morphology (LCCNM), which lacked only biological neuroendocrine differentiation among the criteria of LCNEC. Immunohistochemically, disruption of the RB pathway, namely a lack of RB expression and simultaneous overexpression of p16 protein, was characteristic of LCNEC, but not LCCNM. In G2/M cell cycle regulation, 14-3-3 sigma expression was markedly reduced in LCNEC. Moreover, the antibody 34 beta E12 recognizing a set of large-sized keratin gave a different staining pattern between LCNEC and LCCNM. The immunohistochemical data suggested that LCNEC has a similar biological marker profile to SCLC and different from LCCNM. However, a loss of heterozygosity (LOH) analysis using microsatellite markers showed a high frequency of LOH at 3p in both LCNEC and LCCNM as well as in SCLC. Morphological neuroendocrine differentiation might not be identical to biological neuroendocrine differentiation in large cell carcinoma of the lung.

Topics: Aged; Antibodies, Neoplasm; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Differentiation; Female; Humans; Immunohistochemistry; Keratins; Male; Microsatellite Repeats; Middle Aged; Retinoblastoma Protein; Retrospective Studies

We present 51 cases of primary small cell carcinoma of the bladder in a clinicopathological study with emphasis on features that aid in the initial recognition and diagnosis of small cell carcinoma of the bladder.. The patients were 40 men and 11 women between the ages of 39 and 87 years (mean age 67 years). Clinical data were available in 41 cases. The most common symptomatology was haematuria in 63% of the patients while dysuria was present in 12%. Thirty-eight patients were caucasians; seven patients were Hispanics; two patients were Asian; one patient was African-American; in the three additional patients no racial information was obtained. Biopsy material was obtained in all of the patients. Cystectomy was performed in 20 patients. At diagnosis, clinical stage was as follows: stage I in two (5%), stage II in 18 (44%), stage III in 10 (24%), and stage IV in 11 (27%). Histologically, urothelial carcinoma was present in 70% of the cases, adenocarcinoma in 8%, and squamous cell carcinoma in 10% of the cases. Small cell carcinoma was the only histology present in only 12% of the cases studied. Immunohistochemical studies using chromogranin, synaptophysin and chromogranin were positive in 30-70% of the cases.. The present study highlights the unusual phenomenon of pure small cell carcinoma of the bladder and its association with other non-small cell carcinomas in that anatomical location. In addition, the study highlights the different modalities employed to treat patients in whom there is a component of small cell carcinoma of the bladder.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chromogranins; Disease-Free Survival; Female; Follow-Up Studies; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Neoplasm Staging; Synaptophysin; Urinary Bladder Neoplasms

The aim of the present study was to evaluate the usefulness of immunohistochemical markers in the differential diagnosis of pulmonary neuroendocrine tumors with particular emphasis on the preservation of immunoreactivity in areas showing crush artifacts. Specimens from 9 carcinoid tumors (CTs) and 13 small cell carcinomas (SCCs) with crush artifact were stained with antibodies to Ki-67, chromogranin A, synaptophysin, and cytokeratin. The immunoreactivity was well preserved in the crushed areas. Ki-67 was expressed in the crushed areas of all SCCs. Reactivity was diffuse or at least present in 25% of the crushed areas. In contrast, the immunoreactive areas in CTs never exceeded 10%. Immunoreactivity for Ki-67, synaptophysin, chromogranin A, and cytokeratin is well preserved in tissue with crush artifacts and can be interpreted reliably. The diagnosis of SCC should be questioned if fewer than 25% of cells show reactivity for Ki-67.

Topics: Artifacts; Biopsy; Bronchoscopy; Carcinoid Tumor; Carcinoma, Small Cell; Chromogranin A; Chromogranins; Diagnosis, Differential; Humans; Immunoenzyme Techniques; Keratins; Ki-67 Antigen; Lung Neoplasms; Synaptophysin

This study was designed to consider the cytomorphological spectrum, differential diagnosis, and the role of ancillary studies in small-cell tumors of the liver. Three independent pathologists reviewed cytological slides from 91 cases of small-cell tumors of the liver. The results were compared with the findings of three recently published studies (Cytopathology 11 (2000) 262-267; Diagn Cytopathol 19 (1998) 29-32; and Acta Cytol 40 (1996) 937-947). The role of immunohistochemistry in reaching timely and specific diagnoses was also examined. The diagnostic categories included 44 cases of metastatic small-cell undifferentiated carcinoma, 15 cases of metastatic neuroendocrine carcinoma, 10 cases of metastatic adenocarcinoma, 7 cases of malignant lymphoma, 4 cases of hepatocellular carcinoma with small-cell features, 2 cases of cholangiocarcinoma, 1 case of poorly differentiated carcinoma, and 8 cases of rare tumors including granulosa cell tumor (2 cases), sarcoma (4 cases), malignant melanoma with small-cell features (1 case), and meningioma with small-cell features (1 case). Metastatic granulosa cell-tumor, metastatic melanoma, and metastatic meningioma should be included in the differential diagnoses of small-cell malignancies found in the liver.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biopsy, Fine-Needle; Carcinoma, Hepatocellular; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Cholangiocarcinoma; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Liver; Liver Neoplasms; Lymphoma; Male; Middle Aged; Mucin-1; Review Literature as Topic; S100 Proteins; Vimentin

Small cell carcinoma is a rare malignant disease with high mortality, which is pathologically diagnosed by using routine neuroendocrinal markers, such as neuron-specific enolase (NSE), synaptophysin (SYN), chromogranin A (CgA). This study was to investigate the expression of CD56, a neural cell adhesion molecule (NCAM), in small cell carcinoma tissues, and to explore the possibility of CD56 as a diagnostic marker of small cell carcinoma.. Eighty samples of small cell carcinoma were collected, including 42 samples of small cell lung carcinoma (with 20 cases of lymph node metastases), 21 samples of small cell esophageal carcinoma, and 17 samples of small cell colorectal carcinoma. Thirty-eight samples of non-small cell lung cancer (with 28 cases of lymph node metastases), including 26 samples of squamous cell carcinoma and 12 samples of adenocarcinoma, were used as control. All samples were detected using markers of CD56, NSE, SYN, CgA, cytokeratin (CK), and epithelial membrane antigen (EMA) immunohistochemically.. Positive rate of CD56 was significantly higher in either small cell lung carcinoma or their metastatic lymph nodes than in either non-small cell lung carcinoma or their metastatic lymph nodes [90.5% (38/42) vs. 7.8% (3/38), 90.0% (18/20) vs. 3.5% (1/28); H=85.731, P<0.001]. Positive rate of CD56 in small cell carcinoma samples (86.3%, 69/80) were significantly higher than those of SYN (78.8%, 63/80), CgA (73.8%, 59/80), EMA (66.3%, 53/80), CK (61.3%, 49/80), and NSE (56.3%, 45/80) (H=38.871, P<0.001). Positive rate of CD56 in small cell lung carcinoma (90.5%, 38/42) was similar to those in small cell esophageal carcinoma (81.0%, 17/21) and small cell colorectal carcinoma (82.4%, 14/17) (H=1.651, P=0.438).. CD56 is highly expressed in either small cell carcinoma or their metastatic lymph nodes without organ-specificity. It could serve as a potential diagnostic marker of small cell carcinoma.

Topics: Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; CD56 Antigen; Chromogranin A; Colorectal Neoplasms; Diagnosis, Differential; Esophageal Neoplasms; Follow-Up Studies; Humans; Keratins; Lung Neoplasms; Lymphatic Metastasis; Mucin-1; Phosphopyruvate Hydratase; Synaptophysin

Primary small cell carcinoma of the breast is exceedingly rare, with fewer than 25 reported cases. The case presented herein is that of a 61-year-old woman with a 2.5-cm mass of the left breast. She underwent mastectomy with axillary node dissection. Histologic examination revealed sheets and nests of small, hyperchromatic, malignant cells with indistinct nucleoli and scant cytoplasm. High-grade solid and comedo ductal carcinoma in situ also was present. Two of 5 axillary lymph nodes contained metastatic disease. Immunohistochemical analysis demonstrated weak immunoreactivity for cytokeratin, neuron-specific enolase, and bcl-2. This histologic and immunohistochemical profile was consistent with that of a primary small cell carcinoma. Interestingly, this neoplasm lacked immunoreactivity for E-cadherin. E-cadherin expression has been documented in all 11 (100%) of 11 previously reported cases of primary small cell carcinoma of the breast, suggesting that this tumor is a form of ductal carcinoma. To our knowledge, this is the first reported case of E-cadherin-negative small cell carcinoma of the breast, which raises the question of a possible lobular histogenesis in some of these neoplasms.

Topics: Biomarkers, Tumor; Breast Neoplasms; Cadherins; Carcinoma in Situ; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Small Cell; Female; Humans; Immunohistochemistry; Keratins; Lymph Node Excision; Middle Aged; Phosphopyruvate Hydratase; Proto-Oncogene Proteins c-bcl-2; Treatment Outcome

The purpose of this study was to assess the feasibility of using rare event imaging system (REIS)-assisted analysis to detect occult tumor cells (OTCs) in peripheral blood (PB). The study also sought to determine whether REIS-assisted OTC detection presents a clinically viable alternative to manual microscopic detection to establish the true significance of OTC from solid epithelial tumors.. We recently demonstrated proof of concept using a fluorescence-based automated microscope system, REIS, for OTC detection from the PB. For this study, the prototype of the system was adopted for high-throughput and high-content cellular analysis.. The performance of the improved REIS was examined using normal blood (n = 10), normal blood added to cancer cells (n = 20), and blood samples obtained from cancer patients (n = 80). Data from the screening of 80 clinical slides from breast and lung cancer patients, by manual microscopy and by the REIS, revealed that as many as 14 of 35 positive slides (40%) were missed by manual screening but positively identified by REIS. In addition, REIS-assisted scanning reliably and reproducibly quantified the total number of cells analyzed in the assay and categorized positive cells based on their marker expression profile.. REIS-assisted analysis provides excellent sensitivity and reproducibility for OTC detection. This approach may enable an improved method for screening of PB samples and for obtaining novel information about disease staging and about risk evaluation in cancer patients.

Topics: Breast Neoplasms; Carcinoma, Small Cell; Cell Count; Cell Line, Tumor; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Keratins; Lung Neoplasms; Microscopy, Fluorescence; Neoplastic Cells, Circulating; Reproducibility of Results; Sensitivity and Specificity

To investigate the expression of CEA mRNA and CK(19) mRNA in peripheral blood cells of patients with lung cancer and evaluate its clinical significance.. Peripheral blood nucleated cells of 50 patients with lung cancer were studied by RT-PCR to detect the expression of CEA mRNA and CK(19) mRNA.. The combined positive rate of CEA mRNA and CK(19) mRNA in patients with lung cancer (82.0%) was significantly higher than that in patients with benign lung diseases (28.0%) and healthy volunteers (8.1%) (P < 0.001). The expression rate had no relation to the clinical staging or histological type. Compared with single detection, combined detection increased the detection rate but did not decrease the specificity.. Combined detection of CEA mRNA and CK(19) mRNA expression in peripheral blood nucleated cells increase the sensitivity of detecting hematogenous dissemination of cancer cells. Long-term survival analysis and more specimens would be helpful for evaluating its clinical significance.

Topics: Adenocarcinoma; Adult; Aged; Carcinoembryonic Antigen; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Keratins; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Aged; Aged, 80 and over; Asbestos; Biomarkers; Biomarkers, Tumor; Calbindin 2; Carcinoembryonic Antigen; Carcinoma, Small Cell; CD56 Antigen; Fatal Outcome; Histocytochemistry; Humans; Keratin-5; Keratins; Lung Neoplasms; Male; Mesothelioma; Neoplasms, Multiple Primary; Nuclear Proteins; Occupational Exposure; Pleural Neoplasms; S100 Calcium Binding Protein G; Thyroid Nuclear Factor 1; Transcription Factors; Vimentin

Serum tumor markers are non-invasive diagnostic tools for malignant tumor and commonly used for screening of cancer and as an indicator of treatment-effect. In small cell lung cancer, NSE and proGRP are effective markers. In non-small cell lung cancer (NSCLC), CEA, SCC, CYFRA21-1, SLX and CA19-9 are commonly used for screening, and at least one marker among CEA, SCC or CYFRA21-1 is positive in 77% of patients with NSCLC. According to the histological type, the positive rate of CEA and CYFRA21-1 is high in adenocarcinoma patients, and the positive rate of CYFRA21-1 and SCC is high in squamous cell carcinoma patients. This review summarizes the clinical usefulness of tumor markers in primary lung cancer.

Topics: Antigens, Neoplasm; Biomarkers, Tumor; CA-19-9 Antigen; Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Humans; Keratin-19; Keratins; Lewis X Antigen; Lung Neoplasms; Peptide Fragments; Peptides; Recombinant Proteins; Serpins

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

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

This retrospective study aimed at determining the prognostic significance of neuroendocrine markers chromogranin A (CgA), pro-gastrin releasing peptide (ProGRP) and neuron-specific enolase (NSE), together with the cytokeratin 19 marker CYFRA 21-1 in small cell lung cancer (SCLC). A total of 148 histologically proven and previously untreated SCLC patients were included. Among them 118 patients received a cisplatin-etoposide combination or cisplatin-etoposide-cyclophosphamide-4'-epidoxorubicin combination. All tumour markers were tested using immunoradiometric assays except for ProGRP which was tested using an enzyme-linked immunosorbent assay. The thresholds for marker serum titrations were 53 pg/ml, 65, 17, and 3.6 ng/ml for ProGRP, CgA, NSE and CYFRA 21-1 respectively. Univariate analysis showed that patients affected by one of the following characteristics proved to have a significant shorter survival in comparison with the opposite status of each variable: age over 63 years, extensive-stage, serum LDH level higher than 600 U/l, serum NSE level higher than 17 ng/ml, serum CgA level higher than 65 ng/ml and serum CYFRA 21-1 level higher than 3.6 ng/ml. In addition, there was a trend towards a statistical significance for a high serum alkaline phosphatase level and a performance status equal to or worse than two. The following variables were independent determinants of a poor outcome: a poor performance status (hazard ratio [95% confidence interval]: 1.51 [1.02-2.22]), a high CgA level (HR: 1.61 [1.06-2.45]), a high CYFRA 21-1 level (HR: 2.10 [1.40-3.14]) and an age older than 63 years (HR: 1.68 [1.14-2.48]). When the multivariate analysis was restricted to patients receiving a cisplatin-etoposide-based chemotherapy, the same variables were prognostic determinants with nearly similar hazard ratios. In conclusion, aside classical variables such as age and performance status, high serum CYFRA 21-1 and high serum CgA level in SCLC are both prognostic determinants of prognosis, in particular in patients receiving conventional chemotherapy consisting of cisplatin and etoposide-based combinations.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma, Small Cell; Chromogranin A; Chromogranins; Female; Humans; Keratin-19; Keratins; Lung Neoplasms; Male; Middle Aged; Neoplasm Proteins; Peptide Fragments; Peptides; Phosphopyruvate Hydratase; Prognosis; Recombinant Proteins; Retrospective Studies; Survival Rate

Cytokeratin 8 (CK8) is one of the cytoskeletal components and shows caspase-mediated degradation when cells undergo apoptosis. We previously reported that CK8 is highly expressed in non-small cell lung cancer (NSCLC) cell lines and increasing values of serum CK8 are significantly associated with tumor progression in patients with NSCLC. In this investigation, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in lung cancer cell lines, revealed a shorter PCR product, which differed from the wild-type product of CK8. The nucleotide sequence of the shorter PCR products and genomic DNA for CK8 demonstrated that the shorter product was an aberrantly spliced form of CK8 (AS-CK8) which lacked a caspases cleavage site within the linker lesion in exon 5. The putative protein products predicted by the mRNA of AS-CK8 were demonstrated by Western blotting with monoclonal antibodies for CK8. In addition, AS-CK8 mRNA and its protein products were highly expressed in NSCLC cell lines compared with small-cell lung cancer (SCLC) cell lines. Tissue samples obtained from NSCLC patients also expressed mRNA of AS-CK8. In conclusion, we identified aberrantly spliced CK8 (AS-CK8) which lacked a caspases cleavage site in lung cancer cell lines and primary tumors of NSCLC. AS-CK8 was preferentially expressed in NSCLC, rather than SCLC. These findings lead to speculation that cancer cells expressing AS-CK8 may have a resistance to apoptosis and may perturb keratin network formation.

Topics: Apoptosis; Base Sequence; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Humans; Keratins; Lung Neoplasms; Molecular Sequence Data; Reverse Transcriptase Polymerase Chain Reaction; RNA Splice Sites; RNA, Messenger; Tumor Cells, Cultured

Desmoplastic small round cell tumor is a rare, aggressive neoplasm that mainly affects young male patients and is characterized by a reciprocal translocation t(11;22)(p13;q12) associated with the EWS-WT1 gene fusion transcript. Clinical, histopathologic, immunohistochemical, and molecular genetics features were reviewed for 32 tumors. There were 29 male and three female patients, with ages from 6 to 54 years (mean, 25 years). The main clinical signs and symptoms included abdominal pain (eight patients), weight loss (five patients), and presence of umbilical hernia (four patients). Two tumors primarily involved the ethmoid sinus and the soft tissues of the scalp; the other tumors (mean size, 10 cm) involved the abdominal cavity (88%). One patient presented initially with an axillary lymph node metastasis. Generally, all tumors showed the typical histologic findings of variably sized clusters of small, round, or spindled cells lying in a desmoplastic stroma. The neoplastic cells in formalin-fixed, paraffin-embedded tissue sections were positive for desmin (dot pattern) (81% of the cases), WT1 (91%), keratin (87%), neuron-specific enolase (84%), CD99 (23%), and actin (3%). The EWS-WT1 gene fusion transcript was detected in 29 of 30 tumors. One tumor with typical clinicopathologic and immunohistochemical features did not show the gene fusion. Follow-up for 27 patients showed that 19 patients (70%) died of uncontrolled, local, or widespread metastatic disease 3-46 months (mean, 20 months) after diagnosis, and eight patients were alive with known evidence of disease. Occasionally, desmoplastic small round cell tumor lacks the classic clinical, histologic, and immunohistochemical features. This study emphasizes the utility of analysis of the EWS-WT1 gene fusion transcript, which was performed on paraffin-embedded tissues, to confirm the diagnosis.

Topics: Abdominal Neoplasms; Adolescent; Adult; Blotting, Southern; Carcinoma, Small Cell; Child; Desmin; Female; Follow-Up Studies; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Nucleic Acid Hybridization; Oncogene Proteins, Fusion; Phosphopyruvate Hydratase; Polymerase Chain Reaction

It has been reported that cytokeratin 8 (CK8) can be expressed in several cancers and expression of CK8 is correlated with increased invasiveness of the tumor in vitro and in vivo. In the present study, we investigated expressions of CK8 in human lung cancer cell lines. In addition, we also evaluated the clinical significance of CK8 measurements in sera of patients with lung cancer. Expression of mRNA for CK8 was semi-quantitatively evaluated by the competitive reverse transcriptase-polymerase chain reaction (competitive RT-PCR), using human lung cancer cell lines. The level of CK8 protein in culture supernatants of lung cancer cell lines and 70 sera of patients with lung cancer was measured by enzyme-linked immunosorbent assay (ELISA). Levels of serum CK8 according to clinical parameters were also examined. The level of expression of CK8 mRNA in non-small cell lung cancer (NSCLC) cell lines was significantly high compared with that of small cell lung cancer (SCLC) cell lines (P<0.05). The level of CK8 in culture supernatants in NSCLC was significantly high compared with that of SCLC. The level of serum CK8 in patients with NSCLC was significantly high compared with that of normal non-smokers and compared with that of SCLC (P<0.05). Patients with a CK8 value of 50.0 ng/ml, or higher, had a statistically significant diminished survival compared with those patients whose CK8 values were lower. In conclusion, CK8 was preferentially expressed in NSCLC. Increasing values of CK8 were significantly associated with tumor progression and decreased survival in patients with NSCLC. Therefore, CK8 in sera may become a novel tumor marker in patients with lung cancer.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation, Neoplastic; Humans; Keratins; Lung Neoplasms; Male; Middle Aged; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Survival; Tumor Cells, Cultured

Twenty-three patients with primary small cell carcinoma of the uterine cervix are presented. Their ages ranged between 23 and 63 years (average, 43 years). Blood spotting or vaginal bleeding was the most common clinical presentation. Histologically, the tumors were densely cellular and showed trabecular nesting or a sheet-like pattern. The neoplastic cells had scant cytoplasm, round nuclei, absence of nucleoli, and finely dispersed chromatin. Nuclear molding, single cell necrosis, and high mitotic activity were found in all tumors. There was a minor component of large cell neuroendocrine carcinoma in three cases, while foci of adenocarcinoma were identified in two cases. Immunohistochemical studies were performed in all 23 tumors which showed immunoreactivity for cytokeratin. Ten small cell carcinomas were immunoreactive for chromogranin, 13 for synaptophysin, and 10 expressed p53 protein. Treatment modalities included hysterectomy alone or combined with chemotherapy and/or radiation therapy. A few patients received chemotherapy and/or radiation alone. Follow-up information was obtained in 22 cases; 15 patients died of tumor between 6 and 43 months, while seven patients have remained alive 12 to 273 months. One patient was lost to follow-up. Small cell carcinoma of the cervix is a highly aggressive neoplasm. However, early diagnosis and combined therapeutic modalities may lead to longer survival in some patients. Although the use of immunohistochemistry may be helpful in the diagnosis, small cell carcinoma still remains a morphologic diagnosis.

Topics: Adenocarcinoma; Adult; Biomarkers; Carcinoma, Small Cell; Chromogranins; Female; Follow-Up Studies; Humans; Immunohistochemistry; Keratins; Middle Aged; Synaptophysin; Treatment Outcome; Tumor Suppressor Protein p53; Uterine Cervical Neoplasms

A 58-year-old woman with a history of Cushing's syndrome for three years presented with a mediastinal mass and received the diagnosis of small cell neuroendocrine carcinoma of the thymus invading the pericardium. On immunohistochemical study, the neoplastic cells reacted with antibodies against cytokeratin, epithelial membrane antigen, neuron-specific enolase, chromogranin, synaptophysin, and ACTH. Clinicopathologic findings of this rare case of ectopic adrenocorticotropic hormone (ACTH) syndrome are discussed with a literature review.

Topics: Adrenocorticotropic Hormone; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Chromogranins; Cushing Syndrome; Dexamethasone; Female; Humans; Immunoenzyme Techniques; Keratins; Middle Aged; Mucin-1; Phosphopyruvate Hydratase; Radiography, Thoracic; Synaptophysin; Thymus Neoplasms

Evaluation of prognosis-associated parameters in patients with small cell lung carcinoma.. Biopsies of 46 patients suffering from a non-treated small cell lung carcinoma were stained with Feulgen and immunohistochemically with Ki-67 antibody. The integrated optical density (IOD) and proliferation rate was measured by syntactic structure analysis and correlated with survival.. About 85% of patients had a smoking history (46 pack years on average). The median survival time was 13.5 months, the proliferation rate (Ki-67 positive tumor cell nuclei) 68.2% and S-phase percentage 9.2%. Ot average, 25 proliferating tumor cell nuclei formed clusters (mean diameter 95 microns). The prognosis was associated with the proliferation rate (p < 0.04), tumor stage (stage I versus lib, p < 0.05), at threshold limits with S-phase rate (p < 0.07) and serum levels of LDH and NSE (p < 0.06 and p < 0.07 respectively).. Immune histochemical determination of the Ki-67 protein is a useful method to estimate the prognosis of patients with small cell lung carcinoma.

Topics: Antigens, Neoplasm; Biopsy; Carcinoembryonic Antigen; Carcinoma, Small Cell; Female; Follow-Up Studies; Histocytochemistry; Humans; Immunohistochemistry; Keratin-19; Keratins; Ki-67 Antigen; L-Lactate Dehydrogenase; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Predictive Value of Tests; Prognosis; Retrospective Studies; Smoking; Survival Rate; Time Factors

The distinction of a primary lung carcinoma from a metastatic lesion is important, because the treatment and prognosis differ for patients with these malignancies. Such a distinction can be difficult because of overlapping cytologic features. It has been shown that antibodies to thyroid transcription factor 1 (TTF-1) and PE-10 are fairly specific markers for primary lung tumors in histologic specimens. TTF-1 regulates the expression of surfactant protein production, and PE-10 is a monoclonal antibody against components of human surfactant proteins. The combination of cytokeratin 7 (CK7) and cytokeratin 20 (CK20) immunoprofiling has been helpful in the identification of the primary site of origin of lung tumors.. In the current study, the authors evaluated the utility of TTF-1 and PE-10 immunostaining and also compared the staining with expression of CK7 and CK20 in the discrimination between primary lung tumors and metastatic lesions in 55 specimens from fine-needle aspiration (FNA) biopsies of the lung. Formalin fixed, paraffin embedded cell blocks from 35 primary lung tumors (16 adenocarcinomas, 8 squamous cell carcinomas, 6 large cell undifferentiated carcinomas, and 5 small cell carcinomas) and 20 metastatic carcinomas (6 breast lesions, 6 colon lesions, 3 urinary bladder lesions, 2 kidney lesions, 1 biliary tract lesion, 1 endometrial lesion, and 1 thyroid lesion) were immunostained with monoclonal antibodies to TTF-1, PE-10, CK7, and CK 20. Positive immunostaining for CK7, CK20, and PE-10 was based on cytoplasmic staining, whereas TTF-1 positive staining was based on nuclear staining of the neoplastic cells.. Positive immunostaining with TTF-1 and PE-10 was noted in six primary lung tumors (17%). One metastatic lesion (5%) and two metastatic lesions (10%) were positive for TTF-1 and PE-10, respectively. The CK7 positive/CK20 negative immunophenotype was noted in 30 primary lung tumors (86%) and in 11 metastatic lesions (55%). The CK7 negative/CK20 negative immunophenotype was seen in four metastatic lesions and in the remaining five primary lung tumors. The CK7 negative/CK20 positive and CK7 positive/CK20 positive immunophenotypes were seen in two and three metastatic lesions, respectively, but in none of the primary lung tumors. When a CK7 positive/CK20 negative adenocarcinoma also demonstrated either TTF-1 positive or PE-10 positive staining, it was likely that the adenocarcinoma was of pulmonary origin (P < 0.035; Fisher exact test). The specificity of such a combination for discriminating between primary and metastatic adenocarcinomas was 94%.. The results suggest that TTF-1, PE-10, or CK7/CK20 alone did not distinguish reliably between primary pulmonary tumors carcinomas and metastatic neoplasms of the lung in FNA biopsy specimens because of low sensitivity and specificity. The use of a panel of antibodies that includes CK7/CK20, TTF-1, and PE-10 may be helpful in discriminating between primary and metastatic adenocarcinomas of the lung. An adenocarcinoma is likely a primary lung tumor when it is of the CK7 positive/CK20 negative phenotype and demonstrates either TTF-1 positive or PE-10 positive staining.

Topics: Adenocarcinoma; Biomarkers, Tumor; Biopsy, Needle; Carcinoma, Large Cell; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Lung Neoplasms; Neoplasm Metastasis; Nuclear Proteins; Predictive Value of Tests; Pulmonary Surfactants; Sensitivity and Specificity; Thyroid Gland; Thyroid Nuclear Factor 1; Transcription Factors

In small-cell lung carcinoma (SCLC) tumour cell contamination of leukaphereses is unknown. The present study was performed to define appropriate markers for reverse transcriptase polymerase chain reaction (RT-PCR), then to assess the contamination rate of leukaphereses and corresponding bone marrow samples. Immunocytochemistry (ICC) and RT-PCR methods were also compared. Among the 33 patients included, analyses were performed in 16 who had multiple leukaphereses and 17 who had only bone marrow. Leukapheresis products and bone marrow were analysed by ICC using several specific monoclonal antibodies against neural-cell adhesion molecule (N-CAM), epithelial glycoprotein (EGP-40) and cytokeratins (CK). Samples were also analyzed by RT-PCR for expression for N-CAM, synaptophysin, neuron-specific enolase, chromogranin, cytokeratin-18/-19, CEA, EGP-40, apomucin type 1 (MUC-1) and human endothelial cell-specific molecule (ESM-1). Using ICC staining, contaminating tumour cells were detected in 34% of leukaphereses (27% in patients with limited disease and 43% in those with extensive disease). N-CAM was the most reliable marker for detection of contamination. For RT-PCR, CK-19 and CEA were the only appropriate markers. Positive signal rate in leukaphereses increased to 78% (89% for patients with limited disease and 67% for extensive disease). In bone marrow, both techniques were in agreement whereas in leukaphereses, RT-PCR was better than ICC. A high rate of tumour cell contamination was demonstrated not only in bone marrow but also in leukaphereses from SCLC patients. The most appropriate technique was RT-PCR mainly in patients with limited disease.

Topics: Adult; Aged; Antigens, Neoplasm; Bone Marrow; Carcinoembryonic Antigen; Carcinoma, Small Cell; Cell Adhesion Molecules; Chromogranins; Epithelial Cell Adhesion Molecule; Female; Gastric Mucins; Humans; Immunohistochemistry; Keratins; Leukapheresis; Lung Neoplasms; Male; Middle Aged; Neoplasm Proteins; Neoplastic Cells, Circulating; Neural Cell Adhesion Molecules; Phosphopyruvate Hydratase; Proteins; Proteoglycans; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; Synaptophysin

Serum pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) is a metabolite of type I collagen comprising 90% or more of organic substances in bone. Its usefulness as a marker of bone metastasis from malignant tumors is expected.. We measured ICTP to evaluate its clinical usefulness for diagnosis of bone metastasis in 140 patients with lung cancer. For comparison, serum carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA 21-1), gastrin-releasing peptide precursor (ProGRP), alkaline phosphatase and calcium were simultaneously measured. ICTP was measured by double-antibody radioimmunoassay.. ICTP was significantly higher in patients with bone metastasis from lung cancer than in the group without bone metastasis, patients with other pulmonary diseases or healthy control subjects and showed excellent sensitivity and specificity, indicating that this marker is highly useful for complementary diagnosis of bone metastasis from lung cancer. Moreover, the survival duration was significantly shorter in the ICTP-positive group than in the ICTP-negative group, suggesting that ICTP can be a prognostic factor in lung cancer.. It is suggested that measurement of ICTP is worthwhile as a serological diagnostic method of bone metastasis from lung cancer. Moreover, since repeated measurements are possible, this measure was considered very helpful in complementary diagnosis of bone metastasis and also as a standard to determine the timing of examinations such as bone scintigraphy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Antigens, Neoplasm; Biomarkers; Biomarkers, Tumor; Bone Neoplasms; Calcium; Carcinoembryonic Antigen; Carcinoma, Large Cell; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Collagen; Collagen Type I; Female; Gastrointestinal Hormones; Humans; Keratin-19; Keratins; Lung; Lung Diseases; Lung Neoplasms; Male; Middle Aged; Peptide Fragments; Peptides; Prognosis; Recombinant Proteins; Sensitivity and Specificity; Survival Rate

Small Cell Lung Cancer (SCLC), a clinically aggressive cancer, accounts for approximately 25% of primary lung cancers. We carried out suppression subtractive hybridization (SSH), a PCR-based method for cDNA subtraction, between the human classic, NCI-H69 and variant, more aggressive NCI-N417 SCLC cell lines to isolate and characterize variable expression of genes, which may be responsible for differential degree of tumorigenicity of SCLC. Using NCI-N417 as a tester, we obtained 28 differentially expressed cDNA clones from a total of 60 arbitrarily picked clones. Among the 28 cDNA clones, 4 were unknown genes, 2 were fatty acid binding protein (FABP) with specific identification of mRNA for mammary-derived growth inhibitor (MDGI), 1 was human alpha-enolase, 4 were ribosomal proteins, 2 were structural genes, vimentin and moesin (membrane-organizing extension spike protein), and 9 were homologous with murine leukemia viruses, whereas 2 others had enhanced expression in NCI-H69 and A549 cell lines, and 4 were cell surface proteins and murine type C retrovirus. Expression of FABP/MDGI was significantly high in NCI-H417, which may influence mitosis and cell growth as implicated in other tissues, contrary to the conclusion drawn for the role of MDGI in human breast cancer. Higher expression of ribosomal proteins in NCI-N417 compared to NCI-H69 may have a role in differential tumorigenicity and metastatic ability. Further, we obtained 14 differentially expressed cDNA clones by reversing the tester and driver, using NCI-H69 as a tester. Of these 14 differential cDNAs, 5 were unknown genes, 2 were specific for keratins, others had similarities with protease inhibitor, human BAC clone, Alu RNA binding protein, and tumor expression-enhanced gene. Characterization of these differentially expressed cDNA clones will provide useful information in understanding of the genes responsible for differential tumorigenicity of SCLC.

Topics: Base Sequence; Blotting, Northern; Carcinoma, Small Cell; Carrier Proteins; DNA, Complementary; Fatty Acid Binding Protein 3; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Gene Expression; Glutathione Transferase; Humans; Keratins; Lung Neoplasms; Molecular Sequence Data; Myelin P2 Protein; Neoplasm Proteins; Ribosomal Proteins; Tumor Cells, Cultured; Tumor Suppressor Proteins; Vimentin

Small cell carcinoma of the breast is an uncommon neoplasm that has been reported rarely in the literature. The aim of this study was to characterize better the pathologic and immunohistochemical features of this neoplasm. Nine examples of mammary small cell carcinoma were retrieved from the authors' consultation files and reviewed. The patients ranged in age from 43 to 70 years. Two patients had a previous history of cutaneous malignant melanoma and one had prior lobular carcinoma in situ and atypical duct hyperplasia in the same breast as the small cell carcinoma. Eight patients presented with a mass in the breast; one patient had an axillary tumor. Tumor size ranged from 1.3 to 5.0 cm (mean, 2.6 cm). Histologically, the nine tumors had characteristics of small cell carcinoma with high mitotic activity and necrosis. A dimorphic histologic appearance was observed in four tumors. In one instance, this consisted of small cell carcinoma merging with invasive lobular carcinoma. In three cases, small cell carcinoma was present together with invasive, poorly differentiated duct carcinoma; invasive carcinoma with "lobular and gland-forming elements"; and focal squamous differentiation, respectively. Lymphatic tumor emboli were identified in four instances. An in situ component was seen in seven tumors; five were of the small cell type in ducts and two were of the ductal type with high nuclear grade. Immunohistochemical analysis showed consistent staining for cytokeratin markers but variable staining with neuroendocrine markers. Sixty-six percent of the tumors (six of nine) were reactive for chromogranin, synaptophysin, or peptide hormones, including four positive for chromogranin and synaptophysin, one positive for synaptophysin and calcitonin, and one positive for calcitonin alone. One tumor that was reactive for chromogranin and synaptophysin also contained calcitonin immunoreactive cells, whereas gastrin-releasing peptide was present in two other tumors that were also positive for chromogranin. Leu 7 was positive in three cases that were reactive for either chromogranin or synaptophysin. Five tumors were estrogen and progesterone receptor-positive. All tumors were positive for bcl-2 and negative for HER2/neu. Patients were treated by mastectomy (n = 3) or lumpectomy (n = 6). Eight underwent an axillary dissection that revealed metastatic carcinoma in four patients. Seven patients received adjuvant chemotherapy and four patients received radiation. Two patien

Topics: Adult; Aged; Breast Neoplasms; Carcinoma, Small Cell; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Immunohistochemistry; Keratins; Middle Aged; Receptors, Estrogen

The histologic classification of pulmonary neoplasms can have important implications regarding appropriate management of patients. Although the histologic classification of lung tumors is predominantly based on morphology, ancillary studies such as immunohistochemistry can be used in difficult cases, and the diagnosis of large cell neuroendocrine carcinoma requires confirmation of neuroendocrine differentiation by immunohistochemistry or electron microscopy. We immunostained 142 lung tumors for B72.3, keratin 34betaE12, keratin 7, keratin 14, keratin 17, synaptophysin, and chromogranin to determine the utility of neuroendocrine markers and epithelial markers in the differential diagnosis. Among neuroendocrine carcinomas (small cell carcinoma and large cell neuroendocrine carcinoma), 84% (37 of 44) were chromogranin positive, 64% (21 of 36 small cell, 6 of 6 large cell neuroendocrine) were synaptophysin positive, 5% (2 of 43) were keratin 34betaE12 positive, 9% (4 of 44) were keratin 7 positive, and 5% (2 of 37) of small cell carcinomas and 50% (3 of 6) of large cell neuroendocrine carcinomas were B72.3 positive. Among non-neuroendocrine carcinomas, 5% (5 of 98) were chromogranin positive, 3% (3 of 96) were synaptophysin positive, and 97% (95 of 98) were positive for either keratin 34betaE12 or keratin 7 and 99% (97 of 98) were positive for either keratin 34betaE12, keratin 7 or B72.3. An antibody panel consisting of keratin 7, keratin 34betaE12, chromogranin, and synaptophysin separated 132 of 141 tumors (94%) into distinct groups. We conclude that immunostaining with both neuroendocrine markers and epithelial markers can be useful in the differential diagnosis of lung neoplasms.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chromogranins; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Pilot Projects; Synaptophysin

The CYFRA 21-1 assay which detects cytokeratin 19 (CK19) fragment is widely used as a tumor marker for lung cancer. However, the reason why some lung cancer cell lines release CK19 fragment in culture supernatants and others do not, remains unclear. It was hypothesized that the release of CK19 fragment may be elucidated by the expression of mRNA for CK19. In order to prove this, the mRNA for CK19 was quantitatively evaluated by the competitive reverse transcriptase-polymerase chain reaction (competitive RT-PCR). The level of CYFRA 21-1 in the culture supernatant was measured by an immunoradiometric assay. CK19 protein synthesis was evaluated by a Western blotting and immunohistochemistry. Fourteen lung cancer cell lines were evaluated, and the amount of mRNA correlated well with the level of CYFRA 21-1 in culture supernatants. Analysis of genomic DNA for CK19 demonstrated that three cell lines which could not produce CYFRA 21-1, conjectured that some abnormalities in exon 1 or the 5'-region upstream from exon 1. In conclusion, it was demonstrated that the release of CK19 fragment was closely related to the expression of mRNA for CK19, and the possibility that genomic change of CK19 DNA down-regulated the expression of mRNA for CK19 was suggested.

Topics: Antigens, Neoplasm; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; DNA, Neoplasm; Down-Regulation; Gene Expression Profiling; Humans; Immunohistochemistry; Keratin-19; Keratins; Lung Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

The aim of the study was to assess diagnosis value of tumor markers for differential diagnosis between mesothelioma and other pleural tumors.. Prospective study of 85 patients attending our hospital with malignant pleural effusion. The diagnostic approach involved routine pleurocentesis followed by pleural needle. When precise diagnosis was not achieved, thoracoscopy with pleural biopsies was performed. Carcinoembryonic antigen (CEA), hyaluronic acid, tissue polypeptide antigen and cyfra 21 to 1 were measured in serum and pleural fluid.. By using receiver operating characteristics curves and area under curves, the best diagnostic characteristics were obtained with pleural and serum CEA concentrations. The area under the curve was larger for pleural ACE than for serum ACE. The sensitivity and specificity of a pleural CEA level exceeding 3 ng/mL for ruling out the diagnosis of mesothelioma were 100% and 77%, respectively.. A CEA level above 3 ng/mL in pleural fluid eliminated the diagnosis of mesothelioma, whereas the other markers were not sufficiently discriminant. However, despite a negative predictive value of 100% at a cutoff of 3 ng/mL, CEA assay in pleural fluid only avoids a small number of diagnostic thoracoscopies.

Topics: Adenocarcinoma; Aged; Antigens, Neoplasm; Area Under Curve; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Diagnosis, Differential; Female; Humans; Hyaluronic Acid; Keratin-19; Keratins; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Pleural Effusion; Pleural Neoplasms; Prospective Studies; ROC Curve; Sensitivity and Specificity; Tissue Polypeptide Antigen

Topics: Adult; Carcinoma, Small Cell; Desmin; Humans; Immunohistochemistry; Keratins; Male; Mucin-1; Peritoneal Neoplasms; Phosphopyruvate Hydratase; Vimentin

High serum NSE and advanced tumour stage are well-known negative prognostic determinants of small cell lung cancer (SCLC) when observed at presentation. However, such variables are reversible disease indicators as they can change during the course of therapy. The relationship between risk of death and marker level and disease state during treatment of SCLC chemotherapy is not known. A total of 52 patients with SCLC were followed during cisplatin-based chemotherapy (the median number of tumour status and marker level assessments was 4). The time-homogeneous Markov model was used in order to analyse separately the prognostic significance of change in the state of the serum marker level (NSE, CYFRA 21-1, TPS) or the change in tumour status. In this model, transition rate intensities were analysed according to three different states: alive with low marker level (state 0), alive with high marker level (state 1) and dead (absorbing state). The model analysing NSE levels showed that the mean time to move out of state 'high marker level' was short (123 days). There was a 44% probability of the opposite reversible state 'low marker level' being reached, which demonstrated the reversible property of the state 'high marker level'. The relative risk of death from this state 'high marker level' was about 2.24 times greater in comparison with that of state 0 'low marker level' (Wald's test; P < 0.01). For patients in state 'high marker level' at time of sampling, the probability of death increased dramatically, a transition explaining the rapid decrease in the probability of remaining stationary at this state. However, a non-nil probability to change from state 1 'high marker level' to the opposite transient level, state 0 'low marker level', was observed suggesting that, however infrequently, patients in state 1 'high marker level' might still return to state 0 'low marker level'. Almost similar conclusions can be drawn regarding the three-state model constructed using the tumour response status. For the two cytokeratin markers, the Markov model suggests the lack of a true reversible property of these variables as there was only a very weak probability of a patient returning to state 'low marker level' once having entered state 'high marker level'. In conclusion, The Markov model suggests that the observation of an increase in serum NSE level or a lack of response of the disease at any time during follow-up (according to the homogeneous assumption) was strongly associ

Topics: Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Small Cell; Cisplatin; Cyclophosphamide; Epirubicin; Etoposide; Humans; Keratin-19; Keratins; Lung Neoplasms; Markov Chains; Prognosis; Proportional Hazards Models; Prospective Studies; Tissue Polypeptide Antigen

Keratin intermediate filaments are formed in epithelial cells in a cell- and tissue-specific manner, but much remains unknown regarding the mechanisms which control the synthesis of these proteins. We examined the effect of the differentiation modulation agent, bromodeoxyuridine (BrdU), on two human keratin-negative (by immunocytochemistry) lung cell lines, DLKP and H82, and showed immunohistochemically that treatment with 10 microM BrdU over 7 days induced K8 and K18 protein synthesis in both lines. Immunoprecipitation and Western blot analyses revealed low levels of K8 and K18 proteins in untreated cell homogenates. These levels increased following treatment with BrdU for 7 days. K8 and K18 mRNAs were detected by Northern blot and reverse transcriptase polymerase chain reaction analyses in both lines before BrdU treatment, but no increase in mRNA levels was observed in either cell line over 21 days of treatment. This suggests, firstly, that keratin synthesis is normally blocked at a posttranscriptional level in DLKP and H82 cells, and secondly, that BrdU can reverse this block. A549 is a human lung cell line which contains K8 and K18 proteins. Treatment with BrdU increased K8 and K18 protein levels in these cells. No corresponding increase in K8 mRNA levels occurred, while an apparent increase in K18 mRNA levels was detected. HL-60 is a leukaemic cell-line of haematopoietic rather than epithelial lineage which contains K8 and K18 mRNA transcripts prior to BrdU treatment, but does not contain keratin proteins. Again, K8 and K18 mRNA levels remained unchanged during BrdU treatment. However, neither K8 nor K18 proteins were detected following treatment, although BrdU is known to alter expression of other genes in HL-60 cells. BrdU thus appears to act at a posttranscriptional level and in an epithelial-specific manner to reverse a block in keratin synthesis in keratin-negative lung cancer cells and increase synthesis in keratin-positive lung cancer cells. This may represent a regulatory step in early lung development or a mechanism whereby tumour cells downregulate expression of a differentiated phenotype.

Topics: Antimetabolites, Antineoplastic; Bromodeoxyuridine; Carcinoma, Small Cell; Down-Regulation; Humans; Keratins; Lung Neoplasms; Protein Processing, Post-Translational; RNA, Messenger; Tumor Cells, Cultured

The present study was designed to clarify the mechanism by which some lung cancer cell lines can produce cytokeratin 19 (CK19) fragment and others cannot. We hypothesized that some lung cancer cell lines which cannot release CK19 express an incomplete sequence of CK19 mRNA. Expression of mRNA was evaluated by RT-PCR using several primer pairs for CK19. CK19 in the culture supernatant was measured by an immuno-radiometric assay. CK19 protein synthesis was evaluated by Western immunoblot and immunohistochemistry. Among 16 lung cancer cell lines, 7 released significant amounts of CK19 in the supernatant. In some cell lines, expression of CK19 mRNA was observed only in some combinations of primers, suggesting that incomplete mRNA was expressed. 3'-RACE analysis detected amplified products of a shorter size compared with normal amplified products in cell lines which expressed incomplete CK19 mRNA, suggesting that 3'-ends of mRNA for CK19 were deleted. Results of Western immunoblot and immuno-histochemical staining using anti-human CK19 monoclonal antibody completely correlated with the results on CK19 levels in culture supernatants as well as with complete expression of mRNA. We conclude that levels of CK19 closely relate to the expression of complete mRNA for CK19.

Topics: Adenocarcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; DNA Primers; Gene Expression Regulation, Neoplastic; Humans; Keratins; Lung Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured

Small cell (neuroendocrine) carcinoma of the urinary bladder is clinically more aggressive than urothelial (transitional cell) carcinoma. We have investigated the immunohistochemical markers most useful in diagnosing small cell carcinoma in bladder.. We evaluated the expression of chromogranin A, CD44 variant 6 (CD44v6), cytokeratin (CAM 5.2), gamma-enolase, synaptophysin, and CD45 in 46 small cell carcinomas of the bladder. Small cell and urothelial carcinoma were mixed in 21 (46%) cases. The two immunohistochemical markers with best ability to discriminate between small cell and urothelial carcinoma were chromogranin A and CD44v6. Chromogranin A had 97% specificity for small cell carcinoma, staining 65% of cases with 2+/3+ mean intensity; only one case (5%) of urothelial carcinoma was weakly (1+/3+) positive. CD44v6 was 80% specific for urothelial carcinoma, with immunoreactivity in 60% of cases, compared with 7% of small cell carcinoma cases. In cases positive for CD44v6, the mean percentage of reactive urothelial carcinoma cells was 75% (range 10-100%), greater than the 12% of cells in three cases of small cell carcinoma (P = 0.31); further, the pattern of immunoreactivity was membranous vs. focal cytoplasmic, respectively. All small cell carcinomas stained with one of the three neuroendocrine markers tested; 76% of cases were reactive for synaptophysin and 93% for gamma-enolase, with specificities of 86% and 73% in comparison to urothelial carcinoma. gamma-enolase staining of small cell carcinoma was more intense (P = 0.01) than for urothelial carcinoma. Cytokeratin CAM 5.2 stained a mean 47% of cells in small cell carcinoma, always in a punctate perinuclear pattern, and 75% in urothelial carcinoma, in a membranous pattern.. CD44v6, chromogranin A, and possibly gamma-enolase and cytokeratin (CAM 5.2) help differentiate small cell carcinoma from urothelial carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Small Cell; Carcinoma, Transitional Cell; Chromogranins; Diagnosis, Differential; Female; Glycoproteins; Humans; Hyaluronan Receptors; Immunoenzyme Techniques; Keratins; Male; Middle Aged; Phosphopyruvate Hydratase; Urinary Bladder Neoplasms

Desmoplastic small round cell tumor (DSRCT) is a unique, highly aggressive neoplasm that chiefly affects male adolescents and young adults. This tumor is characterized by nests of small undifferentiated cells that show immunohistochemical evidence of epithelial, mesenchymal, and neural differentiation. We report two cases of DSRCT that lacked immunohistochemical evidence of epithelial differentiation, but were found to have the fusion transcripts characteristic of this tumor. Both patients (a 41-year-old male and a 31-year-old female) presented with large intra-abdominal masses. After diagnostic biopsy, both were treated with multi-agent chemotherapy. One patient expired 18 days after diagnosis, and the other is currently alive 28 months later. Histologically, both tumors had the characteristic features of DSRCT and were composed of small round cells with hyperchromatic nuclei and scanty cytoplasm. In one of the cases, perinuclear intracytoplasmic hyaline inclusions were seen. Immunohistochemically, neither case expressed any of the epithelial markers tested, including AE1/AE3, CAM 5.2 and EMA. Both tumors were diffusely immunoreactive for desmin with a prominent globoid "dot-like" pattern of staining in one case. Both tumors stained for vimentin, neuron specific enolase, and synaptophysin, but were negative for CD99, muscle-specific actin, and myogenin. Reverse transcriptase-polymerase chain reaction revealed EWS-WT1 fusion transcripts characteristic of this neoplasm. In conclusion, we describe two cases of DSRCT that lacked immunohistochemical evidence of epithelial differentiation but had histologic and other immunohistochemical features which suggested this diagnosis. The ability to confirm the diagnosis of this rare tumor using molecular genetic techniques is particularly useful in those cases with unusual histologic or immunophenotypic features.

Topics: Abdominal Neoplasms; Adult; Carcinoma, Small Cell; Female; Humans; Immunohistochemistry; Keratins; Male; Oncogene Proteins, Fusion; Phosphopyruvate Hydratase; Reverse Transcriptase Polymerase Chain Reaction; Synaptophysin; Tumor Cells, Cultured; Vimentin

The aim was to investigate the diagnostic utility of CYFRA 21-1 (cytokeratin 19 fragment) as a tumor marker in pleural effusion and evaluate the value of combining CYFRA 21-1 and carcinoembryonic antigen (CEA) assays as a diagnostic aid in the malignant pleural effusion.. One hundred and twenty-six patients (72 malignant and 54 benign pleural effusion) were included in this retrospective study. The effusion levels of CYFRA 21-1 and CEA were measured using radioimmunometric assay.. The median values of CYFRA 21-1 in benign and malignant pleural effusion are 15 and 70 ng/ml, respectively. Using a cut-off value of 50 ng/ml, defined at 94% specificity, the diagnostic sensitivity of CYFRA 21-1 for non-small cell lung carcinoma (n = 61), squamous cell carcinoma (n = 21), adenocarcinoma (n = 40) and small cell lung cancer (n = 11) was 64, 71, 60 and 18%, respectively. Regardless of cell types, the diagnostic sensitivity of CYFRA 21-1 and CEA in malignant pleural effusion (n = 72) was 57 and 60%, respectively (cut-off value of 10 ng/ml in CEA assay). Combining CEA with CYFRA 21-1, the diagnostic sensitivity may increase up to 72%, which was defined at 89% specificity.. CYFRA 21-1 assay may be a useful tumor marker for discriminating benign from malignant pleural effusion, especially in those of non-small cell lung cancer. The combined use of CEA and CYFRA 21-1 assay in the malignant effusion may increase the diagnostic yield compared with CEA or CYFRA 21-1 alone.

Topics: Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Humans; Keratin-19; Keratins; Lung Neoplasms; Pleural Effusion, Malignant; Radioimmunoassay; Retrospective Studies; Sensitivity and Specificity

Small cell lung carcinoma (SCLC) is the most aggressive of lung tumors, metastasize widely and are virtually incurable by surgical means. Therefore, the classification of lung cancer into SCLC and non-small cell lung carcinoma is essential for disease prognosis and treatment. For this purpose we have compared the immunohistochemical distribution of different cytoskeletal proteins as tumor markers. Analysis was performed by using of monoclonal antibodies directed against cytokeratins, neurofilaments, betaIII-tubulin, epithelial membrane antigen and neuron-specific enolase. Our results indicate that keratin and epithelial membrane antigen are reliable epithelial markers for SCLC. In addition, the positive staining with monoclonal antibodies TU-20 against betaIII-tubulin and neuron-specific enolase was found in some cases of SCLC. We suggest, that these antibodies could be a useful tool for complex immunohistochemical diagnosis of SCLC.

Topics: Antibodies, Monoclonal; Biomarkers, Tumor; Carcinoma, Small Cell; Cytoskeletal Proteins; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Mucin-1; Phosphopyruvate Hydratase; Tubulin

Ovarian sex cord-stromal tumors are a morphologically diverse group of neoplasms that can mimic the appearance of other ovarian tumors. Because the treatment and prognosis of sex cord-stromal tumors differs substantially from those of other ovarian neoplasms, the development of an immunohistochemical panel to support the diagnosis of the former group of tumors would be useful. In this report, the utility of immunostaining for inhibin alpha, epithelial membrane antigen, MIC2 gene protein product, and keratin in the differential diagnosis of sex cord-stromal tumors was assessed in formalin-fixed, paraffin-embedded sections. In addition, the immunohistochemical staining pattern of ovarian small cell carcinomas (SCCs), hypercalcemic type, was analyzed in an attempt to clarify the histogenesis of these tumors. Thirty-two (97%) of 33 granulosa cell tumors (GCTs), 10 (91%) of 11 Sertoli-Leydig cell tumors (SLCTs), and 4 (8%) of 51 carcinomas showed inhibin alpha immunopositivity. None of the 3 lymphomas, 5 carcinoids, 6 dysgerminomas, or 12 SCCs showed inhibin alpha positivity. Eighteen (55%) GCTs, 6 (55%) SLCTs, 6 (12%) carcinomas, and 7 (58%) SCCs showed MIC2 gene expression. None of the GCTs and only one SLCT showed epithelial membrane antigen (EMA) positivity, although 92% of surface epithelial carcinomas and 75% of SCCs were immunoreactive. These data suggest that detection of inhibin immunoreactivity in an ovarian tumor that is EMA-negative provides both sensitive and specific support for the diagnosis of a sex cord-stromal tumor. Because SCCs generally stain for EMA but not for inhibin, it appears that SCCs probably represent a variant of surface epithelial tumor rather than a type of sex cord-stromal tumor.

Topics: 12E7 Antigen; Antigens, CD; Biomarkers, Tumor; Carcinoma, Small Cell; Cell Adhesion Molecules; Diagnosis, Differential; Female; Granulosa Cell Tumor; Humans; Hypercalcemia; Immunohistochemistry; Inhibins; Keratins; Mucin-1; Ovarian Neoplasms; Sertoli-Leydig Cell Tumor; Sex Cord-Gonadal Stromal Tumors

Serum assays for CA 125 are often used in the diagnosis and follow-up of patients with gynecologic neoplasms. A case of a 34-year-old woman with desmoplastic small round cell tumor (DSRCT) having an unusual morphology, including the presence of a signet ring cell component, and high serum CA 125 levels that was initially diagnosed as poorly differentiated carcinoma of the ovary is herein reported. Ultrastructurally, the signet ring appearance was shown to be the result of either the presence of intracytoplasmic vacuoles or dilatation of the intercellular space. Immunoperoxidase staining showed strong reactivity for desmin, keratin, vimentin, and CA 125. Immunohistochemical studies were performed on six additional DSRCTs but only two showed focal staining for CA 125. Because the patient's CA 125 serum level decreased after she received chemotherapy and her tumor was removed, and it became elevated again when the disease recurred, it is possible that CA 125 could be used as a marker of persistent and recurrent disease in those uncommon cases of DSRCT in which there are elevated serum levels of this marker at the onset of treatment.

Topics: Adult; CA-125 Antigen; Carcinoma, Signet Ring Cell; Carcinoma, Small Cell; Desmin; Fatal Outcome; Female; Humans; Immunoenzyme Techniques; Keratins; Neoplasm Recurrence, Local; Ovarian Neoplasms; Vimentin

Basaloid squamous cell carcinoma (BSCC) is a recently recognized variant of squamous cell carcinoma (SCC) with a predilection to occur in the tongue base, hypopharynx, and supraglottic larynx. In smal biopsy specimens, these tumors can be difficult to distinguish from small cell undifferentiated carcinoma (SCUC) and adenoid cystic carcinoma (ACC). Monoclonal antibodies reactive with cytokeratin (AE1/AE3, 34betaE12, Cam 5.2) as well as a variety of other cellular antigens (vimentin, actin, desmin, chromogranin, synaptophysin, CD57, neuron-specific enolase [NSE], and S100) were used in an immunoperoxidase method with paraffin-embedded tissue to phenotypically characterize 23 cases of BSCC, 10 cases of SCUC, and 15 cases of ACC. The neoplastic cells in 22 of the 23 cases of BSCC reacted with the high-molecular-weight cytokeratin antibody 34betaE12, whereas no reactivity was seen in any of the 10 cases of SCUC. This pattern of 34betaE12 reactivity more consistently differentiated BSCC from SCUC than did reactivity with the neuroendocrine markers chromogranin, synaptophysin, CD57, and NSE. These findings show that immunoperoxidase stains performed on paraffin-embedded tissue are potentially useful in establishing a diagnosis of basaloid squamous cell carcinoma.

Topics: Aged; Aged, 80 and over; Antibodies, Neoplasm; Biomarkers, Tumor; Carcinoma, Adenoid Cystic; Carcinoma, Basosquamous; Carcinoma, Small Cell; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Otorhinolaryngologic Neoplasms

The aim of this study was (i) to determine predictive factors of a complete response to chemotherapy in small cell lung cancer (SCLC) and predictive factors of an objective response in non-small cell lung cancer (NSCLC) and (ii) to determine whether prognostic factors are different with regard to treatment response and survival. Ninety-nine patients with SCLC and two hundred and two patients with NSCLC received chemotherapy. The following variables were recorded prior to treatment: tumor, node, metastasis status, performance status, body weight loss, blood leukocyte count, serum sodium, serum albumin, lactate dehydrogenase (LDH), alkaline phosphatase, serum NSE, serum TPS, and serum CYFRA 21-1. Tumor response was analyzed at the 10th week. Analysis of survival were done using the landmark method. Hazard ratios of the significant prognostic variables of survival were calculated using the Cox's model. Odds ratios of the significant predicting factors of response were calculated by stepwise logistic regression. In SCLC, the significant determinants of poor survival were: lack of complete response (HR: 2.04), weight loss (HR: 1.76), high serum LDH level (HR: 1.64), and high serum TPS level (HR: 2.47). A high serum TPS level was the only factor among those studied able to predict lack of achievement of complete response (OR: 0.39). In NSCLC, significant determinants of poor survival were: no objective response (HR: 2.28), poor performance status (HR: 2.52), presence of metastases (HR: 1.51), and high serum CYFRA 21-1 level (HR: 1.84). On the other hand, a high serum TPS level (OR: 0.50), the presence of metastases (OR: 0.45), and a leukocyte blood count over 10,000/microl (OR: 0.43) were independent determinants for a patient not to achieve an objective response. We concluded that the predictive factors of complete response in SCLC remain to be defined. On the other hand, in NSCLC three variables contribute to the prediction of an objective response. Finally, determinants of survival differ from predictive factors of response.

Topics: Analysis of Variance; Antibiotics, Antineoplastic; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cisplatin; Cyclophosphamide; Etoposide; Humans; Keratin-19; Keratins; L-Lactate Dehydrogenase; Lung Neoplasms; Phosphopyruvate Hydratase; Prognosis; Regression Analysis; Tissue Polypeptide Antigen

Merkel cell carcinoma (MCC) has a small cell variant, indistinguishable in hematoxylin-eosin sections from metastatic small cell carcinoma of the lung (SCCL). To investigate whether intermediate filament expression is helpful in this distinction, 17 MCCs of the small cell type were examined for cytokeratin, as well as neurofilament protein immunostaining, and compared with 59 intermediate-type MCCs and 22 SCCL. With a pan-cytokeratin cocktail (cytokeratin 1-8, 10, 13-16, 19), most (39 of 55) intermediate-type tumors and, more important, 11 of 16 cases of the small cell variant exhibited focal paranuclear staining with dot-like positivity, crescentic positivity, or both. A combined focal (dot-like/crescentic) and diffuse cytoplasmic pan-cytokeratin staining was seen in additional 8 of 55 intermediate and 4 of 16 small cell MCCs. Cytokeratin 20 also evoked focal cytoplasmic staining and occasionally focal and diffuse positivity in the MCCs, irrespective of the subtype. Exclusively diffuse cytokeratin 20 patterns did not occur. Conversely, most SCCL showed a diffuse expression of pancytokeratin, and all cases remained cytokeratin 20 negative. When neurofilament protein was applied, approximately half of the MCCs (25 of 40), including 7 of 11 of the small cell variant, were positive, whereas all SCCL were negative. In conclusion, the cytokeratin and neurofilament protein patterns of small cell MCCs are identical to the pattern of intermediate MCCs but differ from the profile of SCCL, which may help in the differential diagnosis.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Merkel Cell; Carcinoma, Small Cell; Diagnosis, Differential; Female; Genetic Variation; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratins; Lung Neoplasms; Male; Middle Aged; Neurofilament Proteins; Phenotype; Skin; Skin Neoplasms

Merkel cell carcinomas (MCC) not infrequently involve the periorbital region and the eyelids. Clinically, they are relatively characteristic but often unsuspected. Histologically, MCC are often misdiagnosed as lymphoma, melanoma, or metastatic small cell carcinoma of the lung (SCCL).. We present clinical, histological, and immunohistochemical data on six eyelid cases (all females; age 63-102 years; one with concomitant CLL) from our files of 77 MCC with special respect to differential diagnosis. For comparison, 22 SCCL were analyzed. Immunohistochemistry was done with antibodies against pan-cytokeratin (pan-CK), cytokeratin-20 (CK-20), neurofilament protein (NF), neuron-specific enolase (NSE), chromogranin (CHR), and S100 protein (S100).. Morphologically, five of six MCC were prototypic, one was of the small cell variant. Immunohistochemically, dot-like positivities for pan-CK and CK-20 were seen in all six MCC, and for NF in five tumors. None of the 22 SCCL stained positively for CK-20 or NF but 21/22 cases were positive for pan-CK. Only 1/21 SCCL showed dot-like patterns for pan-CK; 20/21 reacted diffusely. All MCC and 13/22 SCCL displayed CHR-positive cells. All MCC and all SCCL were positive for NSE and negative for S100.. Dot-like positivities for CK-20 or NF are important to prove MCC and to exclude SCCL in clinically and morphologically doubtful cases. Dot-like positivities for pan-CK favor MCC, but do not always exclude SCCL. NSE and CHR are of no value for the differential diagnosis of MCC and SCCL. Melanoma and lymphoma are ruled out by negativity for S100 and pan-CK, respectively.

Topics: Aged; Aged, 80 and over; Carcinoma, Merkel Cell; Carcinoma, Small Cell; Diagnosis, Differential; Eyelid Neoplasms; Female; Humans; Immunoenzyme Techniques; Keratins; Leukemia, Lymphocytic, Chronic, B-Cell; Lung Neoplasms; Middle Aged; Neurofilament Proteins; Phosphopyruvate Hydratase; S100 Proteins

To set the serum cut-off value of CYFRA21-1 in lung cancer patients in china, and to evaluate the clinical usefulness of CYFRA21-1 as a new tumor marker of lung cancer.. CYFRA21-1 levels were measured with two monoclonal antibodies (Ks19.1 and BM19.21) in the serum of 72 patients with lung cancer, 50 patients with benign lung diseases and 33 post-therapy lung cancer patients. To set the cut-off value, ROC curve was use.. (1) Serum concentrations of CYFRA21-1 in patients with lung cancer were significantly higher than those with benign lung diseases (P < 0.001). CYFRA21-1 levels in patients with squamous cell carcinoma were significantly higher than those in patients with any other subtypes. The more advanced the clinical stages, the higher the levels of CYFRA21-1. (2) If the threshold of CYFRA21-1 was set at 5.5 micrograms/L, its sensitivity and specificity for lung cancer were 63% and 94%, respectively. The sensitivity for squamous cell carcinoma was 78%, which was the highest among all the pathological subtypes. (3) The sensitivity of CYFRA21-1 in non-small cell lung cancer increased with the advancement of clinical stages. (4) CYFRA21-1 could be a good index in monitoring patient's condition and predicting prognosis for lung cancer. (5) When CYFRA21-1 was used as a screening index for lung cancer, the threshold of CYFRA21-1 should be set at the upper left corner of the receiver operating characteristic curve of stage I-II. The value of CYFRA21-1 in early diagnosis for non-small cell lung cancer was found limited.. CYFRA21-1 is a sensitive and specific tumor marker of non-small cell lung cancer, especially of squamous cell carcinoma.

Topics: Adenocarcinoma; Adult; Aged; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Keratin-19; Keratins; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging

By means of a mathematical score previously generated by discriminant analysis on 90 lung cancer patients, a new and larger group of 261 subjects [209 with non-small-cell lung cancer (NSCLC) and 52 with small-cell lung cancer (SCLC)] was analysed to confirm the ability of the method to distinguish between these two types of cancers. The score, which included the serum neuron-specific enolase (NSE) and CYFRA-21.1 levels, permitted correct classification of 93% of the patients. When the misclassifications were analysed in detail, the most frequent errors were associated with limited disease SCLC with low NSE levels and with advanced NSCLC with high NSE levels. This demonstrates the importance of the marker in correctly categorizing patients.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Analysis of Variance; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Diagnosis, Differential; Discriminant Analysis; Female; Humans; Keratin-19; Keratins; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Phosphopyruvate Hydratase; Reproducibility of Results

The aim of this study was to evaluate the diagnostic value of three tumour markers, squamous cell carcinoma (SCC) antigen, carcinoembryonic antigen (CEA) and CYFRA 21.1, in lung cancer using a Bayesian analysis to obtain the predictive values for different pretest probabilities or prevalences. A cross-sectional study included 94 patients with lung cancer, 40 with benign lung disease, and 40 healthy controls. SCC antigen and CEA were measured in blood samples by microparticle enzyme immunoassay (MEIA), and CYFRA by enzyme-linked immunosorbent assay (ELISA). The results of tumour marker determinations were expressed as percentiles, and showed significantly higher levels in the cancer group than in the two control groups. Taking the 95th percentile of benign lung diseases as the cut-off point (specificity 95%), the following sensitivities were found: SCC 41%, CEA 31% and CYFRA 79%. After a Bayesian analysis, the best results for the three tumour markers were found in prevalences of 30-40%. The highest incremental gain was obtained by CYFRA (at prevalence of 36%, positive and negative predictive value approximately 90%). The three tumour markers were included in a stepwise regression analysis to predict lung cancer, and CYFRA was the only selected variable. We conclude that CYFRA 21.1 may be a useful marker in lung cancer when there is an intermediate pretest probability of disease.

Topics: Adenocarcinoma; Aged; Antigens, Neoplasm; Bayes Theorem; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoenzyme Techniques; Keratin-19; Keratins; Logistic Models; Lung Diseases; Lung Neoplasms; Male; Middle Aged; Predictive Value of Tests; ROC Curve; Sensitivity and Specificity; Serpins

Small-cell carcinoma of the endometrium is a rare neoplasm, and its aggressive behavior has been reported. We report a case of small-cell carcinoma occurring primarily in the endometrium of a 62-year-old woman with postmenopausal vaginal bleeding and lower abdominal pain. The excised uterus showed a necrotic polypoid mass and histologically displayed an endometrial small-cell carcinoma. Immuno-histochemically, the tumor cells were positive for cytokeratin, the epithelial membrane antigen, neuron-specific enolase, and chromogranin, but were negative for the leukocyte common antigen and Grimelius stain. Ultrastructural analysis revealed the presence of dense core granules in the cytoplasm of tumor cells. The patient died 2 months after surgery because of aggressive behavior of the tumor. We wish to distinguish small-cell carcinoma of the endometrium from conventional epithelial tumors of the endometrium, because of the former's distinctive histopathologic, immunohistochemical, and ultrastructural characteristics.

Topics: Carcinoma, Small Cell; Chromogranin A; Chromogranins; Cytoplasmic Granules; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Keratins; Magnetic Resonance Imaging; Microscopy, Electron; Middle Aged; Mucin-1; Phosphopyruvate Hydratase; Tomography, X-Ray Computed; Urography

We report an intra-abdominal round cell tumor in a young man which exhibited the light and electron microscopic appearance of a peripheral primitive neuroectodermal tumor (PNET), in addition to the clinical and topographic characteristics, desmoplasia and a complex immunophenotypic profile of the intra-abdominal desmoplastic round cell tumor (DSRCT). Reverse transcription polymerase chain reaction revealed a EWS/FLI-1 fusion transcript as in PNET/Ewing's sarcoma, instead of the EWS/WT1 transcript of DSRCT. The tumor was also strongly positive for the mic2 protein. This is a unique case of a hybrid tumor arising in the peritoneal cavity of a young male. The existence of such a hybrid tumor in this location suggests that DSRCT and PNET may be related and possibly share a common histogenesis.

Topics: Abdominal Neoplasms; Adult; Biomarkers; Blotting, Western; Carcinoma, Small Cell; Desmin; DNA-Binding Proteins; Fatal Outcome; Humans; Immunohistochemistry; Keratins; Male; Microscopy, Electron; Neuroectodermal Tumors, Primitive; Oncogene Proteins, Fusion; Polymerase Chain Reaction; Proto-Oncogene Protein c-fli-1; Proto-Oncogene Proteins; Sarcoma, Ewing; Tomography, X-Ray Computed; Trans-Activators

To elevate the diagnostic value of the serum cytokeratin 19 fragment (CYFRA 21-1) and compare it with carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA) in bronchogenic carcinoma, the sera of 161 patients (58 with benign pulmonary disease and 103 with bronchogenic carcinoma) was investigated using immunoradiometric assay. Sensitivities for CYFRA 21-1, CEA and TPA (using 3.5 ng ml-1, 5.0 ng ml-1, 110 U l-1, respectively, cut-off values corresponding to a 95% specificity for benign pulmonary disease) in bronchogenic carcinoma were 64, 47 and 61%, respectively. Positive CYFRA 21-1 levels were identified in 75% of patients with squamous cell carcinoma (n = 36), in 67% with adenocarcinoma (n = 45), in 17% with large cell carcinoma (n = 6), and in 50% with small cell lung cancer (SCLC) (n = 16). However, CYFRA 21-1 levels were not significantly different between squamous cell carcinoma and the other histological types. The sensitivity of the combined measurement of CYFRA 21-1 with any other tumour marker was significantly higher than that of CYFRA 21-1 measurement alone. Elevated CYFRA 21-1 levels were observed in 44% of Stages I and II (n = 18) and 72% of Stage III and IV (n = 69) patients with non-small cell lung cancer (P < 0.05). A significant inter-marker correlation was observed between CYFRA 21-1 and TPA (n = 103, r = 0.448, P < 0.0001). Twenty-one patients were monitored by CYFRA 21-1, and significantly different changes in progressive patients (P = 0.0058) and regressive patients (P = 0.016) were obtained. These results indicate that CYFRA 21-1 may be not only a sensitive tumour marker in the diagnosis of bronchogenic carcinoma, but also a useful marker for the monitoring of bronchogenic carcinoma.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Bronchogenic; Carcinoma, Large Cell; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Immunoradiometric Assay; Keratin-19; Keratins; Lung Diseases; Lung Neoplasms; Male; Middle Aged; Sensitivity and Specificity; Tissue Polypeptide Antigen

Topics: Adenocarcinoma; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Humans; Keratin-19; Keratins; Lung Neoplasms; Neoplasm Staging; Phosphopyruvate Hydratase

A case of small cell carcinoma arising in the outer urethral orifice is presented. The resected tumor showed a proliferation of small round or fusiform neoplastic cells in the submucosa. Tumor cells were arranged in sheets or a trabecular manner and possessed markedly hyperchromatic nuclei with a high N:C ratio, closely resembling small cell carcinoma of the lung. Characteristically, pagetoid intraepithelial spreading could be identified. However, there was no evidence of in situ transitional cell carcinoma and adeno- or squamous cell carcinoma components anywhere. Ultrastructurally, each tumor cell contained only a few membrane-bound cored granules measuring 60-100 nm, which were compatible with neurosecretory granules, and desmosome-like intercellular attachments, but lacked aggregated microfilaments. By immunohistochemical examination, tumor cells were positive for epithelial markers, such as cytokeratin and epithelial membrane antigen, and neuron specific enolase, but negative for any other neuro-endocrine markers. Extensive systemic examination failed to show the primary site to be other than the outer urethral orifice. These findings indicate that the current tumor is a small cell carcinoma with neuro-endocrine differentiation arising from the outer urethral orifice.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Small Cell; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Microscopy, Electron; Mucin-1; Phosphopyruvate Hydratase; Urethral Neoplasms

Cytokeratins (CK) are one of the main families of intermediate filaments which make up the cytoskeleton. CK19 is strongly expressed by normal simple bronchial and respiratory epithelium as well as by their malignant counterpart. Although CK19 is a part of the cytoskeleton, a soluble fragment of this polypeptide can be released and assayed in the blood as CYFRA 21-1, new sensitive and valuable marker of non small cell lung cancer. In some cases, however, discrepancies between the serum level of CYFRA 21-1 and presence of tumor and its histological type have been observed. We studied immunohistochemically tissue localization of CK19 in tumors and non invaded lung parenchyma in a series of 34 patients surgically treated due to lung cancer. CK 19 was detected in cancer cells as well as in non neoplastic epithelium covering bronchial tree and alveolar surfaces. We found a different expression of CK19 in different histological type of tumors. The most intensive expression revealed squamous cell carcinomas and adenocarcinomas. Small cell cancer revealed poor expression of CK19. In non invaded parts of the resected lungs we found the strong expression of CK19 in the cytoplasm of regenerative II type pneumocytes occurring in large quantity in the cases of interstitial lung fibrosis concomitant with some tumors. We suggest it may be a cause of unexpectedly elevated serum levels of CYFRA 19-21 in some not oncological patients or patients with small cell lung cancer.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal; Biomarkers, Tumor; Bronchi; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cytoplasm; Epithelium; Female; Humans; Infant; Keratins; Lung Neoplasms; Male; Middle Aged; Neoplasm Proteins; Pulmonary Alveoli; Pulmonary Fibrosis

Topics: Aged; Biomarkers, Tumor; Carcinoma, Small Cell; Humans; Keratins; Male; Microscopy, Electron; Neck Dissection; Parotid Gland; Parotid Neoplasms; Tomography, X-Ray Computed

The CYFRA 21-1, a newly developed sandwich enzyme-linked immunosorbent assay (ELISA), was used to measure soluble cytokeratin 19 fragment in serum that is expressed in simple epithelium and its malignant counterpart. The present study was designed to investigate whether CYFRA 21-1 is a sensitive and specific tumor marker for non-small cell lung cancer.. CYFRA 21-1 assay, using two specific monoclonal antibodies (KS 19.1 and BM 19.21) for cytokeratin 19, was measured in 312 serum samples, including 164 lung cancer, 118 benign pulmonary disease, and 30 healthy individuals. The sensitivity of CYFRA 21-1 was also compared with two other markers, carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC), in 164 patients with lung cancer.. The median value of healthy individuals was 1.3 ng/mL (95th percentile 1.8). In patients with benign pulmonary diseases, the median was 1.5 ng/mL (95th percentile 2.9). There is no significant difference between sexes, smoking habit, and the subgroups of benign pulmonary disease, such as tuberculosis, pneumonia, or COPD. Using the cutoff value of 3.3 ng/mL, defined at 95% specificity for benign lung disease, the sensitivities of CYFRA 21-1 for squamous cell carcinoma (n=74), adenocarcinoma (n=54), undifferentiated large cell carcinoma (n=11), and small cell lung cancer (n=25) were 62%, 39%, 36%, and 20%, respectively. Despite the cell types, the sensitivities of CYFRA 21-1 in non-small cell lung cancer (NSCLC, n=169) were 51% (CEA 42%, SCC 20%). The sensitivity of CEA was significantly higher in patients with adenocarcinoma (58%) than other markers; while in patients with squamous cell carcinoma, CYFRA 21-1 assay has the highest sensitivity. The median level of CYFRA 21-1 in squamous cell carcinoma is significantly higher than that of other cell types (Mann-Whitney test, p<0.001). The serum level and sensitivity of CYFRA 21-1 were well correlated with staging and tumor size in squamous cell carcinoma. The CYFRA 21-1 values were measured for monitoring progression of disease in 20 patients with squamous cell carcinoma. There is significant difference in paired observation of CYFRA 21-1 level in patients with progressive disease (Wilcoxon signed-rank test, p<0.05), but no difference was observed in patients with stabilized disease (p>0.1).. For patients with NSCLC, especially in squamous cell carcinoma, CYFRA 21-1 is not only a sensitive and specific tumor marker, but also may be a useful adjunctive marker for disease monitoring.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Disease Progression; Enzyme-Linked Immunosorbent Assay; Epithelium; Female; Humans; Keratins; Lung Diseases; Lung Diseases, Obstructive; Lung Neoplasms; Male; Neoplasm Staging; Pneumonia; Sensitivity and Specificity; Serine Proteinase Inhibitors; Serpins; Sex Factors; Smoking; Tuberculosis, Pulmonary

Primary small cell undifferentiated carcinomas (SCUCs) are unusual tumors of the colon and rectum. Histologically, these lesions represent a spectrum of neuroendocrine differentiation, with oat cell carcinoma being the most primitive subtype and carcinoid tumors being the most differentiated. This observation is supported by immunohistochemical and ultrastructural findings. We report a case of SCUC of the rectum in a patient with ulcerative colitis. To date, there have been only two reported cases of primary SCUC associated with ulcerative colitis. Recent theories of tumorigenesis attribute most colorectal cancers to a single, pluripotential mucosal stem cell, regardless of the tumor's histologic type.

Topics: Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Colitis, Ulcerative; Fatal Outcome; Female; Humans; Immunohistochemistry; Intestinal Mucosa; Keratins; Middle Aged; Neoplastic Stem Cells; Phosphopyruvate Hydratase; Rectal Neoplasms; Rectum; Synaptophysin; Tumor Suppressor Protein p53

The sensitivity and specificity of Cyfra 21-1 as marker for lung cancer was evaluated in comparison with carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and neuron-specific enolase (NSE). Patients with histologically verified lung cancer and different groups without lung cancer were investigated. Sensitivity of Cyfra 21-1 (cut-off level 2.9 micrograms/l) was 40% for non-small cell lung cancer (NSCLC), 60% for rare histological types and 21% for small cell lung cancer (SCLC). In NSCLC sensitivity of Cyfra 21-1 was 35% for squamous cell carcinoma and 41% for adenomous carcinoma. The highest sensitivity for CEA was 45% in NSCLC, with 57% in the subtype of adenomous cell carcinoma; for SCC 30% was achieved in squamous cell carcinoma and for NSE 66% sensitivity was reached in SCLC. In our patients Cyfra 21-1 and CEA appeared equally useful for evaluating patients with NSCLC.

Topics: Adult; Aged; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Diagnosis, Differential; Humans; Immunoradiometric Assay; Keratins; Lung Diseases; Lung Neoplasms; Middle Aged; Neoplasm Staging; Phosphopyruvate Hydratase; Sensitivity and Specificity; Serpins

We examined two recently described cytokeratin markers, CYFRA 21-1 (cytokeratin fragment recognized by KS 19-1 and BM 19-21 antibodies) and TPS (specific M3 epitope of the tissue polypeptide antigen), in 405 lung cancer patients (91 small-cell and 314 non-small-cell lung cancers) and 59 patients presenting with nonmalignant pulmonary disease. Sensitivity-specificity relationship, as analyzed by receiver operating characteristic curves, demonstrated a higher accuracy of CYFRA 21-1 in comparison with TPS in both small-cell and non-small-cell lung cancers. Thresholds of 3.6 ng/ml and 140 U/L for CYFRA 21-1 and TPS respectively gave a 90% to 95% specificity. Sensitivity of CYFRA 21-1 was the highest in squamous-cell carcinomas (0.61) and the lowest in small-cell lung cancers (0.36), whereas sensitivity of TPS did not vary significantly according to histology (overall sensitivity, 0.40). In non-small-cell lung cancers, both serum CYFRA 21-1 and serum TPS distributions varied significantly according to Mountain's stage of the disease, nodal status, tumor status, and performance status, inasmuch as the worse each above-mentioned variable became, the higher the median and interquartile serum marker level was. Neither CYFRA 21-1 nor TPS was able to accurately discriminate between stage IIIa (marginally resectable) and stage IIIb (unresectable) non-small-cell lung cancers, however. In both small-cell and non-small-cell lung cancers, univariate survival analyses demonstrated that either a CYFRA 21-1 level over 3.6 ng/ml or a TPS level over 140 U/L significantly indicated a poor survival rate. In the whole population, taking into account other significant variables, Cox's model analysis demonstrated that a poor performance index, an advanced stage of the disease, the presence of metastases, elevated serum lactate dehydrogenase, and high serum CYFRA 21-1 (odds ratio, 1.74; 95% confidence interval, [1.33-2.27] were independent prognostic variables. We concluded that CYFRA 21-1 is a significant determinant of survival. Other applications of cytokeratin markers in lung cancer are still limited.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Female; Humans; Keratins; Lung Diseases; Lung Neoplasms; Male; Middle Aged; Peptides; Prognosis; Prospective Studies; Sensitivity and Specificity; Tissue Polypeptide Antigen

A case is reported of intra-abdominal desmoplastic small cell tumor (IDSCT) with biphasic histologic features in a patient with proximal spinal muscular atrophy. The tumor was composed of small epithelial cell nests with spindle cell sarcomatous areas. Both areas were surrounded by a desmoplastic stroma. Immunohistochemical studies revealed reactivity for low molecular weight cytokeratin, epithelial membrane antigen, vimentin, desmin and Leu-7 in both areas. Electron microscopic examination demonstrated paranuclear aggregates of intermediate filaments, zonula adherens and basement membrane-like material in the epithelial cells, while spindle cells in the tumor had fewer intracytoplasmic organelles. However, intermediate or transitional forms of both types of tumor cells were frequently observed. Although IDSCT are known to express multi-phenotypes immunohistochemically, attention should be paid to the broad spectrum of cell morphology in these tumors.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Combined Modality Therapy; Desmin; Fatal Outcome; Humans; Immunoenzyme Techniques; Keratins; Male; Muscular Atrophy, Spinal; Neoplasm Recurrence, Local; Omentum; Peritoneal Neoplasms; Sarcoma, Small Cell

Soluble cytokeratin fragment 19 levels were measured with an enzyme immunoassay method developed by Boehringer Mannheim (Enzymun-Test CYFRA 21-1) in the serum of 185 patients with lung cancer [149 with non-small-cell lung cancer (NSCLC) and 36 with small-cell lung cancer (SCLC)] and 97 patients with benign lung diseases in order to determine its clinical usefulness in the diagnosis of lung cancer and follow-up of treatment. We used the cut-off value of 3.5 ng ml-1, established by the Japan CYFRA research group. This cut-off value is based on calculations using the receiver operating characteristic approach instead of using the 95% specificity approach recommended by other authors. The resulting sensitivity and specificity for the group of all lung cancer patients were 65.4% and 84.5% respectively. The sensitivity was highest (76.1%) for squamous cell carcinoma and lowest (44.4%) for SCLC. For NSCLC patients, when CYFRA 21-1 levels were analysed by node (N) factor, patients who presented with mediastinal lymph node metastasis (N2 or N3) demonstrated higher serum CYFRA 21-1 levels (5.6; interquartile range 3.2-11.5 ng ml-1) than patients without mediastinal node metastasis (N0 or N1, 3.9; interquartile range 2.2-10.0 ng ml-1; Mann-Whitney U-test, P = 0.0373). We compared the discriminatory power of CYFRA 21-1 with that of other tumour markers including carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and neuron-specific enolase (NSE). The area under the curve (AUC) of each ROC curve was calculated using the CLABROC program for statistical analysis. CYFRA 21-1 appeared to have the most discriminatory power of the markers tested in the diagnosis of lung cancer. In serial measurements of 14 patients receiving chemotherapy or radiotherapy, a high degree of correlation was noted between serum levels of CYFRA 21-1 and extent of clinical response (Wilcoxon, P = 0.0093).

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Female; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Male; Middle Aged; Peptide Fragments

Cyfra 21-1 is a novel marker for non small cell lung cancer. Up to now only few data about the value of Cyfra 21-1 in the diagnosis of malignant and non-malignant pulmonary diseases are available. Further the effect of long-time cigarette consumption on serum concentrations of Cyfra 21-1 has not been described. Aim of this study therefore was the determination of Cyfra 21-1 in different malignant and non-malignant pulmonary diseases and in healthy smokers and nonsmokers.. Sera of healthy individuals (control group, n = 121; 63 smokers and 58 nonsmokers), patients with chronic bronchitis (n = 50), lung fibrosis (n = 38), exogen allergic alveolitis (n = 32), lung tuberculosis (n = 45), sarcoidosis (n = 30), small cell lung cancer (n = 60), squamous cell carcinoma (n = 53), non-small cell carcinoma (n = 29) and adenocarcinoma (n = 52) were analyzed.. Within the control group no significant differences of the Cyfra 21-1 serum concentration were observed between smokers and nonsmokers. Serum concentrations of Cyfra 21-1 were similar in the control group, patients with non-malignant pulmonary diseases and patients with small cell lung cancer whereas serum concentrations were significantly increased in patients with non-small cell lung cancer, adenocarcinoma and squamous cell carcinoma.. The data confirm the high sensitivity and specific of Cyfra 21-1 for the differential diagnosis between malignant and non-malignant pulmonary diseases as well as small cell and non-small cell lung cancer.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Diagnosis, Differential; Female; Humans; Keratins; Lung Diseases; Lung Neoplasms; Male; Middle Aged; Predictive Value of Tests; Reference Values; Smoking

A correct diagnosis of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) is essential both for prognostic and therapeutic reasons. We used discriminant analysis as a method to optimize the discriminant power of serum tumour marker levels for differentiation between SCLC and NSCLC. A panel of serum markers, including neurone specific enolase (NSE), cytokeratin fragment antigen 21.1 (CYFRA-21.1), tissue polypeptide antigen (TPA) and carcinoembryonic antigen (CEA) was obtained in 50 consecutive NSCLC and 17 SCLC. Data were analysed by the BMDP statistical program after logarithmic transformation of marker levels. The variables selected were NSE and CYFRA-21.1. Considered together, they were able to give a 97% rate of correct classification. The formula generated (canonic variable, CV) was validated on a group of seven SCLC and 22 NSCLC patients. Only two errors occurred. We therefore conclude that the canonic variable tested, based on NSE and CYFRA-21.1, provides a good discrimination between the two types of lung cancer. The method is rapid, relatively inexpensive, and based on simple serum tests.

Topics: Aged; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Diagnosis, Differential; Discriminant Analysis; Female; Humans; Keratins; Lung Neoplasms; Male; Middle Aged; Peptides; Phosphopyruvate Hydratase; Tissue Polypeptide Antigen

This report represents an attempt to combine the serum levels of more tumor markers together to evaluate the response to chemotherapy in 26 patients affected with small cell lung cancer (SCLC), by means of discriminant analysis. A pilot prospective study was performed on 26 subjects affected with inoperable SCLC (18 extensive diseases, and 8 limited diseases) and treated with chemotherapy (etoposide plus cisplatin regimen). Serum levels of a panel of tumor markers: Carcinoembryonic antigen (CEA), Tissue Polypeptide Antigen (TPA), Neuron Specific Enolase (NSE) and CYFRA -21.1 were determined before starting chemotherapy and at the restaging time (after 3 months). To optimize the classification power of these markers, a discriminant analysis was done, which permitted generating two classification functions, based on Tissue Polypeptide Antigen and Neuron Specific Enolase levels able to correctly classify 25 out of 26 subjects (8 progressions and 18 non progressions). The results obtained, furtherly confirm that tumor markers are useful to evaluate the chemotherapy response and indicate a possible approach to obtain the maximum usefulness of the serum marker levels.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Small Cell; Discriminant Analysis; Female; Humans; Keratins; Lung Neoplasms; Male; Middle Aged; Peptides; Phosphopyruvate Hydratase; Pilot Projects; Prospective Studies; Tissue Polypeptide Antigen

To study the clinical, histological, and immunohistochemical findings of small cell carcinoma (SCC) of the urinary bladder, and also to delineate its behaviour in comparison with transitional cell carcinomas of the bladder.. A retrospective review of 552 patients with bladder cancer yielded six cases (1%) of small cell carcinoma which were histologically identical to pulmonary small cell anaplastic carcinoma. Clinical data and follow-up were collected. Aside from the conventional histological parameters, an immunohistochemical study with AE1-AE3 and Cam 5.2 keratins, epithelial membrane antigen, neuron-specific enolase, chromogranin, synaptophysin, ACTH, calcitonin, and prostatic specific antigen was performed.. The clinical presentation did not differ from conventional transitional cell carcinoma, haematuria being the most frequent complaint (four cases). All the cases presented as flat tumours. On light microscopy, there were oat cell (four cases), intermediate (one case) and mixed oat-cell/intermediate (one case) variants. Three cases were associated with transitional cell carcinoma. Dysplastic changes were observed in the adjacent urothelium in one case only. At the time of diagnosis, all tumours were deeply invasive (pT3). Three cases were Stage III and three Stage IV, with involvement of regional lymph nodes and metastases to the liver (two cases) and lung (one case). Immunohistochemically, epithelial markers were variably expressed as AE1-AE3 keratin (5/6), Cam 5.2 keratin (2/6) and epithelial membrane antigen (3/6). Neuron specific enolase was demonstrated in every case. Chromogranin, however, was expressed in only one case. Synaptophysin, ACTH, calcitonin, and prostatic specific antigen all gave negative results. All the patients died of the disease and the overall length of survival was very poor (range 5-25 months, mean 13.3).. Small cell carcinomas show the same histological patterns as their pulmonary counterpart. Immunohistochemistry reveals a wide spectrum of activity, enolase and keratins being the most constant. The present study confirms that the overall prognosis of this tumour is very poor.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Small Cell; Carcinoma, Transitional Cell; Humans; Immunohistochemistry; Keratins; Male; Phosphopyruvate Hydratase; Retrospective Studies; Urinary Bladder Neoplasms

During the treatment of five cases of thymic carcinoma, we conducted a clinicopathological and immunohistochemical study. The patients included four males and one female, whose ages ranged from 50 to 69 years. The histologic breakdown was squamous cell carcinoma in four and small cell carcinoma in one. Immunohistochemically, the squamous cell carcinomas were positive for cytokeratin (intermediate molecular weight) and keratin. However, staining was negative for Leu-7 and chromogranin. A complete resection was achieved in only one case. In all four of the remaining cases, the resection was incomplete due to invasion into adjacent organs and disseminated lesions. Thymic carcinoma is a tumor for which a higher response rate can be expected from multidisciplinary therapy than that for lung cancer. Therefore, it is desirable, from the clinical view, to determine clinical staging and to establish standard operative procedures comprising mediastinal lymph node dissection as well as effective chemotherapy. With respect to pathology, it is hoped that an improved histologic classification will be developed.

Topics: Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Phosphopyruvate Hydratase; Thymoma; Thymus Gland; Thymus Neoplasms

The present study was designed to determine whether CYFRA 21-1, measuring cytokeratin 19, could be a specific and sensitive tumour marker for non-small cell lung cancer (NSCLC). Serum measurements were made at diagnosis in 2250 patient samples by an immunoradiometric "sandwich type" assay, using two cytokeratin 19 specific monoclonal antibodies. Among healthy individuals (n = 711) and patients with benign lung disease (n = 546), 95 percentiles were 1.2 and 2.95 ng/ml, respectively. Cumulative distribution analysis curves were established. From these data, 3.3 ng/ml gave 96% specificity. Using this cutoff, the sensitivity for small cell lung cancer was 16% (n = 74) compared to 41% for NSCLC (n = 547). In histological sub-groups, sensitivity was 57% for squamous cell lung cancer, 34% for undifferentiated large cell carcinoma and 27% for adenocarcinoma, the level of CYFRA 21-1 was correlated with tumour size and UICC stage. In squamous cell lung cancer, the sensitivity of the squamous cell carcinoma marker was 30%, 25% for carcinoembryonic antigen and 46% for tissue polypeptide antigen, using the same series of samples and cutoffs defined at 96% specificity. In conclusion, CYFRA 21-1 is a sensitive tumour marker for NSCLC, especially squamous cell lung cancer.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Keratins; Lung Diseases; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Neoplasms; Peptide Fragments; Retrospective Studies; Sensitivity and Specificity

Small cell carcinomas (SCCs) and peripheral neuroectodermal tumors (PNETs) are two distinct neoplasms that show considerable histologic, immunohistochemical, and clinical overlap, but differ in their therapies and prognoses. In an attempt to further diagnostically distinguish the two, 33 SSCs were analyzed from both pulmonary and extrapulmonary sites for the MIC2 gene product, a cell surface antigen strongly and reliably expressed in PNETs and Ewing's sarcoma (ES). Two of the 33 SCCs stained positively, but the staining was less intense than that seen with PNET and ES. The remaining 31 tumors did not stain. These data indicate that, in combination with a panel of immunohistochemical stains, analysis of neuroendocrine tumors for MIC2 expression may be useful in distinguishing between small cell carcinomas of both pulmonary and extrapulmonary origins and soft tissue PNETs.

Topics: 12E7 Antigen; Antibodies, Monoclonal; Antigens, CD; Carcinoma, Small Cell; Cell Adhesion Molecules; Female; Humans; Immunohistochemistry; Keratins; Male; Membrane Glycoproteins; Middle Aged; Neuroectodermal Tumors, Primitive, Peripheral; Paraffin Embedding

Serum samples from 137 lung cancer patients were examined by RIA to evaluate the clinical efficacy of the new tumor marker, CYFRA 21-1, which could identify the soluble fragment of cytokeratin 19. The cut-off value was determined to be 2.2 ng/ml according to the receiver operating characteristic curve. The sensitivity, specificity and accuracy of the RIA for CYFRA 21-1 were 57.7, 91.9 and 64.9%, respectively. The serum concentration of CYFRA 21-1 and the sensitivity of the assay increased as the disease progressed. Histologically, the sensitivity was highest for squamous cell carcinomas (SQ) (76.5%) in comparison with adenocarcinomas (47.8%) and small cell lung cancers (42.1%) (P < 0.01, P < 0.05, respectively). The sensitivities for SQ were 60.0, 83.3, 80.0 and 100% at stages I, II, III and IV, respectively. When compared with CEA (45.3%) and squamous cell carcinoma related antigen (SCC) (22.6%) in all lung carcinomas, CYFRA 21-1 showed the highest sensitivity (57.7%), (P < 0.05, P < 0.01, respectively). In SQ, the sensitivity of the CYFRA 21-1 RIA was significantly higher than that of the assay for SCC (47.1%) (P < 0.05). In patients with adenocarcinomas, the sensitivity of the CYFRA 21-1 assay was almost the same as that for CEA (49.3%). In a combination of CYFRA 21-1 and CEA for non-small cell lung cancers (NSCLC), the sensitivity and accuracy increased to 75.4 and 78.1%, respectively, although the specificity decreased to 86.5%. It is concluded that CYFRA 21-1 could replace SCC, a less satisfactory tumor marker, for SQ of the lung. The potentiality of the combination of CYFRA 21-1 and CEA for NSCLC should be estimated using larger samples in the near future.

Topics: Adenocarcinoma; Biomarkers, Tumor; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Keratins; Lung Neoplasms; Male; Middle Aged; Radioimmunoassay; Sensitivity and Specificity

Thymus consists of some distinct epithelial cells that contain different sets of cytokeratins (CK). Epithelium-derived tumors maintain the expression of some of the CK of the specific nontransformed cells. Therefore, it seems reasonable to hypothesize that thymic epithelial tumors may differentiate toward distinct subsets of intrathymic epithelial cells in terms of CK expression.. Eighty-one thymomas and 14 thymic carcinomas were studied immunohistologically using monoclonal antibodies specific for a single CK or a CK pair.. Thymic epithelial neoplasms could not be distinguished from each other on the basis of the profile of CK expression because the degree of overlap was extensive. However, polygonal cell thymomas differentiate toward a CK13-positive cortical subset that is rare in normal thymus. Spindle cell thymomas differentiate toward a CK13-positive medullary subset. Mixed cell thymomas are comprised of a CK13-positive medullary subset and a CK13-negative medullary subset, both of which are typical in normal thymus. CK18 was expressed to a greater extent on the epithelium of thymic carcinomas than on that of thymomas. Polygonal cell thymomas more frequently were invasive than spindle and mixed cell thymomas.. There is a possibility that the epithelium of polygonal cell thymomas is immature because it is a phenotypically unusual subset in normal thymus. A thymic carcinoma arising in a thymoma has been reported, although the relationship between the thymoma and the thymic carcinoma was not clear. Nevertheless, given the similar cellular differentiation of thymoma and thymic carcinoma, CK18-positive epithelium in thymomas may be transformed into thymic carcinoma cells in certain conditions.

Topics: Adenocarcinoma; Carcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Child; Child, Preschool; Humans; Infant; Keratins; Thymoma; Thymus Gland; Thymus Neoplasms

Cytokeratin 19 is a subunit of cytokeratin intermediate filament expressed in simple epithelia and their malignant counterparts. Therefore, it is expressed by respiratory epithelium cells and has been detected in lung cancer specimens. An immunoradiometric assay was used to detect a fragment of the cytokeratin 19, referred to as CYFRA 21-1, in the serum of 165 patients with histologically proved lung cancer (128 non-small cell and 37 small cell lung cancers). This prospective study was conducted to evaluate the reliability of this immunoradiometric assay and to identify the relationship between serum CYFRA 21-1 and different features of lung cancer including prognosis. The minimal detectable concentration detected by this assay was 0.06 ng/ml. The reliability of the immunoradiometric assay was demonstrated by the linear relationship between CYFRA 21-1 measurement and dilution of the serum, the reproducibility of the dosage in intraassay and interassay, and the high sensitivity of the method in discriminating low CYFRA 21-1 concentrations. Using a threshold of 3.6 ng/ml, sensitivity and specificity were 0.52 and 0.87, respectively. The sensitivity of the marker was highest in squamous cell carcinoma and lowest in small cell carcinoma. In non-small cell lung cancer patients, the marker varied significantly according to both stage of the disease (Kruskal-Wallis, 13.7; P < 0.005) and performance status (Kruskal-Wallis, 9.16; P < 0.05) inasmuch as a high serum CYFRA 21-1 level was associated with advanced stages, mediastinal lymph nodes, and poor performance status. Consequently, the marker was significantly lower in patients who were operated upon when compared with unresectable ones. Lung cancer patients with serum CYFRA 21-1 over 3.6 ng/ml proved to have a significantly shorter overall survival than those with a normal serum level (log rank, P = 0.007; Wilcoxon, P = 0.001). The negative prognostic effect of CYFRA 21-1 was highly significant in squamous cell carcinomas whereas it was nonsignificant for the other histologies. In Cox's model analysis, performance status, stage grouping, and CYFRA 21-1 were the only significant determinants of survival. This study supports the use of the serum fragment of cytokeratin subunit 19 CYFRA 21-1 as an independent prognostic marker of squamous cell carcinoma of the lung.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Antibodies, Monoclonal; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Evaluation Studies as Topic; Female; Genetic Variation; Humans; Immunoradiometric Assay; Keratins; Lung Neoplasms; Macromolecular Substances; Male; Middle Aged; Peptide Fragments; Prospective Studies; Sensitivity and Specificity

To differentiate Merkel-cell tumor (MCT) from other neuroendocrine (NE) carcinomas, we immunostained (using avidin-biotin-peroxidase method) nine MCT and 37 NE (including 28 small-cell) carcinomas for NE markers (neuron-specific enolase and chromogranin), cytokeratin, neurofilament, vimentin, and a number of other markers. Cytokeratin was positive in 100% of MCT and in 85% of small-cell carcinomas; neurofilament and vimentin were positive in respectively 100% and 22% of MCT and 0% of NE carcinomas. Our data suggest that the coexpression of cytokeratin and neurofilament by an undifferentiated dermal or visceral tumor is of significant help in diagnosing MCT and differentiating it from small-cell carcinomas. The vimentin reactivity is a weak and insignificant discriminant.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Merkel Cell; Carcinoma, Small Cell; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Neurofilament Proteins; Phosphopyruvate Hydratase; Skin Neoplasms

We developed a new and automated assay for the detection of lung cancer associated cytokeratin 19 fragments in patients' sera/plasma. This new tumour marker assay CYFRA 21-1 was evaluated in technical and clinical studies using the multibatch analysers ES 300 and ES 600 from Boehringer Mannheim GmbH. The analytical performance was shown to be excellent. The clinical data from 2,037 patients demonstrate that for non-small-cell lung carcinoma CYFRA 21-1 has a higher diagnostic sensitivity compared to the established markers. Mainly for squamous cell carcinoma CYFRA 21-1 was superior (60%) to CEA (18%) or SCC (31%).

Topics: Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Enzyme-Linked Immunosorbent Assay; Female; Humans; Keratins; Lung Neoplasms; Male; Ovarian Neoplasms; Peptide Fragments; Sensitivity and Specificity; Stomach Neoplasms

The clinicopathological features of two carcinosarcomas of the urinary bladder are reported. The tumours occurred in a 64- and a 66-year-old patient presenting with haematuria and both were polypoid. The epithelial component was consistent with small cell undifferentiated carcinoma with neuroendocrine differentiation, whereas the sarcomatous component did not display specific features. The carcinomatous component showed immunohistochemical reactivity for different epithelial markers as well as for chromogranin and neuron specific enolase. Conversely, the sarcomatous cells stained strongly for vimentin and in one case for muscle actin and smooth muscle actin. The differential diagnosis of biphasic tumours of the bladder is discussed and the literature reviewed.

Topics: Actins; Aged; Carcinoembryonic Antigen; Carcinoma, Small Cell; Carcinosarcoma; Chromogranins; Diagnosis, Differential; Female; Humans; Keratins; Male; Middle Aged; Phosphopyruvate Hydratase; Synaptophysin; Urinary Bladder Neoplasms; Vimentin

Topics: Abdominal Neoplasms; Adult; Carcinoma, Small Cell; Child; Desmin; Female; Humans; Keratins; Male; Vimentin

Using conventional examination (CE) of H&E stained slides from bone marrow aspirates, metastases can be detected in approximately 25% of patients with small cell lung cancer. We investigated a panel of monoclonal antibodies using immunohistochemistry in the diagnosis of bone marrow infiltration from SCLC and compared the results with CE. Seven monoclonal antibodies raised against epithelial antigens (CAM 5.2, MOV 15, NCCST 433, PE 35, LCA1/L38, HMFG 1 AND HMFG 2) were applied on bone marrow sections from three groups of patients (pts): (1) 19 pts in whom SCLC-metastases were detected by CE, (2) 44 pts with SCLC in whom metastases could not be detected by CE, and (3) 20 pts with non-malignant bone marrow diseases. All the antibodies except LCA1/L38 were positive in 60-90% of the slides with infiltrating tumour cells in group 1. No positive tumour cells were detected in group 2. A few plasma cells and megakaryocytes were slightly positive for MOV 15 and NCCST 433, but no other positive cells were detected in group 3. In conclusion, the monoclonal antibodies used in this study may be useful for diagnostic purposes when a suspicious looking infiltration is detected by CE. However, these antibodies could not detect metastatic tumour cells in the bone marrow sections from patients in whom CE did not reveal any tumour cells.

Topics: Antibodies, Monoclonal; Bone Marrow Diseases; Carcinoma, Small Cell; Humans; Keratins; Lung Neoplasms; Membrane Glycoproteins; Mucin-1; Neoplasm Metastasis; Survival Analysis

The expression patterns of basement membrane components and keratin intermediate filament proteins were studied in normal human bronchial epithelium and 56 lung carcinomas using monoclonal antibodies to laminin, type VII collagen and the individual keratins 14, 16, 17 and 18. In normal lung, laminin and type VII collagen were present between the epithelium and the lamina propria of bronchi and bronchioles. Keratin 14 was expressed in the basal cells, keratin 17 in the basal and some suprabasal cells and keratin 18 in the columnar cells of the bronchi and bronchioles. Keratin 16 was not present in normal bronchial epithelium. Laminin was found in all subtypes of lung carcinoma, but type VII collagen was present only in squamous cell carcinomas, where it showed a reduction in expression with decreasing differentiation. Type VII collagen was not identified in adenocarcinomas, small cell carcinomas or carcinoids. Antibodies to basal cell keratins 14 and 17 also displayed positivity only in squamous cell carcinomas, although no correlation with the degree of differentiation could be observed. Keratin 16 appeared to be a marker of the squamous phenotype, rather than of hyperproliferation. The keratin 18 marker for columnar epithelial cells showed a reaction pattern opposite to that of the basal cell keratins, being extensively present in adenocarcinomas, small cell carcinomas and carcinoids, with less expression in squamous cell carcinomas. This study shows a correlation between the presence of type VII collagen and the basal cell keratins 14 and 17, and a negative correlation between these components and keratin 18. These findings are likely to be useful in identifying lung cancer subtypes.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Carcinoid Tumor; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Collagen; Humans; Immunoenzyme Techniques; Keratins; Laminin; Lung Neoplasms

This paper is a report of a large cell carcinoma (solid carcinoma with mucus formation-WHO) which developed in the right upper lobe of a 71-year-old woman and in which cytoplasmic Mallory body-like inclusions (MBL) similar to Mallory bodies (MB) often found in alcoholic liver disease and hepatocellular carcinoma were noted in the tumor cells. MBL was an eosinophilic massive or reticular hyalin, and showed staining properties similar to those of MB in general stainings. Electron microscopically, it was made up mainly of a fine granular amorphous substance with high electron density and was not surrounded by a membrane. A part of the margin was in close contact with filaments approximately 10 nm in diameter, with tonofibril-like structures around it, which suggested a relationship with cytokeratin. On immunoperoxidase staining using a couple of cytokeratin antibodies, definitely positive findings were not obtained with MBL themselves. MBL of this case basically has the same character as that of MBL which appears in fibrous lesions in the lung and MB in liver disease. It was concluded that it is necessary to preoperatively distinguish this entity cytologically or histologically from pulmonary metastasis of hepatocellular carcinoma.

Topics: Aged; Carcinoma, Hepatocellular; Carcinoma, Small Cell; Diagnosis, Differential; Female; Humans; Inclusion Bodies; Keratins; Liver Neoplasms; Lung Neoplasms

Eleven primary ovarian tumors that resembled small cell carcinoma of the lung are reported. They occurred in women 28-85 (mean 59) years of age, most of whom presented with abdominal swelling. Six of the tumors were unilateral and five bilateral; seven had spread beyond the ovary. The tumors ranged from 4.5 to 26 (mean 13.5) cm in greatest dimension and were mostly solid, with a variable minor cystic component. Microscopic examination showed small to medium-sized round to spindle-shaped cells with scanty cytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli growing in sheets, closely packed nests, and occasionally islands and trabeculae. A component of endometrioid carcinoma was present in four tumors, another tumor showed squamous differentiation, another contained a cyst lined by atypical mucinous cells, and two others were associated with a Brenner tumor. Argyrophil granules were present focally in two of six tumors appropriately stained. Immunohistochemical staining was performed in nine cases: in six there was staining of the small cell component for keratin, in five for epithelial membrane antigen, in seven for neuron-specific enolase, in two for chromogranin, and in one for Leu-7. Vimentin staining was not observed. Flow cytometry was performed on eight tumors: five were aneuploid and three diploid. Five of seven patients with long-term follow-up died of, or with, disease at 1-13 (mean 8) months, one died after an unknown interval, and one was alive at 7.5 years. Two other patients had recurrent or residual disease at 6 and 8 months.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Small Cell; Chromogranins; DNA, Neoplasm; Female; Flow Cytometry; Humans; Immunohistochemistry; Keratins; Membrane Glycoproteins; Middle Aged; Mucin-1; Ovarian Neoplasms; Phosphopyruvate Hydratase; Recurrence

Despite the high response rates resulting from chemotherapy, the majority of small-cell lung cancer (SCLC) patients relapse with chemoresistant tumors. To analyze the phenotypic changes that are precursors of chemoresistant status, and to investigate the role of chemotherapy in these changes, tumor samples from 20 patients, taken before chemotherapy (etoposide, doxorubicin, and cyclophosphamide) and again at the onset of chemoresistance (after at least three courses of chemotherapy), were compared. The histologic changes were minor in 10 of 20 patients, as shown by an increase in cell size; they were major in 10 of 20 patients, with the appearance of mixed composite tumors in which neuroendocrine (NE), epidermoid, and glandular components were mixed. Major changes correlated with a good response to chemotherapy (P = .001). Ultrastructural studies showed an increase in neurosecretory granules and desmosomes, and a high frequency of multidirectional differentiation (45%) when comparison was made with pretherapy samples (10%) (P less than .01). Immunohistochemical (IH) analysis showed an increase in cytokeratin (CK) expression in treated patients, with a different labeling pattern and the expression of higher molecular weight CK. The expression of NE lineage markers (Leu 19, Sy 38, SL 11-14) remained stable, while that of NE differentiation markers (Leu 7, chromogranin) increased in the treated patients. The neuron-specific enolase (NSE) activity remained stable in treated SCLC. Large cells with a more differentiated phenotype and proliferative capacity (as shown by Ki 67 labeling), appeared to be characteristic of treated and secondary chemoresistant SCLC. The acquisition of a more complex phenotype, which correlates with primary response to therapy, implies a drug-induced differentiation in SCLC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Cell Differentiation; Cyclophosphamide; Cytoplasmic Granules; Desmosomes; Doxorubicin; Drug Resistance; Etoposide; Female; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Molecular Weight; Neoplasm Staging; Phenotype; Phosphopyruvate Hydratase; Survival Rate

Topics: Aged; Antibodies, Monoclonal; Antigens, Neoplasm; Biomarkers, Tumor; Biopsy, Needle; Bone Marrow; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Epithelium; Female; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Membrane Glycoproteins; Mucin-1; Phosphopyruvate Hydratase

Nineteen cases of a distinctive type of malignant small-cell tumor are presented. The main features of the entity are as follows: a predilection for adolescent males (mean age: 18.6 years); predominant or exclusive intra-abdominal location, with only inconstant and secondary organ involvement; nesting pattern of growth; focal rhabdoid features; intense desmoplastic reaction; immunohistochemical reactivity for epithelial [keratin, epithelial membrane antigen (EMA)], neural [neuron-specific enolase (NSE)], and muscle (desmin) markers; and highly aggressive behavior. It is proposed that this represents yet another member of the continuously enlarging and evolving family of small round (blue) cell tumors of infancy and childhood that features, more than any other member of this group, the capacity for simultaneous multidirectional phenotypical expression.

Topics: Abdominal Neoplasms; Adolescent; Adult; Carcinoma, Small Cell; Child; Desmin; Female; Humans; Immunohistochemistry; Keratins; Male; Membrane Glycoproteins; Microscopy, Electron; Mucin-1; Phenotype; Phosphopyruvate Hydratase; Vimentin

Based on our review of 35 cases and the literature, we found the spectrum of pulmonary neuroendocrine (NE) tumors to be too broad to fit into the traditional three-category classification scheme of typical carcinoid (TC), atypical carcinoid (AC), and small-cell lung carcinoma (SCLC). We found that a spectrum of high- and low-grade tumors exist between TC and SCLC and that in the past many of these tumors have been called AC. We chose to adhere to Arrigoni's definition of AC, as his original criteria characterized a low-grade tumor. For the higher grade non-small-cell tumors (NSCLC), we propose a fourth category of large-cell neuroendocrine carcinoma (LCNEC), which is characterized by: (a) light microscopic NE appearance; (b) cells of large size, polygonal shape, low nuclear-cytoplasmic ratio (N:C), coarse nuclear chromatin, and frequent nucleoli; (c) high mitotic rate [greater than 10/10 high-power fields (HPF)] and frequent necrosis; and (d) NE features by immunohistochemistry (IHC) or electron microscopy (EM). Thus, after deciding that a pulmonary NE tumor is high grade, the major diagnostic issue is separation of LCNEC from SCLC. This distinction is based not only on cell size, but on a variety of morphologic features. We studied 20 TC, six AC, five LCNEC, and four SCLC and characterized the clinical, light microscopic, EM, IHC, and flow cytometric features of each type of tumor. We did not find any advantage to IHC, EM, or flow cytometry over light microscopy in the subclassification or prediction of prognosis; however, these methods were useful in characterizing these four types of pulmonary NE tumors and in demonstrating their NE properties. LCNEC must be distinguished from a fifth category pulmonary NE tumor: NSCLC with NE features in which NE differentiation is not evident by light microscopy and must be demonstrated by EM or IHC. Although the prognosis of LCNEC appears to be intermediate between AC and SCLC, larger numbers of patients will be needed to demonstrate significant differences in survival.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Antigens, Differentiation; Bombesin; Calcitonin; Carcinoembryonic Antigen; Carcinoid Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; CD57 Antigens; Chromogranins; Female; Flow Cytometry; Follow-Up Studies; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Male; Membrane Proteins; Microscopy, Electron; Middle Aged; Synaptophysin; Terminology as Topic

Of 17 cases of small cell carcinoma of the stomach, three were early and 14 were advanced. Grossly, the tumors were mostly polypoid at the early stage, and as they advanced, deep ulcerations developed. Histologically, only one tumor was "oat cell type," and the other 16 were "intermediate cell type." With regard to tumor components, five were "pure" tumor, and 12 were "composite" admixing glandular and/or squamous differentiation. Argyrophil cells were seen in eight tumors. Immunohistochemically positive cells for chromogranin, neuron-specific enolase, and keratin were seen in 12, 10, and 7 tumors, respectively. Carcinoembryonic antigen was negative in the small cell component of most tumors as opposed to strong positivity in the glandular component. Electron-dense core granules were evident in seven of nine tumors examined. These findings suggest that histologic variety is quite characteristic of the small cell carcinomas of the stomach, and this type of carcinoma takes an aggressive clinical course like its counterparts in other organs.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Carcinoembryonic Antigen; Carcinoma, Small Cell; Chromogranins; Female; Humans; Immunoenzyme Techniques; Keratins; Male; Middle Aged; Phosphopyruvate Hydratase; Stomach Neoplasms; Survival Analysis

Clinicopathologic analyses including immunohistochemical, morphometric, virologic, and DNA ploidy studies were performed on seven cases of small cell (undifferentiated) carcinoma (SCC) and 13 cases of small cell squamous carcinoma (SCSC) of the uterine cervix in an attempt to evaluate which criteria are the most useful in identifying aggressive cervical carcinomas composed of small cells. Highly malignant behavior was found to correlate most closely with the histologic pattern of the tumor. Diffuse infiltration by round to spindle-shaped cells with hyperchromatic nuclei similar to small cell carcinoma in other organs correlated with a high frequency of lymph node metastasis and tumor recurrence. In contrast, tumors with well-defined nests similar to large cell nonkeratinizing squamous cell carcinoma were associated with low rates of lymph node metastasis and recurrence. Although there were trends in the distribution of neuroendocrine and cytokeratin immunohistochemical markers, frequency of detection of HPV 16 and 18 DNA sequences, and ploidy patterns, these features showed considerable overlap and none assisted in consistently separating these two types of neoplasms. Consideration of several features, however, could assist in the differential diagnosis. Women with SCC tended to be younger (mean age 36 yr) compared to women with SCSC (mean age 50 yr). A squamous intraepithelial lesion, i.e., cervical intraepithelial neoplasia, was present in association with 60% of SCSC but was not found in any case of SCC. Tumors positive for keratin and negative for neuroendocrine markers were invariably SCSC, whereas those negative for keratin and positive for neuroendocrine markers were always SCC.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Diagnosis, Differential; DNA, Neoplasm; DNA, Viral; Female; Humans; Immunohistochemistry; Keratins; Middle Aged; Papillomaviridae; Ploidies; Polymerase Chain Reaction; Uterine Cervical Neoplasms

Thymic carcinoma (TCA) is a thymic epithelial neoplasm with obvious cytologic atypia. We studied 13 cases of TCA by light microscopy, immunohistochemistry, and electron microscopy and correlated the findings with clinical features. The patients' mean age was 54.2 years (range 30-74); the male/female ratio was 7/6. Twelve of the 13 patients presented with signs and symptoms caused by compression of mediastinal organs; the other patient was asymptomatic. Paraneoplastic syndromes were never seen. At thoracotomy, 11 tumors invaded or adhered to surrounding structures; the other two were encapsulated. The histologic types include squamous carcinoma including the lymphoepithelioma-like subtype (seven cases), small cell carcinoma (four cases), clear cell carcinoma (one case), and adenosquamous carcinoma (one case). Positive immunoperoxidase studies were as follows: keratin (13 cases), epithelial membrane antigen (EMA) (13 cases), leukocyte common antigen (none), carcinoembryonic antigen (CEA) (five cases), B72.3 (seven cases), Leu 7 (two cases), human placental alkaline phosphatase (none), vimentin (none), and chromogranin (one case). This profile is similar to those of normal thymus and thymoma except for the absence of CEA, B72.3, EMA in normal thymus, and the absence of CEA and B72.3 in thymoma. Electron-microscopic studies performed on eight cases showed glandular and squamous differentiation in one adenosquamous carcinoma, squamous differentiation in five squamous carcinomas, and neuroendocrine differentiation in one small-cell carcinoma. Nine patients died (three due to postoperative complications and six due to recurrences or metastasis at 3-36 months). Four patients (all with squamous carcinoma) were alive without disease at 2-60 months. The clinical and pathologic features were comparable with those of approximately 62 other cases of TCA previously reported. There are a number of well-defined histologic types of TCA that allow the pathologist to make a differential diagnosis of TCA from tumors extending or metastatic to thymus or other primary mediastinal tumors. Although neither asymptomatic presentation nor encapsulation improves the poor prognosis of TCA, the squamous carcinoma subtype is associated with a better outcome than the other subtypes. Based on the electronmicroscopic and immunohistochemical findings, the presence of normal thymic tissue at the periphery of several tumors, and the observation that several TCA arose from preexisting thymomas

Topics: Adenocarcinoma; Adult; Aged; Alkaline Phosphatase; Carcinoembryonic Antigen; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Immunohistochemistry; Isoenzymes; Keratins; Male; Membrane Glycoproteins; Middle Aged; Mucin-1; Thymus Neoplasms

Primary small cell carcinoma of the oesophagus (SCCO), histologically indistinguishable from its counterpart of the lung, is a rare tumour. Less than 100 cases are reported. A review of 558 consecutive patients with oesophageal carcinomas referred to our department revealed seven cases. These were studied and compared to a survey of 80 cases collected from 24 reports. The present results, as well as the survey, indicate a poor prognosis with rapid and widespread dissemination, and that death is attributed to distant metastases rather than local failure. Freedom from local symptoms was achieved in all seven patients, regardless of therapy modalities employed. A complete response of the primary lesion was observed in three patients after chemo- and subsequent radiotherapy. According to these findings the most suitable treatment approach seems to be the same as for small cell carcinoma of the lung. A detailed immunohistochemical analysis revealed more characteristics similar to small cell carcinoma of the lung than that of the skin, viz 'Merkel cell carcinoma'.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Small Cell; Combined Modality Therapy; Esophageal Neoplasms; Female; Humans; Immunohistochemistry; Keratins; Male; Membrane Glycoproteins; Mucin-1; Neoplasm Metastasis; Prognosis; Remission Induction; Retrospective Studies

Three patients are described who presented with a large colonic adenoma in which a solid, undifferentiated carcinomatous component was found on microscopic examination. Despite small size (1.0 and 1.5 cm) and submucosal location in two cases, the tumours had metastasized to regional lymph nodes and the liver and death ensued at 4, 11 and 18 weeks after surgery. Immunocytochemistry was positive for carcino-embryonic antigen, low molecular weight cytokeratins and neuron specific enolase in all three cases and scanty dense core granules of neurosecretory type were found in one of two examined by electron microscopy. These 'neuroendocrine' carcinomas are compared with 'pure' adenomas and 'ordinary' poorly differentiated adenocarcinomas of the colon from which they differ, mainly by lack of glandular differentiation and mucus secretion, although two adenocarcinomas also showed patchy reactivity for neuron specific enolase. The term 'neuroendocrine' may be disputed but is now well established to describe a tumour that runs a uniquely aggressive course and for which radical surgery alone cannot provide a cure.

Topics: Adenocarcinoma; Adenoma; Aged; Aged, 80 and over; Carcinoma, Small Cell; Cell Differentiation; Colonic Neoplasms; Female; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Phosphopyruvate Hydratase

We report the clinicopathologic, immunohistochemical, and ultrastructural features of three small-cell neuroendocrine carcinomas of the ampullary region of the duodenum. All patients were men; their ages were 51, 62, and 66 years. The therapy consisted of pancreatoduodenectomy. All patients died of the disease; median survival was 10 months from the diagnosis. The histological appearance was identical to pulmonary and extrapulmonary small-cell carcinoma. The neuroendocrine differentiation was demonstrated ultrastructurally by the presence of dense-core granules, and by the positive immunoreaction for neuron-specific enolase and Leu-7 in each case. One case expressed a focal positivity for chromogranin A (PHE-5) and argyrophilic granules. The same case showed the presence of neurofilaments on frozen material. Neurofilament proteins could not be demonstrated in any case in paraffin sections. Neoplastic cells exhibited cytoplasmic immunostaining for cytokeratins (CAM 5.2) in all cases. In one case, a large number of neoplastic cells (60-70%) exhibited nuclear Ki-67 positivity. We postulate that the disease's histogenesis was from epithelial stem cell expressing both epithelial and neuroendocrine characteristics. The clinical behavior of small-cell neuroendocrine carcinomas of the ampullary region appears to be extremely aggressive, with early metastases and fatal outcome.

Topics: Adenocarcinoma; Aged; Antigens, Differentiation; Antigens, Surface; Carcinoma, Small Cell; CD57 Antigens; Chromogranin A; Chromogranins; Common Bile Duct Neoplasms; Humans; Immunohistochemistry; Keratins; Ki-67 Antigen; Male; Microscopy, Electron; Middle Aged; Phosphopyruvate Hydratase

In 17 cases of resected small cell carcinoma of the lung, there were 4 cases of central type and 13 cases of peripheral type. Histologic subtypes were classified into oat cell carcinoma (OAT), intermediate cell type (INT), and small cell carcinoma with large cell component (SC/LC). SC/LC was divided according to the criteria of Radice et al. Immunohistochemically, gastrin-releasing peptide (GRP) and neuron specific enolase (NSE) were used as markers for neuroendocrine cells, and keratin and secretory component (SC) were used as markers for epithelial and gland epithelial cells, respectively. Histologically, 4 cases of the central type were divided into 3 cases of INT and one case of SC/LC. Thirteen cases of the peripheral type were divided into 3 cases of OAT, 6 cases of INT, and 4 cases of SC/LC. SC/LC was more frequently seen in the peripheral type than in the central type. Immunohistochemically, there was no difference in the frequency of positive staining for GRP and NSE between the central and peripheral types, but positive staining for keratin and SC were more frequent in the peripheral type than in the central type. Three cases who survived more than 3 years were histologically divided into two cases of INT and one case of SC/LC. Immunohistochemically, these 3 cases showed positive staining for GRP or NSE, but also showed positive staining for keratin or SC. Our results showed that some of the peripheral type small cell carcinoma of the lung had histologic and immunohistochemical features which were different from those of typical small cell carcinoma. Long survival time after resection in some of the peripheral cases might be due to these features.

Topics: Aged; Aged, 80 and over; Carcinoma, Small Cell; Gastrin-Releasing Peptide; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Middle Aged; Peptides; Phosphopyruvate Hydratase; Prognosis; Secretory Component

Sixty-seven cases of small cell lung carcinoma (SCLA) in Tri-Service General Hospital (TSGH) during the past 16 years were studied. For patients with extensive stage of disease, the mean survival time and 2-year survival rate were 7.2 months and 3.1% versus 13.4 months and 16.7% for patients with limited stage. A better prognosis was obtained by treatment with a combination of intensive chemotherapy and radiotherapy. Immunohistochemical studies were performed by the peroxidase-antiperoxidase method. The positive rates in descending order were bombesin (80%), synaptophysin (74.3%), neurofilament (68.6%), neuron-specific enolase (60%), low molecular weight cytokeratin (54.3%), high molecular weight cytokeratin (25.7%), chromogranin-A (22.9%), adrenocorticotrophic hormone (0). Seven cases were examined and found to be ultrastructure; only 3 cases were found to contain neurosecretory granules. We emphasize that electron microscopy is not necessary as a routine diagnostic procedure, while light microscopy should be employed whenever possible; the immunohistochemical study should be considered within this context.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Bombesin; Carcinoma, Small Cell; Chromogranins; Female; Humans; Immunohistochemistry; Intermediate Filaments; Keratins; Lung Neoplasms; Male; Membrane Proteins; Microscopy, Electron; Middle Aged; Phosphopyruvate Hydratase; Survival Rate; Synaptophysin

Small-cell lung cancer (SCLC) lines are distinguished from non-small-cell lung cancer (NSCLC) lines by their growth in floating aggregates, in contrast to the adherent monolayers formed by NSCLC cells in culture. Of 50 well-characterized SCLC lines recently described by the National Cancer Institute (NCI)-Navy Medical Oncology Branch, only four variant cell lines (SCLC-v) grew as adherent monolayers. One line, NCI-H446, was unique in growing long-term with coexisting floating and surface adherent subpopulations. We have physically segregated these two populations over many passages in vitro to enrich for relatively pure cultures of floating and adherent cells. No differences in c-myc expression, keratin pattern, or cytogenetic appearance were found between the adherent and floating sublines. However, expression of the neuroendocrine marker neuron-specific enolase in the floating cells was three times that found in the adherent cells. The floating subline also had much greater surface expression of neuroendocrine tumor antigens detected by monoclonal antibodies UJ13A and HNK-1, which have been recently shown to detect the neural cell adhesion molecule (NCAM) on SCLC cells. Two other adherent SCLC-v lines were also found to be unreactive with UJ13A and HNK-1, generalizing the association between NCAM expression and the growth of most SCLC cultures as floating aggregates. In conclusion, we have an interesting model to study expression of NCAM as related to the adhesive properties of SCLC cells.

Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Blotting, Northern; Blotting, Western; Carcinoma, Small Cell; Cell Adhesion; Cell Adhesion Molecules, Neuronal; Cell Division; Cytogenetics; Down-Regulation; Gene Expression; Humans; In Vitro Techniques; Keratins; Lung Neoplasms; Phosphopyruvate Hydratase; Proto-Oncogene Proteins c-myc; Tumor Cells, Cultured

Routinely-fixed and Papanicolaou stained smears with the cytologic diagnosis of undifferentiated malignant neoplasm that had been prepared with cells obtained by fine needle aspiration biopsy (n = 7), pulmonary lavage (n = 5), or thoracentesis (n = 3) from 15 unselected patients were stained by an immunocytochemical technique to evaluate the presence of keratin proteins and the leukocyte common antigen (LCA). Commercially available, well-characterized monoclonal antibodies with specificities for keratin proteins and the leukocyte common antigen, and a streptavidin-biotin-horseradish peroxidase labelling method were used. Evaluation of the stained smears revealed the presence of one of the two antigens in material obtained from each patient, thus indicating the probable cell-lineage of the neoplastic cells. The specificity of the monoclonal antibody reagents used was further evaluated in routinely-fixed and stained cytologic material from 24 histologically confirmed carcinomas and 12 lymphomas. In conclusion, immunocytochemical techniques may be successfully applied to routinely processed archival cytologic smears to determine the antigenic profile of morphologically undifferentiated cells and therefore aid in the differential diagnosis of undifferentiated malignant neoplasms.

Topics: Adult; Aged; Antigens, CD; Antigens, Neoplasm; Carcinoma, Small Cell; Cell Membrane; Cytoplasm; Diagnosis, Differential; Female; Histological Techniques; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Lymphoma; Male; Middle Aged; Staining and Labeling

Keratin and carcinoembryonic antigen immunoperoxidase staining were applied to lung cancer cells in paraffin sections of cell blocks from sputa and bronchial washings. The results correlate well with cytologic diagnosis. The large cell carcinomas are nonreactive with both antibodies.

Topics: Adenocarcinoma; Bronchi; Bronchoalveolar Lavage Fluid; Carcinoembryonic Antigen; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Histological Techniques; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Paraffin; Sputum

Thirty-three patients with small cell carcinoma of the lung were treated surgically, and immunohistochemistry of the cell differentiations was examined in detail. The overall 5-year survival rate was 38% and the rates in patients with stage I or stage III were 57% and 11%, respectively (P less than 0.05). Survival rates in patients with the oat cell type and intermediate type were 24% and 44%, respectively, but with no significant difference. This carcinoma seemed to originate from primitive multipotential stem cells, i.e., those of a neuroendocrine or epithelial nature. Histochemically and immunohistochemically, argyrophilic granules and neuron-specific enolase, neuroendocrine markers, were detected more frequently in the oat cell type rather than in the intermediate type. In contrast, keratin, epithelial membrane antigen, and carcinoembryonic antigen, epithelial origin markers, were present more frequently in the intermediate type than in oat cell type. However, the difference was significant only in case of detection of argyrophilic granules and the carcinoembryonic antigen (P less than 0.05). Our current recommendation is that surgical resection should be done in the earlier stage in both subtypes. A more favorable prognosis can be expected when adjuvant chemotherapy is prescribed.

Topics: Adult; Aged; Carcinoembryonic Antigen; Carcinoma, Small Cell; Cytoplasmic Granules; Female; Histocytochemistry; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Male; Membrane Glycoproteins; Middle Aged; Mucin-1; Phosphopyruvate Hydratase

Small-cell and poorly differentiated carcinomas of the cervix were studied immunohistochemically for several neuroendocrine and epithelial markers. Neuroendocrine markers were frequently expressed in small-cell carcinomas with argyrophilia; of the seven such tumors, four were immunoreactive with anti-chromogranin, seven with antineuroendocrine, five with anti-Leu 7, and seven with anti-neuron-specific enolase. Only neuron-specific enolase, however, was expressed in two of the three small-cell carcinomas without argyrophilia. On the other hand, one of the epithelial markers, epithelial membrane antigen, was strongly positive in all three small-cell carcinomas without argyrophilia and all seven poorly differentiated carcinomas, while it was expressed only weakly and focally in all small-cell carcinomas with argyrophilia except in one case. In conclusion, it is suggested that the immunohistochemical demonstration of several neuroendocrine markers may be helpful in diagnosing neuroendocrine carcinoma of the cervix as a supplement to conventional light microscopy, silver staining, and electron microscopy.

Topics: Adenocarcinoma; Antigens, Neoplasm; Carcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chromogranins; Female; Humans; Immunohistochemistry; Keratins; Membrane Glycoproteins; Mucin-1; Phosphopyruvate Hydratase; Uterine Cervical Neoplasms

Small cell carcinoma of the ovary is a rare, poorly understood aggressive tumor of young women, associated with paraendocrine hypercalcemia in two-thirds of the cases. Immunohistochemical staining of 15 small cell carcinomas, one-third of which were associated with hypercalcemia, 15 adult granulosa cell tumors, 15 juvenile granulosa cell tumors, and 5 Sertoli cell tumors, was performed with the use of antibodies against cytokeratins (AE-1/AE-3, CAM 5.2, 902), epithelial tumor-associated antigens (B72.3, epithelial membrane antigen [EMA]), vimentin, S-100, neuron-specific enolase (NSE), lysozyme, parathyroid hormone, and chromogranin-A in an attempt to define histogenetically this tumor type. One-third of the small cell carcinomas were positive for EMA, whereas all of them were negative for B72.3 and S-100. In contrast, one-third of the granulosa cell tumors were positive for S-100 and all of them were negative for EMA and B72.3. One of five Sertoli cell tumors were positive for EMA and two were positive for B72.3, but all were negative for S-100. Differences existed in the frequency, intensity, and/or pattern of staining for cytokeratin, vimentin, lysozyme, and NSE among the various tumor types. A single small cell carcinoma from a patient with hypercalcemia stained focally for parathyroid hormone, whereas all 30 granulosa cell tumors and 4 of 5 Sertoli cell tumors were nonreactive. Chromogranin-A staining was noted in four of five small cell carcinomas, none of ten granulosa cell tumors, and two of five Sertoli cell tumors. These immunohistochemical findings, as well as previous light and electron microscopic data, do not clearly indicate any specific cell as the cell of origin of the ovarian small cell carcinoma.

Topics: Adult; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma, Small Cell; Chromogranin A; Chromogranins; Female; Granulosa Cell Tumor; Humans; Immunoenzyme Techniques; Keratins; Male; Membrane Glycoproteins; Mucin-1; Ovarian Neoplasms; S100 Proteins; Sertoli Cell Tumor; Testicular Neoplasms; Vimentin

In order to validate xenografted small cell lung carcinomas (SCLC) for biological studies, the authors established 12 lung neuroendocrine (NE) tumors (eight typical SCLC and four atypical NE tumors [ANE]) by heterotransplantation onto nude mice. Their characterization was performed using serial ultrastructural, enzymatic, and immunohistochemical methods on primary tumors and after xenografts. These were subclassified into epithelial (one), neuroendocrine (three), and multidifferenciated (eight) types. The phenotypic characters (cytokeratins, neurofilaments, neurone-specific enolase) and the proliferative rate (Ki 67 labelling) of original tumor were maintained until the last passage studied. Although further acquisition of subsets of cytokeratin or neurofilaments was observed in some cases, the authors could not detect any morphologic and/or biological spontaneous change comparable to those described in in vitro cell lines. In addition, ANE are not quite identical to variant subclasses described in vitro. The authors conclude that the stability of heterotransplanted SCLC is an advantage in further biological studies.

Topics: Animals; Antibodies, Monoclonal; Biomarkers, Tumor; Carcinoma, Small Cell; Cytoplasm; Female; Humans; Immunoenzyme Techniques; Intermediate Filament Proteins; Keratins; Lung Neoplasms; Mice; Mice, Nude; Molecular Weight; Neoplasm Transplantation; Neurofilament Proteins; Phenotype; Phosphopyruvate Hydratase

In this study antibodies specific for different intermediate-sized proteins (cytokeratins and neurofilaments) have been tested on a series of neuroendocrine (NE) lung tumors in order to evaluate their diagnostic validity. In particular we used a panel of polyclonal anti-neurofilament 200-kilodalton subunits whose reactivity against phospho-dependent epitopes was known. At least one NF subunit was constantly present and in all cases coexpression of cytokeratins and neurofilaments was confirmed. However, in cases of carcinoid tumor (CT) the results were homogeneous, while the cases of small cell lung carcinoma (SCLC) showed a much wider range of immunostaining. Our investigation confirms the hypothesis that the phosphorylation state is a significant determinant of immunohistochemical properties of neurofilaments. This might explain the large number of negative results obtained in previous investigations on NE tumors. The phosphorylation of neurofilaments may also be considered an indication of the degree of differentiation of the tumor.

Topics: Biomarkers, Tumor; Carcinoma; Carcinoma, Small Cell; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratins; Lung Neoplasms; Phosphorylation

According to the World Health Organization histological classification of bronchial tumors, clear and giant cell carcinomas are two subtypes of large cell carcinoma. As clear and giant cells can also be observed in other types of bronchial carcinoma, we investigated the frequency of the finding of these cells in different histological types. The tumor size and degree of differentiation, the amount of necrosis and keratinization, and the presence of giant and clear cells were analyzed. Statistical analysis by X2 test showed (for all classified histological types of bronchial carcinomas, except small cell carcinoma) that: 1) larger tumors had a great quantity of giant cells (P less than 0.05; P less than 0.01), 2) large tumors had more clear cells (P less than 0.05; P less than 0.01) and 3) tumors with a greater amount of necrosis had a larger number of giant and clear cells (P less than 0.05; P less than 0.01). Findings of an identical cytological characteristic can cause some difficulty in determination of bronchial cancer.

Topics: Adenocarcinoma; Carcinoma, Bronchogenic; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Keratins; Lung Neoplasms; Male; Middle Aged; Necrosis; World Health Organization

The molecular forms of keratin in small cell lung cancer (SCLC) cell lines and tumors were examined with antikeratin monoclonal antibodies. Immunostaining of SCLC by antikeratin antibody and examination by fluorescence microscopy indicates population heterogeneity in keratin content. Intensity of immunostaining is often weak. However, polyacrylamide gel electrophoresis and immunoblotting reproducibly demonstrate the presence of keratin and allow analysis of the keratin subtypes. The finding of keratin subtypes closely associated with the development of keratinizing epithelium (the 68 kDa basic keratin) in SCLC was unexpected in a tumor that is regarded as poorly differentiated. The cytoskeletal composition of SCLC suggests the presence of a heterogeneous population with a significant proportion of cells expressing highly differentiated epithelial properties.

Topics: Carcinoma, Small Cell; Electrophoresis; Fluorescent Antibody Technique; Humans; Keratins; Lung Neoplasms; Tumor Cells, Cultured; Vimentin

Formalin fixed paraffin sections of previously resected surgical specimens and ethanol fixed stamped samples of newly obtained specimens from patients with thyroid neoplastic lesions were investigated for the presence of cytokeratin by the help of avidin-biotin peroxidase complex (ABC) method using anticytokeratin monoclonal antibody PKK-1. The result showed that PKK-1 reacted only to a large cell variant of anaplastic carcinoma of the thyroid and not to a small cell type. Therefore this method appears not to be useful for differentiation between small cell carcinoma and lymphoma. The differentiation between papillary carcinoma and follicularly growing tumor was possible by this method because the former reacted to PKK-1 at a high rate, whereas most of the latter were negative to it. Freshly prepared stamped samples showed a better reaction to the monoclonal antibody, and thus this technique appears to be applicable to an aspiration biopsy cytology.

Topics: Antibodies, Monoclonal; Biomarkers, Tumor; Carcinoma, Small Cell; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Lymphoma; Thyroid Neoplasms

A panel of human lung carcinoma lines was studied with respect to hormone production and intermediate filament expression to distinguish between endodermal and neuroendocrine differentiation. An index of the degree of neuroendocrine differentiation of each line was derived from the presence or absence of hormone production, cytokeratins, neurofilaments and an embryonic endodermal cell marker, which allowed identification of three groups showing high, intermediate or low neuroendocrine expression. This grouping correlated well with the in vitro radiosensitivity of the lines, those expressing pure neuroendocrine features being significantly more radiosensitive than those with an endodermal phenotype, with the intermediate group having intermediate sensitivity. Use of such an index might predict those patients likely to benefit from the use of radiotherapy in their management.

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Calcitonin; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Line; Humans; Intermediate Filaments; Keratins; Lung Neoplasms; Radiation Tolerance; Vasopressins

Topics: Carcinoembryonic Antigen; Carcinoma, Small Cell; Humans; Keratins; Lung Neoplasms

The usefulness of cell lines in the study and prediction of the clinical behaviour of lung cancer is still a matter of debate. However, lung tumour cell cultures have been of value in investigations concerning molecular and cell biological aspects of these neoplasms. Especially in the examination of characteristics specific for the main types of differentiation (squamous cell carcinoma, adenocarcinoma, small cell carcinoma), in vitro studies have been most important. Twenty eight lung cancer cell lines were cultured for up to four years, and were examined at regular intervals for their intermediate filament protein (IFP) expression patterns using a panel of cytokeratin (CK) and neurofilament (NF) antibodies. These studies showed that the classic type of small cell lung cancer (SCLC) cell lines contain CKs 8, 18, and occasionally CK 19, while the variant-type SCLC cell lines generally express no CKs but can contain NFs. Non-SCLC cell lines, such as squamous cell carcinoma and adenocarcinoma cell lines, contain CKs 7 (in most cases), 8, 18 and 19. In one variant SCLC cell line and in one adenocarcinoma cell line CKs 4, 10 and 13, characteristic of squamous cell differentiation, were found. Although most cell lines have remained stable with respect to growth characteristics and IFP expression patterns, five lung cancer cultures exhibited a transition from one cell type to another, paralleled by changes in IFP expression. Progressions from classic to variant SCLC cell lines have been observed, next to conversions from variant SCLC to cell lines re-expressing cytokeratins. In some cases this resulted in a coexpression of CKs and NFs within a cell line and even within individual tumour cells. These results strongly support the earlier finding that CK expression in SCLC cell lines is a reliable marker for the classic type of differentiation, while the absence of CKs and the presence of NFs marks the variant type of differentiation. Our results are discussed in view of previous histological findings.

Topics: Carcinoma, Small Cell; Cell Line; Humans; Immunoblotting; Intermediate Filament Proteins; Keratins; Lung Neoplasms; Microscopy, Fluorescence; Microscopy, Phase-Contrast; Tumor Cells, Cultured

Sections of primary lung carcinomas, lung metastases, mesotheliomas, and lung metastases of some rare mesenchymal tumors were incubated with different cytokeratin (CK), vimentin, desmin, and tissue polypeptide antigen (TPA) antibodies and with antibodies reactive with different hormones (ACTH, PTH, alpha-HCG, Calcitonin CT), CEA, carcinoma-associated antigen (CA1), secretory component (SC), neuron-specific enolase (NSE), alpha-1-antitrypsin (alpha-1-AT), lysozyme (lyso), and S-100 protein (S 100). CK antibodies derived from a 49 kD (reactive with simple epithelia [SE]) and a 67 kD CK polypeptide fraction (reaction with complex epithelia [CE] were useful differentiation markers for the four major groups of lung carcinomas. In one half of small cell carcinomas a positive reaction with NSE antibodies was found. S 100 and SC were good markers for papillary and bronchioloalveolar adenocarcinomas, whereas CEA was less important because of its reactivity with different types of lung carcinomas. To discern clear cell carcinomas of lung and renal origin a positive reaction with vimentin antibodies (some renal but not lung types) and with CA1 (no renal but all lung types) seemed to be useful. All hormone antibodies were of no importance as markers for difficult differential diagnosis, because positive reactivities were found in cases from every major carcinoma group. In addition, a Ca2+-activated adenosine triphosphatase (ATPase) was found in mesotheliomas but not in papillary adenocarcinomas.

Topics: Adenocarcinoma; Carcinoembryonic Antigen; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Differentiation; Desmin; Diagnosis, Differential; Histocytochemistry; Hormones; Humans; Immunologic Techniques; Keratins; Kidney Neoplasms; Lung Neoplasms; Mesothelioma; Muramidase; Neoplasm Metastasis; Peptides; Phosphopyruvate Hydratase; Pleural Neoplasms; S100 Proteins; Secretory Component; Tissue Polypeptide Antigen; Vimentin

In order to investigate the intermediate filament protein content of hormone producing lung tumor cell cultures a panel of 16 different cytokeratin antisera were tested using immunocytochemical and biochemical techniques on lung carcinoma cell cultures from different origin. These included three cell cultures derived from small cell lung carcinoma, two large cell carcinoma cell cultures, and two cell cultures derived from squamous cell carcinomas. Flow cytometric analysis of the cell cultures demonstrated that all cell lines examined were aneuploid with DNA-indices ranging from 1.7 to 3.1 rimes the DNA-content of normal human lymphocytes. In both immunofluorescence and immunoperoxidase techniques six out of seven cell cultures reacted with most of the cytokeratin antisera used in a filamentous manner, while a large cell carcinoma cell culture did not react with any of the cytokeratin antisera used. None of the cell cultures examined reacted with the antibodies to neurofilament proteins, suggesting that none of these (neuro)hormone producing cell cultures were of neural origin. All cell cultures which were growing as adherent cell cultures did express vimentin. The cell culture that grew with cells floating in aggregates did not express this intermediate filament protein while a subline which did attach, expressed vimentin. This findings strongly indicates the relation between growth pattern in vitro (floating vs. adherent) and the expression of vimentin. No reaction was found with antisera to desmin and GFAP. The presence of cytokeratins and vimentin in most cell cultures could be confirmed using one- and two-dimensional gel electrophoresis. Cytokeratins 7, 8, 18 and 19 were most commonly present.

Topics: Carcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Line; Cytoskeleton; Electrophoresis, Polyacrylamide Gel; Flow Cytometry; Fluorescent Antibody Technique; Histocytochemistry; Humans; Immunoenzyme Techniques; Intermediate Filament Proteins; Intermediate Filaments; Keratins; Lung Neoplasms; Neurofilament Proteins

Lung cancers were investigated for their heterogeneity as expressed by their immunoreactivity for cytokeratins and neurofilament proteins, as well as for the neuroendocrine differentiation antigen MOC-1. Using broadly cross-reacting antibodies, cytokeratins were detected in nearly all cases of lung carcinomas. Keratinization could be detected only in cases of moderately to well-differentiated squamous cell carcinoma (SQC) using a monoclonal antibody to cytokeratin 10, while a monoclonal antibody reactive with cytokeratin 18, and specific for glandular epithelia, reacted with adenocarcinomas, small cell lung carcinomas (SCLC), and lung carcinoids. In SQC this antibody could detect non-squamous cell differentiation, showing increasing numbers of positive cells with decrease of histologically detectable SQC differentiation. Cells positive for neurofilaments were demonstrated in some of the poorly differentiated SQCs and in some of the cases of SCLC, possibly representing the variant type of SCLC. Also in some of the lung carcinoids neurofilament proteins were present, colocalizing with cytokeratins. MOC-1 was present in all SCLC and lung carcinoids. This antibody could also detect neuroendocrine differentiation in all combined small cell carcinomas, in one poorly differentiated adenocarcinoma, and in about 30% of the poorly differentiated SQCs. Therefore, lung cancer heterogeneity can be detected using a panel of well-defined antibodies to intermediate filaments in combination with the MOC-1 antibody. The use of these antibodies in diagnosis can have prognostic significance and can lead to a more selective therapeutic approach.

Topics: Adenocarcinoma; Antibodies; Antigens, Neoplasm; Carcinoid Tumor; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cross Reactions; Cytoskeleton; Histocytochemistry; Humans; Immunoenzyme Techniques; Intermediate Filaments; Keratins; Lung Neoplasms

A cultured small cell lung cancer cell line (Lu-134-B-S) established from a xenotransplanted tumor in a nude mouse, which had originated from a primary focus of small cell lung cancer, showed morphological changes when the medium was changed from RPMI 1640 supplemented with 10% fetal calf serum to RPMI 1640 supplemented with 10% delipidized fetal calf serum. That is, it consisted of "classic" small cells in the former medium, but after eight passages in the latter medium many cells became squamous cells, possessing abundant eosinophilic cytoplasm and intercellular bridges. Immunohistochemically, they reacted to antikeratin and antiinvolucrin antibodies. Electron microscopically, well developed desmosomes and associated tonofibrils were noted, and electrophoretically, the amount of medium (Mr 57,000 and 59,000) and large-sized (Mr 67,000) keratins were found to increase with the change of the medium. These changes reversed to the original small cell morphology within 4 weeks after addition of vitamin A (retinoic acid) to the medium. These findings suggested that deficiency of vitamin A caused the change of the cell from small to squamous cell and vice versa.

Topics: Aromatic-L-Amino-Acid Decarboxylases; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Line; Creatine Kinase; Culture Media; Humans; Isoenzymes; Keratins; Lung Neoplasms; Microscopy, Electron; Phosphopyruvate Hydratase; Vitamin A

Monoclonal antibody based immunohistochemistry is a very powerful tool for the establishment of a pathological diagnosis of lung cancer. Applying a panel of intermediate filament antisera and an antibody recognizing neuroendocrine differentiation we have tested about 240 human lung tumors and 15 human lung tumor cell lines. Our results can be summarized as follows: a differential diagnosis between neuroendocrine and non-neuroendocrine lung tumors can be obtained by the application of the monoclonal antibody MOC-1 directed against neuroendocrine antigens. Immunohistochemistry can lead to a better recognition of lung tumor heterogeneity within the established histologies. Examples of this phenomenon are: the presence of neuroendocrine and/or neural components within non-neuroendocrine tumors. The presence of squamous cell or adenocarcinomatous differentiation in non-SCLC can be detected by chain specific anti-cytokeratin antibodies. The degree of differentiation towards the variant type within SCLC can be detected by the monoclonal antibody directed against neurofilaments. lung cancer cell lines can serve as an in vitro model for immunohistochemical studies on different lung cancer subtypes.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Differentiation; Cells, Cultured; Diagnosis, Differential; Humans; Intermediate Filaments; Keratins; Lung Neoplasms

The reaction patterns in 80 adenocarcinomas of the lung were examined with PAP-method using a monoclonal antibody against keratin and one against carcinoembryonic antigen (CEA) and a polyclonal antiserum against CEA. Almost all tumors showed a positive reaction to the antibodies which, however, varied quantitatively. Even though a reliable correlation of positive immunohistochemical reaction with the different light microscopical types was not possible according to WHO subtypes and degrees of differentiation, specific localization of the reaction within the tumor cells was seen with increasing differentiation. There was no correlation between the immunohistochemical reactions and 14 clinically measured plasma CEA levels. The plasma CEA level not only depends on CEA production by the tumor but also on other factors.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Carcinoembryonic Antigen; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms

The light microscopic, electron microscopic and immunohistochemical features of a small cell undifferentiated carcinoma of the minor salivary gland are presented. The tumor was composed predominantly of undifferentiated small cells with focally admixed neuroendocrine, exocrine and squamous cells, occasionally arranged in an organoid manner. The presence of vasoactive intestinal polypeptide in the tumor was found immunohistochemically. In addition, the tumor cells stained with Grimelius' impregnation. Immunohistochemically the tumor contained cells that reacted positively with the antibodies to carcinoembryonic antigen, 66K keratin polypeptide, or human salivary amylase. These findings indicate that a small cell undifferentiated carcinoma of the minor salivary gland, reported here, exhibits focally multidirectional differentiation as well as neuroendocrine cell derivation.

Topics: Amylases; Carcinoembryonic Antigen; Carcinoma, Small Cell; Histocytochemistry; Humans; Immunoenzyme Techniques; Keratins; Male; Microscopy, Electron; Middle Aged; Salivary Gland Neoplasms; Salivary Glands; Salivary Glands, Minor; Vasoactive Intestinal Peptide

Three cases of primary small cell carcinoma of the kidney with light microscopic, immunohistochemical, and electron microscopic findings are reported. Two patients died of disseminated disease 8 months and 1 year, respectively, after the diagnosis and the third was free of tumor after 18 months. Immunohistochemical studies revealed keratin immunostaining of tumor cells in two cases and staining for neuron-specific enolase in the third. The third case also showed a few dense neurosecretory granules at the ultrastructural level. Although no strong conclusions regarding histogenesis can be drawn, this study indicates that small cell carcinoma of the kidney exists and does not necessarily exhibit a neuroendocrine differentiation. Small cell carcinoma of the kidney must be considered in the differential diagnosis of malignant renal tumor, especially in cases in which a large necrotic tumor is present. Based on the few cases presented in this study and on the one previously reported case, small cell carcinoma of the kidney appears to be an aggressive tumor.

Topics: Aged; Carcinoma, Small Cell; Cytoplasmic Granules; Female; Humans; Immunoenzyme Techniques; Keratins; Kidney; Kidney Neoplasms; Microscopy, Electron; Middle Aged; Phosphopyruvate Hydratase

Using a polyclonal antibody against human epidermal keratins and a monoclonal antibody against cytokeratins characteristic of simple epithelia, and the Avidin-Biotin system of immunohistochemistry, we have demonstrated cytokeratin expression in 46% and in 60% of small cell carcinomas of the lung at autopsy respectively. The latter gave a diffuse stronger reaction product than the polyclonal antibody. The results suggest that there is a cytokeratin rich and a cytokeratin poor type of small cell carcinoma. Neuron-specific enolase immunohistochemistry was positive in 60% of the cases. Coexpression with cytokeratin was seen in ten cases (30%). The expression of cytokeratin and neuron-specific enolase in small cell carcinomas strongly suggests that they are of an epithelial origin, but are capable of neuroendocrine differentiation.

Topics: Aged; Autopsy; Carcinoma, Small Cell; Female; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Male; Middle Aged; Phosphopyruvate Hydratase; Retrospective Studies

Paraffin sections of formalin-fixed tumor samples from 26 patients with neuroendocrine (Merkel cell) carcinoma of the skin (NECS) were studied immunohistochemically with three monoclonal antibodies to low molecular weight keratin (MAB-K) and with antibodies to leukocyte common antigen (LCA), neurofilament (NF), neuron-specific enolase (NSE), S100 protein (S100), and chromogranin (CGN), to investigate the relative diagnostic value of these antibodies. Samples from 20 lymphomas, 10 non-oat cell undifferentiated carcinomas, 10 oat cell carcinomas, and 10 melanomas served as controls. Keratin was found in 25 of the 26 NECS and in all undifferentiated and oat cell carcinomas. A ball-like immunostaining for keratins, resembling an inclusion body was seen only in cases of NECS and some carcinoids. Neurofilament, NSE, and CGN were expressed by fewer NECS than was keratin and all NECS were negative for LCA and S100. None of the lymphomas and melanomas contained detectable keratin, NF, NSE, or CGN. Only the lymphomas stained with LCA. Only the melanomas were S100-positive. It is concluded that keratin is the most useful single discriminating marker in the separation of neuroendocrine (Merkel cell) carcinoma of the skin from lymphoma, melanoma and, when the characteristic inclusion-like pattern is seen, from metastatic oat cell carcinoma.

Topics: Adult; Aged; Antibodies, Monoclonal; Carcinoid Tumor; Carcinoma; Carcinoma, Small Cell; Diagnosis, Differential; Female; Gastrointestinal Neoplasms; Histocytochemistry; Humans; Immunochemistry; Keratins; Lung Neoplasms; Lymphoma; Male; Melanoma; Microscopy, Electron; Middle Aged; Nerve Tissue Proteins; Skin Neoplasms

The expression of vimentin in pulmonary carcinomas was studied in 285 cases of surgically resected lung cancer from our hospital files. Formalin fixed, paraffin-embedded sections were studied by immunoreactive staining techniques using two monoclonal antibodies against vimentin. Cases demonstrating vimentin positivity by the avidin-biotin-peroxidase method included 11 of 129 adenocarcinomas studied (8.5%), and 15 of 61 large cell carcinomas studied (24.6%). Vimentin expression was not seen in any of the 51 squamous cell carcinomas or 35 small cell carcinomas in our series. The positive cases of adenocarcinoma were in moderately and poorly differentiated cancers. Four of the eight giant cell carcinomas (50%) demonstrated vimentin expression. All cases that exhibited vimentin positivity were studied for cytokeratin expression. Coexpression of vimentin and cytokeratin was demonstrated not only within the same tumor but also within the same cells in some cases stained by double antibody technique, including both adenocarcinomas and large cell carcinomas. Similar immunoreactive methods were also applied to sections from human lung cancer transplants grown in the nude mouse. Of 28 tumors studied, four of 11 adenocarcinomas (36%) and all 4 large cell carcinomas demonstrated coexpression of vimentin and cytokeratin, while none of the five squamous cell carcinomas or eight small cell carcinomas expressed vimentin.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Histocytochemistry; Humans; Keratins; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Transplantation, Heterologous; Vimentin

Three cases of Merkel cell (small cell) carcinoma of the skin are presented with immunohistochemistry for epithelial and neuroendocrine antigens. All three cases showed distinctive punctate perinuclear cytoplasmic positivity for cytokeratin which corresponded to aggregates of intermediate filaments, seen ultrastructurally in two cases. Epithelial membrane antigen was also identified in two cases. Only one case showed cytoplasmic positivity for neuron specific enolase, and immunostaining for a battery of polypeptide hormones was negative. The demonstration of cytokeratin perinuclear inclusions provides a distinctive immunohistochemical feature to aid in their diagnosis. Two of the three patients had chronic lymphocytic leukaemia years before the diagnosis of Merkel cell carcinoma. The possible association of lymphoproliferative disorders, particularly B cell tumours, and Merkel cell carcinoma is discussed.

Topics: Aged; Antigens, Neoplasm; Carcinoma, Small Cell; Cell Nucleus; Cytoplasm; Epithelium; Female; Humans; Immunoenzyme Techniques; Intermediate Filaments; Keratins; Male; Microscopy, Electron; Middle Aged; Phosphopyruvate Hydratase; Skin Neoplasms

Forty one cases of large cell anaplastic carcinoma of the lung (LCACL) were investigated by electron microscopy and immunoperoxidase studies for cytokeratin, enolase, and carcinoembryonic antigen. The results indicated that these neoplasias, grouped as an unique entity by ordinary histopathologic findings, may be further divided into five groups as follows: squamous, adenomatous, adenosquamous, neuroendocrine, and undifferentiated. The authors suggest that this subclassification may be useful in treatment orientation and in the prognostic evaluation of these neoplasias.

Topics: Carcinoembryonic Antigen; Carcinoma, Small Cell; Histocytochemistry; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Phosphopyruvate Hydratase

The results of neuron-specific enolase (NSE) and keratin immunodetection in cytological specimens of sputum secured from 41 patients with lung cancer are presented. All 19 cases of small-cell carcinoma showed intense immunoreactivity for NSE. No such immunoreactivity was found in 21 of 22 cases of non-small-cell carcinoma. The single positive result was from a case of large-cell undifferentiated carcinoma. All 10 cases of squamous-cell carcinoma showed immunoreactivity for keratin. The 19 cases of small-cell carcinoma showed no such reactivity. Our findings indicate that immunostaining for NSE and keratin is a valuable aid when a definite diagnosis of small-cell carcinoma of the lung can not be made on the basis of conventional cytologic features.

Topics: Adenocarcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Clinical Enzyme Tests; Diagnosis, Differential; Histocytochemistry; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Phosphopyruvate Hydratase; Sputum

Forty-seven surgically resected small cell lung carcinomas (SCLC) were immunohistochemically studied by using antibodies to various neuroendocrine and epithelial markers. SCLC was shown to be subdivided into two categories, with and without the immunoreactive neuroendocrine markers aromatic L-amino acid decarboxylase, gastrin-releasing peptide, serotonin, chromogranin A and neurofilament protein. Neuron-specific enolase (NSE) and creatine kinase BB isoenzyme (CK-BB), which are also considered to be neuroendocrine markers, had a tendency to be widely distributed in the SCLC with a neuroendocrine marker, but the immunoreactivity for both NSE and CK-BB varied in the SCLC without neuroendocrine markers. Therefore they were not included in the classification. Epithelial markers keratin, involucrin and epithelial membrane antigen were frequently observed in the SCLC with neuroendocrine markers, but less so in the SCLC without neuroendocrine markers. The data are discussed briefly in relation to "classic and variant" forms of SCLC in vitro and to a recently proposed histological classification of SCLC.

Topics: Aromatic-L-Amino-Acid Decarboxylases; Carcinoma, Small Cell; Creatine Kinase; Gastrin-Releasing Peptide; Histocytochemistry; Humans; Immunochemistry; Isoenzymes; Keratins; Lung Neoplasms; Neurosecretory Systems; Peptides; Phosphopyruvate Hydratase; Protein Precursors

The intermediate filament protein (IFP) characteristics of a panel of lung cancer cell lines including adenocarcinoma (two cell lines) and small cell lung cancer (SCLC, three classic and three variant cell lines) were examined using one- and two-dimensional gel electrophoretic techniques, immunocytochemical techniques and immunoblotting assays. A panel of 28 monoclonal and polyclonal antibodies to the five different types of IFP were used. The results of our studies indicate that these human lung adenocarcinoma, classic SCLC and variant SCLC cell lines can be differentiated on the basis of their pattern of IFP. The main conclusions from this study can be summarized as follows. The two adenocarcinoma cell lines contain cytokeratins 7, 8, 18, and sometimes 19, next to vimentin intermediate filament (IF). The three classic-type SCLC cell lines contain only cytokeratin IFs but not vimentin IF or neurofilaments (NFs). Cytokeratin polypeptides 7, 8, 18 and 19 could be detected. All three variant-type SCLC cell lines do not contain detectable amounts of cytokeratins. In contrast, two out of three variant SCLC cell lines contain neurofilament proteins. All three variant-type SCLC cell lines contain vimentin IF. Using immunoblotting assays with monoclonal and polyclonal antibodies to defined NF proteins the presence of the 68 X 10(3) Mr and the 160 X 10(3) Mr NF polypeptide could be demonstrated in two variant SCLC cell lines. As patients with SCLC-variant phenotype have a poorer prognosis after cytotoxic therapy than patients with 'pure' SCLC, the use of antibodies to IFP in staining fresh lung tumours, especially anaplastic ones, may differentiate the two subtypes of SCLC. Such a distinction would have a major impact on therapy selections and may be of prognostic importance.

Topics: Antibodies, Monoclonal; Carcinoma, Small Cell; Cell Line; Electrophoresis, Polyacrylamide Gel; Fluorescent Antibody Technique; Humans; Intermediate Filament Proteins; Keratins; Lung Neoplasms; Vimentin

The expression of intermediate filament proteins in classic and variant-type small-cell lung carcinoma (SCLC) cell lines was studied using immunocytochemical techniques, two-dimensional gel electrophoresis and immunoblotting assays. Classic SCLC cell lines contain cytokeratin proteins but no neurofilaments. In contrast, variant cell lines do not contain detectable amounts of cytokeratins but partly express neurofilaments and vimentin. These results explain apparent discrepancies on the intermediate filament content of SCLC described in the recent literature. The application of antibodies to fresh biopsy specimens of SCLC may in the future allow the identification of the variant type of cells in clinical SCLC specimens and may have a major impact on therapeutic strategy and prognosis in these patients.

Topics: Carcinoma, Small Cell; Cell Line; Electrophoresis, Polyacrylamide Gel; Fluorescent Antibody Technique; Humans; Immunosorbent Techniques; Intermediate Filament Proteins; Isoelectric Focusing; Keratins; Lung Neoplasms; Vimentin

Twenty-seven cases of surgically resected large cell carcinoma of the lung including nine cases of giant cell carcinoma were examined ultrastructurally and immunohistochemically. Ultrastructurally, of 18 large cell carcinomas other than giant cell carcinoma eight showed characteristic differentiation toward adenocarcinoma, four toward adenosquamous carcinoma, and one each toward squamous cell carcinoma and neuroendocrine cell carcinoma, but the remaining four were undifferentiated. Six of the nine giant cell carcinomas also showed features of adenocarcinoma, two showed features of squamous cell carcinoma, and one was undifferentiated carcinoma. Immunohistochemically, secretory component (SC) was observed in seven of 14 cases with features of adenocarcinoma and two of four cases with features of adenosquamous carcinoma. Carcinomas with only squamous cell differentiation did not stain for SC. Keratin staining was positive in five of the 14 with features of adenocarcinoma, three of the four cases with features of adenosquamous carcinoma and two of the three cases with features of squamous cell carcinoma. The numbers of tumor cells positive for keratin and/or SC were small. One carcinoma with neurosecretory type granules was stained positively for calcitonin. These findings indicate that many large cell carcinomas showed differentiation toward glandular cells and/or squamous cells, and some did not show any differentiation ultrastructurally or immunohistochemically, indicating that the majority of large cell carcinomas are poorly differentiated form of either adenocarcinomas or squamous cell carcinomas.

Topics: Adenocarcinoma; Calcitonin; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cytoplasmic Granules; Gastrin-Releasing Peptide; Histocytochemistry; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Peptides; Secretory Component; Staining and Labeling

A 60-year-old white woman with laryngeal oat cell carcinoma is described. She was a heavy smoker who had been treated seven years earlier with 5,000 rads for a well differentiated squamous cell carcinoma metastatic to a left submandibular lymph node. She presented this time with a two month history of hoarseness and tumor of the supraglottic larynx was found. There was clinical and chemical evidence of an ectopic ACTH syndrome. The histology and fine structure of the tumor were typical of oat cell carcinoma. Immunoreactive ACTH, GRP, NSE, Beta-endorphin, calcitonin, and keratin were found in the cytoplasm of the tumor cells by indirect immunoperoxidase techniques. We could find no previously reported case of laryngeal oat cell carcinoma with ectopic ACTH syndrome or cytoplasmic localization of polypeptides.

Topics: Adrenocorticotropic Hormone; Autopsy; Carcinoma, Small Cell; Female; Gastrin-Releasing Peptide; Gastrins; Hormones; Humans; Immunoenzyme Techniques; Keratins; Laryngeal Neoplasms; Middle Aged; Peptides; Phosphopyruvate Hydratase

Topics: Aged; Carcinoma, Adenoid Cystic; Carcinoma, Small Cell; Female; Histocytochemistry; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Male; Middle Aged

Immunohistochemical staining utilizing a peroxidase-antiperoxidase (PAP) technique for keratin, carcinoembryonic antigen (CEA), human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) was performed on paraffin sections from 72 cases of lung cancer obtained at autopsy. Positive reaction was shown in 44% of the cases for keratin, 77% for CEA, and 58% for HCG. AFP was positive in only one case of large cell carcinoma. Keratin was positive in 100% of squamous cell carcinoma, 53% of adenocarcinoma, 15% of small cell carcinoma and 45% of large cell carcinoma. CEA showed positive staining in 90% of squamous cell carcinoma, 88% of adenocarcinoma, 58% of small cell carcinoma and 69% of large cell carcinoma. CEA was the most useful tumor marker for detection of all types of lung cancer. HCG was positive in 30% of squamous cell carcinoma, 100% of adenocarcinoma, 23% of small cell carcinoma and 56% of large cell carcinoma.

Topics: Adenocarcinoma; alpha-Fetoproteins; Carcinoembryonic Antigen; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chorionic Gonadotropin; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms

Small cell bronchial carcinoma (SCC) xenografts with differing sensitivity to cyclophosphamide (CY) were investigated using a variety of techniques. Two xenografts (HX78 and HX88) were relatively sensitive to CY, one xenograft (HX72) was inherently resistant to CY and a fourth xenograft (HX78Cy) was a CY induced resistant subline of HX78 and was unstable when maintained without CY exposure. Conventional light microscopy, cytology and electron microscopy examination of the xenografts revealed appearances consistent with SCC. An antikeratin antibody demonstrated the presence of keratin in the inherent and the induced resistant xenografts (and in the unstable revertant) but not in the two sensitive xenografts; the presence of keratin suggested squamous differentiation. Monolayer culture morphology of the sensitive HX78 and the unstable revertant was anchorage independent with the cells forming floating aggregates; the induced resistant subline of this xenograft (HX78Cy) showed, by contrast, flattened, angular adherent cells. Beta HCG production was detected in the monolayer culture supernatant of sensitive HX78 cells; the level of production of beta HCG was increased in the induced resistant HX78Cy cells. Karyotype and flow cytometry studies were also performed. The morphological responses of small cell lung cancer to treatment are discussed.

Topics: Animals; Carcinoma, Small Cell; Cell Transformation, Neoplastic; Cells, Cultured; Chorionic Gonadotropin; Cyclophosphamide; Drug Resistance; Flow Cytometry; Humans; Karyotyping; Keratins; Lung Neoplasms; Mice; Neoplasm Transplantation; Transplantation, Heterologous

18 cases of small cell carcinoma were studied by means of scanning electron microscopy and immunohistochemical analysis. 4 cases showed ultrastructural and immunohistochemical features of poorly differentiated epidermoid carcinoma. A strict correlation has been demonstrated between ultrastructural and immunohistochemical findings.

Topics: Aged; Bronchial Neoplasms; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Diagnosis, Differential; Female; Humans; Immunoenzyme Techniques; Keratins; Male; Microscopy, Electron, Scanning; Middle Aged

One hundred and twenty seven cases of lung tumors were studied by the immunoperoxidase technique for the presence of CEA and beta-HCG. Twenty-nine of these tumors were additionally stained for keratin and SP1, CEA and SP1 could be demonstrated in 80% of the studied cases, while beta-HCG was found in only 9%. SP1 revealed an almost identical staining pattern to CEA and keratin was found only in squamous cell carcinomas. The tissue positivity of none of these three markers correlated with tumor size, lymphnodal involvement or histological type.

Topics: Adenocarcinoma; Aged; Bronchial Neoplasms; Carcinoembryonic Antigen; Carcinoid Tumor; Carcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chorionic Gonadotropin; Female; Histocytochemistry; Humans; Keratins; Lung Neoplasms; Male; Middle Aged; Pregnancy Proteins; Pregnancy-Specific beta 1-Glycoproteins

A panel of established human pulmonary cancer cell lines, representing the major histopathologic groups according to the World Health Organization (WHO) classification (WHO 1, squamous cell carcinoma; WHO 2, small cell carcinoma; WHO 3, adenocarcinoma; WHO 4, large cell carcinoma) were examined for their expression of various types of intermediate filaments in order to determine their phenotypic differences and to attempt to disclose their histogenetic origin. The cells were investigated with antibodies specific for cytokeratin, vimentin, and neurofilament polypeptides with both immunofluorescence microscopy and immunoblotting techniques. Squamous cell carcinoma and adenocarcinomas expressed cytokeratin in accordance with the epithelial nature of these tumors but not neurofilament polypeptides. Small cell carcinomas, on the other hand, were positive for neurofilaments but negative for keratin. In contrast to small cell carcinoma, adenocarcinoma, and squamous cell carcinoma, one cell line derived from large cell carcinoma appeared to express both neurofilaments and keratin. All cell lines studied also contained variable amounts of vimentin, a phenotypic characteristic obtained by many cells under in vitro conditions. The results demonstrate, in accordance with our earlier observations in vivo, a distinctly divergent expression of intermediate filament proteins in different types of lung cancers. The persistence of this phenotypic heterogeneity in vitro consolidates the use of cell cultures as useful models to study the biologic behavior and interrelationships of lung cancers. Based on the present studies, and taking into account the occurrence of mixed forms of lung cancers, we present a hypothetical scheme of the histogenetic derivation of different types of lung cancers.

Topics: Adenocarcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Differentiation; Cell Line; Female; Fluorescent Antibody Technique; Humans; Immunochemistry; Intermediate Filament Proteins; Keratins; Lung Neoplasms; Male; Microscopy, Fluorescence; Neoplasm Proteins; Phenotype; Vimentin

Three monoclonal antibodies, one directed against cytokeratin (clone 80) and two directed against neurofilament (clones 2F11 and 3G6), were used in the study of a series of 77 lung carcinomas by immunohistochemical staining. The anti-cytokeratin antibody, a very broadly reacting antibody directed against an antigenic determinant common to a great number of cytokeratins, was applicable on frozen sections. The two anti-neurofilament antibodies, directed against the 70 kD protein (clone 2F11) and the 160 kD and 200 kD proteins (clone 3G6) of neurofilament, were applicable on both frozen sections and paraffin sections. The staining results on the lung carcinomas indicate that all types of tumors studied, including small-cell anaplastic carcinoma, are markedly positive for cytokeratin. Frozen sections of five and formalin-fixed and paraffin-embedded sections of six other small-cell anaplastic carcinomas were negative with both anti-neurofilament monoclonal antibodies. One poorly differentiated squamous cell carcinoma positive with anti-neurofilament clone 2F11 but negative with clone 3G6. This distribution of cytoskeletal proteins demonstrates the epithelial differentiation of all types of lung carcinomas. Neuroendocrine differentiation of lung carcinomas as found in the small-cell anaplastic types does not result in expression of neurofilament proteins.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Antibodies, Monoclonal; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Histocytochemistry; Humans; Intermediate Filament Proteins; Keratins; Lung Neoplasms; Neoplasm Proteins; Neurofilament Proteins

Two cases of olfactory neuroblastoma mixed with other neoplastic elements are reported. One tumor contained foci of adenocarcinoma and of ganglioneuroblastoma in addition to an undifferentiated small cell component consistent with neuroblastoma; the other tumor histologically resembled small cell undifferentiated carcinoma with foci of squamous differentiation, but was shown by electron microscopy to be neuroblastoma. The histogenesis and treatment of mixed tumors of this type are discussed.

Topics: Adenocarcinoma; Aged; Carcinoma; Carcinoma, Small Cell; Cytoplasm; Humans; Keratins; Male; Nasopharyngeal Neoplasms; Neuroblastoma; Nose Neoplasms

A histological review of 72 undifferentiated thyroid tumors was performed in order to discover small cell anaplastic carcinomas and Non-Hodgkin lymphomas. Cases suspected to be lymphoma were examined for the presence of Ig and keratin and lectins with a PAP-procedure. Among the 72 cases, 68 (94,5%) were anaplastic carcinomas of various types. Four cases (5,5%) were diffuse small cell tumors, which had previously been regarded as anaplastic carcinomas. All four could be identified as Non-Hodgkin lymphomas by histology, immunohistochemistry, repeat biopsy or autopsy. The findings suggest that the majority of small cell anaplastic thyroid tumors are lymphomas and that true anaplastic small cell carcinoma of the thyroid must be extremely rare. Its diagnosis requires electronmicroscopy and/or immunohistochemistry to demonstrate the epithelial nature of tumor cells.

Topics: Adenocarcinoma; Biopsy; Carcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Diagnosis, Differential; Humans; Immunoenzyme Techniques; Immunoglobulins; Keratins; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Thyroid Gland; Thyroid Neoplasms

Immunohistochemical localisation of keratin was assessed on 45 diagnostic specimens of small cell carcinoma of the lung in patients who subsequently received combination chemotherapy. Nine out of 45 (20%) contained keratin immunoreactive cells. Six of these achieved a complete response to treatment compared to 12 of the tumours which did not show positive staining for keratin. For 2 patients the tumours were shown to contain nests of keratin immunoreactive cells. Both of these are alive and free of disease more than 5 yr after the initial diagnosis. The results indicate that the presence of keratin immunoreactive cells may not directly equate with squamous differentiation and therefore not constitute an adverse prognostic factor in terms of response to chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Prognosis

Antisera against total keratin extracts of human callus have been used to identify keratins in lung tumours of different histological type. Forty-three were classified by the WHO scheme. Keratin immunoreactive cells were identified in all 8 epidermoid carcinomas; 6 out of 12 large cell carcinomas; 2 out of 6 adenocarcinomas; 2 out of 15 small cell carcinomas and in the only muco-epidermoid carcinoma. These cases demonstrate the heterogeneity of phenotypic expression in lung tumours not recognisable without the use of immunohistochemical techniques.

Topics: Adenocarcinoma; Bronchial Neoplasms; Carcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Humans; Immune Sera; Keratins; Lung Neoplasms; Phenotype

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