bromochloroacetic-acid and Carcinoma--Large-Cell

The diagnosis of large cell carcinoma can only be made on a sampled resected tumor and should not be applied to biopsies or cytology. In the 2015 WHO classification, the definition of large cell carcinoma is restricted to carcinomas both lacking morphological signs of glandular, squamous or neuroendocrine differentiation and exhibiting a null or unclear phenotype (TTF1-/p40 ou p63 ou CK5/6+ focally). These carcinomas have an adenocarcinoma molecular profile because they harbor a significant number of KRAS and BRAF mutations, a profile that is more similar to adenocarcinoma than squamous cell carcinoma. They also have a worse prognosis than the other types of non-small cell lung carcinoma. Many large cell carcinomas previously classified on morphological data alone are now reclassified in the adenocarcinoma and squamous cell carcinoma types, including immunohistochemical features. The other large cell carcinoma subtypes from the 2004 WHO classification, i.e. large cell neuroendocrine carcinoma and basaloid carcinoma, are grouped respectively with the other neuroendocrine tumors and squamous cell carcinomas. Clear cell and rhabdoid features are now considered as cytological variants that can occur in any histopathological subtype and not as distinct subtypes. Lymphoepithelioma-like carcinoma is moved to the group of other and unclassified carcinomas as NUT carcinoma.

Topics: Adenocarcinoma; Biomarkers, Tumor; Carcinoma, Large Cell; Cell Differentiation; DNA-Binding Proteins; Genes, ras; Humans; Immunophenotyping; Keratins; Lung Neoplasms; Prognosis; Proto-Oncogene Proteins B-raf; Transcription Factors; Tumor Suppressor Proteins

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 undifferentiated carcinoma of the salivary glands is a rare, high-grade neoplasm which accounts for a very small number (1-5.5%) of malignant salivary gland tumors. The large-cell variant (LCU) is less well-characterized than the small-cell form. We report on the fine-needle aspiration (FNA) biopsy findings of 2 cases of LCU, one arising in the parotid gland, and the other in a buccal mucosa accessory salivary gland. The 2 cases were similar in composition: isolated and loosely cohesive large cells with abundant cytoplasm, and variability pleomorphic nuclei with prominent nucleoli. One case also featured multinucleated tumor giant cells and macrophage polykaryons; the latter has not previously been described in FNA biopsies of LCU. There was no evidence of squamous, myoepithelial, or widespread mucinous differentiation by morphological, cytochemical, or immunohistochemical analyses (focal rare mucin production identified on special stains in one case). The differential diagnosis is lengthy and consists of other high-grade primary salivary gland malignancies as well as metastatic lesions, including melanoma. The pattern of immunohistochemical reactivity (positive keratin, negative S-100, and HMB-45 antigens), and lack of conspicuous mucin production of significant lymphoidinfiltrate, were useful in establishing the correct diagnosis.

Topics: Aged; Aged, 80 and over; Antigens, Neoplasm; Biopsy, Needle; Carcinoma, Large Cell; Cell Nucleolus; Cell Nucleus; Cytoplasm; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Male; Melanoma-Specific Antigens; Neoplasm Proteins; S100 Proteins; Salivary Gland Neoplasms

Malignant mesenchymomas are uncommon tumors of soft tissues. Three such tumors involving the pleura have been reported in the literature. We report a case of malignant mesenchymoma of the pleura that had liposarcomatous, rhabdomyosarcomatous, chondrosarcomatous, and osteosarcomatous elements.

Topics: Adipose Tissue; Aged; Carcinoma, Large Cell; Diagnosis, Differential; Humans; Keratins; Lung Neoplasms; Male; Mesenchymoma; Necrosis; Pleural Neoplasms

Topics: Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Keratins; Middle Aged; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1

The aim of the present study was to clarify protein profiling in small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC). The proteomic approach was used, and involved cell lysate from two cell lines (N231 derived from SCLC and LCN1 derived from LCNEC), with 2-D gel electrophoresis (2-DE). In the present study, 25 protein spots with greater than twofold quantitative differences between LCN1 and N231 cells on 2-DE gels were confirmed. Within the 25 identified proteins, cytokeratins (CK) 7, 8, 18 and 19 were upregulated in LCN1 cells compared with N231 cells. The expression of CK7, 8, 18, and 19 was further studied on immunohistochemistry with 81 formalin-fixed and paraffin-embedded pulmonary carcinomas, which included 27 SCLC, 30 LCNEC, 14 adenocarcinomas, and 10 squamous cell carcinomas. Although the expression of CK7, 8, 18, and 19 was observed in all histological types, the mean immunostaining scores of CK7, 8, 18, and 19 were significantly higher in LCNEC than in SCLC (P < 0.001, P < 0.001, P < 0.01 and P < 0.001, respectively). These data suggest that the biological characteristics of LCNEC and SCLC may be different and the expression of CK may serve as differential diagnostic markers.

Topics: Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Electrophoresis, Gel, Two-Dimensional; Humans; Immunohistochemistry; Keratin-18; Keratin-19; Keratin-7; Keratin-8; Keratins; Lung Neoplasms; Small Cell Lung Carcinoma; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tissue Array Analysis

Tumor-to-tumor metastasis is a very rare event. We report three cases of tumor metastasizing in another tumor: a clear cell renal cell carcinoma in a vesicular thyroid adenoma, a lung carcinoma in a meningioma and a neuroendocrine lung carcinoma in a clear cell renal cell carcinoma. According to the literature, clear cell renal cell carcinoma is the most common tumor recipient of metastasis while lung carcinoma is the most common donor tumor. Several physiopathological mechanisms can explain this phenomenon, but many of them are still unknown.

Topics: Adenocarcinoma, Clear Cell; Aged; Biopsy; Carcinoma, Large Cell; Cell Division; Female; Hemoptysis; Humans; Immunohistochemistry; Keratins; Kidney Neoplasms; Lung Neoplasms; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Neoplasm Metastasis; Nephrectomy; Thyroid Neoplasms

High circulating serum vascular endothelial growth factor (VEGF) levels might reflect enhanced angiogenesis in patients suffering from non-small cell lung cancer (NSCLC). This study aimed at determining the prognostic significance of circulating VEGF as a prognostic factor in NSCLC.. Four hundred fifty-one histologically or cytologically proven and previously untreated NSCLC patients have been studied. Median follow-up was 13 years and 9 months. Eleven clinical and biologic variables were recorded. The levels of circulating VEGF were measured in the serum by quantitative immunoassay. Patients have had received conventional treatment (without anti-VEGF therapy) according to the international guidelines. All statistical tests were two-sided.. Receiver operating characteristic curves (area under the ROC curve: 0.66 +/- 0.05) showed that circulating VEGF serum level did not demonstrate a high sensitivity-specificity relationship, and therefore, demonstrated a low ability to differentiate NSCLC from benign lung diseases. A 600 pg/mL level of circulating VEGF serum was considered as threshold with 40.8% of NSCLC patients presenting with a high level. The circulating VEGF distribution differed significantly according to disease stage, nodal status, and performance status (PS), with the highest levels observed in metastatic stage, positive mediastinal nodal status, and poor PS. In univariate survival analysis, patients with a high pretreatment circulating VEGF serum level proved to have a shorter overall survival when compared with patients presenting with a circulating VEGF serum level /=2, nodal status N2-3, metastatic disease, neuron-specific enolase >12.5 ng/mL, CYFRA 21-1 >3.6 ng/mL.. The prognostic information given by a high circulating VEGF serum level is not an independent determinant of survival owing to a high relationship with main prognostic variables such as PS, stage of the disease, and nodal status. This finding does not preclude a putative prognostic impact of in situ detection of VEGF and VEGF receptors in tumor specimen.

Topics: Adenocarcinoma; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Humans; Keratin-19; Keratins; Lung Neoplasms; Male; Middle Aged; Phosphopyruvate Hydratase; Prognosis; Prospective Studies; ROC Curve; Survival Rate; Vascular Endothelial Growth Factor A

Prognostic implication of serum cytokeratin 19 fragments (CYFRA 21-1) was explored in 60 advanced NSCLC patients, whereas in 45 patients assessable for serological response a >or=35% CYFRA 21-1 decline after two chemotherapy cycles was strongly associated with non-progression (NP), defined as a sum of objective response (OR)+stable disease (P<0.0001) and survival (P=0.0002). Association of OR with survival was not significant. In multivariate survival analysis, >or=35% marker decline and radiological NP status were found as major determinants of prolonged survival with RR: 0.37 (P=0.01) and 0.63 (P=0.01), respectively. In advanced NSCLC patients, NP reflects therapeutic efficacy better than traditional OR. CYFRA 21-1 >or=35% decline seems to be a reliable surrogate marker of treatment efficacy in terms of survival.

Topics: Adenocarcinoma; Adult; Aged; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Humans; Keratin-19; Keratins; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Prospective Studies; Survival Rate; Treatment Outcome

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

We investigated 27 pleomorphic carcinomas of the lung for exon 1 K-ras gene mutations using polymerase chain reaction-single-strand conformation polymophism analysis and direct sequencing. All pleomorphic carcinomas were biphasic, that is, composed of an adeno-, squamous- or large-cell-carcinomatous component associated with a spindle- and/or giant-cell component. Of 27 cases, six (22%) showed K-ras codon 12 mutations, which is a figure higher than that previously reported on in pure sarcoma-like pleomorphic carcinomas. Five tumors displayed the same mutation in both the epithelial and the sarcomatoid components, whereas in one tumor the mutation was restricted to the epithelial component. All mutations occurred in smokers, and were transversions, including GGT (glycine) to TGT (cysteine) change in two cases, to GCT (alanine) in two and to GTT (valine) in two. No significant relationships were found between the occurrence and type of mutations and patients' survival or any other clinicopathological variable, suggesting that K-ras mutations are early events in the development of these tumors. Our results indicate that most, though not all, biphasic pleomorphic carcinomas of the lung are monoclonal in origin, and that cigarette smoking may have a causative role in the development of K-ras alterations in these tumors, as all mutations are transversions.

Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Clone Cells; DNA Mutational Analysis; DNA, Neoplasm; Female; Genes, ras; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Male; Middle Aged; Mutation; Mutation, Missense; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Smoking; Survival Analysis; Vimentin

Recently, the authors identified molecular signatures and pathways associated with nonsmall cell lung carcinoma histology and lung development. They hypothesized that genetic classifiers of histology would provide insight into lung tumorigenesis and would be associated with clinical outcome when evaluated in a broader set of specimens.. Associations between patient survival and immunostaining for 11 representative histologic classifiers (epidermal growth factor receptor [EGFR], CDK4, syndecan-1, singed-like, TTF-1, keratin 5, HDAC2, docking protein 1, integrin alpha3, P63, and cyclin D1) were examined using a tissue microarray constructed from nonsmall cell lung carcinoma specimens.. Sixty-three tumors were examined, including 43 adenocarcinomas, 11 large cell carcinomas, and 9 squamous cell carcinomas. Sixty-three percent of tumors were clinical Stage I lesions, and 37% were Stage II-III lesions. In a multivariate analysis that controlled for age, gender, and race, syndecan-1 expression was found to be associated with a significant reduction in the risk of death (hazard ratio, 0.31 [95% confidence interval, 0.18-0.87]; P < 0.05). Multivariate analysis also indicated that EGFR expression was associated with a significant reduced risk of death.. The authors demonstrated that expression of either of the nonsmall cell lung carcinoma subtype classifiers syndecan-1 and EGFR was associated with a 30% reduction in the risk of death, with this reduction being independent of histology and other confounders. The results of the current study suggest that loss of expression of these histologic classifiers is associated with biologic aggressiveness in lung tumors and with poor outcome for patients with such tumors. If their significance can be validated prospectively, these biomarkers may be used to guide therapeutic planning for patients with nonsmall cell lung carcinoma.

Topics: Adenocarcinoma; Aged; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases; ErbB Receptors; Female; Histone Deacetylase 2; Histone Deacetylases; Humans; Immunohistochemistry; Integrin alpha Chains; Keratin-5; Keratins; Lung Neoplasms; Male; Membrane Glycoproteins; Membrane Proteins; Multivariate Analysis; Nuclear Proteins; Proteoglycans; Proto-Oncogene Proteins; Repressor Proteins; Syndecan-1; Syndecans; Thyroid Nuclear Factor 1; Transcription Factors

We selected a 4-stain immunopanel including thyroid transcription factor (7ITF)-], cytokeratin (CK)7, 34betaE12, and CD56/neural cell adhesion molecule(NCAM) to subclassify a series of 45 pulmonary large cell carcinomas (LCCs) on bronchial biopsy. All cases consisted of a large tumor cell proliferation with abundant cytoplasm, vesicular nuclei, and prominent nucleoli. Immunohistochemically, 27 tumors (60%)were subclassified as adenocarcinoma (7TF-1 +/CK7+,24; CK7+ only, 3), 10 (22%) as squamous cell carcinoma (34betaE12+ only), and 4 (9%) as LCC with neuroendocrine differentiation (CD56+, variably stained with TTF-I and CK7, 34betaE12-). In 4 cases, the tumors coexpressed CK7 and 34betaE12 (3 cases) or were completely unstained (I case). Surgically resected tumors matched exactly with the corresponding original biopsy specimens in 21 of 23 cases; consistent CD56 expression was a reliable marker in confirming a diagnosis of large cell neuroendocrine carcinoma even on biopsy. Our results suggest that the proposed 4-stainset of commercially available markers might help subclassify LCC even in small biopsy material, validating expression-profiling studies aimed at lung cancer classification and permitting more consistent patient enrollment for trials with targeted treatments.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Squamous Cell; CD56 Antigen; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratin-7; Keratins; Lung Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Nuclear Proteins; Thyroid Nuclear Factor 1; Transcription Factors

The role of tumor markers in the diagnosis and prognosis of lung cancer is under investigation.. The aim of this study was to investigate the diagnostic and prognostic significance of pre-therapeutic levels of various serum tumor markers, CYFRA 21-1, neuron-specific enolase (NSE), tissue polypeptide antigen (TPA), carcinoembryonic antigen (CEA), CA 125 and squamous cell carcinoma antigen (SCCAg), in patients with lung cancer.. We studied 102 consecutive patients (mean age 65.2 +/- 11 years) with newly diagnosed lung cancer (96 males, 94%, with a mean age of 66.3 +/-10.5 years). All patients had a 5-year follow-up. Measurements of the serum tumor markers were performed on initial diagnosis.. Eighty-four patients (82%) had non-small-cell lung cancer (NSCLC) and 18 (18%) small-cell lung cancer (SCLC). From the 84 patients with NSCLC, 34 patients (33%) had squamous-cell lung cancer, 23 (22%) adenocarcinoma and 23 (22%) large-cell carcinomas. The overall median survival was 8.5 months. All SCLC patients had extensive disease with a median survival of 10.1 months and NSCLC patients of 8.4 months. Significant differences in the mean values of NSE and CYFRA 21-1 were observed between SCLC and NSCLC. In NSCLC, CYFRA 21-1, TPA, CA 125 and SCCAg serum levels were related to the stage of the disease at diagnosis, and CYFRA 21-1, NSE, TPA and CA-125 were related to a poor outcome. None of the above tumor markers was related to survival in the SCLC group.. CYFRA 21-1 and NSE may help to differentiate cell types in lung cancer patients. Also, CYFRA 21-1 with TPA and CA 125 may provide useful information regarding the staging of the disease at diagnosis and the prognosis of patients with NSCLC.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Analysis of Variance; Antigens, Neoplasm; Biomarkers, Tumor; CA-125 Antigen; Carcinoembryonic Antigen; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Humans; Keratin-19; Keratins; Lung Neoplasms; Male; Middle Aged; Phosphopyruvate Hydratase; Probability; Prognosis; Prospective Studies; Regression Analysis; Sensitivity and Specificity; Survival Analysis

Basaloid carcinoma (BC) and large-cell neuroendocrine carcinoma (LCNEC) are 2 recently recognized variants of large-cell lung carcinomas that may overlap in their morphology, and are discriminated by expression of neuroendocrine markers in LCNEC. Because thyroid transcription factor 1 (TTF-1) is expressed in lung adenocarcinomas but not in squamous cell carcinomas (SCC), and 34betaE12 recognizes a set of high-molecular-weight cytokeratins characteristic of basal stem cells, we hypothesized that these 2 markers could help in distinguishing BC from LCNEC. Immunostaining for TTF-1 was detected in 40.9% of pure LCNEC but in no BC or basaloid variant of SCC. In contrast, immunoreactivity for 34betaE12 was shown in all BC and basaloid variant of SCC but in only 1 LCNEC. Bouin fixation was less efficient than formalin in the immunodetection of both markers for its well-known deleterious effect on antigen preservation. Specificity of TTF-1 for LCNEC (100%) and that of 34betaE12 for BC (98.3%) exceeded that of NE markers for distinction of these 2 entities. These data show that TTF-1 and 34betaE12, in association with specific neuroendocrine markers, represent a useful panel of antibodies in differentiating carcinomas presenting with a solid pattern, palisading, or pseudorosettes, the expression of TTF-1 excluding the diagnosis of BC, and staining with 34betaE12 excluding pure LCNEC.

Topics: Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Nuclear Proteins; Retrospective Studies; Sensitivity and Specificity; Thyroid Nuclear Factor 1; Transcription 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

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a newly proposed clinicopathologic entity; a few cases of LCNEC have been reported in other sites, such as the uterine cervix and the thymus. In the salivary glands, LCNEC is extremely rare and is not recognized as a specific entity in the World Health Organization classification. We retrospectively reviewed from our files 1675 cases of surgically resected primary parotid gland tumors and found 2 cases of LCNEC that fulfilled the criteria of pulmonary LCNEC. These cases occurred in 72- and 73-year-old men who had short histories of enlarging parotid gland tumors. The tumors were composed of large cells that exhibited organoid, solid, trabecular, and rosette-like growth patterns with a high mitotic rate and a conspicuous tendency for necrosis. The tumor cells were polygonal and characterized by a moderate nuclear:cytoplasmic ratio, coarse chromatin, and conspicuous nucleoli. Immunohistochemical examination revealed that the tumor cells were positive for six general neuroendocrine markers, cytokeratin, p53, bcl-2, epidermal growth factor receptor, and cyclin D1. Markedly reduced expressions of p21Waf1 and p27Kip1 were also noticed. The Ki-67 labeling index was more than 50% in both cases. One case showed loss of heterozygosity at TP53 accompanied by a p53 gene point mutation. Loss of heterozygosity at chromosome 9p21 was detected in both cases; one was accompanied by a p16 gene silent point mutation. Both patients died of the disease, with recurrence 5 months and 4 years after surgery, respectively. These findings indicate that LCNEC is a rare but distinct salivary gland tumor with highly aggressive biologic behavior. Multiple alterations of cell cycle regulators and tumor suppressor genes may play an important role in presenting the biologic characteristics of this rare parotid gland tumor.

Topics: Aged; Base Sequence; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; Cyclin D1; Diagnosis, Differential; DNA Mutational Analysis; DNA, Neoplasm; ErbB Receptors; Humans; Keratins; Ki-67 Antigen; Loss of Heterozygosity; Lung Neoplasms; Male; Microscopy, Electron; Parotid Neoplasms; Point Mutation; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53

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

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

A clinicopathological study of 10 patients with pleomorphic carcinoma of the lung.. Histopathological and immunohistochemical staining for keratin, vimentin, Mac387, desmin, actin and S-100 protein were used for this study.. Pleomorphic carcinoma of the lung was found to often occur in males above 50 years of age and with clinical symptoms including cough, expectoration, haemoptysis and chest pain. The most frequent microscopic diagnosis was squamous cell carcinoma, and adenocarcinoma, accompanied by spindle and giant cells. The epithelial component of pleomorphic carcinoma of the lung displayed positivity for keratin and the spindle cells displayed positivity for vimentin. In some cases the neoplastic epithelial component and spindle cells showed positive expression of both keratin and vimentin.. Pleomorphic carcinoma of the lung may display various histopathological changes making it easy to be misdiagnosed as carcinosarcoma. Understanding its pathogenesis and histopathology is important for the diagnosis and differential diagnosis.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Carcinoma; Carcinoma, Giant Cell; Carcinoma, Large Cell; Carcinoma, Squamous Cell; Carcinosarcoma; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Keratins; Lung Neoplasms; Male; Middle Aged; Pneumonectomy; Vimentin

To analyze messenger RNA (mRNA) levels for the alpha, beta, and gamma subunits of the human amiloride-sensitive epithelial Na+ channel (hENaC) in respiratory epithelia, we developed a competitive quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) assay specific for each subunit, using two human respiratory epithelial-cell lines. We next determined the relation between hENaC mRNA levels and the biologic activity of the hENaC in the respiratory epithelium of eight normal men. The electrical potential difference (PD) between the epithelium of the inferior nasal turbinate and the subcutaneous space was measured, using control and amiloride (100 microM) solutions. QRT-PCR measurement of hENaC-subunit mRNAs and epithelial-specific cytokeratin 18 mRNA allowed us to normalize hENaC expression to epithelial-cell RNA. Respective values for alpha, beta, and gamma hENaC mRNA levels in epithelium obtained at the site of maximal PD were 39 +/- 4.0, 7.5 +/- 0.92, and 1.8 +/- 0.25 attomol/fmol cytokeratin mRNA, respectively. Respiratory epithelial PD exhibited a significant negative correlation with gamma hENaC (r2 = 0.72, p < 0.01), tended to increase with increasing alpha hENaC, and was unaffected by beta hENaC mRNA levels. Our results suggest that hENaC activity in vivo is influenced by expression of the gene for gamma hENaC. The assay used in the study provides a useful tool for evaluating Na+-channel expression in clinically relevant patient populations.

Topics: Adenocarcinoma, Papillary; Adult; Amiloride; Carcinoma, Large Cell; Diuretics; Epithelium; Humans; Keratins; Linear Models; Lung Neoplasms; Male; Membrane Potentials; Middle Aged; Nasal Mucosa; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; RNA, Messenger; Skin; Sodium Channels; Tumor Cells, Cultured; Turbinates

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

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

Eight cases of a distinctive histological variant of bowel cancer characterized by an anaplastic morphology were identified from 2,650 colonic malignancies (0.3%). The tumors were histologically composed of sheets of anaplastic tumor cells with frequent atypical mitoses, absence of gland formation, and mucicarmine and periodic acid-Schiff (PAS) negativity. Positive immunostaining for cytokeratin and vimentin was observed in eight cases and for epithelial membrane antigen in three; whereas carcinoembryonic antigen, alpha-fetoprotein, S-100 protein, HMB-45 antimelanoma antigen, leukocyte common antigen, and neuroendocrine markers were uniformly negative. Ultrastructural examination demonstrated intercellular tight junctions, focal surface microvilli, and apical terminal webs or long rootlets of microfilaments supporting a colonic derivation. At the time of diagnosis, metastases to regional lymph nodes were found in seven cases and to the liver in six. All patients in this study died of tumor within 9 months. This report emphasizes a poorly recognized variant of colonic carcinoma, characterized by a high degree of anaplasia and malignant behavior. The differential diagnosis for these lesions is discussed.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Carcinoma; Carcinoma, Large Cell; Colonic Neoplasms; Diagnosis, Differential; Humans; Immunoenzyme Techniques; Keratins; Liver Neoplasms; Lymphatic Metastasis; Male; Microvilli; Middle Aged; Mucin-1; Survival Analysis; Tight Junctions; Vimentin

Serum soluble cytokeratin 19 fragment (CYFRA) levels were measured in 251 patients with lung cancer and 139 patients with benign lung diseases to determine the clinical usefulness of CYFRA level determination in the diagnosis and monitoring of lung cancer. Serum levels of CYFRA were measured by a 2-step sandwich ELISA method. When the cut-off value was defined as 3.5 ng/ml, which was associated with a specificity of 95% for benign lung diseases, CYFRA had a high sensitivity (53%) in all patients with lung cancer. Both the serum level of CYFRA and its sensitivity increased significantly with the increase in clinical stage. A comparison of areas under receiver operating characteristic curves showed that CYFRA had the most power of discrimination in the diagnosis of lung cancer among markers including carcinoembryonic antigen, squamous cell carcinoma antigen, carbohydrate antigen 19-9, and neuron-specific enolase. A good correlation was found between serial changes in serum CYFRA levels during therapy and clinical responses for 18 patients who underwent chemotherapy and/or radiotherapy. Our findings suggest that CYFRA may be a marker of choice for screening and monitoring of lung cancer, particularly squamous cell carcinoma.

Topics: Adenocarcinoma; Aged; Biomarkers, Tumor; Carcinoma; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Enzyme-Linked Immunosorbent Assay; Female; Humans; Keratins; Lung Neoplasms; Male; Neoplasm Staging; Prognosis; Retrospective Studies; Sensitivity and Specificity; Survival Rate

The analysis of the cell cycle distributions by univariate flow cytometric DNA measurement has been widely applied in the clinic to determine kinetic parameters of human malignancies. A common problem with measurements of cell cycle phase distributions in tumor biopsy material is the presence of non-malignant diploid cells. Furthermore, such a static measurement might not be accurate enough to describe the dynamic process of cell proliferation. For this purpose alternative methods have been developed to include BrdUrd incorporation or the presence of intrinsic proliferation associated markers such as PCNA or Ki67-Ag into the analysis. However, the presence of nonmalignant diploid cells will influence also these bivariate analyses, especially in case of DNA-diploidy of the tumor cells. Here we present a three parameter flow cytometric assay based on the simultaneous detection of cytokeratin, DNA and a proliferation associated marker, such as BrdUrd, PCNA or Ki67-Ag. Based on the presence of cytokeratin, epithelial cells can be selected for a detailed cell cycle analysis. This method can be applied to frozen tissue, which makes this assay useful for multicentre clinical studies.

Topics: Analysis of Variance; Antibodies; Biomarkers; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Division; Cell Line; DNA, Neoplasm; Flow Cytometry; Humans; Interphase; Keratins; Ki-67 Antigen; Lung Neoplasms; Microscopy, Confocal; Mitosis; Neoplasm Proteins; Nuclear Proteins; Nucleic Acid Denaturation; Proliferating Cell Nuclear Antigen; Regression Analysis; Tumor Cells, Cultured

The levels of the new tumour marker CYFRA 21-1 were assessed in 115 patients with non-small cell lung cancer (NSCLC) and in 45 patients with non-malignant lung disease. Increased levels of CYFRA 21-1 were observed in 47.8%, mostly in patients with squamous cell carcinoma (SCC; 69.1%). Serum CYFRA 21-1 levels were correlated with the stage of SCC type. Positive CYFRA 21-1 levels in patients with SCC were present in 40% of stage I, 61.1% of stage II, and 85.2% of stage III. In addition, SCC patients who presented mediastinal lymph nodes (N2) demonstrated higher serum CYFRA 21-1 levels, compared with patients without mediastinal lymph nodes metastases (N0 or N1). With regard to tumour size, significant difference was observed between T1, T2 and T3. The study also showed that the percentage of patients who survived 18 months with normal preoperative level of CYFRA 21-1 was higher compared with those patients with elevated preoperative levels of this marker, but the differences were not statistically significant.

Topics: Adenocarcinoma; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Evaluation Studies as Topic; Female; Humans; Keratins; Lung Diseases; Lung Neoplasms; Lymphatic Metastasis; Male; Neoplasm Staging; Peptide Fragments; Serpins