Value of cytokeratin 5/6 immunostaining in distinguishing epithelial mesothelioma of the pleura from lung adenocarcinoma

The immunohistochemical diagnosis of mesothelioma is commonly made by using a battery of antibodies that reacts with lung adenocarcinomas but not with epithelial mesotheliomas. Only recently have markers that are often expressed in mesotheliomas but not in adenocarcinomas been recognized. Some of these markers, however, require frozen tissue sections, whereas others are not commercially available, or their value remains controversial. In a recent publication, it was suggested that immunostaining for cytokeratin 5/6 could assist in distinguishing epithelial mesothelioma from lung adenocarcinoma. To determine the practical value of cytokeratin 5/6 immunostaining in the diagnosis of mesothelioma, 40 formalin-fixed, paraffin-embedded epithelial pleural mesotheliomas, 30 pulmonary adenocarcinomas, 93 nonpulmonary adenocarcinomas, 15 squamous carcinomas of the lung, 5 large cell undifferentiated carcinomas of the lung, and 12 metastatic transitional cell carcinomas to the lung were stained with the same antibody, which was obtained from a commercial source. Cytokeratin 5/6 reactivity was observed in all 40 mesotheliomas, but there was none in any of the 30 pulmonary adenocarcinomas. Focal or weak reactivity was observed in 14 of 93 nonpulmonary adenocarcinomas (10 of 30 ovarian, 2 of 10 endometrial, 1 of 18 breast, I of 7 thyroid, 0 of 10 kidney, 0 of 10 colonic, and 0 of 8 prostatic). All 15 squamous carcinomas of the lung, 6 of 12 transitional cell carcinomas metastatic to the lung, and 3 of 5 large cell undifferentiated carcinomas of the lung expressed cytokeratin 5/6. It is concluded that cytokeratin 5/6 immunostaining is not only useful in separating epithelial pleural mesotheliomas from pulmonary adenocarcinomas but also can assist in distinguishing epithelial mesotheliomas from nonpulmonary adenocarcinomas metastatic to the pleura.     

Fluorotyping of HLA-A by sequence-specific priming and fluorogenic probing

AIMS: To determine the value of immunocytochemistry in differentiation of malignant pleural mesothelioma from carcinoma in a pleural biopsy using commercially available monoclonal antibodies. METHODS AND RESULTS: A panel of monoclonal antibodies against keratins, epithelial membrane antigen (EMA), epithelial antigen Ber-EP4, carcinoembryonic antigen (CEA), tumour-associated glycoprotein (B72.3), Leu-M1, CD30 (Ber-H2), vimentin and desmin, was applied to 40 cases of malignant pleural mesothelioma and 23 cases of carcinoma metastatic to the pleura (16 pulmonary and seven extrapulmonary). Positivities for Ber-EP4, CEA, B72.3 and Leu-M1 were found to have the highest nosologic sensitivities (87.0%, 65.2%, 52.5% and 43.5%, respectively) and specificities (97.5%, 97.5%, 100% and 95%, respectively) for carcinoma. Positive staining for vimentin had the highest sensitivity (87.5%) with 95.7% specificity for mesothelioma. Positive staining for desmin was found in 45% of mesotheliomas and 0% of carcinomas. Diagnostic sensitivity and diagnostic specificity (P-values) were calculated for these markers. In respect to the diagnostic power defined by the clinically relevant predictive values of positive and negative tests, we found that a two-marker panel of antibodies including vimentin and Ber-EP4 is most useful for the histopathological distinction between carcinoma (pulmonary or extrapulmonary) and malignant pleural mesothelioma. CONCLUSIONS: A combination of Ber-EP4 and vimentin provides the most sensitive and specific pair of markers for distinguishing between malignant pleural mesothelioma and carcinoma metastatic to the pleura. The prevalence of the tested tumours should be taken into account when evaluating the clinical value of ancillary techniques in pathology.     

The value of antibodies 44-3A6, SM3, HBME-1, and thrombomodulin in differentiating epithelial pleural mesothelioma from lung adenocarcinoma: a comparative study with other commonly used antibodies

The distinction between pleural mesothelioma and peripheral pulmonary adenocarcinoma involving the pleura continues to be a diagnostic problem in surgical pathology. In recent years, the use of various immunohistochemical markers to facilitate this differential diagnosis has become common. In this study, the value of monoclonal antibodies 44-3A6, SM3, HBME-1, and thrombomodulin is compared in the differentiation of these conditions. Fifteen (68.2%) of 22, and 10 (52.6%) of 19 mesotheliomas stained positively with 44-3A6 and SM3, respectively, whereas all 23 (100%) adenocarcinomas reacted with both antibodies. Sixteen (80%) of 20 mesotheliomas and 14 (63.6%) of 22 lung adenocarcinomas reacted with HBME-1, whereas 16 (80%) of 20 mesotheliomas and only three (11.1%) of 27 adenocarcinomas were positive for thrombomodulin. Because thrombomodulin was expressed in most mesotheliomas but in only a few lung adenocarcinomas, this marker may have some diagnostic value when it is included in the standard immunohistochemical panel of markers used in the evaluation of mesotheliomas, especially when a positive marker for mesothelioma is needed. Antibodies 44-3A6, SM3, and HBME-1 have no practical value in discriminating epithelial pleural mesothelioma from lung adenocarcinoma.     

Bacterial production and purification of the fish pituitary hormone somatolactin

Paraffin sections from 29 lung carcinomas (28 primary and 1 metastatic) and 9 pleural malignant mesotheliomas were immunostained with antisera to human hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, met. For HGF/SF, immunoreactivity was demonstrated in all 9 mesotheliomas, 9 of 12 adenocarcinomas, and 7 of 10 squamous cell carcinomas. None of seven cases of small cell anaplastic carcinoma was positive. The adenocarcinomas frequently showed enhanced luminal staining, suggesting possible secretion of HGF/SF, and this pattern of staining was also seen occasionally in bronchial epithelium adjacent to the tumour. Stromal fibroblasts also showed immunoreactivity for HGF/SF in 6/8 cases of mesothelioma but in only 3/12 adenocarcinomas, 1/10 squamous cell carcinomas, and 1/4 small cell anaplastic carcinomas. All tumours stained for met, usually strongly. The staining was mainly cytoplasmic in nature, but some plasma membrane staining was usually evident. Adenocarcinomas showed strong luminal membrane staining, as did adjacent, histologically normal bronchial epithelium. This study demonstrates the presence of HGF/SF and met in most of the tumour types described, particularly mesotheliomas, and suggests that the HGF/SF/met signalling system may play a role in the development of these tumours, either by autocrine or by paracrine mechanisms.     

Allergic eye disease mechanisms

The histologic distinction between epithelial peritoneal mesothelioma and papillary serous carcinoma diffusely involving the peritoneum may be difficult. Although some investigators have indicated that immunohistochemistry can facilitate this differential diagnosis. only a few studies using a limited number of markers have been published. In this study, the immunoreactivity of keratin 5/6, vimentin, epithelial membrane antigen, thrombomodulin, calretinin, MOC-31, Ber-EP4, carcinoembryonic antigen, TAG-72 (B72.3), CD15 (Leu-M1), placental alkaline phosphatase, CA19-9, CA-125, HBME-1, 44-3A6, and S-100 protein was investigated in 35 epithelial peritoneal mesotheliomas, and 45 papillary serous carcinomas [30 ovarian (10 primary and 20 metastatic to the peritoneum) and 15 papillary serous carcinomas of the peritoneum]. After analyzing the results, it is concluded that calretinin, thrombomodulin, and keratin 5/6 are the best positive markers for differentiating epithelial malignant mesotheliomas from papillary serous carcinomas diffusely involving the peritoneum. The best diagnostic discriminators among the antibodies considered to be negative markers for mesothelioma are MOC-31, B72.3, Ber-EP4, CA19-9, and Leu-M1. Immunostaining for carcinoembryonic antigen, placental alkaline phosphatase, epithelial membrane antigen, vimentin, HBME-1, 44-3A6, CA-125, or S-100 have little or no diagnostic utility in establishing the differential diagnosis between these conditions. The results of this study also confirm previous observations indicating that both papillary serous carcinomas of the peritoneum and serous carcinomas of the ovary have a similar phenotype and, therefore, immunohistochemical studies are not useful in separating these entities.     

Anti-MOC-31: a potential addition to the pulmonary adenocarcinoma versus mesothelioma immunohistochemistry panel

MOC-31 expression has recently been advocated as an immunohistochemical marker for distinguishing mesothelioma from adenocarcinoma in tissue sections. We studied formalin-fixed, paraffin-embedded tissue from 23 pleural mesotheliomas and 23 primary pulmonary adenocarcinomas for immunoreactivity with anti-MOC-31, a human epithelial-related antigen. All of the 23 adenocarcinomas strongly expressed the marker, whereas only one of the mesotheliomas showed weak reactivity. These results demonstrate the usefulness of anti-MOC-31 in differentiating pulmonary adenocarcinoma from mesothelioma.     

The comparative study on occupational mortality, 1980 between Japan and Great Britain

Pleural and pulmonary malignancies are usually associated with well-known carcinogen exposure. Recently, the presence of simian virus 40 (SV40)-like DNA sequences has been detected in brain and bone-related human cancers and in pleural mesothelioma. In order to determine whether SV40-like DNA sequences are also present in bronchopulmonary carcinoma and non-malignant lung samples, 125 frozen pleural and pulmonary samples (including 21 mesotheliomas, 63 bronchopulmonary carcinomas, 8 other tumours, and 33 non-malignant samples) and 38 additional samples distant from tumours were studied for the occurrence of SV40-like DNA sequences by polymerase chain reaction (PCR) amplification followed by hybridization with specific probes. Sequences related to SV40 large T antigen (Tag) were present in 28.6 per cent of bronchopulmonary carcinomas, 47.6 per cent of mesotheliomas, and 16.0 per cent of cases with non-neoplastic pleural and pulmonary disease. No statistically significant difference in the occurrence of these DNA sequences was found between malignant mesothelioma and bronchopulmonary carcinoma, but a significantly higher number of mesothelioma cases exhibited SV40-like DNA sequences in comparison with cases of non-malignant pleural or pulmonary disease (P < 0.04). Among cases positive for SV40-like DNA sequences, a history of asbestos exposure was found in 3 out of 12 bronchopulmonary carcinomas and 8 out of 10 mesotheliomas. Immunohistochemistry using monoclonal antibodies directed against Tag did not demonstrate nuclear staining. The DNA sequences were not related to BK virus sequences, but three samples were positive with probes hybridizing with JC virus DNA sequences. In conclusion, this study demonstrates the presence of SV40-like DNA sequences in pulmonary neoplasms and in non-malignant lung tissues. It appears that the presence of SV40-like DNA is not unique to cancer.     

Metastatic adenocarcinoma of an unknown primary site. A comparison of the relative contributions of morphology, minimal essential clinical data and CEA immunostaining status

Measurement of the relative contributions of morphology alone; minimal essential clinical data; immunohistologic reactivity of a prototypic tumor marker, carcinoembryonic antigen (CEA); and the process by which a pathologist can identify the origin of a metastatic adenocarcinoma of unknown primary site is the subject of this report. To standardize the case material, we used an image digitizing and archival system to present 100 metastatic adenocarcinomas of known primary site as unknowns to two pathologists. The images were selected to show only gland-forming areas of the carcinomas and excluded all normal tissue elements. They were viewed, initially without, and then with, identification of gender and metastatic site. Subsequently, the results of immunoperoxidase staining for CEA, assessed independently by a third pathologist, were provided. Our analysis showed that, overall, the correct primary site was chosen as choice 1, 2, or 3 in 72% and 76%, and as choice 1 in 49% and 47% of cases, respectively. Accuracy was highest for prostatic, ovarian, and breast carcinomas, and lowest for upper-gastrointestinal tract, biliary tract, and pancreatic adenocarcinoma. Statistical analysis showed the largest increments in accuracy in the choice 1 prediction in each tumor category were achieved by provision of minimal essential clinical data. Knowledge of CEA status did not affect overall accuracy; however, it increased the odds of making the correct diagnosis for ovarian, colorectal, and endometrial (both pathologists) carcinomas, and for prostatic, pulmonary and esophago-gastric adenocarcinomas (one pathologist). The study exemplifies a model for the objective measurement of the contribution of ancillary studies, such as immunoperoxidase markers, to the accuracy of pathologic diagnosis.     

The so-called malignant pleural effusion: a new review of direct data obtained with diagnostic pleuroscopy

We analyze a series of 896 thoracoscopies for pleural effusion, of which 78% (662/896) were due to pleural carcinomatosis, primary or metastatic. Pleural malignancy was observed mainly, in the right hemithorax (65%), arising from tumors within the diaphragm. The likelihood of finding pleural metastasis in lung cancer was 77%. When the pleural effusion is slight (less than 500 ml) the likelihood falls to 22%. We therefore advise thoracoscopy in the former and thoracotomy in the latter. Blood-stained effusion continues to have the worst prognosis (84% stemming from metastasis) and signifies an advanced stage of pleural metastasis. The pleura parietal is involved in 69% of pleural carcinomatosis cases, and in 80% when the lower hemithorax or the area around breast or lung tumors are involved. The cytology yield was 45.9%, though always depending on extent of metastasis. When metastasis was slight, the likelihood of positive cytology was less (19%) and when metastasis was generalized throughout the entire pleura the likelihood increased to 73%. We found no reason to think that the cells in most pleural liquids are able to nest and form tumoral niches. The origin of such cell nests was rather found to be in shedding from the metastases themselves, from lung tumors or from carcinomatous lymphangitis by lymphatic obstruction. The diagnostic yield of thoracoscopy once again proved to be superior to that of pleural biopsy.     

Expression of ICAM-1, VCAM-1, and LFA-1 in adenocarcinoma of the lung with observations on the expression of these adhesion molecules in non-neoplastic lung tissue

Intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), and the lymphocyte function-associated antigen (LFA-1) are cell adhesion molecules thought to play an important role in the complex process of airway inflammation and tumor cell growth. The aim of this study was to examine the distribution of ICAM-1, VCAM-1, and LFA-1 in adenocarcinoma of lung and in major cellular compartments of non-neoplastic lung tissue. We examined cellular compartments in tissue from five bronchoalveolar carcinomas, three acinar adenocarcinomas, and one colon cancer metastatic to the lung. The compartments in neoplasms included the tumor cells proper, endothelial cells within the tumor vasculature, tumor stromal cells, and tumor-infiltrating lymphocytes. The compartments in non-neoplastic lung tissue included lung endothelial cells, pulmonary lymphocytes, interstitial fibroblasts, Type II alveolar pneumocytes, and bronchial epithelial cells. ICAM-1 was expressed in tumor cells from all of the nine adenocarcinomas. In contrast, VCAM-1 expression was not identified in tumor cells from any of the nine adenocarcinomas. ICAM-1 was expressed in all cellular compartments of the non-neoplastic lung tissue, whereas VCAM-1 was expressed only in pulmonary lymphocytes and interstitial fibroblastic cells. LFA-1 was uniformly expressed in tumor-infiltrating lymphocytes from each of the nine tumors and all of the lymphocytes in non-neoplastic lung tissue. This study showed major differences in the expression of ICAM-1 and VCAM-1 in tumor cells from pulmonary adenocarcinoma and also provided evidence for a wider distribution of ICAM-1, compared with VCAM-1, in non-neoplastic cellular compartments of the lung. ICAM-1 expression was particularly noticeable in bronchial and alveolar epithelial cells. Upregulation of ICAM-1 in pulmonary adenocarcinoma might foster binding by LFA-1-bearing lymphocytes, with a possible impact on the vulnerability of tumor cells to host defense mechanisms.     

Acute bacterial endocarditis following burns: case report and review

A 64-year-old man was admitted to our hospital because of abnormal shadows on chest X-ray films. Malignant mesothelioma was suspected. However a CT scan revealed a large mass in the right kidney and many nodules in the liver and pleura. This suggested that primary renal cell carcinoma had metastasized to the liver and pleura. The patient was treated with transarterial embolization (TAE), alpha and gamma interferon, and UFT, but died of respiratory failure caused by massive bleeding from the pleural metastases. At autopsy, renal cell carcinoma, clear cell subtype, was noted. The many pleural lesions were of the same histologic type, which suggested that they were metastases from the kidney. Renal cell carcinoma frequently metastasizes to the lungs or bones via the arteries. However, many pleural metastases without lung metastasis is rare. We report a case of renal cell carcinoma with many pleural metastases via Batson's venous plexus.     

Metastatic adenocarcinoma to the brain: an immunohistochemical approach

The diagnosis of metastatic adenocarcinoma to the brain of unknown primary is problematic, and the role of immunohistochemistry in identifying a source has not been fully characterized. Sixty-eight metastatic adenocarcinomas of the brain with known primaries were immunostained with antibodies to cytokeratin 7 (CK7), cytokeratin 20 (CK20), CAM 5.2, wide-spectrum keratin (WSK), gross cystic disease fluid protein-15 (GCDFP-15), glial fibrillary acidic protein (GFAP), estrogen receptor (ER), and progesterone receptor (PR). True positive staining was defined as CK7 in lung or breast; CK20 in gastrointestinal; and GCDFP-15, ER, and PR in breast carcinomas. CK7 immunoreactivity was present in all 27 lung carcinomas and 14 of 15 breast carcinomas with a sensitivity of 98% and specificity of 78%. CK20 stained 15 of 16 GI carcinomas with a sensitivity and specificity of 94%. None of the cytokeratins stained surrounding brain tissue. GCDFP-15, ER, and PR had sensitivities of 33%, 33%, and 87%, with specificities of 92%, 84%, and 28%, respectively. PR often stained nuclei of normal brain tissue and was accentuated in areas of necrosis or cautery artifact. CK7 and CK20 are highly sensitive and specific in patients with metastatic adenocarcinoma to the brain of unknown primary. GCDFP-15 and ER are relatively specific, but insensitive markers, and PR is nonspecific and difficult to interpret.     

Analysis of the t(2;5) (p23;q35) translocation in CD30+ primary cutaneous lymphoproliferative disorders and Hodgkin''s disease

To observe the expression of p16, pRb, cdk4 and cyclinD1 in non-small cell lung cancers, 104 cases of resected lung cancers were collected, which included squamous cell carcinomas, adenocarcinomas and large cell carcinomas. Immunohistochemistry assay was carried out. The results showed that 67% of squamous cell carcinomas and 46% of adenocarcinomas expressed p16, 64% of squamous cell carcinomas and 85% of adenocarcinomas expressed pRb and 66% of cancers expressed p16 or pRb. About 70% of the tumors expressed cyclinD1. More than 90% of the tumors expressed cdk4 and there was an increased trend with decreasing differentiation of both squamous cell carcinomas and adenocarcinomas. Sixty-seven percent of the highly differentiated and 100% of the poorly differentiated squamous cell carcinomas expressed cdk4. The aberrant p16 and pRb gene product expression played a significant role in the development and histological subtype of lung cancers by conditioning the biological behavior of NSCLC. cdk4 was an important factor in histological differentiation.     

Ultrastructure of human malignant diffuse mesothelioma

Eleven cases of malignant diffuse mesotheliomas, histologically classified into two groups, epithelial (5 pleural and 3 peritoneal) and biphasic or mixed (2 pleural and 1 peritoneal) forms, were stuied by electron microscopy to elucidate their ultrastructural characteristics. The neoplastic cells of the epithelial forms were varied in ultrastructure, from well differentiated (marked by polarity, micovilli, glycogen granules, junctional structures, tonofilaments, intracellular vacuoles, and a basement membrane) to poorly differentiated (which lacked some of these epithelial characteristics). In four of eight instances in epithelial type tumors, nonepithelial or mesenchymal neoplastic cells were recognized. The biphasic or mixed cases included three major cell types: epithelial, atypical epithelial, and mesenchymal. It appeared that there were transitional forms among the three cell types. The observations support the concept that the neoplastic cell of malignant mesothelioma can differentiate into a number of cell lines.     

Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors

Neural cell adhesion molecules (NCAM) represent specific markers of neuroendocrine (NE) differentiation in lung cancer. Because the polysialic acid form (NCAM-PSA) has reduced adhesion properties, we hypothesized that NCAM-PSA expression could favor metastatic spread. Immunostaining of NCAM and NCAM-PSA were therefore compared in 120 NE lung tumors, including 17 typical carcinoids, 3 atypical carcinoids, 30 large cell NE carcinomas and 70 small cell lung carcinomas, as compared with 25 adenocarcinomas and 25 squamous cell carcinomas. Neural cell adhesion molecules were negative in adenocarcinomas and squamous cell carcinomas but were constantly expressed in all NE tumors from typical carcinoids to small cell lung carcinomas. NCAM-PSA expression was significantly more frequent in high-grade tumors, with 24 of 30 positive cases in large cell NE carcinomas and 65 of 70 positive cases in small cell lung carcinoma, than in carcinoids with 10 of 17 and 2 of 3 positive cases in typical carcinoids and atypical carcinoids, respectively. The neural cell adhesion molecule-polysialic acid form scores of staining were significantly higher in high-grade as compared with low-grade tumors (p = 0.002), and were correlated with nodal spread (p = 0.04) and metastasis (p = 0.016) across histologic classes but not in individual tumor type. We conclude that NCAM-PSA connotes poor differentiation and aggressive clinical behavior in the spectrum of NE lung tumors, but cannot be regarded as a prognostic factor in individual tumor classes.     

Spontaneous regression of pulmonary metastases from transitional cell carcinoma

Spontaneous regression of metastatic cancers occurs rarely and has been reported only once for pulmonary metastases from transitional cell carcinoma. Two cases of spontaneous complete regression of lung metastases from transitional cell carcinoma are presented. In one case, regression occurred after a course of radiation to the primary bladder cancer, but in the other patient, lung lesions disappeared without treatment to the primary or metastatic cancers. The factors that alter the tumor-host relationship to allow spontaneous regression of cancers are unknown, but observation of these phenomena may help reveal parameters that influence tumor progression in the majority of cancer patients.     

Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas

Cyclooxygenase (COX)-2 expression was immunohistochemically examined in 59 human lung cancers as well as in normal and premalignant lung specimens. In contrast to scattered weak reactivity seen in normal peripheral airway epithelial cells, markedly up-regulated COX-2 expression was detected in about one-third of atypical adenomatous hyperplasias and carcinoma in situ specimens, and a significant increase in COX-2 expression was observed in 70% of invasive adenocarcinoma cases. Interestingly, the proportion of adenocarcinoma cells with marked COX-2 expression was much greater in lymph node metastases than in the corresponding primary tumors. In contrast, small cell carcinomas showed virtually negligible expression, and squamous cell carcinomas showed infrequent and low expression. These findings suggest that an increase in COX-2 expression may be associated with the development of adenocarcinomas and possibly with acquisition of an invasive and metastatic phenotype.