Membranous HEG1 expression is a useful marker in the differential diagnosis of epithelioid and biphasic malignant mesothelioma versus carcinomas.

Sialylated HEG1 has been reported as a highly specific and sensitive mesothelioma marker but a comprehensive evaluation of its expression in carcinomas in different organs, various sarcomas and reactive mesothelial proliferations has not been reported. The aim of this study was to evaluate the clinical applicability of HEG1 as a marker in the diagnosis of mesothelioma. HEG1 immunoreactivity was evaluated in whole sections of 122 mesotheliomas, 75 pulmonary carcinomas, 55 other carcinomas, 16 mesenchymal tumors, and 24 reactive mesothelial proliferations and in tissue microarrays containing 70 epithelioid (EM), 36 biphasic (BM), and 2 sarcomatoid mesotheliomas (SM). In whole sections and tissue microarrays, respectively, membranous HEG1 was expressed in 93.0% and 85.5% of EM, 81.3% and 69.4% of BM, 0% and 0% of SM. HEG1 was not expressed in pulmonary adenocarcinomas. HEG1 was expressed as cytoplasmic immunoreactivity in pulmonary squamous cell carcinomas (21.7%). Membranous HEG1 staining was seen in ovarian carcinomas (66.7%), thyroid carcinomas (100%), reactive conditions (16.7%), and mesenchymal tumors (18.8%). The sensitivity of membranous HEG1 expression to distinguish EM/BM from all carcinomas was 88.8%. The specificity for the differential diagnosis between EM/BM and all carcinomas and pulmonary carcinomas was 92.3% and 98.7%, respectively.

Diffuse pleural thickening and thoracic contraction: An indistinguishable case from malignant pleural mesothelioma.

The differential diagnosis of reactive mesothelial hyperplasia and mesothelioma is difficult. We present a rare case of diffuse pleural thickening with thoracic contraction that was indistinguishable from mesothelioma. A 66-year-old woman with no history of asbestos exposure visited our hospital with a complaint of dyspnea. The clinical findings included circumferential pleural thickening on chest computed tomography image and a high concentration of hyaluronic acid in the pleural fluid. Pleural biopsies obtained by thoracoscopy under local anesthesia were pathologically consistent with mesothelioma, but the patient refused to take any kind of mesothelioma treatments. Four months later, she consented to a surgical pleural biopsy under general anesthesia to obtain larger tissue samples, which included typical proliferating polygonal cells positive for CAM5.2, calretinin, WT-1, D2-40, CK5/6, epithelial membrane antigen, and glucose transporter-1 and negative for carcinoembryonic antigen, BerEP4, and MOC31. The analysis was consistent with diagnosis of epithelioid mesothelioma. Fluorescence in situ hybridization, however, showed the presence of p16 gene, and the expression of BRCA1-associated protein-1 was detected by immunohistochemistry. Our final diagnosis was diffuse pleural thickening unrelated to asbestos exposure. Differential diagnosis of diffuse pleural thickening and malignant mesothelioma is thus difficult and routine immunohistochemical examinations are often insufficient for accurate diagnosis. Multiple diagnostic methods are required for correct diagnosis in a clinically marginal case.

HEG1 is a novel mucin-like membrane protein that serves as a diagnostic and therapeutic target for malignant mesothelioma.

The absence of highly specific markers for malignant mesothelioma (MM) has served an obstacle for its diagnosis and development of molecular-targeting therapy against MM. Here, we show that a novel mucin-like membrane protein, sialylated protein HEG homolog 1 (HEG1), is a highly specific marker for MM. A monoclonal antibody against sialylated HEG1, SKM9-2, can detect even sarcomatoid and desmoplastic MM. The specificity and sensitivity of SKM9-2 to MM reached 99% and 92%, respectively; this antibody did not react with normal tissues. This accurate discrimination by SKM9-2 was due to the recognition of a sialylated O-linked glycan with HEG1 peptide. We also found that gene silencing of HEG1 significantly suppressed the survival and proliferation of mesothelioma cells; this result suggests that HEG1 may be a worthwhile target for function-inhibition drugs. Taken together, our results indicate that sialylated HEG1 may be useful as a diagnostic and therapeutic target for MM.

Usefulness of p16/CDKN2A fluorescence in situ hybridization and BAP1 immunohistochemistry for the diagnosis of biphasic mesothelioma.

Malignant mesothelioma is a highly aggressive neoplasm, and the histologic subtype is one of the most reliable prognostic factors. Some biphasic mesotheliomas are difficult to distinguish from epithelioid mesotheliomas with atypical fibrous stroma. The aim of this study was to analyze p16/CDKN2A deletions in mesotheliomas by fluorescence in situ hybridization (FISH) and BAP1 immunohistochemistry to evaluate their potential role in the diagnosis of biphasic mesothelioma. We collected 38 cases of pleural mesotheliomas. The results of this study clearly distinguished 29 cases of biphasic mesothelioma from 9 cases of epithelioid mesothelioma. The proportion of biphasic mesotheliomas with homozygous deletions of p16/CDKN2A in total was 96.6% (28/29). Homozygous deletion of p16/CDKN2A was observed in 18 (94.7%) of 19 biphasic mesotheliomas with 100% concordance of the p16/CDKN2A deletion status between the epithelioid and sarcomatoid components in each case. Homozygous deletion of the p16/CDKN2A was observed in 7 (77.8%) of 9 epithelioid mesotheliomas but not in fibrous stroma. BAP1 loss was observed in 5 (38.5%) of 13 biphasic mesotheliomas and in both epithelioid and sarcomatoid components. BAP1 loss was observed in 5 (62.5%) of 8 epithelioid mesotheliomas but not in fibrous stroma. Homozygous deletion of p16/CDKN2A is common in biphasic mesotheliomas, and the analysis of only one component of mesothelioma is sufficient to show that the tumor is malignant. However, compared with histology alone, FISH analysis of the p16/CDKN2A status and BAP1 immunohistochemistry in the spindled mesothelium provide a more objective means to differentiate between biphasic mesothelioma and epithelioid mesothelioma with atypical stromal cells.

Cytologic Differential Diagnosis of Malignant Mesothelioma and Reactive Mesothelial Cells With FISH Analysis of p16.

BACKGROUND: Mesothelioma patients often present with serosal effusions, which are ideal for cytopathological diagnoses. However, the morphological overlap between malignant and benign mesothelial proliferation can make a conclusive cytological diagnosis of mesothelioma elusive because immunohistochemical staining does not discriminate definitively between the two in this setting. p16 is deleted in up to 80% of pleural mesotheliomas. The aim of this study was to establish the correlation between the p16 deletion status of the cell block with that of its corresponding tumor using fluorescence in situ hybridization (FISH) analysis for individual patient tumors. METHODS: Twenty-two biopsies and 24 corresponding cell blocks, containing serosal effusions with atypical mesothelial cells from 22 patients with histologically confirmed pleural mesotheliomas, were analyzed with p16 FISH. Seventeen cell blocks consisting of serosal effusions with reactive mesothelial cells from nonmesothelioma cases were also analyzed. Combined immunofluorescence and FISH were also performed. RESULTS: Seventeen of the 22 mesothelioma patients (77.3%) showed homozygous deletions of p16 in the tumor tissue and in the atypical mesothelial cells from the cell blocks. p16 FISH followed by immunofluorescence with EMA was helpful towards identifying the mesothelioma cells in the cell blocks. CONCLUSION: We confirmed that the p16 FISH results obtained from the cell blocks are as reliable as those from the tissue sections. Cell block analysis is recommended for patients with serosal effusions of unknown origins with the following methods: immunohistochemistry should be performed to validate the mesothelial origin, and p16 FISH should be performed to confirm malignancy. Diagn. Cytopathol. 2016;44:591-598. © 2016 Wiley Periodicals, Inc.

Clinical Investigation of Benign Asbestos Pleural Effusion.

There is no detailed information about benign asbestos pleural effusion (BAPE). The aim of the study was to clarify the clinical features of BAPE. The criteria of enrolled patients were as follows: (1) history of asbestos exposure; (2) presence of pleural effusion determined by chest X-ray, CT, and thoracentesis; and (3) the absence of other causes of effusion. Clinical information was retrospectively analysed and the radiological images were reviewed. There were 110 BAPE patients between 1991 and 2012. All were males and the median age at diagnosis was 74 years. The median duration of asbestos exposure and period of latency for disease onset of BAPE were 31 and 48 years, respectively. Mean values of hyaluronic acid, adenosine deaminase, and carcinoembryonic antigen in the pleural fluid were 39,840 ng/mL, 23.9 IU/L, and 1.8 ng/mL, respectively. Pleural plaques were detected in 98 cases (89.1%). Asbestosis was present in 6 (5.5%) cases, rounded atelectasis was detected in 41 (37.3%) cases, and diffuse pleural thickening (DPT) was detected in 30 (27.3%) cases. One case developed lung cancer (LC) before and after BAPE. None of the cases developed malignant pleural mesothelioma (MPM) during the follow-up.

Asbestos textile production linked to malignant peritoneal and pleural mesothelioma in women: Analysis of 28 cases in Southeast China.

BACKGROUND: Chrysotile had been used in asbestos textile workshops in Southeast China but a clear relation to mesothelioma is lacking. METHODS: All patients diagnosed with mesothelioma from 2003 to 2010 at Yuyao People's Hospital were re-evaluated by multiple expert pathologists with immunohistochemistry and asbestos exposure data were collected. RESULTS: Of 43 patients with a mesothelioma diagnosis, 19 peritoneal and nine pleural cases were finally diagnosed as mesothelioma. All were females, and the mean age of the patients with peritoneal or pleural mesothelioma was 52.4 and 58.2 years, respectively. All these cases had a history of domestic or occupational exposure to chrysotile. Two-thirds of the patients were from two adjoining towns with multiple small asbestos textile workshops. Contamination of tremolite was estimated to be less than 0.3%. CONCLUSIONS: This is a report of mesothelioma in women exposed to chrysotile asbestos at home and at work, with an over-representation of peritoneal mesothelioma.

Significant relationship between the extent of pleural plaques and pulmonary asbestos body concentration in lung cancer patients with occupational asbestos exposure.

BACKGROUND: The aim of this study was to elucidate whether there is a relationship between the extent of pleural plaques and pulmonary asbestos body concentration (PABC). METHODS: The subjects were 207 lung cancer patients with occupational asbestos exposure. We determined the plaque extent by findings on chest images using our own criteria. PABCs were measured in resected or autopsy lung specimens. RESULTS: There was a significant relationship between plaque extent and PABC. Seventy-five percent of the patients determined to have extensive plaques based on our criteria had a PABC of ≥5,000 asbestos bodies per gram of dry lung tissue, which is one of the certification criteria of lung cancer caused by asbestos for workers' compensation in Japan. CONCLUSIONS: In lung cancer patients, the plaque extent had a significant positive relationship with the PABC. The plaque extent would be useful as a proxy for PABC for lung cancer compensation purposes.

CD90 is a diagnostic marker to differentiate between malignant pleural mesothelioma and lung carcinoma with immunohistochemistry.

OBJECTIVES: To pathologically distinguish mesothelioma from lung carcinoma, particularly adenocarcinoma. METHODS: We conducted immunohistochemical analyses on clinical specimens, including 26 cases of mesothelioma, 28 cases of lung adenocarcinoma, and 33 cases of lung squamous cell carcinoma. RESULTS: We found that CD90 expression was useful in making a differential diagnosis between epithelioid mesothelioma and lung adenocarcinoma, whereas sarcomatoid mesothelioma and lung carcinoma specimens, irrespective of the histologic types, were negative in general. The sensitivity and specificity of CD90 expression in epithelioid mesothelioma and lung adenocarcinoma were comparable to those of well-established markers used for the differential diagnosis. CONCLUSIONS: These data collectively indicate that CD90 is a novel diagnostic marker that contributes to a diagnosis of epithelioid mesothelioma.

Diagnostic usefulness of p16/CDKN2A FISH in distinguishing between sarcomatoid mesothelioma and fibrous pleuritis.

The distinction between sarcomatoid mesothelioma and fibrous pleuritis is difficult based on histology, especially when the amount of tumor tissue examined via biopsy is small and immunohistochemical examination is inconclusive. We studied the usefulness of deletion of p16 with fluorescence in situ hybridization (FISH) and p16 hypermethylation with polymerase chain reaction for the diagnosis and prognosis of malignant pleural mesothelioma (MPM). We analyzed 50 MPMs, including 22 sarcomatoid mesothelioma cases and 10 fibrous pleuritis cases. We set the cutoff value of homozygous deletion pattern as 14.4% based on FISH signaling patterns using samples of fibrous pleuritis. The percentage of homozygous deletion pattern was higher than 14.4% in 55.6% of the epithelioid mesotheliomas (10/18) and in all of the sarcomatoid mesotheliomas (22/22). Methylation of p16 was observed in 7 (20.6%) of 34 informative cases. p16 FISH analysis can be a reliable test for distinguishing between sarcomatoid mesothelioma and fibrous pleuritis and a prognostic factor for MPM.

Extraskeletal osteosarcoma of the pleura:report of a case.

Extraskeletal osteosarcoma is a rare malignant tumor occurring very rarely in the pleura. We herein report the case of 67-year-old man with asbestos exposure, who underwent biopsies of the large tumor from the chest wall, and diagnosed as a suspicious of fibrosarcoma. Surgical resection was done, and the pathological diagnosis was extraskeletal osteosarcoma arising from the pleura. The differential diagnosis is malignant pleural mesothelioma with osseous and cartilaginous which is also very rare and one of the histopathological subtypes with heterologous elements. Identification of epithelial components, labeling for cytokeratins in spindle cells and its' anatomical distribution may help to distinguish them. In the neoplasm arising from the parietal pleura, primary extraskeletal osteosarcoma of the pleura is very rare, but should be considered.

Malignant pleural mesothelioma: clinicopathology of 16 extrapleural pneumonectomy patients with special reference to early stage features.

The earliest pathological events in the development of malignant pleural mesothelioma (MPM) are not understood. The aim of the present study was to elucidate the early histopathological features of MPM. A total of 16 extrapleural MPM pneumonectomy patients were investigated. Early stage mesothelioma was arbitrarily defined as a tumor < or =5 mm in thickness regardless of the nodal status or other organ involvement. Eight of these patients (six with epithelioid, two with biphasic) had early stage mesothelioma by this definition. Macroscopically there was no visible tumor, but the parietal and visceral pleura were thickened and there was focal adhesion between them. Microscopically, the mesothelioma lesions were multifocal and discontinuous on the pleura. In extremely early cases of epithelioid mesothelioma, tumor cells were generally arrayed in a single layer, but papillary proliferation was observed elsewhere. In sarcomatoid mesothelioma, mesothelioma cells proliferated, forming multiple small polypoid nodules on the pleura. Epithelial membrane antigen was helpful to distinguish reactive from neoplastic mesothelium, but glucose transporter-1 was not. Mesothelioma cells disseminate diffusely throughout the parietal and visceral pleura and mediastinal fat tissue before becoming visible. Stage Ia mesothelioma (neoplasm limited to the parietal pleura) would not be observed in daily practice.

Diffuse malignant pleural mesothelioma: a multi-institutional clinicopathological study.

PURPOSE: The relative rarity of malignant pleural mesothelioma (MPM) in Japan makes it difficult to perform a large-scale clinicopathological study of this tumor at a single institute. Thus, we performed a multiinstitutional study to evaluate the current status of diagnosis and treatment in Japan. METHODS: We analyzed the records of 65 patients with MPM, obtained from the 13 institutions comprising the Japanese Chiba Multicenter Study Group. RESULTS: In 56 patients, the tumor was detected after a visit to a medical facility for subjective symptoms such as chest pain, shortness of breath, and cough. It took a median period of 2 months from the initial visit to establish the diagnosis. The overall survival rates of 33 patients with unresectable MPM 1, 2, and 3 years after the diagnosis were 40.5%, 10.8%, and 0%, respectively, whereas those of 32 patients who underwent surgery were 67.9%, 35.0% and 10.9%, respectively (P=0.0035). According to multivariate analysis, histological type, International Mesothelioma Interest Group clinical stage, sex, and the presenting symptom of shortness of breath were significant prognostic factors. CONCLUSIONS: The definitive diagnosis of early MPM is difficult, but establishing the best diagnostic modality would improve survival rates, since radical surgery is likely to be effective for resectable disease.

[Treatment of malignant pleural mesothelioma].

In Japan, it is predicted that mesothelioma will rapidly increase in the future. Malignant pleural mesothelioma that accounts for approximately 90% of mesothelioma as a whole has a median survival time of approximately nine months which is considered a poor prognosis. As for the treatment of this disease,extrapleural pneumonectomy or pleurectomy/decortication are available for those patients who can be surgically operated on. However, since a complete cure rate is low when only surgical treatment is performed, generally a multimodality treatment is performed wherein chemotherapy and/or radiotherapy are combined. For chemotherapy, a large-scale randomized phase III study demonstrated that a treatment using two agents: pemetrexed, which is a new multitargeted antifolate, and cisplatin is effective. Pemetrexed will be the drug of first choice for mesothelioma in the future. As other treatment methods, chemohyperthermia, treatments using various kinds of cytokines and angiogenesis inhibitors, genetic treatment and photodynamic therapy have been attempted. The current treatment results for this disease are very poor, and there has been a strong demand for establishing an effective treatment method.

Mucoepidermoid carcinoma of the thymus.

Mucoepidermoid carcinoma of the thymus is a rare carcinoma and there is little agreement about the treatment of this tumor. According to the analysis of previously reported tumors, biologic behavior of the tumor correlated with the spread of the lesion and degree of differentiation. We report a case of this tumor in a 31-year-old man. Resection of the tumor included the left upper lobe of the lung, the phrenic nerve, pericardium and disseminations in the pleura. The clinicopathological feature of this case was high-stage disease and low-grade histology. Postoperative chemotherapy and radiotherapy were performed, and the patient is alive without recurrence 14 months after surgery.

Lymphangioleiomyomatosis with a giant bulla: report of a case.

We report a case of lymphangioleiomyomatosis (LAM) with a giant bulla. A 33-year-old woman was referred to our department for treatment of dyspnea. Chest computed tomography showed a giant bulla with many smaller bullae. To obtain a definitive diagnosis and relieve the dyspnea, we performed a lung biopsy and bullectomy, after which her symptoms and pulmonary function improved remarkably. She was commenced on progesterone, which improved her condition even further. This case report retrospectively follows the progression of her disease from the onset of symptoms 5 years before she was referred to us for treatment.