Lymphohistiocytoid mesothelioma of the pleura: A case report with cytological findings

Lymphohistiocytoid malignant mesothelioma is an infrequent variant of sarcomatoid mesothelioma representing approximately 0.5–3.3% of malignant mesotheliomas. It has been related to asbestos exposure. The tumor is characterized by a diffuse large histiocyte‐like cells proliferation mixed with an inflammatory infiltrate of lymphocytes and plasma cells. Its cytological diagnosis is difficult. We present a case of a 67‐year‐old female with lymphohistiocytoid mesothelioma involving the left pleura. The cytological, histological, and immunohistochemical features are discussed. Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.     

Synchronous diffuse malignant mesothelioma and carcinomas in asbestos-exposed individuals

AIMS: The development of synchronous diffuse malignant mesothelioma and carcinoma in individuals exposed to asbestos is rare. We report nine cases and discuss the medico-legal implications. METHODS AND RESULTS: Five hundred patients seeking compensation for asbestos-related diffuse malignant mesothelioma were reviewed with access to post-mortem data. The study group comprised cases in which a second (non-mesothelial) neoplasm was identified. The study group comprised eight males, one female, mean age 68 years (range 60-75). All individuals gave a history of asbestos exposure. Synchronous malignant mesothelioma with carcinoma was identified in 9/500 (1.8%). Eight malignant mesotheliomas were pleural, one was primary peritoneal in origin. By morphological subtyping there were four epithelioid, three biphasic and two sarcomatoid mesotheliomas. In 6/9 (67%) the second tumour was a primary bronchogenic carcinoma (three adenocarcinomas, two squamous cell carcinomas and one small-cell carcinoma). In 3/9 (33%) the second tumour was a non-bronchogenic carcinoma (colonic, pancreatic and breast ductal adenocarcinoma). No other neoplasms were identified in the cohort of malignant mesotheliomas studied. Five persons had pathological evidence of asbestosis (four had bronchogenic carcinomas, one colorectal adenocarcinoma). Two persons with non-bronchogenic carcinomas had identifiable asbestos bodies but no interstitial fibrosis. In two cases the second neoplasms (primary bronchogenic squamous cell and small-cell carcinomas) were associated with diffuse interstitial fibrosis but no asbestos bodies were seen on light microscopy. In each case transmission electron microscopic mineral analysis revealed an asbestos fibre burden within the background population range for control subjects and well below that seen in cases of established asbestosis. These cases were considered to represent cryptogenic fibrosing alveolitis in subjects with a history of asbestos exposure. CONCLUSIONS: Synchronous malignant mesothelioma with carcinomas in asbestos-exposed workers is rare and identified in 1.8% of 500 malignant mesotheliomas in this series. In most cases the carcinoma represents a primary bronchogenic neoplasm. Primary lung carcinomas are recognized to be asbestos related only when occurring in association with asbestosis. In this series this combination (bronchogenic carcinoma and asbestosis) was seen in four (0.8%) cases. In post-mortem cases for possible malignant mesothelioma it is important to identify any other neoplasia and determine whether it is related to asbestos. Their presence impact upon anticipated life expectancy and in the presence of malignant mesothelioma will affect the compensation settlement.     

Malignant peritoneal mesothelioma: Quantitative analysis of asbestos burden

Malignant mesotheliomas develop commonly in the pleural cavity and rarely arise in the peritoneal cavity. It is well established that asbestos exposure is related to malignant pleural mesothelioma, but the asbestos burden in the abdominal cavity in patients with malignant peritoneal mesothelioma has not been well studied. The purpose of the present study was therefore to report on an autopsy case of malignant peritoneal mesothelioma with quantitative analysis of the asbestos burden in tissues from the pleura and organs in the abdominal cavity. The patient was a 67-year-old man with a history of asbestos exposure. The peritoneum was thickened with diffuse tumor proliferation. This patient was diagnosed as having malignant peritoneal epithelioid mesothelioma. The number of asbestos fibers was >10 000/g dry tissue in all samples examined except in the small intestine. The number of asbestos fibers in the stomach was 53 000/g, which was higher than that in a control asbestosis subject. The existence of numerous asbestos fibers found in the abdominal cavity suggests that asbestos stimuli are related to the tumorigenesis of malignant peritoneal mesothelioma.     

Evaluation of simian virus-40 as a biological prognostic factor in Egyptian patients with malignant pleural mesothelioma

The association between simian virus (SV40) and malignant pleural mesothelioma (MPM) suggests an etiological role for SV40. However, exact pathogenetic mechanisms and possible prognostic value are not clear. The purpose of the present paper was to investigate 40 Egyptian MPM patients for the presence of SV40 DNA, altered Rb expression and p53 gene status using immunohistochemistry and molecular techniques. The relation between SV40, asbestos exposure, Rb, p53 and their contribution to the overall survival (OS) were also assessed. SV40 DNA was detected in 20/40 patients and asbestos exposure in 31 patients; 18 of them were SV40 positive. Altered p53 and Rb expression were detected in 57.5% and 52.5%, respectively, with no p53 mutation. Univariate analysis showed a significant correlation between OS and stage (P = 0.03), performance status (P = 0.04), p53 overexpression (P = 0.05), asbestos exposure (P = 0.002) and SV40 (P = 0.001). Multivariate analysis showed that when SV40 and asbestos exposure were considered together, only combined positivity of both was an independent prognostic factor affecting the OS (P = 0.001). SV40 and asbestos exposure are common in Egyptian MPM, denoting a possible etiological role and a synergistic effect for both agents. Combined positivity for SV40 and asbestos exposure is an independent prognostic factor in MPM, having a detrimental effect on OS.     

Pathology of malignant mesothelioma

The diagnosis of malignant mesothelioma can pose several problems to the surgical pathologist. First, the morphological appearances of the tumour are known to be diverse with mimicry of a range of both reactive and neoplastic conditions. Second, due to the relative inaccessibility of the serosa, biopsy material is often scanty and fragmentary, producing a plethora of interpretive ambiguities. Third, adjunct techniques such as mucin histochemistry and immunohistochemistry, whilst useful in excluding malignant mesothelioma have little role in confirming the diagnosis. The accurate diagnosis of diffuse malignant mesothelioma is important for two reasons: (1) In relation to prognosis as it has an almost invariable fatal outcome, which contrasts with the other mesothelial neoplasms such as the benign adenomatoid tumour and the borderline malignant tumours, namely the well-differentiated papillary mesothelioma and multicystic mesothelioma; (2) In relation to occupational-related compensation claims following asbestos exposure. This review summarizes the aetiology of asbestos-induced neoplasia, possible mechanisms of tumour development and highlights potential diagnostic pitfalls.     

Role of fragile histidine triad protein expression in pathogenesis of malignant pleural mesothelioma

AIM:To investigate the relationship of fragile histidine triad (FHIT) and Ki-67 expression with clinicopathological variables of patients with malignant pleural mesothelioma (MPM). METHODS: Formalin-fixed, paraffin-embedded tissue sections of 30 asbestos induced MPM (epithelial and biphasic) patients were examined for FHIT and Ki-67 expression using immunohistochemical techniques and results were compared with clinicopathological variables. RESULTS: Immunohistochemical study results were as follows: 12 (40%) cases showed low FHIT expression and 18 (60%) showed high expression. There was no significant relationship between FHIT and age, gender or histological subtypes (p > 0.05). Ki-67 expression was 'low' in 13 (43.3%) cases and 'high' in 17 (56.7%) cases. No correlation could be demonstrated between Ki-67 expression and age, gender or histological subtypes (p > 0.05). No significant association was observed between FHIT and Ki-67 expression in MPM. CONCLUSION: The results support the role of FHIT as a tumour suppressor gene in asbestos induced MPM. There is no significant correlation between FHIT and cell proliferation marker expressions in malignant pleural mesothelioma. Therefore, it can be concluded that loss of FHIT does not interfere with tumour proliferation. This can be accepted as evidence for an early role of FHIT loss in carcinogenesis; however, it needs to be strengthened by further studies.     

The comparative accuracy of different pleural biopsy techniques in the diagnosis of malignant mesothelioma

Aims:  To evaluate the diagnostic accuracy of closed and open pleural biopsies in diagnosing malignant pleural mesothelioma.
Methods and results:  The autopsy study group comprised 45 malignant mesotheliomas. All prior pleural biopsy investigations were reviewed. Forty-one of 45 (91%) had had an antemortem diagnosis of malignant mesothelioma. In these 41 cases, 57 prior diagnostic pleural biopsies had been performed [36 closed needle biopsies: 31 blind; five computed tomography (CT)-guided and 21 open pleural biopsies]. For definitive diagnosis open pleural biopsy yielded a sensitivity of 95% and specificity of 100%. For definitive diagnosis closed blind pleural biopsies yielded a sensitivity of 16% and specificity of 94%. Thirty-two per cent of 'blind' biopsies were inadequate. CT-guided pleural biopsies yielded a definitive diagnostic accuracy of 100% (5/5). Biopsy specimen size was important in obtaining a positive definitive diagnosis. Diagnosis was attained in 75% of specimens >10 mm in size compared with 8% <10 mm in size.
Conclusions:  Overall, all procedures had utility but definitive diagnostic accuracy for 'blind' closed pleural biopsy was low (16%), dependent on biopsy specimen size and tumour subtype. Sarcomatoid subtype malignant mesothelioma yielded the lowest diagnostic accuracy. For all subtypes of malignant mesothelioma, open pleural biopsy produced the highest diagnostic accuracy (100% sensitivity, 95% specificity).     

Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma

Vascular endothelial growth factor (VEGF), a potent mitogen for vascular endothelium, is expressed in malignant pleural mesothelioma (MM). The present report examines the effect of VEGF on MM growth. Four MM cell lines produced significantly higher VEGF levels than normal mesothelial cells (1946+/-14 pg/ml vs. 180+/-17 pg/ml; p<0.001). In addition, MM cells expressed the tyrosine kinase-related VEGF receptors Flt-1 and KDR. Recombinant human VEGF phosphorylated both Flt-1 and KDR and increased proliferation of all four MM cell lines in a dose-dependent fashion. Neutralizing antibodies against either VEGF, Flt-1 or KDR significantly reduced MM cellular proliferation. In addition, expression of VEGF, Flt-1, and KDR was observed in MM biopsies. Moreover, higher VEGF levels were found in the pleural effusions of MM patients than in the effusions of patients with non-malignant pleural disease (1885.7+/-894.9 pg/ml vs. 266.9+/-180.5 pg/ml; p<0.001). Linear regression analysis showed a significant inverse correlation between serum VEGF levels and MM patient survival (r=0.72; p<0.01). No correlation was found between tumour vessel density and either serum (r=0.26; p=0.42) or pleural effusion (r=0.35; p=0.26) VEGF levels. These results indicate that VEGF, via activation of its tyrosine kinase receptors, may be a key regulator of MM growth. In addition, VEGF production could have an impact on patient survival, not only by promoting tumour angiogenesis but also by directly stimulating tumour growth.     

Asbestos fibres inhibit the in vitro activity of lymphokine-activated killer (LAK) cells from healthy individuals and patients with malignant mesothelioma.

Asbestos exposure is associated with an increased incidence of several malignancies, including malignant mesothelioma (MM). This study evaluates the relationship between asbestos exposure and the in vitro generation and function of LAK cells, an immune effector cell population with powerful lytic activity against MM cells. Both serpentine (chrysotile) and amphibole (amosite and crocidolite) forms of asbestos fibres suppress LAK cell generation, viability (by 5-11%, P less than 0.02) and cell recovery (by 13-15%, P less than 0.02). However, the LAK cells generated in the presence of the amphiboles were as effective as unexposed cells in lysing both standard tumour cell targets (K562, 56.4% lysis versus 61.5%, respectively, P greater than 0.5; NS; Daudi, 60.5% lysis versus 64.5% P greater than 0.5; NS), and MM tumour cell targets (mean of three MM cell lines 48.3% versus 46.3%, P greater than 0.5; NS), whereas the function of LAK cells generated in the presence of chrysotile was significantly reduced against three out of the five tumour cell targets tested (P less than 0.03). In the presence of asbestos fibres, LAK cell function was reduced against all five tumour cell targets (P less than 0.01), irrespective of whether the cell donors were healthy individuals or patients with MM. NK cell activity was also suppressed (P less than 0.01). The serpentine form of asbestos, chrysotile, was significantly more suppressive of both effector cell functions than either of the amphiboles (P less than 0.01). These findings suggest that asbestos exposure may suppress the function and in some instances the generation of immune effector cell mechanisms, thereby increasing the risk of disease and malignancy.     

BRCA1 is an essential mediator of vinorelbine-induced apoptosis in mesothelioma

Therapeutic options for malignant pleural mesothelioma (MPM) are limited despite the increasing incidence globally. The vinca alkaloid vinorelbine exhibits clinical activity; however, to date, treatment optimization has not been achieved using biomarkers. BRCA1 regulates sensitivity to microtubule poisons; however, its role in regulating vinorelbine-induced apoptosis in mesothelioma is unknown. Here we demonstrate that BRCA1 plays an essential role in mediating vinorelbine-induced apoptosis, as evidenced by (1) the strong correlation between vinorelbine sensitivity and BRCA1 expression level; (2) induction of resistance to vinorelbine by BRCA1 using siRNA oligonucleotides; (3) dramatic down-regulation of BRCA1 following selection for vinorelbine resistance; and (4) the re-activation of vinorelbine-induced apoptosis following re-expression of BRCA1 in resistant cells. To determine whether loss of BRCA1 expression in mesothelioma was potentially relevant in vivo, BRCA1 immunohistochemistry was subsequently performed on 144 primary mesothelioma specimens. Loss of BRCA1 protein expression was identified in 38.9% of samples. Together, these data suggest that BRCA1 plays a critical role in mediating apoptosis by vinorelbine in mesothelioma, warranting its clinical evaluation as a predictive biomarker.     

Desmoplastic malignant mesothelioma of the pleura: autopsy reveals asbestos exposure

Desmoplastic mesothelioma is a rare subtype of diffuse malignant mesothelioma, and is often difficult to distinguish from reactive pleural fibrosis because of associated extensive collagen fibrosis. An 82-year-old woman with a severe cough was revealed to have pleural effusion and diffuse pleural thickening on the right side. Antibiotics were ineffective, and a compression fracture of the ninth and tenth thoracic vertebral bodies was recognized on X-ray. Autopsy revealed a diffuse pleural thickening with hyalinized collagen tissue in the central part of the pleura. However, the peripheral part of the fibrous tissue was composed of spindle and polygonal cell proliferation that were immunohistochemically positive for antibodies against cytokeratin and vimentin. In addition, the ninth and tenth thoracic spines were infiltrated by similar cells. The condition was diagnosed as desmoplastic mesothelioma with bone metastases. Asbestos bodies were detected in the thickened pleura and fibrosed alveolar septa, and it was suggested retrospectively that the patient had been exposed to asbestos. Thus, autopsy analyses of fibrous pleurisy are necessary to detect a desmoplastic variant of mesothelioma of the pleura and its association with asbestos exposure.     

Transforming growth factor-beta 1 (TGF-beta 1)- and beta 2-like activities in malignant pleural effusions caused by malignant mesothelioma or primary lung cancer.

We investigated the levels of TGF-beta in malignant pleural effusions (MPE) caused by malignant mesothelioma (MESO) or primary lung cancer. TGF-beta levels in MPE caused by MESO were 283.9 +/- 219.2 pm (mean +/- s.d.) and were three to six times higher than those due to primary lung cancers (P < 0.01 or P < 0.05). We also evaluated TGF-beta 1- and beta 2-like activities in MPE using specific polyclonal antibodies. Although TGF-beta 1-like activity could be detected in all cases, TGF-beta 2-like activities were detected in five of seven in MESO and in a few cases with primary lung cancer. These results demonstrate that the levels of total TGF-beta and TGF-beta 2-like activity may be clinically useful to differentiate MESO from primary lung cancer. Our data also suggest that TGF-beta may help further characterize the clinical features of MESO.     

Ten cases of feline mesothelioma: an immunohistochemical and ultrastructural study

In the cat only 10 cases of mesothelioma, mainly of the peritoneum, have been previously reported. This paper describes a further 10 cases, eight pleural and two peritoneal, in males and females aged 1-17 years. Histologically, five tumours were epithelial, three fibrosarcomatous and two biphasic. Immunohistochemical markers used in human pathology for the identification of mesotheliomas include vimentin, cytokeratin (CK) AE1/AE3, HBME-1, CK 5/6, calretinin, thrombomodulin, carcinoembryonic antigen (CEA), CD15, E-cadherin and desmin. All 10 feline mesotheliomas were positive for vimentin and CK AE1/AE3, six were positive for HBME-1, two for CK5/6, three for CEA and four for E-cadherin. All were negative for desmin and calretinin. Antibodies to thrombomodulin and CD15 failed to cross-react with feline tissues. Electron microscopy, performed in four cases, revealed microvillar structures, desmosomes and intracytoplasmic lumina, confirming its value as a diagnostic tool. The study showed that mesothelial marker antibodies commonly used in human patients can be used for the diagnosis of feline mesothelioma, preferably as a panel of antibodies rather than only one.     

Measurement of telomere length in cells from pleural effusion: Asbestos exposure causes telomere shortening in pleural mesothelial cells

We estimated the telomere lengths of neoplastic and non‐neoplastic mesothelial cells and examined their correlation with asbestos exposure and the expression of markers of mesothelial malignancy. Cell blocks of pleural effusion obtained from 35 cases of non‐neoplastic disease (NN), 12 cases of malignant mesothelioma (MM) and 12 cases of carcinomatous effusion due to lung adenocarcinoma (LA) were examined. Fifteen of the 35 NN cases had pleural plaques (NNpp+) suggestive of asbestos exposure, and the other 20 cases had no pleural plaques (NNpp‐). Telomere length was measured using the tissue quantitative fluorescence in situ hybridization method, and expressed as normalized telomere‐to‐centromere ratio. NN cases had significantly longer telomeres than MM (P < 0.001) and LA (P < 0.001) cases. Telomeres in NNpp+ cases were slightly shorter than those of NNpp‐ cases (P = 0.047). MM and LA showed almost the same telomere length. NN cases with shorter telomeres tended to show aberrant expression of epithelial membrane antigen (EMA), CD146, glucose transporter 1 (GLUT1) and IGF‐II messenger RNA‐binding protein 3 (IMP3). These results suggest that telomere shortening and subsequent genetic instability play an important role in the development of MM. Measurement of telomere length of cells in pleural effusion might be helpful for earlier detection of MM.     

High frequency of immune dysfunctions in asbestos workers and in patients with malignant mesothelioma

We have examined the primary immune responses, the numbers of total T (T11⁺) cells, T-helper (T4⁺) cells, T-suppressor (T8⁺) cells, and natural killer (NK) (Leu7⁺) cells, in 118 healthy control subjects and compared the data to those obtained from 20 patients with clinically diagnosed malignant mesothelioma and 375 long-term asbestos workers without neoplasia. The absolute numbers of total T (T11⁺) and T-helper (T4⁺) cells were normal in asbestos workers without neoplasia but were significantly reduced in patients with mesothelioma. T-suppressor (T8⁺) cells, on the other hand, remained unchanged in the patients but were significantly elevated among the asbestos workers. This resulted in a marked reduction in T-helper (Th) to T-suppressor (Ts) ratios in mesothelioma patients and in asbestos workers. Seventy percent of the mesothelioma patients (14 of 20) had significantly depressed NK-cell activity which could be augmented but not normalized by coincubation in patients' peripheral blood lymphocytes (PBL) with interferon (IFN). Among the asbestos workers three distinctive subgroups could be identified: heightened (H-NK), normal (N-NK), and low (L-NK) NK activity. The NK activity of the L-NK group could be stimulated but not normalized by coincubation with IFN, a finding closely resembling that in malignant mesothelioma patients. Phenotyping of the circulating NK cells revealed a unique Leu7⁺ subset in increased numbers with a brightly fluorescent property in stable mesothelioma patients with relatively stable or slowly progressive disease and in more than 30% of the asbestos workers. The reduced Th/Ts ratio and NK-cell function among these asbestos workers at high risk may be a direct consequence of asbestos exposure and might not be related to neoplastic processes.