Localized pleural malignant mesothelioma

The occurrence of pleural malignant mesothelioma (MM) is unusual and the cases that appear as a localized tumor are extremely rare. A case of localized pleural MM including immunohistochemical findings is presented. A 70-year-old man had an abnormal shadow found during a routine roentgenogram at an annual health checkup and was admitted to Toneyama National Hospital (Toyonaka, Osaka, Japan) for detailed examinations. Chest X-rays showed a 2 x 5 cm-sized nodule with relatively smooth margins in the right segment three. Computed tomography (CT) showed an extrapleural mass with a smooth surface and a thickened parietal pleura, and results of a biopsy performed under CT scanning yielded MM. Systematic examinations did not show any metastasis and the patient underwent surgery for removal of the mass. The resected tumor, measuring 3.2 x 3.1 cm, was firm, partially encapsulated, and irregularly shaped. Pathological examinations revealed that it consisted of large polygonal cells, partially showing myxoid patterns, which led to a diagnosis of localized pleural MM. Tumor recurrence was seen, and the duration between initial symptoms and death was 29 months. This case suggests that localized pleural MM has a high proliferative potential and aggressive course, and is considered an early stage of diffuse pleural MM.     

Localized pleural malignant mesothelioma

Pleural malignant mesothelioma (PMM) is a rare tumor and it is commonly seen in the form of multiple nodules or a diffuse tumor. A localized tumor mass in the pleura is extremely rare. Only seven cases have been reported. In this report, we present an additional case of localized PMM and describe the immunohistochemical and flow cytometric findings. A 61-year-old woman, without a history of smoking or asbestos exposure, presented with a severe pain in her right shoulder and arm. Chest radiography showed a solitary mass in the right upper lung field. Computed tomography showed a 5 cm right upper lung mass. Magnetic resonance imaging showed that the mass extended to the wall of the thorax. The patient underwent surgery for total removal of the tumor. Pathology revealed a localized malignant mesothelioma. Immunohistochemical analysis showed that the tumor was strongly and diffusely positive for cytokeratins with high and low molecular weight, and focally positive for vimentin and epithelial membrane antigen (EMA), but it was negative for carcinoembryonic antigen, Factor VIII, α -fetoprotein and Leu-M1. Flow cytometry showed an aneuploid DNA content in the tumor. The final diagnosis was localized malignant mesothelioma (epithelial type). The patient showed signs of local recurrence 5 months after surgery, and radiotherapy was given.     

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.     

A comparison of epidermal growth factor receptor expression in malignant peritoneal and pleural mesothelioma

An evaluation of epidermal growth factor receptor (EGFR) phenotypic expression in malignant pleural and peritoneal mesothelioma was undertaken, using immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) analysis. Thirty-eight malignant mesothelioma (MM) specimens were subjected to IHC staining and FISH to evaluate the expression of EGFR protein and gene status. Overall positive IHC reaction was detected in 20/38 (53%) cases, in 11/22 (50%) pleural MM, and in 9/16 (56%) peritoneal MM. Our study confirmed that EGFR membranous expression is a common feature in MM, but not in benign mesothelial lesion. Thirty-seven cases did not show a gene copy number gain. Only one case showed a copy number gain. The protein overexpression of EGFR was not related to a gene copy number gain.     

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).     

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.     

The recurrence of malignant pleural mesothelioma 14 years after extrapleural pneumonectomy: Possible histological transformation

A 56‐year‐old man underwent extrapleural pneumonectomy for malignant pleural mesothelioma (MPM). The histological diagnosis was epithelioid mesothelioma with T2N0M0, and no sarcomatoid component was observed. Subsequently, 14 years after complete resection, screening computed tomography detected a rapidly growing right thoracic mass, which was diagnosed as a recurrence of MPM on resection. However, it was composed of both epithelioid (50%) and sarcomatoid (50%) components, suggesting possible histological transformation. Although there have been some previous reports on the recurrence of MPM, to the best of our knowledge, this is the first clinical case which indicated that histological transformation of MPM might occur.     

恶性胸膜间皮瘤13例病理学报道及分析

目的：探讨恶性胸膜间皮瘤的临床及病理学特点。方法：对天津市海河医院13例恶性胸膜间皮瘤患者的临床资料和病理学特征进行回顾性分析。结果：13例患者男性为主(69.2%),中位年龄55岁,主要症状为胸闷(76.7%),放射学主要表现为胸腔积液(69.2%),7例(53.8%)确诊通过胸腔镜获得标本。病理表现上皮样型12例,肉瘤样型1例;免疫组织化学染色calretinin及D2-40阳性率较高(100%、76.7%),CEA及TTF-1阳性率均为0。结论：恶性胸膜间皮瘤恶性程度高,应尽早行胸腔镜检查;除常规染色外,免疫组化染色可帮助鉴别诊断。     

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.     

Cadherins, catenins and APC in pleural malignant mesothelioma

Malignant mesothelioma is an aggressive disease of the pleura, and less commonly the peritoneum, with a very poor prognosis. The present study has examined the expression of cell adhesion molecules including cadherins, catenins, and APC in order to determine whether abnormal expression of components of the Wnt signalling pathway contribute to the variable phenotype of malignant mesothelioma. Sixty-three malignant mesotheliomas and nine cases of reactive mesothelial hyperplasia were analysed by immunohistochemistry for E-cadherin, N-cadherin, alpha-catenin, beta-catenin, and the C- and N-terminals of APC. In addition, DNA was extracted from formalin-fixed, paraffin wax blocks, and a 226 bp fragment of exon 3 of the beta-catenin gene was amplified, sequenced, and screened for activating mutations in the glycogen synthase kinase 3beta (GSK-3beta) phosphorylation targets. E-cadherin expression was detected in 48% of the epithelioid mesotheliomas but was observed in only 7% of sarcomatoid mesotheliomas. N-cadherin, alpha-catenin, beta-catenin, and the C- and N-terminals of APC did not show differential expression between the mesothelioma phenotypes. Abnormal nuclear localization of beta-catenin was demonstrated in 19% of mesotheliomas. Mutations of beta-catenin phosphorylation sites were not detected in any of the 62 mesotheliomas examined. Positive staining for the N-terminal of APC was seen in all of the cases of reactive mesothelial hyperplasia, as well as in all the mesotheliomas. Staining for the C-terminal of APC was negative in 23% mesotheliomas, despite being present in all the cases of reactive hyperplasia. The present study provides the first evidence that beta-catenin accumulates in the nucleus in malignant mesotheliomas. In addition, APC expression was altered in some mesotheliomas, suggesting that a truncated APC gene product may contribute to abnormal Wnt signalling and dysregulation of cell proliferation in malignant mesothelioma.     

Diffuse intrapulmonary malignant mesothelioma presenting with miliary pulmonary nodules: A case report

A 67‐year‐old male with a history of asbestos exposure presented with fever, cough, and dyspnea and was found to have diffuse granular shadowing in both lungs, right pleural effusion, and hilar and mediastinal lymphadenopathy upon chest computed tomography. For definitive diagnosis, a thoracoscopic lung biopsy was performed. Intraoperative findings showed no remarkable macroscopic changes in the visceral and parietal pleura, although a high level of hyaluronic acid in the pleural effusion was noted. Histological findings showed proliferation of atypical cells with round‐to‐oval nuclei, prominent nucleoli, and eosinophilic cytoplasms. These cells were arranged into sheets or tubules and were located predominantly in the lung parenchyma. Lymphovascular invasion was conspicuous. Immunohistochemically, tumor cells were positive for calretinin, D2‐40, and CK5/6, focally positive for Ber‐EP4, but negative for WT‐1, TTF‐1, CEA, and MOC31. Fluorescence in situ hybridization for the tumor suppressor p16 revealed homozygous deletion in the tumor cells. Therefore, we diagnosed the tumor as diffuse intrapulmonary malignant mesothelioma (DIMM). The patient had a poor response to chemotherapy and died 1 year after diagnosis. Although rare, DIMM should be considered when patients present with multiple, tiny intrapulmonary nodules, regardless of macroscopic pleural changes. Furthermore, this is the first report on p16 status in DIMM.     

Localized malignant mesothelioma of the pleura

We describe a case of malignant pleural mesothelioma appearing as a solitary pleural tumor in a 56-year-old Japanese man with no history of exposure to asbestos. A chest radiograph revealed an isolated extrapulmonary mass in the left hemithorax. The patient underwent tumor resection, but the tumor later recurred on the contralateral pleura. The patient developed cerebral metastases and died 16 months after the initial surgery. The resected tumor was sessile with broad-based pleural attachment. Microscopically, the tumor was composed of interlacing fascicles of plump spindle cells intermixed with few polygonal cells. Most of the tumor cells showed positive immunoreactivity for cytokeratins (AE1 and AE3) and vimentin. Many of the tumor cells were positive for epithelial membrane antigen, and a few were positive for desmin. In contrast, the tumor cells were consistently negative for carcinoembryonic antigen, epithelial antigen BerEP4, calretinin, S-100 protein, neuron-specific enolase, muscle actin antigen HHF35, alpha-smooth muscle actin antigen and CD34. Ultrastructurally, the tumor cells had diffusely distributed cytoplasmic intermediate filaments, desmosome-like junctions, and a few microvilli. Some tumor cells contained cytoplasmic tonofilaments. Immunohistochemical and ultrastructural findings supported the mesothelial nature of the tumor, and led us to diagnose this tumor as a sarcomatoid localized malignant mesothelioma.     

An autopsy case of diffuse malignant mesothelioma of the pericardium

A report is presented of an autopsy case of a 71-year-old Japanoae man with a diffuse malignant epithelial mesothelioma of the pericardium with massive pericardlal effusion and a thickened perkardlum. He had no history of exposure to asbestos. He suffamd severe heart failure and later died. Autopsy revealed that tho tumor had developed over the pericardlum. Microscopically, the tumor cells were arranged In an epithelial form, and histochemically. the cytoplasm of these cells contained glycogen and hyaluronlc acid. The tumor tissue showed immunohlstochemical positivity for cytokeratin, epithelial membrane antigen, vimentln, cancer antigen 125, thrombomodulin. mesothellal antigen, muscle actin and human milk fat globule. In contrast, all the tumor cells were negative for human carcinoembryonic antigen and epithelial antigen. ultrastructurally. the tumor cells had long, thin microvilli, abundant lntermedlate filaments, intracyto-plasmic lumina and long deamosomes. It Is considered that the patient had a typical malignant epithelial mesothelioma of the pericardium.