EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an asbestos related tumour difficult to detect early and treat effectively. Asbestos causes genetic modifications and cell signalling events that favour the resistance of MPM to apoptosis and chemotherapy. Only a small number of patients, approximately 10%, survive more than 3 years. The aim of our study was to assess possible differences within signalling pathways between short term survivors (survival <3 years; STS) and long term survivors (survival >3 years; LTS) of MPM. METHODS: 37 antibodies detecting proteins engaged in cell signalling pathways, enforcing proliferation, antiapoptosis, angiogenesis and other cellular activities were investigated by tissue microarray (TMA) technology. RESULTS: Epidermal growth factor receptor (EGFR) was expressed stronger in LTS whereas platelet derived growth factor receptor (PDGFR) signalling was more abundant in STS. Expression of TIE2/Tek, a receptor for tyrosine kinases involved in angiogenesis, was differentially regulated via PDGFR and thus is more important in STS. Antiapoptosis was upregulated in STS by signal transducer and activator of transcription 1 (STAT1)-survivin and related molecules, but not in LTS. Our study provides novel insights into the regulatory mechanisms of signalling pathways in MPM, which differentially promote tumour growth in LTS and STS. CONCLUSION: We have demonstrated that small scale proteomics can be carried out by powerful linkage of TMA, immunohistochemistry and statistical methods to identify proteins which might be relevant targets for therapeutic intervention.

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).

New Insights on Diagnostic Reproducibility of Biphasic Mesotheliomas: A Multi-Institutional Evaluation by the International Mesothelioma Panel From the MESOPATH Reference Center.

INTRODUCTION: The 2015 WHO classification of tumors categorized malignant mesothelioma into epithelioid, biphasic (BMM), and sarcomatoid (SMM) for prognostic relevance and treatment decisions. The survival of BMM is suspected to correlate with the amount of the sarcomatoid component. The criteria for a sarcomatoid component and the interobserver variability between pathologists for identifying this component are not well described. In ambiguous cases, a "transitional" (TMM) subtype has been proposed but was not accepted as a specific subtype in the 2015 WHO classification. The aims of this study were to evaluate the interobserver agreement in the diagnosis of BMM, to determine the nature and the significance of TMM subtype, and to relate the percentage of sarcomatoid component with survival. The value of staining for BRCA-1-associated protein (BAP1) and CDKN2A(p16) fluorescence in situ hybridization (FISH) were also assessed with respect to each of the tumoral components. METHODS: The study was conducted by the International Mesothelioma Panel supported by the French National Cancer Institute, the network of rare cancer (EURACAN) and in collaboration with the International Association for the Study of Lung Cancer (IASLC). The patient cases include a random group of 42 surgical biopsy samples diagnosed as BMM with evaluation of SMM component by the French Panel of MESOPATH experts was selected from the total series of 971 BMM cases collected from 1998 to 2016. Fourteen international pathologists with expertise in mesothelioma reviewed digitally scanned slides (hematoxylin and eosin - stained and pan-cytokeratin) without knowledge of prior diagnosis or outcome. Cases with at least 7 of 14 pathologists recognizing TMM features were selected as a TMM group. Demographic, clinical, histopathologic, treatment, and follow-up data were retrieved from the MESOBANK database. BAP1 (clone C-4) loss and CDKN2A(p16) homozygous deletion (HD) were assessed by immunohistochemistry (IHC) and FISH, respectively. Kappa statistics were applied for interobserver agreement and multivariate analysis with Cox regression adjusted for age and gender was performed for survival analysis. RESULTS: The 14 panelists recorded a total of 544 diagnoses. The interobserver correlation was moderate (weighted Kappa = 0.45). Of the cases originally classified as BMM by MESOPATH, the reviewers agreed in 71% of cases (385 of 544 opinions), with cases classified as pure epithelioid in 17% (93 of 544), and pure sarcomatoid in 12% (66 of 544 opinions). Diagnosis of BMM was made on morphology or IHC alone in 23% of the cases and with additional assessment of IHC in 77% (402 of 544). The median overall survival (OS) of the 42 BMM cases was 8 months. The OS for BMM was significantly different from SMM and epithelioid malignant mesothelioma (p < 0.0001). In BMM, a sarcomatoid component of less than 80% correlated with a better survival (p = 0.02). There was a significant difference in survival between BMM with TMM showing a median survival at 6 months compared to 12 months for those without TMM (p < 0.0001). BAP1 loss was observed in 50% (21 of 42) of the total cases and in both components in 26%. We also compared the TMM group to that of more aggressive patterns of epithelioid subtypes of mesothelioma (solid and pleomorphic of our large MESOPATH cohort). The curve of transitional type was persistently close to the OS curve of the sarcomatoid component. The group of sarcomatoid, transitional, and pleomorphic mesothelioma were very close to each other. We then considered the contribution of BAP1 immunostaining and loss of CDKN2A(p16) by FISH. BAP1 loss was observed in 50% (21 of 41) of the total cases and in both component in 27% of the cases (11 of 41). There was no significant difference in BAP1 loss between the TMM and non-TMM groups. HD CDKN2A(p16) was detected in 74% of the total cases with no significant difference between the TMM and non-TMM groups. In multivariate analysis, TMM morphology was an indicator of poor prognosis with a hazard ratio = 3.2; 95% confidence interval: 1.6 - 8.0; and p = 0.003 even when compared to the presence of HD CDKN2A(p16) on sarcomatoid component (hazard ratio = 4.5; 95% confidence interval: 1.2 - 16.3, p = 0.02). CONCLUSIONS: The interobserver concordance among the international mesothelioma and French mesothelioma panel suggests clinical utility for an updated definition of biphasic mesothelioma that allows better stratification of patients into risk groups for treatment decisions, systemic anticancer therapy, or selection for surgery or palliation. We also have shown the usefulness of FISH detection of CDKN2A(p16) HD compared to BAP1 loss on the spindle cell component for the separation in ambiguous cases between benign florid stromal reaction from true sarcomatoid component of biphasic mesothelioma. Taken together our results further validate the concept of transitional pattern as a poor prognostic indicator.

Molecular pathology of gastric carcinoma: progress and prospects.

Gastric carcinoma is the fourth most common malignancy in Western Europe and a major cause of cancer morbidity and mortality worldwide, particularly in the Far East and in areas of South America. The natural history of the disease is not fully established, and there is a need to elucidate the molecular mechanisms of gastric carcinogenesis in order to understand its pathogenesis and to develop molecular markers for clinical diagnostic use. Molecular analysis of colonic carcinogenesis has increased our understanding of its pathogenesis and has demonstrated multistage carcinogenesis in a human cancer. Research in gastric carcinoma has not achieved such significant progress, although a start has been made. We analyze some of the interpretation problems in molecular pathology affecting progress that are of interest to the histopathologist and review recent studies on the molecular biology of gastric carcinoma involving flow cytometry, cytogenetics, allele loss analysis, and transfection. We also summarize current knowledge about each of the major oncogenes and suppressor genes, attempting, in particular, to correlate gene abnormalities with morphologic appearances. The expanding field of cell proliferation and growth factors is outlined, gastric and colon carcinomas are compared, and gastric carcinoma is considered as a model system for the study of differentiation. This report concludes by suggesting directions for future research.

acp. Best practice no 161. Examination of lung specimens.

This article gives guidance for the handling and examination of various types of lung tissue specimens to provide: (1) accurate diagnosis and assessment of severity of disease; (2) sufficient information for the accurate staging of tumours; and (3) an assessment of the contribution of various occupational disorders to the cause of death.

High temperature antigen retrieval and loss of nuclear morphology: a comparison of microwave and autoclave techniques.

The use of high temperature antigen retrieval methods has been of major importance in increasing the diagnostic utility of immunocytochemistry. However, these techniques are not without their problems and in this report attention is drawn to a loss of nuclear morphological detail, including mitotic figures, following microwave antigen retrieval. This was not seen with an equivalent autoclave technique. This phenomenon was quantified using image analysis in a group of B cell lymphomas stained with the antibody L26. Loss of nuclear morphological detail may lead to difficulty in identifying cells accurately, which is important in the diagnostic setting-for example, when trying to distinguish a malignant lymphoid infiltrate within a mixed cell population. In such cases it would clearly be wise to consider the use of alternative high temperature retrieval methods and accept their slightly lower staining enhancement capability compared with the microwave technique.

Mediastinal mixed dendritic cell sarcoma with hybrid features.

This report describes a recurrent sarcoma involving the soft tissues of the posterior mediastinum with features of both follicular dendritic and interdigitating dendritic cells. Histologically, the tumour, which was a recurrent neoplasm 19 years after the initial removal, was composed of bland spindle shaped cells with interspersed inflammatory cells, predominantly lymphocytes. Immunohistochemically, the spindle cells were positive for S100 protein, CD45, CD68, and vimentin, but negative for CD21 and CD35 (markers of follicular dendritic cells). The immunophenotype was in keeping with interdigitating dendritic cells. However, ultrastructural examination demonstrated elongated cell processes joined by desmosome-like junctions-features in keeping with follicular dendritic cells. Follicular dendritic cell sarcoma and interdigitating dendritic cell sarcoma are rare neoplasms and a high index of suspicion is required to make a correct diagnosis. Immunohistochemistry and/or electron microscopy are required for a definitive diagnosis. This case shows that hybrid neoplasms can occur, which have features of both follicular and interdigitating dendritic cells.

Phraseology in pathology reports. A comparative study of interpretation among pathologists and surgeons.

This questionnaire based study compared the interpretation, use and preferences, among pathologists and surgeons, of descriptive phrases found in surgical reports. The results show that there is a wide variation in individual interpretation of phrases in both groups. The frequency of usage of phrases by pathologists and preference for phrases by surgeons were also diverse. The adoption of a limited number of descriptive phrases that are mutually understood and acceptable for use by both pathologists and clinicians is recommended to avoid interpretive ambiguity in pathology reports.

Consistency in the observation of features used to classify duct carcinoma in situ (DCIS) of the breast.

AIM: To determine interobserver and intra-observer agreement in the assessment of cytological grade and intraduct necrosis in pure duct carcinoma in situ (DCIS) of the breast. METHODS: Sixty unselected cases with illustrated diagnostic criteria were circulated to 19 practising histopathologists. RESULTS: Overall agreement was moderate for cytological grade in three categories: 71% agreement; weighted kappa (kappa w), 0.36; intraduct necrosis in three categories (absent, present, extensive): 76% agreement; kappa w, 0.57; and the Van Nuys classification system: 73% agreement; kappa w, 0.48. Agreement was no better among observers participating in the National External Quality Assurance Programme. Intra-observer agreement for cytological assessment (69.6% agreement; kappa w, 0.52) and intraduct necrosis (68.3% agreement; kappa w, 0.48) was moderate, suggesting that individual variation rather than precision of criteria contributes to the lack of agreement. CONCLUSIONS: Moderate agreement on observations can be achieved by non-specialist pathologists, with better agreement on necrosis than cytological grade. There was evidence of consistent individual bias towards over or under scoring cytological grade, which could be corrected with adequate and prompt feedback.

Primary adenocarcinoma of the cervix. A clinicopathologic study of prognostic variables in 55 cases.

Fifty-five primary invasive adenocarcinomas of the cervix, presenting over a 20-year period, were retrospectively studied with particular reference to clinical and pathologic prognostic indicators. Mean age at presentation was 54.5 years (range 27-91), with an age distribution showing two incidence peaks of equal size in the 31-35 and 61-65 groups, respectively. Twenty-four patients died of the disease and the remaining patients were followed up for a mean of 4.9 years (range 1-17). The results were analyzed using a Cox's proportional hazards survival model. The independent good prognostic indicators were early tumor stage (P < 0.001). and young patient age (P < 0.001) at presentation. The presence within the tumor of numerous intraepithelial lymphocytes and the concomitant occurrence of background in situ carcinoma were also good prognostic indicators, although these did not operate independently of stage and age. Histologic tumor subtype and grade of tumor differentiation were not significant prognostic factors. Treatment did not have a significant independent effect on survival. No definite conclusions could be drawn about the effect of oral contraceptives on the disease process.

Epithelial and neuroendocrine tumors of the duodenum.

This review considers the pathologic features of epithelial tumors and tumor-like lesions of the duodenum and highlights potential pitfalls in their histological diagnosis. The tumor-like lesions include Brunner's gland hamartoma, myoepithelial hamartoma, and the mucosal polyps of the Peutz-Jeghers and juvenile polyposis syndromes. The true neoplasms are of two broad groups. The first includes duodenal adenomas and carcinomas, whose microscopic features, histogenetic relationships, and clinical significance closely mimic their commoner counterparts in the large intestine and which, when multiple, are closely associated with familial adenomatous polyposis coli. The second includes a number of uncommon endocrine cell tumors showing a great diversity of histological pattern, and which may be single or multiple. Among these are typical argyrophil carcinoids, which may secrete gastrin to give rise to the Zollinger-Ellison syndrome, and which may occur as part of the inherited multiple endocrine neoplasia syndrome type 1 (MEN-1); glandular somatostatin-rich, apparently nonargyrophil, carcinoids containing psammoma bodies that can be easily confused histologically with adenocarcinomas, and which are linked to type 1 neurofibromatosis (von Recklinghausen's disease) and phaeochromocytoma; and the gangliocytic paraganglioma, a rare tumor composed of neural elements, ganglion cells, and endocrine cells. Accurate histologic diagnosis of mucosal tumors and tumor-like lesions of the duodenum is important not only for immediate patient management, but also because it may provide the first clue to the existence of an inherited tumor syndrome, with its broader implications for the patient's family and potentially important consequences for genetic counseling.

'Pseudomesotheliomatous' carcinomas of the pleura: a 10-year analysis of cases from the Environmental Lung Disease Research Group, Cardiff.

AIMS: To undertake a clinicopathological study of diffuse serosal neoplasms of epithelial histogenesis which clinically and pathologically mimic malignant pleural mesothelioma. METHODS AND RESULTS: Over a 10-year (1990-2000) study period 53 carcinomas mimicking diffuse pleural mesothelioma ('pseudomesotheliomatous' carcinoma) were identified. The study group comprised 50 men and three females, age range 33-77 (median 68) years. In 46 (87%) cases there was a history of smoking and in 40 (76%) cases a history of asbestos exposure. Histologically the pleural 'pseudomesotheliomatous' carcinomas could be divided into two broad groups: primary pulmonary carcinomas with florid pleurotropic growth (n = 47), of which 34 (70%) were adenocarcinomas; and diffuse carcinomatous involvement of the pleura by metastatic tumour (n = 6). This latter group comprised two transitional cell carcinomas of bladder, one renal (clear) cell carcinoma, one ductal pancreatic adenocarcinoma, one prostatic adenocarcinoma and one squamous cell carcinoma of parotid gland origin. Follow-up data were available in 35 cases. Regardless of tumour type, survival was poor (median 8 months) and comparable to diffuse pleural mesothelioma. CONCLUSIONS: Pleural 'pseudomesotheliomatous' carcinomas are uncommon (comprising 6% of referrals), pathologically heterogeneous tumours with poor prognosis. Tissue diagnosis should be obtained in all cases of suspected diffuse pleural neoplasia. By light microscopy and immunophenotype many of the tumours mimicked malignant mesothelioma. In particular, an awareness that all neoplasms exhibiting squamous differentiation may express cytokeratin 5/6 and thrombomodulin is important to prevent misinterpretation. In this respect, calretinin is regarded as the most specific and sensitive mesothelial marker. Misdiagnosis may have medico-legal implications in asbestos-related compensation claims.

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 pathology associated with therapeutic procedures in malignant mesothelioma.

AIMS: To describe iatrogenic pathological lesions in malignant pleural mesothelioma. METHODS AND RESULTS: All cases of malignant pleural mesothelioma confirmed by antemortem pleural biopsy and undergoing post mortem examination over a 7-year period (1995-2001) formed the study group. This comprised 48 malignant pleural mesotheliomas [epithelioid (n = 21), biphasic (n = 14) and sarcomatoid (n = 13)]. Twenty-eight of 48 (58%) had received chemical (talc) pleurodesis, 30/48 (63%) palliative localized radiotherapy, 6/48 (13%) chemotherapy, and 14/48 (30%) surgery [12/48 (26%) pleural decortication and 2/48 (4%) pleuropneumonectomy]. CONCLUSIONS: Talc pleurodesis induces a marked pseudosarcomatous fibroblastic proliferation which may impart a biphasic pattern to the neoplasm. In more chronic cases, paucicellular fibrosis with a foreign body giant cell reaction is noted. The talc is polarizable and deposited in linear fashion within the tumour. In 2/28 (7%) pleurodesis cases platyform ferruginous bodies were seen in the peripheral alveolated lung parenchyma and these mimicked asbestos bodies. An awareness of this is important to prevent false attribution to asbestos. Talc could be identified by transmission electron microscopic mineral analysis in 5/15 (33%) cases examined. Tumour nodules developing subjacent to iatrogenic wound sites were noted in 8/48 (17%) cases. In 6/8 (75%) of these cases, comparative assessment of the locally irradiated subcutaneous chest wall tumour, with background pleural mesothelioma, showed no morphological difference in architectural tumour growth pattern, extent of necrosis, cytological or nuclear pleomorphism, mitotic activity or tumour immunophenotype. In 2/8 (25%) cases the locally irradiated tumour showed prominent bizarre multinucleated tumour giant cells and intense mixed inflammation, a feature not seen in the background (non-irradiated) tumour. All six malignant pleural mesotheliomas receiving chemotherapy appeared refractory to treatment in that chemotherapy did not appear to have any significant effect on the tumour morphology, cytonuclear pleomorphism, mitotic activity, extent of necrosis or immunophenotype. In the 12 decortication specimens and two pleuropneumonectomy resections, post mortem examination identified evidence of residual malignant mesothelioma of similar morphological subtype and immunophenotype to the resected tumour.

Primary malignant gonadal mesotheliomas and asbestos.

AIMS: The clinicopathological, immunohistochemical and aetiological aspects, with respect to asbestos, of seven primary gonadal mesotheliomas (three intratesticular, four ovarian) are described and compared. These tumours are extremely rare, poorly described and the knowledge of their natural history is very limited. METHODS AND RESULTS: The cases were collated from the UK Health and Safety Executive Mesothelioma Register over a 24-year period (1968-91). Primary mesotheliomas of the tunica vaginalis and ovary comprised 0. 09% (10 cases) and 0.03% (three cases) of mesothelioma deaths, respectively. No primary intratesticular (non-tunica vaginalis) malignant mesotheliomas have been described. In this study, we present seven (three intratesticular, four ovarian) primary malignant gonadal mesotheliomas. In both genders the tumours show a similar age distribution (with median onset in the sixth decade), a similar association with asbestos (in approximately 50% cases), a diverse histological spectrum (with predominantly tubulopapillary epithelial subtype tumours) and an immunophenotype that is comparable with malignant pleural and peritoneal mesothelioma. The clinical course appears variable (mean, 26 months; range, 9-50 months). All tumours in the study presented as localized masses and their prognosis appeared more favourable than that of diffuse pleural and peritoneal cases. CONCLUSIONS: An awareness of the existence of these rare forms of malignant mesothelioma is important to prevent misdiagnosis. Immunohistochemistry has an important role in confirmation of the diagnosis. The accurate diagnosis of primary gonadal mesothelioma has potentially important medicolegal compensation considerations as a significant proportion of these cases are associated with asbestos.

The value of lymph node imprint cytodiagnosis: an assessment of interobserver agreement and diagnostic accuracy.

The aim of this study was to assess the reliability of cytodiagnosis of lymph node imprints without fixed tissue sections. One hundred randomly selected archival cases were used in the study. These air-dried May-Grünwald-Giemsa imprint slides were assessed independently and blind by three pathologists. Cases were assigned to one of four diagnostic categories: reactive changes, non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD) and secondary malignancy. Each broad diagnosis was compared with the 'correct' reviewed histological diagnosis to calculate interobserver agreement and diagnostic accuracy. The overall kappa score (+0.59) was indicative of moderate agreement. The mean pathologist diagnostic accuracy was 78%, with complete agreement with the histological diagnosis in 61% of cases. The main diagnostic difficulties were in the distinction between reactive changes and NHL and distinguishing NHL from HD. Further diagnostic classification, e.g. typing of lymphomas and subclassification of Hodgkin's disease, was not found to be reliable using the imprints alone. With these limitations in mind, pathologists should be able to use lymph node imprints for cytodiagnosis in selected cases. The study also emphasized the utility of imprints as a corollary to the histology and as a tool for cytology training and continuing education.

Unusual intraparenchymal growth patterns of malignant pleural mesothelioma.

AIMS: Malignant pleural mesothelioma is known to mimic morphologically a number of diverse reactive and neoplastic conditions. We describe three unusual intraparenchymal growth patterns of malignant mesothelioma seen in a series of 200 malignant pleural mesotheliomas. The diagnostic pitfalls associated with these findings are described and their potential medico-legal implications are highlighted. METHODS AND RESULTS: The study group comprised 200 malignant pleural mesotheliomas. In each case diagnosis was morphologically confirmed with ancillary immunohistochemistry using a broad panel of both mesothelial and epithelial markers. The patterns of intraparenchymal growth were documented and grouped as: direct subpleural; lymphangitic; and other. The 200 malignant pleural mesotheliomas comprised 118 epithelioid, 57 biphasic and 25 sarcomatoid, subtyped according to the WHO classification. Direct subpleural invasion was seen in 42 cases, lymphangitic spread in 27 cases. Other less well-defined intraparenchymal patterns included three sarcomatoid subtype malignant mesotheliomas exhibiting an intra-alveolar growth pattern mimicking epithelioid haemangioendothelioma. One epithelioid subtype malignant mesothelioma contained an intraparenchymal tumour nodule microscopically comprising lepidic spread of neoplastic cells over maintained alveolar structures mimicking bronchioloalveolar carcinoma. One epithelioid subtype malignant mesothelioma morphologically had areas in which alveoli were distended by discohesive epithelioid neoplastic cells with no interstitial invasion. The appearances mimicked desquamative interstitial pneumonia. Immunohistochemistry played an important role in the definitive diagnosis of each unusual parenchymal tumour deposit. In 126 malignant mesotheliomas no invasion of the subjacent lung parenchyma was identified. CONCLUSIONS: An awareness of the unusual parenchymal growth pattern in malignant mesothelioma is important to prevent misdiagnosis of other entities. In the medico-legal setting, the presence of epithelioid haemangioendothelioma or bronchioloalveolar carcinoma (in the absence of asbestosis) may be deemed to impact upon the patient's anticipated life expectancy and thereby would decrease the compensation settlement.

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.