Challenges and controversies in the diagnosis of mesothelioma: Part 1. Cytology-only diagnosis, biopsies, immunohistochemistry, discrimination between mesothelioma and reactive mesothelial hyperplasia, and biomarkers

Abstract

The detection of neoplastic invasion remains the linchpin for a clear diagnosis of malignant mesothelioma. Cytology-only diagnosis of epithelioid mesothelioma on aspirated effusion fluid remains controversial. A major problem is poor sensitivity, although cytodiagnosis is achievable in many cases at a high order of specificity, especially when a large volume of effusion fluid is submitted for cytological evaluation, enabling the preparation of cell-block sections for immunohistochemical investigation and when the cytological findings can be correlated with imaging studies to assess the anatomical distribution of the lesion and evidence of nodularity of the pleural disorder and, in some cases, to demonstrate evidence of invasion. Although 'positive' and 'negative' immunohistochemical markers have proved remarkably effective in distinguishing between epithelioid mesothelioma and secondary carcinoma and other malignant tumours metastatic to serosal membranes, no mesothelial marker has 100% sensitivity and specificity for mesothelioma diagnosis, so that panels of 'positive' antibodies and markers with negative predictive value are required. At present, no tissue or serum marker (including the molecular detection of p16/CDKN2A) has been proved to have sufficient specificity, consistency and reproducibility that it can replace evidence of invasion as the decisive marker for diagnosis when there is any uncertainty concerning a diagnosis of epithelioid mesothelioma and in the case of atypical fibrous lesions of the pleura (especially collagen-rich lesions, namely fibrous pleuritis vs desmoplastic mesothelioma), in which even the assessment of invasion can be problematical as illustrated in part 2 of this review.

Malignant pleural effusion: from bench to bedside

“…The diagnostic yield of pleural fluid cytology for mesothelioma is even lower and most international guidelines advocate the use of pleural biopsy as a preferred diagnostic method over fluid cytology, though the latter is sometimes sufficient in some experienced laboratories [48][49][50][51]. In conjunction with the above limitations of cytology, the expanding use of cancer therapies targeted to tissue-specific gene expression or receptor status which necessitates the acquisition of ample tumour tissue for immunohistochemistry and/or genotyping, has led to an increasing requirement for adequately-sized pleural biopsies [52].…”

BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations

“…4,5 Moreover, either the late asbestos ban or the long latency period for full transformation to mesothelioma validate the expected increasing incidence trend and peak within 10-15 years in Italy, as well as in other European countries. 4,6,7 Immunohistochemistry is of definite support to the differential diagnosis between mesothelioma and serosal involvement by extraserosal neoplasms, 8,9 and although the distinction of mesothelioma from reactive mesothelial proliferations remains challenging, it is fundamentally based on the demonstration of stromal invasion, [10][11][12] with limited support by immunohistochemistry. 12 In fact, a variety of markers, such as desmin, epithelial membrane antigen, p53, IMP3, GLUT-1, CD146, and CD147, have been evaluated on both tissue and cytological samples, but none of them appeared to achieve sufficient diagnostic adequacy in the separation between malignant and benign mesothelial lesions.…”

“…4,6,7 Immunohistochemistry is of definite support to the differential diagnosis between mesothelioma and serosal involvement by extraserosal neoplasms, 8,9 and although the distinction of mesothelioma from reactive mesothelial proliferations remains challenging, it is fundamentally based on the demonstration of stromal invasion, [10][11][12] with limited support by immunohistochemistry. 12 In fact, a variety of markers, such as desmin, epithelial membrane antigen, p53, IMP3, GLUT-1, CD146, and CD147, have been evaluated on both tissue and cytological samples, but none of them appeared to achieve sufficient diagnostic adequacy in the separation between malignant and benign mesothelial lesions. Using fluorescence in situ hybridization (FISH), the homozygous deletion of CDKN2A gene is found in 52-88% of mesotheliomas, but not in reactive mesothelial proliferations; 23,37-39 using a cut-off value of 10% positive mesothelial cells, p16 protein expression resulted to be closely related to CDKN2A status in some, 23,38 but not all, studies, 37 thus hampering its use as a reliable marker to distinguish mesothelioma from reactive mesothelial proliferations.…”

The pathological and molecular diagnosis of malignant pleural mesothelioma: a literature review

“…However, in selected cases in which more invasive procedures are contraindicated, the cytological diagnosis of MPM, which relies on a different set of both cellular and architectural features and is supported by ancillary techniques, can be performed, although its sensitivity is low compared to histology. In fact, the published sensitivity of cytology for the diagnosis of mesothelioma ranges from 30% to 75% (8)(9)(10)(11). Moreover, in the cases in which histology is not available, a close correlation with clinical and imaging findings is essential for a definitive diagnosis.…”