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Symptoms of malignant pleural mesothelioma (MPM) are often non-specific and whilst a preliminary diagnosis of suspected MPM can be made clinically and radiologically such as by CT scan, the current gold standard diagnostic method is by pathologic examination of tissue biopsy. If not, the very least a cytology specimen from the pleural effusion should be examined. The pathologic examination of the tissue biopsy begins with the histologic examination of the tissue via haematoxylin and eosin (H&E) staining. The histologic examination of the tissue biopsy allows the assessment of the presence of a tumour, or if the cellular proliferation is due to reactive mesothelial hyperplasia (RMH).

If a tumour is present, then it is important to determine the lineage of the tumour by immunohistochemistry (IHC). There are many IHC markers which have varying sensitivity and specificity for mesothelial versus epithelial (carcinoma) lineage. As such, there is no one specific marker, but instead a panel of IHC markers are recommended to determine the lineage of the tumour cells. At least three mesothelial (eg calretinin, CK5/6, D2-40) and three epithelial markers (eg TTF-1, Claudin-4, MOC-31) are suggested in the panel. Once the cells are confirmed to be mesothelial in origin, then the presence of invasion into the adjacent adipose tissue, skeletal muscle or lung is the sine qua non of diagnosing MPM. If the tumour cells are confirmed to be epithelial, then further IHC markers would be warranted in determining the origin of the metastatic carcinoma.

MPM is classified into three specific subtypes – epithelioid, sarcomatoid and biphasic. Epithelioid MPM is composed of cells which display a round to epithelioid morphology and contain abundant cytoplasm. The tumour cells are arranged in various patterns including tubular, papillary and nests. Sarcomatoid mesothelioma is composed of spindled shaped cells which may display mild to marked nuclear pleomorphism. These spindled cells may be arranged in a fascicular or a haphazard pattern. Heterologous elements such as bone or cartilage may also be present. When the spindle cells are set in a thick, dense, collagenous fibrous stroma, then a diagnosis of desmoplastic mesothelioma is more appropriate and this is a variant of sarcomatoid mesothelioma. The biphasic MPM is a combination of both epithelioid and sarcomatoid variants.

At times, a cytology specimen may only be available for assessment. Cytologically, malignant mesothelioma cells are arranged in larger clusters; and the cells have high nuclear to cytoplasmic ratio and scalloped borders. However, RMH may also display such cytologic features. As such, IHC markers should be performed on the cell block preparation of the cytology specimen in order to determine the lineage of the cellular infiltrate. Even after the cells are confirmed to be mesothelial by IHC, and although the above cytologic features may suggest MPM, these features are not specific and a definitive diagnosis of MPM cannot be made on cytologic examination alone.

As mentioned previously, the presence of invasion into adjacent tissue by mesothelial cells is essential in definitively diagnosing MPM. However, often the presence of invasion is not assessable due to the nature of the biopsy, as often the biopsy is too superficial. In addition, cytologic examination will also not allow the assessment of tissue invasion by the tumour cells in the pleural effusion or fine needle aspiration. Recent developments in demonstrating the loss of BAP-1 and/or CDKN2A gene in mesothelial cells have improved the diagnostic yield of superficial biopsies and cytology specimens.

When the cellular proliferation in tissue biopsy or cytology specimen have been determined to be of mesothelial in origin, then the loss of nuclear expression of BAP-1 by IHC and/or homozygous loss of CDKN2A gene by fluorescence in-situ hybridisation (FISH) have shown 100% specificity in the diagnosis of MPM. Since FISH testing is only available in specialised laboratories and also requires expert scientists and/or pathologists to interpret, loss of cytoplasmic MTAP expression by IHC has also been shown to be a good surrogate of homozygous CDKN2A loss.

Many current studies have shown an increased sensitivity in diagnosing MPM by a combination of BAP-1 and MTAP IHC or BAP-1 IHC and CDKN2A loss by FISH, compared to individual biomarker assessment. It is worth noting that all these markers yield 100% specificity with varying sensitivity in diagnosing MPM. As such, a stepwise approach in diagnosing MPM may be employed by performing BAP-1 and MTAP IHC testing first, before embarking on a more complex FISH testing for loss of CDKN2A.

A more comprehensive and detailed explanation on the pathological diagnosis of MPM is available in the paper by Rozitis et al. 2020 The Use of Immunohistochemistry, Fluorescence in situ Hybridization, and Emerging Epigenetic Markers in the Diagnosis of Malignant Pleural Mesothelioma (MPM): A Review

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