Diagnostic mesothelioma biomarkers in effusion cytology

Abstract

Malignant mesothelioma is a rare malignancy with a poor prognosis whose development is related to asbestos fiber exposure. An increasing role of genetic predisposition has been recognized recently. Pleural biopsy is the gold standard for diagnosis, in which the identification of pleural invasion by atypical mesothelial cell is a major criterion. Pleural effusion is usually the first sign of disease; therefore, a cytological specimen is often the initial or the only specimen available for diagnosis. Given that reactive mesothelial cells may show marked atypia, the diagnosis of mesothelioma on cytomorphology alone is challenging. Accordingly, cell block preparation is encouraged, as it permits immunohistochemical staining. Traditional markers of mesothelioma such as glucose transporter 1 (GLUT1) and insulin‐like growth factor 2 mRNA‐binding protein 3 (IMP3) are informative, but difficult to interpret when reactive proliferations aberrantly stain positive. BRCA1‐associated protein 1 (BAP1) nuclear staining loss is highly specific for mesothelioma, but sensitivity is low in sarcomatoid tumors. Cyclin‐dependent kinase inhibitor 2A (CDKN2A)/p16 homozygous deletion, assessed by fluorescence in situ hybridization, is more specific for mesothelioma with better sensitivity, even in the sarcomatoid variant. The surrogate marker methylthioadenosine phosphorylase (MTAP) has been found to demonstrate excellent diagnostic correlation with p16. The purpose of this review is to provide an essential appraisal of the literature regarding the diagnostic value of many of these emerging biomarkers for malignant mesothelioma in effusion cytology.

Molecular cytology of the respiratory tract and pleura

“…The most commonly used clone is C-4 (Santa Cruz Biotechnology, Inc.). 71 BAP1 IPOX has greater than 95% specificity in surgical specimens, approaching 100%. The reported specificity in cell blocks is also close to 100% in the vast majority of reports.…”

“…Studies that report lower accuracy may be affected by suboptimal cutoffs, variable staining intensities, tumour mixing with reactive mesothelial cells, interobserver variation, antigenicity loss from alcohol fixation, lack of internal positive control, and/or tumour subtype variations. 71 It must be noted that the above alterations are seen in other malignancies besides mesothelioma. Thus, mesothelial lineage must be established by other IPOX stains before these tests are used to diagnose mesothelioma.…”

“…A pleural effusion cytology specimen is often the first material available for diagnosing mesothelioma, 71 yet the diagnosis is particularly challenging on cytology. The diagnosis of mesothelioma on effusion specimens is limited to the epithelioid subtype, since generally the sarcomatoid subtype does not shed into fluid 72 .…”

Evidence‐based diagnostic performance of novel biomarkers for the diagnosis of malignant mesothelioma in effusion cytology

“…A metaanalysis to evaluate the diagnostic performance of BAP1 loss has shown that the sensitivity by IHC is 0.74 in epithelioid mesothelioma, 0.50 in biphasic mesothelioma, and 0.07 in sarcomatoid, 8,9 with confirmation provided by subsequent reports. 10,11 CDKN2A has the same unsatisfactory sensitivity (0.48-0.88), which is slightly higher (up to 0.80-1.00) for sarcomatoid mesothelioma, 10,12 and high specificity according to recent reviews 13,14 also in cytological material. 11 Recently, methylthioadenosine (MTAP) IHC loss has emerged as another potentially useful biomarker.…”

Prognostic Significance of JMJD3 Expression in Pleural Mesotheliomas

“…Panels must be modified for diagnosis, as mesothelioma often presents with an acellular/paucicellular effusion where the role of IHC for diagnosis of sarcomatoid mesothelioma is somewhat more limited [7]. IHC for BAP1, MTAP or FISH for CDKN2A homozygous deletion can be useful for determining malignancy and is especially useful in cytology samples as cytological material is usually the first and only sample available in the diagnosis of mesothelioma, hence the use of immunocytochemical biomarkers with high sensitivity and specificity are desirable [8].…”