BAP1 immunohistochemistry and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis: ROC analysis of the two tests

Abstract

Differentiation of malignant pleural mesothelioma (MPM) from benign mesothelial proliferation remains problematic. Loss of nuclear staining of BRCA1-associated protein 1 (BAP1; detected using immunohistochemistry (IHC)) and homozygous deletion (HD) of p16 (detected using fluorescence in situ hybridization (FISH)) are useful for differentiation of MPM from reactive mesothelial hyperplasia (RMH), but the correlation between BAP1 expression loss and p16 HD has not been fully described. We performed BAP1 IHC and p16-specific FISH for 40 MPM and 20 RMH cases, and measured proportions of cells showing BAP1 expression and p16 HD for each case. The diagnostic accuracy for MPM and the cut-off values of the two methods were assessed using receiver operating characteristic (ROC) analysis. BAP1 expression loss, p16 HD and coexistence of both were present in 27 (67.5 %), 27 (67.5 %) and 17 (42.5 %) MPM cases, respectively. Three MPM cases (7.5 %) and all 20 RMH cases had neither BAP1 loss nor p16 HD. There was no correlation between the results of the two methods. Their combination showed higher sensitivity (92.5 %, 37/40) and estimated probability than BAP1 IHC and p16-specific FISH used alone. BAP1 IHC and p16-specific FISH have independent diagnostic value, and have increased reliability when used in combination, for MPM diagnosis.Key words: BAP1, Fluorescence in situ hybridization, Immunohistochemistry, Malignant pleural mesothelioma, p16, ROC analysis Malignant pleural mesothelioma (MPM) is a rare but highly aggressive tumor that typically originates in the parietal pleura.Tumor development is associated with exposure to the principal carcinogen (i.e., asbestos fiber). MPM incidence is predicted to increase worldwide over the coming decades as a result of widespread industrial use of asbestos.1 The prognosis for a patient with MPM is extremely poor; despite recent advancements in treatment efficacy, the median overall survival time is approximately 1 year. 2,3 Prompt treatment at an early stage results in improved outcomes, 2 so methods for early and accurate MPM diagnosis are needed. Malignant pleural mesothelioma is difficult to distinguish from reactive mesothelial hyperplasia (RMH). RMH is a benign process, but often mimics MPM histologically and cytologically. [4][5][6] Mesothelial proliferation that invades into the stromal or fat tissue is an essential histological finding of MPM. 4 This invasion is not always apparent, especially in small surface biopsies. Immunohistochemistry (IHC) assays that differentiate between MPM and RMH have been developed. Biomarkers such as glucose transporter-1 (GLUT-1), 7-11 CD146, 11-13 and oncofetal protein IMP3 9,11,14 have been described for MPM diagnosis. However, the diagnostic value of each biomarker remains controversial. Homozygous deletion (HD) of p16 (CDKN2A) is one of the common gene alterations associated with MPM. Detection of p16 HD using fluorescence in situ hybridization (FISH) can be used to differentiate between MPM and RMH (43 % to 93 % sensitivity; 100 % specific...

Epithelioid malignant mesothelioma metastatic to the skin: A case report and review of the literature

“…Current recommendations for diagnosing MM suggest initial screening panels to include positive staining for at least 2 MM markers (such as calretinin, WT1 and CK5/6) and negative staining for at least 2 carcinoma markers (such as CEA, Leu M1, BerEP4 and TTF‐1) . More recent research has shown promising results using fluorescence in situ hybridization (FISH) analysis to detect homozygous deletion of p16 and immunohistochemistry to detect loss of nuclear staining of BRCA1‐associated protein 1 (BAP1), independently or in combination, for difficult cases of MM . This is especially useful in differentiating between malignant pleural mesothelioma and benign reactive mesothelial hyperplasia, which have cytologic and histologic similarities …”

A combination of MTAP and BAP1 immunohistochemistry in pleural effusion cytology for the diagnosis of mesothelioma

“…Clinically, these markers are quite useful because they have 100% specificity for differentiating malignant mesothelial proliferations from benign proliferations . Although the sensitivity of either of these markers is relatively insufficient, the combination approach of 9p21 FISH and BAP1 IHC has been found to enhance the sensitivity …”

Loss of BRCA1‐associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions

“…So far, the BAP1 antibody has been tested primarily on biopsies. [13][14][15][16][17][18][19][20] Only a few studies have used BAP1…”