New Markers for Separating Benign From Malignant Mesothelial Proliferations: Are We There Yet?

Abstract

The separation of benign from malignant mesothelial proliferations is crucial to patient care but is frequently morphologically difficult.Context.— To briefly review adjunctive tests claimed to be useful in this setting and to examine in detail 2 new tests: p16 fluorescence in situ hybridization (FISH) and BRCA1-associated protein 1 (BAP1) immunohistochemistry.Objective.— Literature review with emphasis on p16 FISH and BAP1 immunohistochemistry.Design.— Glucose transporter-1, p53, insulin-like growth factor 2 messenger RNA–binding protein 3 (IMP-3), desmin, and epithelial membrane antigen have all been claimed to mark either benign or malignant mesothelial processes, but in practice they at best provide statistical differences in large series of cases, without being useful in an individual case. Homozygous deletion of p16 by FISH or loss of BAP1 has only been reported in malignant mesotheliomas and not in benign mesothelial proliferations. BAP1 appears to be lost more frequently in epithelial than mixed or sarcomatous mesotheliomas. Homozygous deletion of p16 by FISH is seen in pleural epithelial, mixed, and sarcomatous mesotheliomas, but it is much less frequent in peritoneal mesothelioma. The major drawback to both these tests is limited sensitivity; moreover, failure to find p16 deletion or BAP1 loss does not make a mesothelial process benign.Results.— In the context of a mesothelial proliferation, the finding of homozygous deletion of p16 by FISH or loss of BAP1 by immunohistochemistry is, thus far, 100% specific for malignant mesothelioma. The limited sensitivity of each test may be improved to some extent by running both tests.Conclusions.—

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

“…However, not all mesotheliomas harbor this deletion, and the sensitivity for epithelioid/biphasic MPM ranges from approximately 45% to 85%. The sensitivity of the p16 FISH test is much higher in sarcomatoid mesothelioma; in some reports, the deletion is reported in up to 100% of cases; however, other studies report a lower proportion of p16-deleted sarcomatous tumors (16).…”

“…Several recent studies have shown that the homozygous deletion of p16 by FISH is found only in mesotheliomas, whereas none of benign mesothelial proliferations showed a loss of p16 with a specificity of 100% (16,(25)(26)(27). However, not all mesotheliomas harbor this deletion, and the sensitivity for epithelioid/biphasic MPM ranges from approximately 45% to 85%.…”

“…The application of immunocytochemistry (ICC) and molecular methods, such as fluorescent in situ hybridization (FISH) performed preferentially on cell blocks, increases the diagnostic accuracy of cytology (13)(14)(15)(16). The differential diagnosis of MPM and the use of ICC and molecular markers in cytological samples are the same as in histological specimens.…”

“…Currently, BAP1 IHC and p16 FISH represent the most effective analyses to discriminate between benign and malignant pleural lesions (16,(25)(26)(27)(28)(29)(30)(31).…”

“…Currently, there is considerable variability in the reported frequency of BAP1 protein loss; epithelioid/mixed mesotheliomas lose BAP1 more frequently than the sarcomatoid pattern, approximately 60-70% and 15%, respectively. Interestingly, recent studies have shown BAP1 protein expression in all benign mesothelial proliferations and, although more data are needed, the specificity of BAP1 loss is 100%, making BAP1 an excellent biomarker in the distinction between benign and malignant mesothelial proliferations (16,(28)(29)(30)(31).…”