Role of p16 deletion and BAP1 loss in the diagnosis of malignant mesothelioma.

Abstract

Malignant mesothelioma (MM) is a rare but highly aggressive neoplasm. It has a poor prognosis and a median survival time of 20 months after diagnosis (1). Tumor development is associated with exposure to several known carcinogens such as asbestos fiber, rhesus virus 40, and radiation, of which asbestos exposure is the most important risk factor (2). The early clinical symptoms of MM lack specificity and are often characterized by large amounts of pleural effusion, which make clinical and imaging diagnoses difficult. Mesothelioma often goes undiagnosed until the late stages of the disease, at which time no marked effects can be achieved, regardless of whether the patient and medical team select surgery or radiotherapy and chemotherapy. Differential diagnosis of MM from reactive mesothelial hyperplasia (RMH) or metastatic carcinoma is crucial to patient care and prognosis, but distinguishing these specific conditions from each other can be very difficult. RMH is a benign condition, but it often mimics the features of neoplasm including high cellularity, the presence of numerous mitotic figures and cytologic atypia, the formation of papillary groups, the presence of necrosis, and entrapment of mesothelial cells within fibrosis, mimicking invasion (3). This makes MM and RMH appear very similar in histological appearance. Immunohistochemistry (IHC) for calretinin, podoplanin, cytokeratin 5/6, and Wilms’ tumor-1 proteins are commonly used to diagnosis MM, with a sensitivity of greater than 90%, 90–100%, 75–100%, and 70–95%, respectively (3). Although these immunohistochemical markers have high sensitivity for MM, they are also positively expressed in some RMH cases (4). Similarly, histopathologic differentiation between MM and lung adenocarcinoma is often challenging. Epithelial MM is a tumor with a small tube, acinar, flaky atypical growth pattern formed by epithelial mesothelial cells, similar to the histological structure of lung adenocarcinoma. Distinguishing MM from lung adenocarcinomas can be difficult, even when multiple immunohistochemical stains are deployed. Sometimes MM expresses “carcinoma” markers such as epithelial membrane antigen (5), and lung adenocarcinomas do not always express thyroid transcription factor 1 or Napsin A, so their sensitivity is not more than 80% (6). For this reason, it is important to identify more specific markers that facilitate the early and accurate diagnosis of MM. Recently two new markers that appeared to be useful for distinguishing benign from MM were discovered, namely p16 [cyclin-dependent kinase inhibitor 2A (CDKN2A)], a tumor suppressor gene, and BRCA1-associated protein 1 (BAP1). Deletion of p16 has proven to be a reliable way of differentiating benign from MM proliferation, which is one of the most common cytogenetic abnormalities in MM and can be detected by fluorescence in situ hybridization (FISH). P16 deletion has been found in 47.4–81.3% of MM cases, but no cases of RMH have been reported to harbor p16 deletion (4,5,7,8). However, even at a specificity of 100%, some MM cases do not show p16 deletion. Thus, another useful marker, BAP1 was identified. Previous studies have shown that BAP1 loss can occur as a result of gene deletion, point mutations, or other indirect mechanisms and BAP1 loss can be assessed by IHC (9,10). Loss of BAP1 staining has been observed in many tumors such as epithelioid atypical Spitz tumors, melanoma, renal cell carcinoma, and MM (11). The relationship between BAP1 loss and MM is significant. BAP1 loss has been reported in 15–67.5% of MM cases, with a specificity of 100% for differentiating between MM and RMH (4,7,12-15). Thus together, p16 and BAP1 are reliable markers for differentiating MM from RMH. BAP1 has also been used to identify MM and lung adenocarcinoma. Although the correlation between BAP1 loss and lung cancer is not completely understood, it is known that loss of BAP1 expression is rare in lung adenocarcinoma (16,17). Thus, it is reasonable to assume that loss of BAP1 in a thoracic malignancy would provide strong support for the diagnosis of MM. The goal of this study was to establish the value of p16 deletion detected by FISH and BAP1 loss detected by IHC for MM diagnosis, and to determine the value of p16 deletion and BAP1 loss in distinguishing MM from RMH and lung adenocarcinoma.