Abstract
The differential diagnosis between pleural malignant mesothelioma (MM) and lung cancer is often challenging. Immunohistochemical (IHC) stains used to distinguish these malignancies include markers that are most often positive in MM and less frequently positive in carcinomas, and vice versa. However, in about 10–20% of the cases, the IHC results can be confusing and inconclusive, and novel markers are sought to increase the diagnostic accuracy.We stained 45 non-small cell lung cancer samples (32 adenocarcinomas and 13 squamous cell carcinomas) with a monoclonal antibody for BRCA1-associated protein 1 (BAP1) and also with an IHC panel we routinely use to help differentiate MM from carcinomas, which include, calretinin, Wilms Tumor 1, cytokeratin 5, podoplanin D2-40, pankeratin CAM5.2, thyroid transcription factor 1, Napsin-A, and p63. Nuclear BAP1 expression was also analyzed in 35 MM biopsies. All 45 non-small cell lung cancer biopsies stained positive for nuclear BAP1, whereas 22/35 (63%) MM biopsies lacked nuclear BAP1 staining, consistent with previous data. Lack of BAP1 nuclear staining was associated with MM (two-tailed Fisher's Exact Test, P = 5.4 × 10−11). Focal BAP1 staining was observed in a subset of samples, suggesting polyclonality. Diagnostic accuracy of other classical IHC markers was in agreement with previous studies. Our study indicated that absence of nuclear BAP1 stain helps differentiate MM from lung carcinomas. We suggest that BAP1 staining should be added to the IHC panel that is currently used to distinguish these malignancies.
Highlights
The incidence of malignant mesothelioma (MM) has increased exponentially in the US since the early ‘60s, reaching 3,200 cases per year at the beginning of this century, and has remained stable since [1]
Following studies of an epidemic of MM in Cappadocia that we linked to gene-environment interaction [13, 14], we discovered that germline truncating mutations in the BRCA1 associated protein-1 (BAP1) gene caused a very high incidence of MM, in some families in the US and abroad, in the absence of occupational exposure to asbestos [15, 16]
Strong nuclear staining was detected in ~100% of the tumor cells in all these tumors, except for 2 adenocarcinomas, in which some tumor areas contained cells showing BRCA1-associated protein 1 (BAP1) nuclear staining and some areas contained tumor nodules that were BAP1 negative
Summary
The incidence of malignant mesothelioma (MM) has increased exponentially in the US since the early ‘60s, reaching 3,200 cases per year at the beginning of this century, and has remained stable since [1]. In about 10–20% of the cases, these malignancies can produce conflicting IHC results, with both MM and lung carcinoma markers being either positive or negative in the same tumor, or showing only a fraction of tumor cells being positive. Our data, confirmed and expanded by others, showed that germline BAP1 mutations are associated with uveal melanoma, renal cell carcinoma and other malignancies, causing a condition that we named “BAP1 cancer syndrome” [18]. We tested the hypothesis that BAP1 immunostain might help improve the accuracy of the differential diagnosis between MM, which often shows no BAP1 nuclear staining, and lung cancer, which we predicted to be BAP1 positive
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