Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Am J Surg Pathol. 2012 Jun;36(6):818-30. doi: 10.1097/PAS.0b013e3182498be5.
We recently reported that germline mutations in BAP1 cause a familial tumor syndrome characterized by high penetrance for melanocytic tumors with distinct clinical and histologic features. Melanocytic neoplasms in affected individuals harbored BRAF mutations, showed loss of BAP1 expression, and histologically resembled so-called "atypical Spitz tumors" (ASTs). ASTs are an ill-defined and probably heterogenous group of melanocytic tumors that display histologic features seen in both Spitz nevi and melanomas. Their biological behavior cannot be reliably predicted. In view of the histologic similarities of the familial tumors and ASTs, we hypothesized that a subset of ASTs might harbor genetic alterations seen in the familial tumors. To address this hypothesis, we analyzed 32 sporadic ASTs for BRAF mutations and for BAP1 expression. Nine (28%) sporadic ASTs showed loss of BAP1 expression, of which 8 (89%) had concomitant BRAF mutations. Only 1 of the BAP1-positive ASTs (4%) had a BRAF mutation (P<0.0001). BRAF-mutated, BAP1-negative tumors were primarily located in the dermis and were composed entirely or predominantly of epithelioid melanocytes with abundant amphophilic cytoplasm and well-defined cytoplasmic borders. Nuclei were commonly vesicular and exhibited substantial pleomorphism and conspicuous nucleoli. The combination of BRAF mutation and loss of nuclear BAP1 expression thus characterizes a subset of ASTs with distinct histologic features. The typical morphology of these tumors and BAP1 immunohistochemistry provide pathologic clues that will enable accurate identification of this subset. Future studies are necessary to determine whether this subset has a predictable clinical behavior.
我们最近报道称，BAP1 种系突变会导致一种家族性肿瘤综合征，其特征为黑色素瘤的高外显率，具有独特的临床和组织学特征。受影响个体的黑色素瘤瘤中存在 BRAF 突变，表现出 BAP1 表达缺失，且在组织学上类似于所谓的“非典型 Spitz 肿瘤”（ASTs）。ASTs 是一组定义不明确且可能异质性的黑色素瘤瘤，其组织学特征可见于 Spitz 痣和黑色素瘤。它们的生物学行为无法可靠预测。鉴于家族性肿瘤和 ASTs 的组织学相似性，我们假设 ASTs 的一部分可能存在家族性肿瘤中所见的遗传改变。为了验证这一假设，我们分析了 32 例散发性 ASTs 的 BRAF 突变和 BAP1 表达情况。9 例（28%）散发性 ASTs 表现出 BAP1 表达缺失，其中 8 例（89%）同时存在 BRAF 突变。BAP1 阳性的 ASTs 中只有 1 例（4%）存在 BRAF 突变（P<0.0001）。BRAF 突变、BAP1 阴性的肿瘤主要位于真皮，完全或主要由上皮样黑色素细胞组成，细胞质丰富且嗜碱性，细胞质边界清晰。细胞核常见泡状，表现出明显的多形性和明显的核仁。因此，BRAF 突变和核 BAP1 表达缺失的组合特征是一组具有独特组织学特征的 ASTs。这些肿瘤的典型形态和 BAP1 免疫组化提供了病理线索，将有助于准确识别这一组。未来的研究有必要确定这一组是否具有可预测的临床行为。
