Donati Michele, Martinek Petr, Steiner Petr, Grossmann Petr, Vanecek Tomas, Kastnerova Liubov, Kolm Isabel, Baneckova Martina, Donati Pietro, Kletskaya Irina, Kalmykova Antonina, Feit Josef, Blasch Petr, Szilagyi Diana, Baldi Alfonso, Persichetti Paolo, Crescenzi Anna, Michal Michal, Kazakov Dmitry V
Department of Pathology, University Hospital Campus Bio-Medico, Rome, Italy.
Sikl's Department of Pathology, Medical Faculty in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
Mod Pathol. 2022 May;35(5):664-675. doi: 10.1038/s41379-021-00976-7. Epub 2021 Dec 2.
BAP1-inactivated melanocytic tumor (BIMT) is a group of melanocytic neoplasms with epithelioid cell morphology molecularly characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, and a mutually exclusive mitogenic driver mutation, more commonly BRAF. BIMTs can occur as a sporadic lesion or, less commonly, in the setting of an autosomal dominant cancer susceptibility syndrome caused by a BAP1 germline inactivating mutation. Owing to the frequent identification of remnants of a conventional nevus, BIMTs are currently classified within the group of combined melanocytic nevi. "Pure" lesions can also be observed. We studied 50 BIMTs from 36 patients. Most lesions were composed of epithelioid melanocytes of varying size and shapes, resulting extreme cytomorphological heterogeneity. Several distinctive morphological variants of multinucleated/giant cells were identified. Some hitherto underrecognized microscopic features, especially regarding nuclear characteristics included nuclear blebbing, nuclear budding, micronuclei, shadow nuclei, peculiar cytoplasmic projections (ant-bear cells) often containing micronuclei and cell-in-cell structures (entosis). In addition, there were mixed nests of conventional and BAP1-inactivated melanocytes and squeezed remnants of the original nevus. Of the 26 lesions studied, 24 yielded a BRAF mutation, while in the remaining two cases there was a RAF1 fusion. BAP1 biallelic and singe allele mutations were found in 4/22 and 16/24 neoplasms, respectively. In five patients, there was a BAP1 germline mutation. Six novel, previously unreported BAP1 mutations have been identified. BAP1 heterozygous loss was detected in 11/22 lesions. Fluorescence in situ hybridization for copy number changes revealed a related amplification of both RREB1 and MYC genes in one tumor, whereas the remaining 20 lesions studied were negative; no TERT-p mutation was found in 14 studied neoplasms. Tetraploidy was identified in 5/21 BIMTs. Of the 21 patients with available follow-up, only one child had a locoregional lymph node metastasis. Our results support a progression of BIMTs from a conventional BRAF mutated in which the original nevus is gradually replaced by epithelioid BAP1-inactivated melanocytes. Some features suggest more complex underlying pathophysiological events that need to be elucidated.
BAP1失活的黑素细胞肿瘤（BIMT）是一组具有上皮样细胞形态的黑素细胞肿瘤，其分子特征是位于3p21染色体上的肿瘤抑制基因BAP1功能丧失，以及相互排斥的促有丝分裂驱动基因突变，最常见的是BRAF。BIMT可作为散发性病变出现，或较少见地出现在由BAP1种系失活突变引起的常染色体显性癌症易感性综合征背景下。由于经常发现传统痣的残余部分，BIMT目前被归类于复合性黑素细胞痣组。也可观察到“单纯性”病变。我们研究了来自36例患者的50个BIMT。大多数病变由大小和形状各异的上皮样黑素细胞组成，导致细胞形态学极度异质性。识别出了几种多核/巨细胞的独特形态变体。一些迄今未被充分认识的微观特征，尤其是关于核特征的，包括核泡、核芽、微核、阴影核、通常含有微核的特殊细胞质突起（蚁熊细胞）和细胞内细胞结构（内吞作用）。此外，还有传统黑素细胞和BAP1失活黑素细胞的混合巢以及原始痣的挤压残余物。在研究的26个病变中，24个检测到BRAF突变，而其余2例存在RAF1融合。在22个肿瘤中的4个和24个肿瘤中的16个分别发现了BAP基因双等位基因突变和单等位基因突变。在5例患者中存在BAP1种系突变。已鉴定出6个新的、以前未报告的BAP1突变体。在22个病变中的11个检测到BAP1杂合性缺失。对拷贝数变化进行的荧光原位杂交显示，1个肿瘤中RREB1和MYC基因均有相关扩增，而其余20个研究病变均为阴性；在14个研究肿瘤中未发现TERT-p突变。在21个BIMT中的5个中鉴定出四倍体。在21例有随访资料的患者中，只有1名儿童发生了局部区域淋巴结转移。我们的结果支持BIMT从传统BRAF突变进展而来，其中原始痣逐渐被上皮样BAP1失活黑素细胞取代。一些特征提示存在更复杂的潜在病理生理事件，需要进一步阐明。
