Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
Am J Surg Pathol. 2020 Dec;44(12):1677-1684. doi: 10.1097/PAS.0000000000001575.
Retiform and composite hemangioendotheliomas (CHEs) are both locally aggressive, rarely metastasizing vascular neoplasms characterized by arborizing vascular channels lined by endothelial cells with a hobnail morphology. CHE displays additional cytologic and architectural components, including often vacuolated epithelioid cells, solid areas, or features reminiscent of well-differentiated angiosarcoma. Triggered by an index case of a soft tissue retiform hemangioendothelioma (RHE) which revealed a YAP1-MAML2 gene fusion by targeted RNA sequencing, we sought to investigate additional cases in this morphologic spectrum for this genetic abnormality. A total of 24 cases, 13 RHE and 11 CHE involving skin and soft tissue were tested by fluorescence in situ hybridization using custom BAC probes for rearrangements involving these genes. An additional visceral CHE with neuroendocrine differentiation was tested by targeted RNA sequencing. Among the soft tissue cohort, 5/13 (38%) RHE and 3/11 (27%) CHE showed YAP1 gene rearrangements, with 5 cases showing a YAP1-MAML2 fusion, including all 3 CHE. The single neuroendocrine CHE showed the presence of a PTBP1-MAML2 fusion. All YAP1-positive CHE lesions occurred in female children at acral sites, compared with fusion-negative cases which occurred in adults, with a wide anatomic distribution. YAP1-positive RHE occurred preferentially in males and lower limb, compared with negative cases. These results suggest that RHE and CHE represent a morphologic continuum, sharing abnormalities in YAP1 and MAML2 genes. In contrast, the neuroendocrine CHE occurring in a 37-year-old male harbored a distinct PTBP1-MAML2 fusion and showed aggressive clinical behavior (pancreatic mass with multiple liver and lung metastases). These preliminary findings raise the possibility that neuroendocrine CHE may be genetically distinct from the conventional RHE/CHE spectrum. Further studies are needed to investigate the pathogenetic relationship of fusion-negative cases with this subset and, less likely, with other members of the HE family of tumors.
网状和复合血管内皮细胞瘤（CHE）均为局部侵袭性、罕见转移的血管肿瘤，特征为具有钉突样形态的内皮细胞衬里的树枝状血管通道。 CHE 具有额外的细胞学和结构成分，包括常有空泡状上皮样细胞、实体区域或类似于分化良好的血管肉瘤的特征。由于软组织网状血管内皮细胞瘤（RHE）的一个索引病例通过靶向 RNA 测序显示存在 YAP1-MAML2 基因融合，我们试图在该形态谱中研究其他病例的这种遗传异常。使用针对这些基因重排的定制 BAC 探针，通过荧光原位杂交检测了总共 24 例涉及皮肤和软组织的 RHE 和 11 例 CHE，其中包括 1 例具有神经内分泌分化的内脏 CHE。在软组织队列中，13 例 RHE 中有 5 例（38%）和 11 例 CHE 中有 3 例（27%）显示 YAP1 基因重排，其中 5 例显示 YAP1-MAML2 融合，包括所有 3 例 CHE。唯一的神经内分泌 CHE 显示存在 PTBP1-MAML2 融合。所有 YAP1 阳性 CHE 病变发生在女性儿童的肢端部位，与融合阴性病例相比，后者发生在成年人中，解剖分布广泛。YAP1 阳性 RHE 更常发生于男性和下肢，而阴性病例则相反。这些结果表明，RHE 和 CHE 代表一种形态连续体，共享 YAP1 和 MAML2 基因的异常。相比之下，发生于 37 岁男性的神经内分泌 CHE 具有独特的 PTBP1-MAML2 融合，表现出侵袭性临床行为（胰腺肿块伴多个肝和肺转移）。这些初步发现提示神经内分泌 CHE 可能在遗传上与常规 RHE/CHE 谱不同。需要进一步研究以探讨融合阴性病例与该亚组的发病机制关系，以及与肿瘤 HE 家族的其他成员的关系不太可能。
