Primary mammary angiosarcomas harbor frequent mutations in KDR and PIK3CA and show evidence of distinct pathogenesis.,Modern Pathology

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Primary mammary angiosarcomas harbor frequent mutations in KDR and PIK3CA and show evidence of distinct pathogenesis.
Modern Pathology ( IF 7.1 ) Pub Date : 2020-03-02 , DOI: 10.1038/s41379-020-0511-6
Francisco Beca ₁ , Gregor Krings ₂ , Yunn-Yi Chen ₂ , Elizabeth M Hosfield ₃ , Poonam Vohra ₂ , Richard K Sibley ₁ , Megan L Troxell ₁ , Robert B West ₁ , Kimberly H Allison ₁ , Gregory R Bean ₁

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Angiosarcoma (AS) is the most frequent primary sarcoma of the breast but nevertheless remains uncommon, accounting for <0.05% of breast malignancies. Secondary mammary AS arise following radiation therapy for breast cancer, in contrast to primary AS which occur sporadically. Essentially all show aggressive clinical behavior independent of histologic grade and most are treated by mastectomy. MYC amplification is frequently identified in radiation-induced AS but only rarely in primary mammary AS (PMAS). As a heterogeneous group, AS from various anatomic sites have been shown to harbor recurrent alterations in TP53, MAP kinase pathway genes, and genes involved in angiogenic signaling including KDR (VEGFR2) and PTPRB. In part due to its rarity, the pathogenesis of PMAS has not been fully characterized. In this study, we examined the clinical, pathologic, and genomic features of ten cases of PMAS, including one patient with bilateral disease. Recurrent genomic alterations were identified in KDR (70%), PIK3CA/PIK3R1 (70%), and PTPRB (30%), each at higher frequencies than reported in AS across all sites. Six tumors harbored a KDR p.T771R hotspot mutation, and all seven KDR-mutant cases showed evidence suggestive of biallelism (four with loss of heterozygosity and three with two aberrations). Of the seven tumors with PI3K alterations, six harbored pathogenic mutations other than in the canonical PIK3CA residues which are most frequent in breast cancer. Three AS were hypermutated (≥10 mutations/megabase (Mb)); hypermutation was seen concurrent with KDR or PIK3CA mutations. The patient with bilateral disease demonstrated shared alterations, indicative of contralateral metastasis. No MYC or TP53 aberrations were detected in this series. Immunohistochemistry for VEGFR2 was unable to discriminate between KDR-mutant tumors and benign vascular lesions of the breast. These findings highlight the underrecognized frequency of KDR and PIK3CA mutation in PMAS, and a significant subset with hypermutation, suggesting a pathogenesis distinct from other AS.

中文翻译：

原发性乳腺血管肉瘤在 KDR 和 PIK3CA 中存在频繁突变，并显示出不同发病机制的证据。

血管肉瘤 (AS) 是最常见的乳腺原发性肉瘤，但仍然不常见，占乳腺恶性肿瘤的 <0.05%。与偶发发生的原发性 AS 相比，继发性乳腺 AS 在乳腺癌放射治疗后出现。基本上所有表现出独立于组织学分级的侵袭性临床行为并且大多数通过乳房切除术治疗。MYC 扩增经常在辐射诱发的 AS 中发现，但在原发性乳腺 AS (PMAS) 中很少见。作为一个异质性群体，来自不同解剖部位的 AS 已被证明在 TP53、MAP 激酶通路基因和参与血管生成信号传导的基因（包括 KDR (VEGFR2) 和 PTPRB）中反复发生改变。部分由于其罕见性，PMAS 的发病机制尚未完全确定。在这项研究中，我们检查了临床、10 例 PMAS 的病理学和基因组特征，包括一名双侧疾病患者。在 KDR (70%)、PIK3CA/PIK3R1 (70%) 和 PTPRB (30%) 中发现了复发性基因组改变，每个改变的频率均高于所有站点在 AS 中报告的频率。6 个肿瘤携带 KDR p.T771R 热点突变，所有 7 个 KDR 突变病例均显示双等位基因的证据（4 个杂合性丢失，3 个有两个畸变）。在具有 PI3K 改变的七种肿瘤中，除了在乳腺癌中最常见的典型 PIK3CA 残基之外，有六种具有致病性突变。三个 AS 发生超突变（≥10 个突变/兆碱基 (Mb)）；超突变与 KDR 或 PIK3CA 突变并发。患有双侧疾病的患者表现出共同的改变，表明对侧转移。在此系列中未检测到 MYC 或 TP53 畸变。VEGFR2 的免疫组织化学无法区分 KDR 突变肿瘤和乳腺良性血管病变。这些发现突出了 PMAS 中 KDR 和 PIK3CA 突变的未被充分认识的频率，以及具有超突变的重要子集，表明与其他 AS 不同的发病机制。

更新日期：2020-03-03

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