Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY, USA.
Mod Pathol. 2022 Oct;35(10):1349-1361. doi: 10.1038/s41379-022-01090-y. Epub 2022 May 19.
Neuroendocrine carcinomas (NEC) of the breast are exceedingly rare tumors, which are classified in the WHO system as small cell (SCNEC) and large cell (LCNEC) carcinoma based on indistinguishable features from their lung counterparts. In contrast to lung and enteropancreatic NEC, the genomics of breast NEC have not been well-characterized. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of 13 breast NEC (7 SCNEC, 4 LCNEC, 2 NEC with ambiguous small versus large cell morphology [ANEC]). Co-alterations of TP53 and RB1 were identified in 86% (6/7) SCNEC, 100% (2/2) ANEC, and 50% (2/4) LCNEC. The one SCNEC without TP53/RB1 alteration had other p53 pathway aberrations (MDM2 and MDM4 amplification) and was immunohistochemically RB negative. PIK3CA/PTEN pathway alterations and ZNF703 amplifications were each identified in 46% (6/13) NEC. Two tumors (1 SCNEC, 1 LCNEC) were CDH1 mutated. By immunohistochemistry, 100% SCNEC (6/6) and ANEC (2/2) and 50% (2/4) LCNEC (83% NEC) showed RB loss, compared to 0% (0/8) grade 3 neuroendocrine tumors (NET) (p < 0.001) and 38% (36/95) grade 3 invasive ductal carcinomas of no special type (IDC-NST) (p = 0.004). NEC were also more often p53 aberrant (60% vs 0%, p = 0.013), ER negative (69% vs 0%, p = 0.005), and GATA3 negative (67% vs 0%, p = 0.013) than grade 3 NET. Two mixed NEC had IDC-NST components, and 69% (9/13) of tumors were associated with carcinoma in situ (6 neuroendocrine DCIS, 2 non-neuroendocrine DCIS, 1 non-neuroendocrine LCIS). NEC and IDC-NST components of mixed tumors were clonally related and immunophenotypically distinct, lacking ER and GATA3 expression in NEC relative to IDC-NST, with RB loss only in NEC of one ANEC. The findings provide insight into the pathogenesis of breast NEC, underscore their classification as a distinct tumor type, and highlight genetic similarities to extramammary NEC, including highly prevalent p53/RB pathway aberrations in SCNEC.
乳腺神经内分泌癌（NEC）是极为罕见的肿瘤，根据其与肺部对应物无法区分的特征，在世界卫生组织（WHO）系统中被归类为小细胞（SCNEC）和大细胞（LCNEC）癌。与肺和肠胰神经内分泌 NEC 不同，乳腺 NEC 的基因组尚未得到很好的描述。在这项研究中，我们检查了 13 例乳腺 NEC（7 例 SCNEC、4 例 LCNEC、2 例小细胞与大细胞形态不确定的 NEC [ANEC]）的临床病理、免疫组织化学和遗传特征。86%（6/7）的 SCNEC、100%（2/2）的 ANEC 和 50%（4/4）的 LCNEC 存在 TP53 和 RB1 的共改变。唯一没有 TP53/RB1 改变的 SCNEC 存在其他 p53 通路异常（MDM2 和 MDM4 扩增），免疫组织化学上 RB 阴性。PIK3CA/PTEN 通路改变和 ZNF703 扩增分别在 46%（6/13）的 NEC 中发现。2 个肿瘤（1 例 SCNEC，1 例 LCNEC）发生 CDH1 突变。通过免疫组织化学，100%的 SCNEC（6/6）和 ANEC（2/2）和 50%的 LCNEC（83%的 NEC）显示 RB 缺失，而 0%（0/8）的 3 级神经内分泌肿瘤（NET）（p < 0.001）和 38%（36/95）的 3 级非特殊型浸润性导管癌（IDC-NST）（p = 0.004）。与 3 级 NET 相比，NEC 也更常出现 p53 异常（60% vs 0%，p = 0.013）、ER 阴性（69% vs 0%，p = 0.005）和 GATA3 阴性（67% vs 0%，p = 0.013）。2 例混合 NEC 有 IDC-NST 成分，69%（9/13）的肿瘤与原位癌相关（6 例神经内分泌 DCIS、2 例非神经内分泌 DCIS、1 例非神经内分泌 LCIS）。混合肿瘤的 NEC 和 IDC-NST 成分存在克隆相关性和免疫表型差异，与 IDC-NST 相比，NEC 缺乏 ER 和 GATA3 表达，仅在 1 例 ANEC 的 NEC 中存在 RB 缺失。这些发现提供了对乳腺 NEC 发病机制的深入了解，强调了它们作为一种独特肿瘤类型的分类，并突出了与乳腺外 NEC 的遗传相似性，包括 SCNEC 中普遍存在的 p53/RB 通路异常。
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