Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Department of Pathology, Ghent University Hospital and Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
Am J Surg Pathol. 2022 Dec 1;46(12):1670-1681. doi: 10.1097/PAS.0000000000001943. Epub 2022 Sep 5.
Neuroendocrine neoplasms (NENs) of the cervix are rare aggressive tumors associated with poor prognosis and only limited treatment options. Although there is some literature on molecular underpinnings of cervical small cell neuroendocrine carcinomas (SCNECs), detailed morphologic and associated molecular characteristics of cervical NENs remains to be elucidated. Herein, 14 NENs (SCNEC: 6, large cell neuroendocrine carcinoma [LCNEC]: 6, neuroendocrine tumor [NET]: 2), including 5 admixed with human papillomavirus (HPV)-associated adenocarcinoma (carcinoma admixed with neuroendocrine carcinoma) were analyzed. All except 3 SCNECs were HPV16/18 positive. TP53 (3) and/or RB1 (4) alterations (3 concurrent) were only seen in SCNECs (4/6) and were enriched in the HPV16/18-negative tumors. The other most common molecular changes in neuroendocrine carcinomas (NECs) overlapping with those reported in the literature for cervical carcinomas involved PI3K/MAPK pathway (4) and MYC (4) and were seen in both SCNECs and LCNECs. In contrast, the 2 NETs lacked any significant alterations. Two LCNECs admixed with adenocarcinoma had enough material to sequence separately each component. In both pathogenic alterations were shared between the 2 components, including ERBB2 amplification in one and an MSH6 mutation with MYC amplification in the other. Overall, these findings suggest that cervical HPV-associated NETs are genomically silent and high-grade NECs (regardless of small or large cell morphology) share molecular pathways with common cervical carcinomas as it has been reported in the endometrium and are different from NECs at other sites. Molecular analysis of these highly malignant neoplasms might inform the clinical management for potential therapeutic targets.
宫颈神经内分泌肿瘤（NENs）是罕见的侵袭性肿瘤，预后不良，治疗选择有限。尽管有一些关于宫颈小细胞神经内分泌癌（SCNECs）分子基础的文献，但宫颈 NENs 的详细形态学和相关分子特征仍有待阐明。本文分析了 14 例 NENs（SCNEC：6 例，大细胞神经内分泌癌 [LCNEC]：6 例，神经内分泌肿瘤 [NET]：2 例），包括 5 例与 HPV 相关的腺癌（神经内分泌癌混合癌）。除 3 例外的所有 SCNEC 均为 HPV16/18 阳性。仅在 SCNEC 中观察到 TP53（3）和/或 RB1（4）改变（3 例同时存在）（6 例中的 4 例），并且在 HPV16/18 阴性肿瘤中更为丰富。重叠文献中报道的与宫颈腺癌重叠的神经内分泌癌（NECs）中其他常见的分子改变涉及 PI3K/MAPK 途径（4）和 MYC（4），见于 SCNEC 和 LCNEC。相比之下，2 例 NET 没有任何显著改变。2 例与腺癌混合的 LCNEC 有足够的材料分别对每个成分进行测序。在这两种成分中都存在相同的致病性改变，包括一个 ERBB2 扩增和另一个 MSH6 突变伴 MYC 扩增。总体而言，这些发现表明，宫颈 HPV 相关的 NET 是基因组沉默的，高级别 NEC（无论小细胞还是大细胞形态）与常见的宫颈腺癌共享分子途径，这在子宫内膜中已有报道，与其他部位的 NEC 不同。对这些高度恶性肿瘤进行分子分析可能有助于为潜在的治疗靶点提供临床管理信息。
