Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York.
Mod Pathol. 2023 Nov;36(11):100295. doi: 10.1016/j.modpat.2023.100295. Epub 2023 Jul 29.
Poorly differentiated neuroendocrine carcinomas (NECs) are rare malignant neoplasms with aggressive behavior. The diagnosis remains challenging due to ever-changing terminologies and morphologic overlaps with other disease entities. Herein, we seek to better define anorectal NECs by high-risk human papillomavirus (HPV) status and molecular profiling. Fourteen cases, including 3 men and 11 women with a median age of 63 years, were included. High-risk HPV RNA in situ hybridization was diffusely positive (+) in 7 cases, focal rarely positive (+/-) in 2 cases, and completely negative (-) in 5 cases. By morphology, all HPV(-) NECs were large-cell type, 3 mixed with a tubular adenoma/dysplasia or invasive adenocarcinoma. HPV-related (+ or +/-) NECs were mostly small-cell type, 3 mixed with squamous dysplasia and/or squamous cell carcinoma. Immunohistochemically, all NECs were positive for at least 2 neuroendocrine markers. The HPV(-) NECs were also positive for CDX2, whereas all HPV-related NECs were negative or only focally positive for CDX2, p40, and p63. Overexpression of p53 was found in 3 HPV(-) and 2 HPV(+/-) NECs but not in any HPV(+) NECs. Molecular analysis revealed MYC gene amplification in 4 cases: 2 HPV(-), 1 HPV(+/-), and 1 HPV(+). This was confirmed by fluorescence in situ hybridization in all but 1 HPV(-) NEC, which showed polysomy 8 but no true MYC amplification. Interestingly, only 2 of the 4 MYC amplification-bearing cases, both p53 normal/wild-type, expressed c-Myc protein by immunohistochemistry. The other 2 cases, both p53 overexpressed, did not show c-Myc expression despite true MYC amplification. Our study demonstrates that anorectal NECs arise in HPV-dependent or -independent pathways, with heterogeneous expression of other lineage markers and different molecular signatures. Expressions of p53 and c-Myc proteins appear to be mutually exclusive regardless of HPV status, likely mediating alternative mechanisms of NEC carcinogenesis.
低分化神经内分泌癌（NEC）是一种罕见的具有侵袭性的恶性肿瘤。由于术语不断变化，以及与其他疾病实体的形态重叠，诊断仍然具有挑战性。在此，我们试图通过高危型人乳头瘤病毒（HPV）状态和分子谱来更好地定义肛门直肠 NEC。纳入 14 例患者，包括 3 例男性和 11 例女性，中位年龄为 63 岁。7 例 HPV 原位杂交呈弥漫阳性（+），2 例局灶弱阳性（+/-），5 例阴性（-）。从形态上看，所有 HPV（-）NEC 均为大细胞型，3 例与管状腺瘤/发育不良或浸润性腺癌混合。HPV 相关（+或+/-）NEC 多为小细胞型，3 例与鳞状发育不良和/或鳞状细胞癌混合。免疫组化染色显示，所有 NEC 均至少有 2 种神经内分泌标志物阳性。HPV（-）NEC 还对 CDX2 阳性，而所有 HPV 相关 NEC 对 CDX2、p40 和 p63 均阴性或仅局灶阳性。3 例 HPV（-）和 2 例 HPV（+/-）NEC 中发现 p53 过表达，但无任何 HPV（+）NEC 过表达。分子分析显示 4 例中有 4 例存在 MYC 基因扩增：2 例 HPV（-），1 例 HPV（+/-），1 例 HPV（+）。除 1 例 HPV（-）NEC 外，所有病例均通过荧光原位杂交证实，该例显示 8 号染色体三体，但无真正的 MYC 扩增。有趣的是，仅在 4 例 MYC 扩增阳性病例中的 2 例中，p53 正常/野生型，免疫组化显示 c-Myc 蛋白表达。另外 2 例 p53 过表达病例尽管存在真正的 MYC 扩增，但未显示 c-Myc 表达。本研究表明，肛门直肠 NEC 发生在 HPV 依赖性或非依赖性途径中，具有其他谱系标志物的异质性表达和不同的分子特征。p53 和 c-Myc 蛋白的表达似乎相互排斥，与 HPV 状态无关，可能介导了 NEC 癌发生的替代机制。
