Williams Guy A, Wu Annie A, Eugene Henrietta C, Tsai Ya-Chea, Wong Margaret, Nonogaki Hiro, Roden Richard B S, Hung Chien-Fu, Wu Tzyy-Choou, Vang Russell, Xing Deyin
Department of Pathology.
Department of Oncology.
Am J Surg Pathol. 2025 May 1;49(5):458-470. doi: 10.1097/PAS.0000000000002367. Epub 2025 Jan 31.
Despite being designated as "noncarcinogenic" human papillomavirus (HPV) types, mono-infection with HPV6 or HPV11 has been found in squamous cell carcinomas (SCCs) at specific sites, including the larynx, penis, anus, and rarely, the lower female genital tract. The association between clinicopathologic features, viral status, and the carcinogenic mechanisms related to these low-risk HPVs remains unclear. The current study characterizes a series of low-risk HPV6 and HPV11-associated SCCs of the uterine cervix (6 cases) and vulva (2 cases). The diagnosis of SCC was made through the identification of stromal invasion in 6 cases. In case 2, the diagnosis of cancer was made after metastases to the sigmoid colon and liver. The patient in case 6 was diagnosed with intramucosal papillary SCC given multiple recurrences. While all tumors displayed a similar verruco-papillary architecture, the cytologic features, and immunostaining patterns suggest 2 groups of lesions: one with high-grade cytology and a high Ki-67 proliferation index (>60% of lesional cells), and the other with low-grade cytology and a low Ki-67 (20% to 30% of lesional cells). The detection of HPV6 in 7 of 8 cases underscores its critical role in carcinogenesis at these anatomic sites. Case 8 represented the only patient who was infected with HPV11 and who had a well-controlled human immunodeficiency virus infection. Correlating with viral status, all cases, except case 7, demonstrated a negative or focal p16 staining pattern. In case 7, despite a block pattern of p16 staining often seen in predicting high-risk HPV, we employed several methods to confirm HPV6 as the sole HPV infection. Although this descriptive study does not establish an etiological mechanism for how HPV6/11 leads to malignant transformation, our results exclude the possibility of viral integration through a quantitative polymerase chain reaction-based analysis of the E2/E6 ratio. Our study highlights and expands upon the clinicopathologic features of a distinct group of low-risk HPV6/11-associated SCCs in the cervix and vulva. Although rare, recognizing this group of lesions is important for pathologists and oncologists, as it provides a basis for guiding appropriate prevention strategies and treatment modalities based on the viral type.
尽管人乳头瘤病毒（HPV）6型和11型被指定为“非致癌性”HPV类型，但在特定部位的鳞状细胞癌（SCC）中发现了HPV6或HPV11的单一感染，这些部位包括喉、阴茎、肛门，女性下生殖道则较为罕见。这些低风险HPV相关的临床病理特征、病毒状态以及致癌机制之间的关联仍不明确。本研究对一系列子宫颈（6例）和外阴（2例）的低风险HPV6和HPV11相关SCC进行了特征描述。6例SCC的诊断是通过确定间质浸润得出的。在病例2中，在出现乙状结肠和肝脏转移后确诊为癌症。病例6的患者因多次复发被诊断为黏膜内乳头状SCC。虽然所有肿瘤都呈现出相似的疣状乳头结构，但细胞学特征和免疫染色模式提示存在两组病变：一组具有高级别细胞学特征和高Ki-67增殖指数（>60%的病变细胞），另一组具有低级别细胞学特征和低Ki-67（20%至30%的病变细胞）。8例中的7例检测到HPV6，这突出了其在这些解剖部位致癌过程中的关键作用。病例8是唯一感染HPV11且人类免疫缺陷病毒感染得到良好控制的患者。与病毒状态相关，除病例7外，所有病例均表现为p16染色阴性或局灶性染色模式。在病例7中，尽管p16染色呈块状模式常用于预测高风险HPV，但我们采用了多种方法来确认HPV6是唯一的HPV感染。虽然这项描述性研究并未确立HPV6/11导致恶性转化的病因机制，但我们的结果通过基于定量聚合酶链反应的E2/E6比率分析排除了病毒整合的可能性。我们的研究突出并扩展了一组独特的子宫颈和外阴低风险HPV6/11相关SCC的临床病理特征。尽管罕见，但认识到这组病变对病理学家和肿瘤学家很重要，因为它为基于病毒类型指导适当的预防策略和治疗方式提供了依据。
