Background Inverted sinonasal (Schneiderian) papilloma (ISP) is a locally aggressive neoplasm often associated with sinonasal squamous cell carcinoma (SNSCC). While the etiology of ISP is not well understood, human papillomavirus (HPV) has been detected in a subset of cases. Our group recently identified activating somatic EGFR mutations in the majority of ISP and ISP-associated SNSCC. However, the relationship between EGFR mutations and HPV infection has not been explored. Patients and methods We evaluated 58 ISP and 22 ISP-associated SNSCC (including 13 patients with matched ISP/SNSCC samples), as well as 14 SNSCC without clinical or pathologic evidence of an associated ISP. Formalin-fixed, paraffin-embedded samples were evaluated for EGFR mutations using Sanger sequencing and for HPV infection using GP5+/GP6+ PCR. HPV subtyping based on the L1 sequence was done for HPV positive cases including temporally distinct tumors for four patients. Clinicopathologic data including progression free survival was also analyzed. Results All ISP and ISP-associated SNSCC demonstrated either an EGFR mutation or HPV infection. HPV and EGFR mutation were mutually exclusive in all cases of ISP-associated SNSCC and all but one ISP; this case was only weakly HPV positive, and analysis of a prior temporally distinct ISP specimen from this patient failed to show HPV infection, suggesting transient infection/incidental colonization. HPV subtypes in ISP and ISP-associated SNSCC were predominantly low-risk, in contrast with SNSCC without ISP association, which showed frequent high-risk HPV. All paired ISP and associated SNSCC samples demonstrated concordant HPV status and EGFR genotypes. ISP progression to SNSCC was significantly associated with the presence of HPV infection and the absence of an EGFR mutation (log-rank = 9.620, P = 0.002). Conclusions Collectively our data show that EGFR mutations and HPV infection represent essential, alternative oncogenic mechanisms in ISP and ISP-associated SNSCC.

中文翻译：

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人乳头瘤病毒 (HPV) 和体细胞 EGFR 突变是倒置鼻窦乳头状瘤和相关鼻窦鳞状细胞癌必不可少的、相互排斥的致癌机制。

背景 鼻内翻（Schneiderian）乳头状瘤（ISP）是一种局部侵袭性肿瘤，通常与鼻窦鳞状细胞癌（SNSCC）相关。虽然 ISP 的病因尚不清楚，但已在部分病例中检测到人乳头瘤病毒 (HPV)。我们小组最近在大多数 ISP 和 ISP 相关的 SNSCC 中发现了激活的体细胞 EGFR 突变。然而，尚未探索 EGFR 突变与 HPV 感染之间的关系。患者和方法 我们评估了 58 例 ISP 和 22 例与 ISP 相关的 SNSCC（包括 13 例具有匹配 ISP/SNSCC 样本的患者），以及 14 例没有相关 ISP 的临床或病理学证据的 SNSCC。福尔马林固定、石蜡包埋的样本使用 Sanger 测序评估 EGFR 突变，使用 GP5+/GP6+ PCR 评估 HPV 感染。对 HPV 阳性病例进行基于 L1 序列的 HPV 亚型分型，包括四名患者的时间上不同的肿瘤。还分析了包括无进展生存期在内的临床病理学数据。结果 所有 ISP 和 ISP 相关的 SNSCC 都表现出 EGFR 突变或 HPV 感染。HPV 和 EGFR 突变在所有 ISP 相关的 SNSCC 病例和除一个 ISP 之外的所有病例中都是相互排斥的；该病例仅是弱 HPV 阳性，并且对该患者先前的时间上不同的 ISP 标本的分析未能显示 HPV 感染，表明短暂感染/偶然定植。ISP 和 ISP 相关的 SNSCC 中的 HPV 亚型主要是低风险的，而没有 ISP 相关的 SNSCC 则显示出频繁的高风险 HPV。所有配对的 ISP 和相关的 SNSCC 样本均显示出一致的 HPV 状态和 EGFR 基因型。ISP 进展为 SNSCC 与存在 HPV 感染和不存在 EGFR 突变显着相关（对数秩 = 9.620，P = 0.002）。结论 总的来说，我们的数据表明 EGFR 突变和 HPV 感染代表 ISP 和 ISP 相关 SNSCC 中必不可少的替代致癌机制。