Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK.
National Specialist Ophthalmic Pathology Service, Department of Histopathology, E-Floor, Royal Hallamshire Hospital, Glossop Rd, Sheffield, S10 2JF, UK.
Mod Pathol. 2020 Jan;33(1):74-90. doi: 10.1038/s41379-019-0350-5. Epub 2019 Sep 4.
Squamous cell carcinoma of the conjunctiva is associated with a number of risk factors, including HIV infection, iatrogenic immunosuppression and atopy. In addition, several studies have suggested an involvement of HPV, based on the presence of viral DNA, but did not establish whether there was active infection or evidence of causal disease association. In this manuscript, 31 cases of conjunctival in situ squamous cell carcinoma were classified as HPV DNA-positive or -negative, before being analysed by immunohistochemistry to establish the distribution of viral and cellular biomarkers of HPV gene expression. Our panel included p16, TP53 and MCM, but also the virally encoded E4 gene product, which is abundantly expressed during productive infection. Subsequent in situ detection of HPV mRNA using an RNAscope approach confirmed that early HPV gene expression was occurring in the majority of cases of HPV DNA-positive conjunctival in situ squamous cell carcinoma, with all of these cases occurring in the atopic group. Viral gene expression correlated with TP53 loss, p16 elevation, and extensive MCM expression, in line with our general understanding of E6 and E7's role during transforming infection at other epithelial sites. A characteristic E4 expression pattern was detected in only one case. HPV mRNA was not detected in lower grades of dysplasia, and was not observed in cases that were HPV DNA-negative. Our study demonstrates an active involvement of HPV in the development of a subset of conjunctival in situ squamous cell carcinoma. No high-risk HPV types were detected other than HPV16. It appears that the conjunctiva is a vulnerable epithelial site for HPV-associated transformation. These cancers are defined by their pattern of viral gene expression, and by the distribution of surrogate markers of HPV infection.
结膜鳞状细胞癌与多种危险因素相关，包括 HIV 感染、医源性免疫抑制和特应性。此外，几项研究基于病毒 DNA 的存在提示 HPV 参与其中，但并未确定是否存在活跃感染或因果疾病关联的证据。在本手稿中，31 例结膜原位鳞状细胞癌根据 HPV DNA 阳性或阴性进行分类，然后通过免疫组织化学分析来确定 HPV 基因表达的病毒和细胞生物标志物的分布。我们的检测面板包括 p16、TP53 和 MCM，但也包括病毒编码的 E4 基因产物，其在有活性的感染期间大量表达。随后使用 RNAscope 方法对 HPV mRNA 的原位检测证实，大多数 HPV DNA 阳性结膜原位鳞状细胞癌中存在早期 HPV 基因表达，所有这些病例均发生在特应性组中。病毒基因表达与 TP53 缺失、p16 升高和广泛的 MCM 表达相关，这与我们对 E6 和 E7 在其他上皮部位转化感染过程中作用的一般理解一致。仅在一例中检测到特征性的 E4 表达模式。HPV mRNA 在低级别异型增生中未检测到，在 HPV DNA 阴性的病例中也未观察到。本研究表明 HPV 活跃参与了一部分结膜原位鳞状细胞癌的发生发展。除 HPV16 外，未检测到其他高危型 HPV。似乎结膜是 HPV 相关转化的易受影响的上皮部位。这些癌症的特征是病毒基因表达模式，以及 HPV 感染的替代标志物的分布。
