Department of Pathology, University of Medicine and Pharmacy of Targu Mures, Targu Mures.
Vancouver General Hospital, Vancouver, BC, Canada.
Am J Surg Pathol. 2018 Feb;42(2):214-226. doi: 10.1097/PAS.0000000000000986.
We sought to classify endocervical adenocarcinomas (ECAs) based on morphologic features linked to etiology (ie, human papillomavirus [HPV] infection), unlike the World Health Organization 2014 classification. The International Endocervical Adenocarcinoma Criteria and Classification (IECC criteria), described herein, distinguishes between human papillomavirus-associated adenocarcinoma (HPVA), recognized by the presence of luminal mitoses and apoptosis seen at scanning magnification, and no or limited HPVA features (nonhuman papillomavirus-associated adenocarcinoma [NHPVA]). HPVAs were then subcategorized based on cytoplasmic features (mostly to provide continuity with preexisting classification schemes), whereas NHPVAs were subclassified based on established criteria (ie, gastric-type, clear cell, etc.). Complete slide sets from 409 cases were collected from 7 institutions worldwide. Tissue microarrays representing 297 cases were constructed; immunohistochemistry (p16, p53, vimentin, progesterone receptor) and chromogenic in situ hybridization using an RNA-based probe set that recognizes 18 varieties of high-risk HPV were performed to validate IECC diagnoses. The 5 most common IECC diagnoses were usual-type (HPVA) (73% of cohort), gastric-type (NHPVA) (10%), mucinous adenocarcinoma of HPVA type, including intestinal, mucinous not otherwise specified, signet-ring, and invasive stratified mucin-producing carcinoma categories (9%), clear cell carcinoma (NHPVA) (3%) and adenocarcinoma, not otherwise specified (2%). Only 3 endometrioid carcinomas were recognized and all were NHPVA. When excluding cases thought to have suboptimal tissue processing, 90% and 95% of usual-type IECC cases overexpressed p16 and were HPV, whereas 37% and 3% of NHPVAs were p16 and HPV, respectively. The 1 HPV gastric-type carcinoma was found to have hybrid HPVA/NHPVA features on secondary review. NHPVA tumors were larger and occurred in significantly older patients, compared with HPVA tumors (P<0.001). The high-risk HPV chromogenic in situ hybridization probe set had superior sensitivity, specificity, and positive and negative predictive values (0.955, 0.968, 0.992, 0.833, respectively) compared with p16 immunohistochemistry (0.872, 0.632, 0.907, 0.545, respectively) to identify HPV-related usual carcinoma and mucinous carcinoma. IECC reliably segregates ECAs into HPVA and NHPVA types using morphology alone. This study confirms that usual-type ECAs are the most common type worldwide and that mucinous carcinomas comprise a mixture of HPVA and NHPVA, with gastric-type carcinoma being the major NHPVA type. Endometrioid and serous carcinomas of the endocervix are extraordinarily rare. Should clinical outcomes and genomic studies continue to support these findings, we recommend replacement of the World Health Organization 2014 criteria with the IECC 2017.
我们试图根据与病因相关的形态特征（即人乳头瘤病毒[HPV]感染）对宫颈腺癌进行分类，与 2014 年世界卫生组织的分类方法不同。本文描述的国际宫颈腺癌标准和分类（IECC 标准）区分了 HPV 相关腺癌（HPVA）和非 HPV 相关腺癌（NHPVA）。HPVA 是通过扫描放大时看到的腔内有丝分裂和凋亡来识别的，而非 HPV 相关腺癌（NHPVA）则没有或仅有有限的 HPVA 特征。HPVAs 然后根据细胞质特征进一步分类（主要是为了与现有的分类方案保持一致），而非 HPVAs 则根据既定标准分类（即胃型、透明细胞型等）。从全球 7 个机构收集了 409 例完整的切片集，并构建了代表 297 例的组织微阵列。进行免疫组织化学（p16、p53、波形蛋白、孕激素受体）和使用基于 RNA 的探针组进行显色原位杂交，该探针组可识别 18 种高危 HPV，以验证 IECC 诊断。最常见的 5 种 IECC 诊断是普通型（HPVA）（队列的 73%）、胃型（NHPVA）（10%）、HPV 相关的黏液性腺癌，包括肠型、黏液型、非特指型、印戒细胞型和侵袭性分层黏液产生型、透明细胞癌（NHPVA）（3%）和非特指型腺癌（2%）。仅识别出 3 例子宫内膜样癌，均为 NHPVA。当排除认为组织处理不充分的病例时，90%和 95%的普通型 IECC 病例过度表达 p16 且 HPV 阳性，而 37%和 3%的 NHPVAs 分别为 p16 和 HPV 阳性。第二次审查发现，1 例 HPV 胃型癌具有混合的 HPVA/NHPVA 特征。与 HPVA 肿瘤相比，NHPVA 肿瘤更大且发生在年龄更大的患者中（P<0.001）。高危 HPV 显色原位杂交探针组的敏感性、特异性、阳性预测值和阴性预测值分别为 0.955、0.968、0.992 和 0.833，均优于 p16 免疫组织化学（分别为 0.872、0.632、0.907 和 0.545），可识别 HPV 相关的普通型和黏液型癌。IECC 仅使用形态学可靠地将 ECAs 分为 HPVA 和 NHPVA 类型。本研究证实，普通型 ECAs 是全球最常见的类型，黏液性腺癌是 HPVA 和 NHPVA 的混合体，胃型癌是主要的 NHPVA 类型。宫颈内膜和浆液性腺癌极为罕见。如果临床结果和基因组研究继续支持这些发现，我们建议用 2017 年的 IECC 标准替代 2014 年的世界卫生组织标准。
