Lin Lawrence Hsu, Kaur Harsimar, Kolin David L, Nucci Marisa R, Parra-Herran Carlos
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School.
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Am J Surg Pathol. 2025 Mar 1;49(3):206-216. doi: 10.1097/PAS.0000000000002342. Epub 2024 Dec 6.
Gastric-type endocervical adenocarcinomas (GAS) are aggressive HPV-independent neoplasms with molecular alterations in TP53 , STK11 , CDKN2A , and SMAD4 . Claudin-18 (CLDN18) has emerged as a useful marker to distinguish GAS from HPV-associated neoplasia. Its role in separating GAS from benign proliferations and exuberant endocervical glands is unknown. We studied the utility of immunohistochemistry for CLDN18, progesterone receptor (PR), and mutation surrogate stains (P53, STK11/LKB1, MTAP, SMAD4/DPC4) in 46 GAS, 12 benign gastric-type endocervical lesions, 54 benign Mullerian endocervical populations, and 11 HPV-associated endocervical adenocarcinomas. PD-L1 and HER2 immunostains were evaluated in GAS. Gastric-type lesions were more often positive for CLDN18 (100% benign, 78% GAS, most often well to moderately differentiated) compared to benign Mullerian endocervical specimens (all negative) and HPV-associated neoplasia (18%, always focal). Conversely, PR was negative in all gastric-type lesions and positive in 92% of benign Mullerian endocervical populations. GAS revealed aberrant/mutant expression of P53 in 35%, STK11/LKB1 in 25%, MTAP in 23%, and SMAD4/DPC4 in 9% of cases. Abnormal staining in at least one of these 4 mutation surrogate markers was present in 63% of GAS. HER2 score of 3+ was seen in 25% of GAS, and PD-L1 was positive in 37% based on a combined positive score. CLDN18 is a sensitive and highly specific marker of gastric-type benign and malignant endocervical lesions. Once a gastric-type phenotype is confirmed, mutation surrogate immunostains can be used to support a diagnosis of GAS. PD-L1 and HER2 expression is seen in a subset of GAS offering therapeutic options for this aggressive tumor.
胃型宫颈内膜腺癌（GAS）是侵袭性的、不依赖人乳头瘤病毒（HPV）的肿瘤，存在TP53、STK11、CDKN2A和SMAD4的分子改变。紧密连接蛋白18（CLDN18）已成为区分GAS与HPV相关肿瘤的有用标志物。其在区分GAS与良性增生及宫颈内膜腺体增生方面的作用尚不清楚。我们研究了CLDN18、孕激素受体（PR）及突变替代染色（P53、STK11/LKB1、MTAP、SMAD4/DPC4）免疫组化在46例GAS、12例良性胃型宫颈病变、54例良性苗勒氏宫颈组织及11例HPV相关宫颈内膜腺癌中的应用。对GAS评估了程序性死亡受体配体1（PD-L1）和人表皮生长因子受体2（HER2）免疫染色情况。与良性苗勒氏宫颈标本（均为阴性）及HPV相关肿瘤（18%，均为局灶性）相比，胃型病变中CLDN18更常呈阳性（良性为100%，GAS为78%，大多为高分化至中分化）。相反，PR在所有胃型病变中均为阴性，而在92%的良性苗勒氏宫颈组织中呈阳性。GAS中，35%的病例P53呈异常/突变表达，25%的病例STK11/LKB1呈异常/突变表达，23%的病例MTAP呈异常/突变表达，9%的病例SMAD4/DPC4呈异常/突变表达。63%的GAS至少有这4种突变替代标志物中的一种染色异常。25%的GAS中HER2评分为3+，基于综合阳性评分，37%的GAS中PD-L1呈阳性。CLDN18是胃型良性和恶性宫颈病变的敏感且高度特异的标志物。一旦确认胃型表型，可使用突变替代免疫染色来支持GAS的诊断。部分GAS中可见PD-L1和HER2表达，为这种侵袭性肿瘤提供了治疗选择。
