Clinical pathological and molecular features of 100 patients with gastric-type cervical adenocarcinoma

Objective: To investigate the clinicopathological and molecular features, diagnosis, and differential diagnosis of gastric-type cervical adenocarcinoma (GAS). Methods: A retrospective analysis was conducted on 100 patients diagnosed with GAS at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, from January 2017 to December 2024. Clinicopathological data were collected, histological characteristics and immunohistochemical expression patterns were analyzed, and the relevant literature was reviewed. Results: The ages of the 100 patients ranged from 25-73 years, with a median age of 50 years. The most common clinical manifestations included abnormal uterine bleeding and vaginal discharge, and the majority of patients were in FIGO stages II-IV. The GAS tumor glands were irregularly branched or cystically dilated, and the cells lining the glands had eosinophilic cytoplasm, with apical mucin secretion observed and the formation of mucus lakes in the stroma. Highly differentiated GAS may be misdiagnosed as heterogeneous hyperplasia of the cervical glands because of its relatively regular glandular structure. Irregularity of glandular architecture is observed in poorly differentiated areas, with fusion and a back-to-back arrangement occurring alongside an interstitial profibrotic reaction. Immunohistochemical markers, including MUC6, P16, P53, PAX8, ER, and PR, can provide additional diagnostic clues for GAS. Intestinal markers, such as CK7, CK20, CDX2, SATB2, Villin, CA19-9, CEA, and CA125, are not substantially helpful in distinguishing GAS from pancreaticobiliary adenocarcinoma. PAX2 aids in differentiating between GAS and precancerous lesions of benign gastric-type adenopathy. Positive staining for gastric markers, such as MUC6, HIK1083, and CAIX, helps indicate gastric-type differentiation. HNF1β in combination with NapsinA aids in differentiating GAS from clear-cell carcinoma. Patients with HER2 overexpression or PD-L1 expression (CPS ≥1) may benefit from targeted therapy or immunotherapy. Next-generation sequencing (NGS) analysis of 11 cases revealed recurrent somatic mutations in critical oncogenic pathways, including TP53 (72.7%, 8/11), KRAS (45.5%, 5/11), SMAD4 (45.5%, 5/11), CDKN2A (36.4%, 4/11), PIK3CA (27.3%, 3/11), and STK11 (18.2%, 2/11). No statistically significant associations were identified between p53 mutation status and FIGO stage (p=0.32), depth of myometrial invasion (p=0.45), lymphovascular invasion (LVSI) (p=0.67), or lymph node metastasis (LNM) (p=0.89), as determined by Fisher’s exact test. Conclusions: GAS is a highly malignant, HPV-independent cervical adenocarcinoma characterized by atypical clinical symptoms and complex, varied histology. It can be accurately diagnosed based on histologic features and immunohistochemical staining.