Rina Jiromaru

Claudin‐18 expression in gastric type adenocarcinoma and HPV ‐associated adenocarcinoma of the uterine cervix

Aims Claudin‐18 (CLDN18) is both a marker for the gastric phenotype and a therapeutic target. However, little is known about its immunoexpression in endocervical adenocarcinomas (ECAs), particularly as detected using the clone 43‐14A antibody, or about the gene expression of its isoforms in ECAs. Methods and results We examined CLDN18, HIK1083, p16 and Rb expression by immunohistochemistry and high‐risk human papillomavirus (HR‐HPV) mRNA by in situ hybridization (ISH) in 121 ECAs, including 35 HPV‐independent adenocarcinomas (gastric type [GAS], n  = 24; non‐GAS, n  = 11) and 86 HPV‐associated ECAs. We also analysed mRNA expression of the CLDN18.1 (lung type) and CLDN18.2 (gastric type) isoforms by quantitative polymerase chain reaction (qPCR) in selected cases. CLDN18 positivity was detected in 8/24 (33%) GASs, 0/11 (0%) non‐GASs and 2/86 (2%) HPV‐associated ECAs, with positivity defined as staining in ≥75% of tumour cells, as in gastric cancer. When a 5% cut‐off was used, CLDN18 positivity was detected in 22/24 (92%) GASs, 0/11 (0%) non‐GASs and 6/86 (7%) HPV‐associated ECAs; CLDN18 expression was thus significantly associated with GAS histology ( P  < 0.0001). Among the 6 cases of HPV‐associated ECAs with CLDN18 expression (ranging from 5% to 80%), the histological patterns included a mix of usual and mucinous features in 4 cases, pure usual type in 1 and villoglandular variant in 1. Otherwise features such as p16 overexpression and the Rb partial loss pattern were consistent with those of HPV‐associated ECAs. Six of 22 (27%) CLDN18‐positive GASs were also positive for p16, but their other features—such as CLDN18 expression and the Rb preserved pattern—were the same as in p16 negative GASs. Expression of CLDN18.2 mRNA but not CLDN18.1 mRNA was confirmed in both GASs and HPV‐associated ECAs. Conclusions CLDN18 (43‐14A) emerged as a potential diagnostic and therapeutic marker for GAS. A minor subset of HPV‐associated ECAs also can be immunoreactive for CLDN18 and express CLDN18.2 mRNA, suggesting divergent gastric phenotypic differentiation. The caution is that GAS and HPV‐associated ECAs can share overlapping histological features and similar expression of CLDN18 and p16.

Immunohistochemical p16 overexpression and Rb loss correlate with high‐risk human papillomavirus infection in endocervical adenocarcinomas

Aimsp16 is a sensitive surrogate marker for transcriptionally active high‐risk human papillomavirus (HR‐HPV) infection in endocervical adenocarcinoma (ECA); however, its specificity is not perfect.Methods and resultsWe examined p16 and Rb expressions by immunohistochemistry (IHC) and the transcriptionally active HR‐HPV infection by mRNA in‐situ hybridisation (ISH) with histological review in 108 ECA cases. Thirteen adenocarcinomas of endometrial or equivocal origin (six endometrioid and seven serous carcinomas) were compared as the control group. HR‐HPV was detected in 83 of 108 ECA cases (77%), including five HPV‐associated adenocarcinomas in situ and 78 invasive HPV‐associated adenocarcinomas. All 83 HPV‐positive cases showed consistent morphology, p16 positivity and partial loss pattern of Rb. Among the 25 cases of HPV‐independent adenocarcinoma, four (16%) were positive for p16, and of these four cases, three of 14 (21%) were gastric type adenocarcinomas and one of 10 (10%) was a clear cell type adenocarcinoma. All 25 HPV‐independent adenocarcinomas showed preserved expression of Rb irrespective of the p16 status. Similarly, all 13 cases of the control group were negative for HR‐HPV with preserved expression of Rb, even though six of 13 (46%) cases were positive for p16. Compared with p16 alone, the combination of p16 overexpression and Rb partial loss pattern showed equally excellent sensitivity (each 100%) and improved specificity (100 versus 73.6%) and positive predictive values (100 versus 89.2%) in the ECA and control groups. Furthermore, HR‐HPV infection correlated with better prognosis among invasive ECAs.ConclusionsThe results suggest that the combined use of p16 and Rb IHC could be a reliable method to predict HR‐HPV infection in primary ECAs and mimics. This finding may contribute to prognostic prediction and therapeutic strategy.