Immunohistochemical Evaluation of Integrin αvβ6 Expression in Gastric and Gastroesophageal Junction Adenocarcinoma as a Histopathology-Driven Biomarker for Integrin αvβ6-Targeted Radiotheranostics.

BACKGROUND

Gastric and gastroesophageal junction adenocarcinomas remain major causes of cancer- related mortality worldwide. Although perioperative chemotherapy, HER2-directed therapy, Claudin-18.2 (CLDN18.2)-targeted treatment, immune checkpoint inhibition, and anti-angiogenic therapy have improved outcomes in selected patients, clinically actionable targets are absent, heterogeneous, or lost in many high-grade, diffuse, poorly cohesive, signet-ring-cell micropapillary, hepatoid, and sarcomatoid carcinomas. Additional histopathology-assessable biomarkers that can support both molecular imaging and targeted therapy are of considerable clinical interest.

METHODS

Integrin αvβ6 is an epithelial-specific adhesion receptor that is minimally expressed in most normal adult tissues but becomes markedly upregulated during epithelial carcinogenesis, tissue remodeling, invasion, and activation of transforming growth factor-β signaling. This retrospective histopathological and immunohistochemical study evaluated integrin αvβ6 expression by immunohistochemistry in 53 formalin-fixed paraffin-embedded diagnostic specimens of untreated primary gastric or gastroesophageal junction adenocarcinoma. Tumors were classified according to the WHO Classification of Tumors of the Digestive System, 5th edition. Membranous integrin αvβ6 staining intensity and the percentage of positive tumor cells were recorded, and an H-score was calculated. Expression patterns were compared descriptively with histological subtype, differentiation grade, HER2 status, and CLDN18.2 expression.

RESULTS

Integrin αvβ6 immunoreactivity was detected in 49 of 53 tumors (92.5%), the clinically more relevant moderate to strong expression (H-score > 100) was present in 27 of 53 cases (50.9%), and strong expression was present in 13 of 53 cases (24.5%). Expression was not confined to conventional intestinal-type tumors; among carcinomas containing a signet-ring-cell component, 14 of 16 assessable cases (87.5%) showed integrin αvβ6 positivity, with 8 of 16 (50.0%) showing moderate to strong staining. By comparison, HER2 positivity was identified in 4 of 53 cases (7.5%; 4 of 52 assessable cases, 7.7%), and clinically relevant CLDN18.2 positivity, defined as moderate-to-strong membranous staining in at least 75% of tumor cells, was present in 7 of 38 assessable cases (18.4%).

CONCLUSIONS

Integrin αvβ6 is frequently expressed in gastric and gastroesophageal junction adenocarcinoma, with moderate to strong expression in approximately half of all cases and in half of signet ring cell-containing tumors, including aggressive histological subtypes that often lack established therapeutic targets. The precise H-Score threshold for theranostic eligibility remains to be determined. The findings support integrin αvβ6 as a promising biomarker for histopathology-based screening, PET-based whole-body target assessment, and future targeted radionuclide therapy. Integration of immunohistochemistry and integrin αvβ6- targeted PET imaging will be essential to validate integrin αvβ6 as a candidate biomarker and to optimize radionuclide selection in gastric cancer, particularly with moderate to strong expression.