AHNAK2 is a novel diagnostic biomarker for gallbladder adenocarcinoma

To investigate the pathological diagnostic value of AHNAK2 in gallbladder carcinoma (GBC), especially in adenocarcinoma (AC).

Tissue microarrays (TMAs) were constructed from 296 gallbladder tumor cases, comprising 562 cores that included normal/atypical epithelium, low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia/carcinoma in situ (HGIN/TIS), and GBC. Immunohistochemical staining for AHNAK2 and IMP3 was performed on these TMAs and another 10 GBC cases, and the sensitivity and specificity of AHNAK2 were assessed across different gallbladder tumor types.

AHNAK2 immunohistochemical expression demonstrated a progressive increase across pathological stages (p<0.001). Among tumor types, AHNAK2 positivity was observed in 67.53% (260/385) of ACs, 97.83% (45/46) of adenosquamous/squamous cell carcinomas (ASC/SCCs), 34.78% (8/23) of neuroendocrine carcinomas/mixed neuroendocrine-non-neuroendocrine neoplasms (NEC/miNEN), but not in areas of NECs, and none in undifferentiated carcinomas (UCs). Importantly, among three grades of well, moderately, and poorly differentiated AC, the positive rate of AHNAK2 decreased from 70.59% (24/34), 70.11% (190/271), to 57.50% (46/80); conversely, IMP3 increased from 58.82%, 78.97% to 83.75%. Given the extremely low positivity rates of AHNAK2 and IMP3 in normal/atypical epithelium, combining these markers significantly improved diagnostic performance, demonstrating 83.73% sensitivity and 91.38% specificity for HGIN/TIS and GBC, achieving sensitivities of 91.18%, 90.77%, and 93.75% across well, moderately, and poorly differentiated ACs.

AHNAK2 demonstrates moderate sensitivity and high specificity in the pathological diagnosis of GBC, particularly for well-differentiated ACs. Combining AHNAK2 with IMP3 significantly enhances diagnostic sensitivity, achieving up to 90% across all AC grades.