Clinicopathologic and Genomic Features of Gastric-Type Intraductal Papillary Neoplasm of the Bile Duct: Potential Role of STK11 in Malignant Progression.

Abstract

Gastric-type intraductal papillary neoplasm of the bile duct (G-type IPNB) remains an underexplored subtype of IPNBs, with limited molecular characterization. This study aimed to elucidate the clinicopathologic and genomic features of G-type IPNB to better understand its malignant potential and progression. Eighty-three IPNB cases, including 21 G-type IPNBs, were analyzed. The clinicopathologic features and prognosis of G-type IPNB were compared with those of other subtypes. Targeted sequencing was performed in 15 G-type cases, comprising 5 with high-grade dysplasia (HGD), 6 with invasive carcinoma (INV), and 4 with lymph node metastasis (LNM). The samples displayed varying histologic grades. The G-type frequently exhibited HGD; however, invasive G-type IPNBs showed significantly higher rates of lymph node metastasis compared with the other subtypes ( P =0.044). Recurrent mutations were detected in KRAS (60%), STK11 (40%), KMT2C (40%), APC (20%), CTNNB1 (13%), and TP53 (13%). Mutational profiles remained highly concordant across histologic grades, with no significant new mutations accumulating during tumor progression. KRAS mutations were predominantly found in preinvasive lesions, supporting their role in early tumorigenesis. STK11 mutations were exclusive to INV and LNM cases, but not detected in HGD cases. Notably, identical mutations were uniformly carried over from preinvasive lesions to invasive carcinoma and metastatic lymph node lesions. Immunohistochemically, aberrant STK11 expression was specific to the G-type compared with other subtypes ( P =0.030). These findings highlight the unique clinicopathologic and molecular features of G-type IPNB, including the association of STK11 mutations with invasive behavior and their potential as indicators of tumor progression.