Gastric-Type Adenomas of the Nonampullary Duodenum: Reappraisal of Clinicopathological and Molecular Features and a Proposal for Novel Classification.

Nonampullary duodenal neoplasms of gastric phenotype include pyloric gland adenoma, foveolar-type adenoma, and duodenal neoplasm of uncertain malignant potential. In addition, previously undesignated epithelial tumors have been observed in the duodenum. Their clinicopathological and molecular characteristics, as well as their pathologic classification, remain incompletely defined due to their rarity. In this study, we examined a total of 105 lesions from 100 patients for histopathologic and immunohistochemical features and analyzed genomic alterations in 20 representative cases using next-generation sequencing (NGS). All 105 cases were classified by a combination of growth pattern (exophytic, dumbbell, and inverted), nuclear grade (low- and high-grade), and predominant gastric phenotype (foveolar, pyloric gland, intermediate mucous cell, fundic gland, and not otherwise specified). Among the 105 tumors, 97 (92%) were low-grade and 8 (8%) were high-grade. Intratumoral heterogeneity in nuclear grade and/or immunophenotype was frequently observed. NGS revealed mutations in GNAS (75%), KRAS (45%), and APC (30%) across the histopathologic subgroups. In addition, 6 of 8 high-grade tumors (75%) harbored MDM2 gene amplification, which was associated with diffuse and strong expression of MDM2 protein and high Ki-67 index. In contrast, low-grade tumors exhibited rare MDM2 amplification (6%), and immunoreactivity for MDM2 and Ki-67 was generally sparse. The patients showed an extremely favorable prognosis without metastases, irrespective of nuclear grade. These findings suggest that nonampullary duodenal neoplasms of gastric phenotype can be reclassified as "gastric-type adenomas" based on excellent prognosis and common genetic alterations, albeit a wide spectrum of morphology and gastric phenotypic expression. MDM2 amplification may contribute to histologic progression.