Histologic variations in juvenile polyp phenotype correlate with genetic defect underlying juvenile polyposis

Juvenile polyps are distinct hamartomatous malformations of the gastrointestinal tract that may occur in the heritable juvenile polyposis syndrome (JPS) or sporadically. Histologically, juvenile polyps are characterized by a marked increase of the stromal cell compartment, but an epithelial phenotype has also been reported. JPS has an increased risk of colorectal cancer but sporadic juvenile polyps do not. In 50% to 60% of patients with JPS, a germline mutation of the transforming growth factor-β/bone morphogenetic protein (BMP) pathway genes SMAD4 or BMPR1A is found. This study compares the histologic phenotype of juvenile polyps with a SMAD4 or BMPR1A germline mutation and sporadic juvenile polyps.

Hematoxylin and Eosin-stained slides of 65 JPS polyps and 25 sporadic juvenile polyps were reviewed for histologic features and dysplasia. Systematic random crypt and stroma counts were obtained by count stereology, and a crypt-stroma ratio was determined. All polyps were subsequently categorized as type A (crypt-stroma ratio <1.00) or type B (crypt-stroma ratio ≥1.00), the latter referring to the epithelial phenotype. Cell cycle activity was assessed using immunohistochemistry ofthe proliferation marker Ki67, and mutation analysis was carried out for KRAS and APC to determine the involvement of the adenoma-carcinoma sequence.

Juvenile polyps with a SMAD4 germline mutation were predominantly type B, whereas type A was more common among juvenile polyps with a BMPR1A germline mutation. However, this distinction could not be ascribed to differences in cell cycle activity. Dysplasia was equally common in JPS polyps with either a SMAD4 or BMPR1A germline mutation, in which the involvement of the adenoma-carcinoma sequence does not seem to play a distinct role.

Juvenile polyps in the setting of JPS exhibit distinct phenotypes correlating with the underlying genetic defect.