Histopathologic and molecular evidence of malignant potential in morules associated with gastrointestinal neoplasia

Gastrointestinal (GI) adenomas with distinct solid cell clusters showing squamous or neuroendocrine differentiation are interchangeably termed as "squamoid morule (SM)" or "microcarcinoid (MC)." Though considered benign, their biogenesis and malignant potential remain contentious. We reviewed 39 cases of GI neoplasms with morules to characterize their histomorphology, immunoprofile, and molecular features. The cohort included 19 women and 20 men with a median age of 65 years. Eight cases were in the upper GI tract, while 31 were colorectal. Among eight (31%) colorectal morules associated with invasion, seven maintained a bland cytomorphology and one longitudinally progressed to an undifferentiated carcinoma component across 5 years. Morphologically, 23 were arbitrarily classified as SM and 16 as MC. SM were larger (p = 0.037) and showed more single cell necrosis (p = 0.003) than MC. Immunohistochemically, both colorectal SM and MC demonstrated high frequency of expression in nuclear β-catenin (91%), CD10 (87%), CK5 (96%), INSM1 (85%), CDX2 (83%), and SATB2 (100%). SM-like morules were more likely to express p63, while the MC-like morules were more likely to express synaptophysin (p = 0.026). Ki67 was generally low (< 1%) except in two invasive cases (> 10%). Molecular analysis showed KRAS as the most common mutated gene in five of seven (71%) tested cases, followed by PIK3CA (43%) and APC (29%). The morules harbored similar or more pathogenic mutations compared to the background neoplasm. In conclusion, SM and MC in the GI tract represent a spectrum of basal stem cells with Wnt/β-catenin activation and multilineage differentiation plasticity, which can progress to malignancy in rare cases.