Intramucosal lipomas of the colon implicate Cowden syndrome

Intramucosal lipomas are rare and easily overlooked by pathologists, despite their diagnostic significance for Cowden syndrome (PTEN hamartoma tumor syndrome), an inherited multiorgan cancer syndrome. Only 25-35% of patients harbor identifiable PTEN mutations, thus clinical features, like intramucosal lipomas, remain the mainstay of diagnosis. The significance and diagnostic approach to intramucosal lipomas have not been thoroughly addressed in the literature. Intramucosal lipomas are mimicked by pseudolipomatosis coli, an artifactual mucosal gas infiltration from endoscopic insufflation. This differential was investigated by morphology and S-100 immunohistochemistry. Twenty-five colonic intramucosal lipomas were identified from 176 archival gastrointestinal lipomas from 1998 to 2017. Controls included 40 submucosal lipomas and 30 pseudolipomatoses. S-100 immunohistochemistry on all 95 lesions confirmed delicate fat vacuole membranous and nuclear S-100 staining in lipomas absent from pseudolipomatoses. Differentiating morphology between intramucosal lipoma and pseudolipomatosis, respectively, included consistently large, regular fat vacuoles (92% vs 7%), associated spindle cells (80% vs 0%), and mucosal lymphoid aggregate involvement (12% vs 80%). Of the 25 intramucosal lipomas. five patients (20%) had confirmed Cowden syndrome (four with PTEN mutations). In four of these Cowden patients, the intramucosal lipoma was the index diagnostic lesion. Three (12%) intramucosal lipoma patients had additional clinical features associated with Cowden syndrome, but did not meet the diagnostic criteria. Sporadic-type intramucosal lipomas were identified in 17 patients (68%) without evidence of Cowden syndrome, including three with normal PTEN genetic testing. No distinguishing endoscopic or pathologic polyp features were identified between sporadic and syndromic intramucosal lipomas. These data provide evidence that intramucosal lipomas are important harbingers of Cowden syndrome, making up approximately one-third of this series, the largest in the literature. We also show for the first time that two-thirds of intramucosal lipomas are sporadic. Gastrointestinal pathologists, gastroenterologists, and geneticists should increase their awareness of this subtle but diagnosable lesion strongly associated with Cowden syndrome.