Answer: Juvenile polyps arising in familial juvenile polyposis

Histology: This specimen from the sister is morphologically very similar to the brother’s and shows polyps with dilated glands, epithelial proliferation, and inflammation. The epithelium shows no evidence of cellular crowding or hyperchromasia. No arborizing smooth muscle proliferation is seen within the polyps. These findings are consistent with juvenile polyps. Given the finding of juvenile polyps in two first-degree relatives, these patients have juvenile polyposis. These polyps are not hamartomas because they do not contain the arborizing smooth muscle pattern diagnostic of this entity. These polyps are not adenomas because they lack the architectural distortion and cellular irregularities characteristic of dysplasia.

Discussion: Juvenile polyposis is an autosomal dominant disease in which patients develop multiple juvenile polyps of the gastrointestinal tract. The majority of the juvenile polyps occur in the colon; however, they also arise in the small intestine and stomach. Patients with juvenile polyposis have an increased risk of developing gastrointestinal cancer, including colorectal, gastric, duodenal, biliary, and pancreatic cancers. They are at increased risk of developing colorectal cancer because
(1) these patients have an increased tendency to develop separate tubulovillous adenomas that can progress to cancer, just like in sporadic cases, and
(2) juvenile polyps themselves may develop adenomatous changes, which likewise represent a progression to invasive carcinoma. It is not surprising that these patients have an increased risk to develop pancreatic and biliary carcinomas, because germline mutations in DPC4 (SMAD4) have been found in a subset of patients with this disease. Approximately 55% of pancreatic ductal adenocarcinomas show inactivation of the DPC4 gene. Other genes that have been implicated in juvenile polyposis include the bone morphogenetic protein receptor 1A and phosphatase and tensin homolog (PTEN) genes. In general, the diagnosis of juvenile polyposis is suspected clinically when one of three criteria is met:
(1) there are more than five juvenile polyps in the colorectum;
(2) there are multiple juvenile polyps throughout the gastrointestinal tract; or
(3) there are two or more family members with juvenile polyps of any number. Clearly, before a definitive diagnosis of juvenile polyposis is made, other polyposis syndromes, such as those listed above, must be ruled out:

Peutz-Jeghers syndrome produces hamartomatous polyps and mucocutaneous melanin pigmentation.

Turcot syndrome produces adenomatous polyps and brain tumors.

Cowden syndrome produces hamartomatous lesions in the gastrointestinal tract and elsewhere (for example, trichilemmomas in the skin) and thyroid and breast cancer.

The histology in this case is not consistent with any of these three diseases.