Frequent Gastrointestinal Polyps and Colorectal Adenocarcinomas in a Prospective Series of PTEN Mutation Carriers

Abstract

BACKGROUND & AIMS Germline PTEN mutations cause Cowden syndrome (CS), associated with breast and thyroid cancers. Case reports found 35–85% of CS patients had gastrointestinal (GI) hamartomas. The association of benign and malignant GI neoplasias with CS remains debatable. Our goal is to describe the GI phenotype in a prospective series of PTEN mutation carriers. METHODS Patients who met relaxed International Cowden Consortium criteria (N=2548) or with ≥5 GI polyps, ≥1 of which was hyperplastic or hamartomatous (N=397) were prospectively recruited. Germline PTEN mutation/deletion analysis was performed. Of the 2945, 127 patients having clear pathogenic PTEN mutations (123/2548+4/397) were eligible for this study. EGD and colonoscopy were performed and pathology reports reviewed. Fisher’s 2-tailed exact test, unpaired t-tests, and age- and gender-adjusted SIR were calculated. RESULTS Of 127 PTEN mutation carriers, 67 underwent ≥1 endoscopy with 62 (95%) having polyps, making GI polyps the second most common feature, after macrocephaly (74.8%). Of the 65, half had hyperplastic polyps and ¼ each with hamartomatous, ganglioneuromatous or adenomatous polyps. There were one to “innumerable” polyps in the colorectum, ileum, duodenum, stomach and/or esophagus, with 24 subjects having both upper and lower GI polyps. Nine (13%) subjects had colorectal cancer, all under the age of 50. The adjusted SIR was 224.1 (95%CI 109.3–411.3, p<0.0001). Cancers were commonly associated with adenomatous and/or hyperplastic polyps. One had gastric signet ring cell carcinoma. CONCLUSIONS PTEN-associated CS should be considered a mixed polyp syndrome, with hyperplastic polyps most prevalent, and a risk of early-onset colorectal cancer. Routine colonoscopy should be considered in PTEN-associated CS especially in the context of hyperplastic and/or adenomatous polyps.

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

“…[24][25][26][27][28] Clinical diagnostic criteria involve combinations of major and minor criteria 29 ( Table 4). We recommend referral for anyone meeting any three criteria from the major or minor diagnostic criteria.…”

The growing complexity of the intestinal polyposis syndromes

“…Instead, true intestinal ganglioneuromas are found in neurofibromatosis type 1 and multiple endocrine neoplasia type 1 [Ledwidge et al, 2007]. Intestinal lipomas, hyperplastic and, less commonly, adenomatous polyps can also occur [Heald et al, 2010].…”

“…The number of polyps can range from none to innumerable, while their incidence is unknown; in a recent study 95% of in PTEN mutation carriers subjected to colonoscopy were found to have intestinal polyps [Heald et al, 2010].…”

“…The most typical manifestations are mucocutaneous hamartomas (Table II). The risk of colorectal malignancy was initially deemed to be low [Eng, 2003], but this concept has been recently revisited based on prospective data obtained on a series of 127 PTEN mutation carriers: 13% developed CRC, all before 50 years of age, with an estimated standardized incidence ratio of 220 [Heald et al, 2010]. All PHTS phenotypes are transmitted as autosomal dominant traits.…”

Screening for gynaecologic cancers in genetically predisposed women

“…This risk has not been quantified sufficiently 63,64], but certainly warrants endometrial cancer screening.…”