Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes

In individuals at risk for or affected with LS, screening for colorectal cancer by colonoscopy should be performed at least every 2 years, beginning between ages 20 and 25 years. Annual colonoscopy should be considered in confirmed mutation carriers.

Colectomy with ileorectal anastomosis (IRA) is the preferred treatment of patients affected with LS with colon cancer or colonic neoplasia not controllable by endoscopy. Segmental colectomy is an option in patients unsuitable for total colectomy if regular postoperative surveillance is conducted.

Hysterectomy and bilateral salpingo-oophorectomy should be offered to women who are known LS mutation carriers and who have finished child bearing, optimally at age 40–45 years.

Screening for endometrial cancer and ovarian cancer should be offered to women at risk for or affected with LS by endometrial biopsy and transvaginal ultrasound annually, starting at age 30 to 35 years before undergoing surgery or if surgery is deferred.

Screening for gastric and duodenal cancer can be considered in individuals at risk for or affected with LS by baseline esophagogastroduodenoscopy (EGD) with gastric biopsy at age 30–35 years, and treatment of H. pylori infection when found. Data for ongoing regular surveillance are limited, but ongoing surveillance every 3–5 years may be considered if there is a family history of gastric or duodenal cancer.

Screening beyond population-based recommendations for cancers of the urinary tract, pancreas, prostate, and breast is not recommended unless there is a family history of the specific cancers.

Although data suggest that daily aspirin may decrease the risk of colorectal and extracolonic cancer in LS, currently the evidence is not suffi ciently robust or mature to make a recommendation for its standard use.

In individuals at risk for or affected with the classic AP syndromes, screening for colorectal cancer by annual colonoscopy or flexible sigmoidoscopy should be performed, beginning at puberty. In families with attenuated familial adenomatous polyposis (AFAP) or MAP, surveillance should be by colonoscopy.

Absolute indications for immediate colectomy in FAP, AFAP, and MAP include: documented or suspected cancer or significant symptoms. Relative indications for surgery include the presence of multiple adenomas >6 mm, a significant increase in adenoma number, and inability to adequately survey the colon because of multiple diminutive polyps.

Screening for gastric and proximal small bowel tumors should be done using upper endoscopy including duodenoscopy starting at age 25–30 years. Surveillance should be repeated every 0.5–4 years depending on Spigelman stage of duodenal polyposis: 0=4 years; I=2–3 years, II=1–3 years, III=6–12 months, and IV=surgical evaluation. Examination of the stomach should include random sampling of fundic gland polyps. Low-grade dysplasia is common in fundic gland polyps, and surgery should be reserved for high-grade dysplasia or cancer.

Annual thyroid screening by ultrasound should be recommended to individuals affected with FAP, MAP, and attenuated polyposis.

Biannual screening should be offered to affected infants until age 7 years with α-fetoprotein and ultrasounds.

Postsurgical surveillance should include yearly endoscopy of rectum or ileal pouch, and examination of an ileostomy every 2 years.

Surveillance in affected or at-risk PJS patients should include monitoring for colon, stomach, small bowel, pancreas, breast, ovary, uterus, cervix, and testes cancers. Risk for lung cancer is increased, but no specific screening has been recommended. It would seem wise to consider annual chest radiograph or chest computed tomography (CT) in smokers.

Surveillance of the gastrointestinal (GI) tract in affected or at-risk JPS patients should include screening for colon, stomach, and small bowel cancers.

Colectomy and ileorectal anastomosis or proctocolectomy and ileal pouch-anal anastomosis is indicated for polyp-related symptoms, or when the polyps cannot be managed endoscopically.

Cardiovascular examination for and evaluation for hereditary hemorrhagic telangiectasia should be considered for SMAD4 mutation carriers.

Surveillance in affected or at-risk Cowden syndrome patients should include screening for colon, stomach, small bowel, thyroid, breast, uterine, kidney, and skin (melanoma) cancers.

Patients with serrated polyposis should undergo colonoscopies every 1–3 years with attempted removal of all polyps >5 mm diameter.

Indications for surgery for serrated polyposis syndrome (SPS) include an inability to control the growth of serrated polyps, or the development of cancer. Colectomy and ileorectal anastomosis is a reasonable option given the risks of metachronous neoplasia.

There is no evidence to support extracolonic cancer surveillance for SPS at this time. Screening recommendations for family members are currently unclear pending further data and should be individualized based on results of baseline evaluations in family members.

Surveillance of individuals with a genetic predisposition for pancreatic adenocarcinoma should ideally be performed in experienced centers utilizing a multidisciplinary approach and under research conditions. These individuals should be known mutation carriers from hereditary syndromes associated with increased risk of pancreatic cancer (Peutz–Jeghers, hereditary pancreatitis, familial atypical multiple melanoma and mole syndrome (FAMMM)) or members of familial pancreatic cancer kindreds with a pancreatic cancer affected first-degree relative. Because of a lower relative risk for pancreatic adenocarcinoma development in BRCA1, BRCA2, PALB2, ATM, and LS families, surveillance should be limited to mutation carriers with a first or second-degree relative affected with pancreatic cancer.

Surveillance for pancreatic cancer should be with endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) of the pancreas annually starting at age 50 years, or 10 years younger than the earliest age of pancreatic cancer in the family. Patients with PJS should start surveillance at age 35 years.

Because of the increased risk for pancreatic cancer development when compared with a pancreatic cyst in the sporadic setting, cystic lesion(s) of the pancreas detected during surveillance of a hereditary pancreatic cancer-prone family member requires evaluation by centers experienced in the care of these high-risk individuals. Determining when surgery is required for pancreatic lesions is difficult and is best individualized after multidisciplinary assessment.

Management for patients with hereditary diffuse gastric cancer should include: (i) prophylactic gastrectomy after age 20 years (>80% risk by age 80); (ii) breast cancer surveillance in women beginning at age 35 years with annual mammography and breast MRI and clinical breast examination every 6 months; and (iii) colonoscopy beginning at age 40 years for families that include colon cancer.