Table 8.

Studies of extracolonic cancer screening in hereditary colorectal cancer syndromes

Organ	Study (years)	Reference	Subjects	Design	Findings
Lynch syndrome (LS)
Endometrial and ovarian	Dove-Edwin et al. (2002)	(56)	292 Women from hereditary nonpolyposis colorectal cancer (HNPCC) or HNPCC-like families.	Observational: all offered transvaginal ultrasounds.	Two cases of endometrial cancer (EC) presented with symptoms, neither detected by ultrasound.
	Rijcken et al. (2003)	(348)	41 Women with MMR mutations or fulfilled Amsterdam I criteria followed for median of 5 years.	Observational: all offered annual pelvic exam, transvaginal ultrasound, CA-125.	17 Of 179 ultrasounds gave reason for endometrial sampling with 3 premalignant lesions noted; one interval endometrial cancer presented symptomatically.
	Renkonen-Sinisalo et al. (2007)	(57)	175 Women with MMR mutations.	Observational: all offered transvaginal ultrasound and endometrial biopsy.	14 cases of EC; 11 diagnosed by surveillance. Biopsy diagnosed 8 of 11 EC and 14 cases of premalignant hyperplasia. Ultrasound indicated 4 EC cases but missed 6 others. 4 case of ovarian cancer, none found by ultrasound.
	Lecuru et al. (2008)	(349)	62 Women (13 with MMR mutation, 49 met Amsterdam II criteria).	Observational: annual hysteroscopy and endometrial biopsy.	3 Malignancies in 3 patients with abnormal bleeding; 3 cases of hyperplasia in asymptomatic patients; hysteroscopy 100% sensitive for cancer or hyperplasia.
	Gerritzen et al. (2009)	(350)	100 Women from families with MMR mutation.	Observational: annual transvaginal ultrasound, CA-125, endometrial sampling.	3 Atypical hyperplasias and 1 endometrial cancer diagnosed. One stage III ovarian cancer developed despite ultrasound.
	Stuckless et al. (2013)	(351)	174 Women with MSH2 gene mutation.	Case–control: Cases:54 patient with at least one screening exam (transvaginal, endometrial biopsy, or CA-125 test); Controls: matched women without screening.	Stage I/II cancer diagnosed in 92% of screened patients compared with 71% in control group (P=0.17). Two of three deaths in the screened group from ovarian cancer.
	Stuckless et al. (2012)	(46)	322 MSH2 mutation carriers.	Observational: cancer incidence and survival in 152 screened vs. 170 not screened by colonoscopy.	Median age to CRC later in screened vs. nonscreened. Survival statistically improved in screened vs. nonscreened.
	Schmeler et al. (2006)	(58)	315 Women with MMR mutation with and without gynecological surgery.	Retrospective: risk of uterine and ovarian cancer in patients with and without prophylactic/clinically indicated gynecological surgery.	No uterine or ovarian cancer in surgery group vs. 33 and 5% cancer respectively in nonsurgery group.
Gastric	Renkonen-Sinisalo et al. (2002)	(352)	73 Patients with MMR mutation; 32 MMR mutation-negative family members.	Observational: Upper endoscopy with gastric biopsies.	In MMR gene-positive patients, H. pylori in 26%, atrophy 14%, intestinal metaplasia 14%. No statistical difference between gene-positive and -negative groups.
Small bowel	Saurin et al. (2010)	(66)	35 Patients with MMR mutations.	Observational: Capsule endoscopy and computed tomographic (CT) enteroclysis screening of small bowel.	Small bowel neoplasms were found in 8.6% of cases (1 patient with jejunal carcinoma and 2 with jejunal adenoma). Capsule endoscopy found all lesions; CT enteroscopy found cancer but missed adenomas.
Urinary tract	Myrhoj et al. (2008)	(68)	977 At-risk individuals in families suspected to have HNPCC/LS.	Observational: Retrospective review of screening urine cytology (UC) and diagnosis of urinary cancer.	0.1% Of UC exams lead to diagnosis of urothelial tumor. 10× more UC exams lead to false-positive diagnosis. Sensitivity of UC was 29%.
Familial adenomatous polyposis (FAP)
Duodenum	Bulow et al. (2004)	(144)	367 FAP cases	Prospective: to describe the long-term natural history of duodenal adenomatosis in FAP and evaluate the indications for prophylactic duodenal surveillance	65% Of cases had duodenal adenomas on their first endoscopy. The cumulative incidence of duodenal carcinoma was 4.5% at 57 years; cases with Spigelman stage IV adenomatosis on initial endoscopy were at higher risk compared with those with stages 0–III
	Biasco et al. (2006)	(353)	50 FAP cases	Prospective: to evaluate the presence and severity of precancerous duodenal mucosal lesions	86% Of cases had duodenal lesions at the end of the study compared with 38% at first endoscopy. Eleven subjects developed stage IV disease and had endoscopic or surgical resection.
Thyroid	Jarrar et al. (2011)	(354)	192 FAP cases	Prospective: to clarify the incidence of thyroid cancer in patients with FAP	38% Of cases had thyroid nodules and 2.6% had thyroid cancer. Clinical history and neck examination did not detect any of the cancers
Peutz–Jeghers syndrome (PJS)
Gastrointestinal (GI) tract	Latchford et al. (2011)	(355)	63 PJS cases from 48 pedigrees	Retrospective review: to assess outcomes from GI surveillance in patients with PJS	Baseline investigations were done in 12 subjects. The rest of the patients were followed for a median of 10 years and 776 procedures were performed. Of the 2,461 polypectomies done, 6 polyps contained atypia or dysplasia; there were two cases of perforation following resection of polyps >2 cm. No luminal GI cancers were diagnosed.
Small bowel	Brown et al. (2006)	(356)	19 Adult PJS cases	Prospective: to evaluate the performance of capsule endoscopy in small bowel surveillance of adults with PJS vs. barium follow-through	Capsule endoscopy detected more significant polyps than barium follow-through but seemed less reliable for accurately sizing 1–2 cm polyps.
	Gupta et al. (2010)	(357)	19 Adult PJS cases	Prospective: to assess the utility of magnetic resonance (MR) enterography compared with capsule endoscopy for small bowel polyp detection in PJS	All cases underwent both procedures. MR enterography detected large polyps (>15 mm) missed in three patients by capsule endoscopy. Size assessments of large polyps appeared more reproducible with MR enterography.
Pancreas	Poley et al. (2009)	(358)	44 Individuals at high risk of developing pancreatic cancer (2 PJS cases)	Prospective: to investigate the use of endoscopic ultrasound for screening individuals at high risk of developing pancreatic cancer	Initial screening detected an asymptomatic mass lesion in 3 cases (6.8%) and premalignant intraductal papillary mucinous neoplasm (IPMN)-like lesions in 16%.
Cowden syndrome
Thyroid	Milas et al. (2012)	(345)	225 PTEN mutative-positive cases	Retrospective: to characterize Cowden syndrome-associated malignant and benign thyroid disease	32 Cases (14%) had thyroid cancer (mostly papillary type) at a median age of 35 years. Initial thyroid ultrasound in 16 of 25 subjects revealed thyroiditis/goiters in all >13 years of age.