Carol A. Burke

Serrated Lesions of the Colorectum: Review and Recommendations From an Expert Panel

Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers (CRCs). Cancers arising in serrated lesions are usually in the proximal colon, and account for a disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification, and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to the World Health Organization criteria as hyperplastic polyp, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premalignant lesions, but SSA/P is the principal serrated precursor of CRCs. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid >5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives.

Folic Acid and Risk of Prostate Cancer: Results From a Randomized Clinical Trial

Data regarding the association between folate status and risk of prostate cancer are sparse and conflicting. We studied prostate cancer occurrence in the Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas conducted between July 6, 1994, and December 31, 2006. Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.0-7.8) years and asked periodically to report all illnesses and hospitalizations. Aspirin alone had no statistically significant effect on prostate cancer incidence, but there were marked differences according to folic acid treatment. Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01). In contrast, baseline dietary folate intake and plasma folate in nonmultivitamin users were inversely associated with risk of prostate cancer, although these associations did not attain statistical significance in adjusted analyses. These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid-containing supplements vs natural sources of folate.

Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer

The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3,4,5,6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.

The utility of capsule endoscopy small bowel surveillance in patients with polyposis

BACKGROUND:Small intestinal (SI) surveillance is recommended for polyposis patients. The utility and safety of capsule endoscopy (CE) for surveillance of SI neoplasia in patients with familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS) is unknown.METHODS:CE was offered to consecutive FAP and PJS patients due for routine upper endoscopic surveillance. The prevalence, location (jejunum, ileum), size (1–5 mm, 6–10 mm, >10 mm) and number (1–5, 6–12, >20) of polyps detected by CE was assessed.RESULTS:19 subjects (15 FAP/4 PJS) with a mean age of 43 were included. All subjects had previous intestinal surgery. No complications occurred with CE. CE in FAP: 9/15 (60%) of subjects with FAP had SI polyps. The prevalence of SI polyps was related to the duodenal polyposis stage and subject age. The location, size and number of polyps progressed as duodenal polyposis stage advanced. CE in PJS: 3/4 (75%) of subjects with PJS had SI polyps. The polyps were diffuse in 2/4 and only in the ileum in one subject. CE findings led to laparotomy with intra-operative endoscopic polypectomy in two PJS patients.CONCLUSION:SI polyps are common in FAP but their importance is unknown. CE should be performed in FAP patients with stage III and IV duodenal disease. Clinically significant polyps are commonly detected by CE in PJS and lead to change in management in 50% of PJS subjects. CE should replace radiographic SI surveillance for PJS patients. CE is safe in polyposis patients who have undergone major intestinal surgery.

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

BACKGROUND & AIMS Germline phosphatase and tensin homolog (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 or more GI polyps, 1 or more of which was hyperplastic or hamartomatous (N = 397), were prospectively recruited. Germline PTEN mutation/deletion analysis was performed. Of the 2945 patients, 127 (123 of 2548 and 4 of 397, respectively) patients having clear pathogenic PTEN mutations were eligible for this study. Esophagogastroduodenoscopy, colonoscopy, and pathology reports were reviewed. The Fisher 2-tailed exact test, unpaired t tests, and age- and sex-adjusted standardized incidence ratio were calculated. RESULTS Of 127 PTEN mutation carriers, 69 underwent 1 or more endoscopies with 64 (93%) having polyps. Of the 64, half had hyperplastic 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 younger than the age of 50. The adjusted standardized incidence ratio was 224.1 (95% confidence interval, 109.3-411.3; P < .0001). CONCLUSIONS PTEN-associated CS should be considered a mixed polyp syndrome, with hyperplastic polyps most prevalent, with 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.

The natural history of untreated duodenal and ampullary adenomas in patients with familial adenomatous polyposis followed in an endoscopic surveillance program

BACKGROUND Endoscopic surveillance is recommended for patients with familial adenomatous polyposis (FAP) because of the high prevalence of duodenal adenomas and the risk of periampullary cancer. The aim of this study was to assess the natural history of untreated duodenal and ampullary adenomas in FAP patients during surveillance. METHODS One hundred fourteen FAP patients who had 2 or more surveillance examinations were followed for a mean of 51 months (range, 10 to 151 months). RESULTS Duodenal polyps progressed in size in 26% (25 of 95), number in 32% (34 of 106), and histology in 11% (5 of 45) of patients. Morphology and histology of the main duodenal papilla progressed in 14% (15 of 110) and 11% (12 of 105) of patients, respectively. The histologic progression was mild except for one patient who developed a periampullary cancer. CONCLUSIONS A minority of FAP patients had progression of endoscopic features and histology of duodenal polyps or the main duodenal papilla when followed over 4 years. An endoscopic surveillance interval of at least 3 years may be appropriate for the majority of untreated patients with FAP. Factors that stratify patients as being at the highest risk of periampullary cancer and thus requiring more intensive surveillance are yet to be determined.

Fundic gland polyp dysplasia is common in familial adenomatous polyposis.

BACKGROUND & AIMS Fundic gland polyps (FGPs) are common in familial adenomatous polyposis (FAP) but have been considered nonneoplastic. Gastric carcinoma arises from FGPs in FAP presumably from a dysplasia-carcinoma pathway. Our study examined the prevalence of FGPs and FGP dysplasia in FAP and identified endoscopic or demographic features associated with FGPs and dysplasia. METHODS Demographic and endoscopic information were obtained prospectively from 75 consecutive subjects undergoing upper-endoscopic surveillance for FAP. Systematic biopsy specimens of FGPs, normal-appearing fundic mucosa, and antral mucosa for Helicobacter pylori were obtained. Multivariable analysis assessed the association of demographic or endoscopic factors with the presence of FGP or FGP dysplasia. RESULTS FGPs were detected in 88% of subjects and were dysplastic in 41% (38% low grade, 3% high grade). H pylori infection was rare in subjects with vs without FGPs (1.5% vs 33.3%, P = .005). In the multivariable analysis larger FGP size (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.1-14.4), higher stage of duodenal polyposis (OR, 2.3; 95% CI, 1.2-4.5), and antral gastritis (OR, 11.2; 95% CI, 1.2-103.9) were associated with FGP dysplasia. Exposure to acid-suppressive medications was associated with a marked decrease in dysplastic FGPs (OR, 0.14; 95% CI, 0.03-0.64). CONCLUSIONS The majority of FAP patients have FGPs and nearly half will have dysplastic FGPs. There is an inverse relationship between H pylori and FGPs. FGP dysplasia is associated with larger polyp size, increased severity of duodenal polyposis, and antral gastritis. Acid-suppressive therapy use appears protective against dysplasia in FGPs.

Risk of rectal cancer in patients after colectomy and ileorectal anastomosis for familial adenomatous polyposis: a function of available surgical options.

AbstractPURPOSE: One of the concerns with colectomy and ileorectal anastomosis as a prophylactic procedure for patients with familial adenomatous polyposis is the risk of metachronous rectal cancer, estimated at from 12 to 43 percent. These estimates are based largely on surgeries performed at a time when the only alternative option to ileorectal anastomosis for patients with severe familial adenomatous polyposis was proctocolectomy and ileostomy. This study was designed to test the hypothesis that in the pouch era severe polyposis is now treated by proctocolectomy and ileal pouch-anal anastomosis. Ileorectal anastomosis is performed mostly in mildly affected patients and will therefore carry a very low risk of metachronous rectal cancer. METHODS: Patients undergoing primary prophylactic surgery for familial adenomatous polyposis between 1950 and 1999 were categorized according to the year of their surgery: prepouch era (before 1983) or pouch era (after 1983). Patients undergoing colectomy and ileorectal anastomosis were the focus of the study, and rate of proctectomy and the incidence of rectal cancer were recorded for each group. Data on the severity of the polyposis for each group were abstracted. RESULTS: A total of 197 patients underwent ileorectal anastomosis, 62 in the prepouch era (median follow-up, 212 months; interquartile range, 148 months) and 135 in the pouch era (median follow-up, 60 months; interquartile range, 80 months). Patients in the prepouch era came to surgery at the same median age as those in the pouch era (median age 23.0 years, interquartile ranges 15.5 years for prepouch and 17 years for pouch). Similar proportions of patients in the prepouch era had severe polyposis (49 percent) as in the pouch era (44 percent), although all severely affected patients had an ileorectal anastomosis in the prepouch era vs. 39 percent in the pouch era. Twenty (32 percent) prepouch-era patients underwent proctectomy compared with three (2 percent) pouch-era patients. No pouch-era patient had rectal cancer on follow-up; eight (12.9 percent) prepouch-era patients did. CONCLUSION: Although follow-up is shorter, ileorectal anastomosis for familial adenomatous polyposis performed since 1983 carries a much lower rate of rectal cancer and proctectomy than ileorectal anastomosis performed before this time, when restorative proctocolectomy was not an option. This is related, at least in part, to a greater number of patients with severe polyposis having their rectum initially spared.

Implementation of Universal Microsatellite Instability and Immunohistochemistry Screening for Diagnosing Lynch Syndrome in a Large Academic Medical Center

PURPOSE In 2009, the Evaluation of Genomic Applications in Practice and Prevention recommended that all colorectal cancers (CRCs) be screened for Lynch syndrome (LS) through microsatellite instability (MSI) or immunohistochemistry (IHC). No studies report how this process is implemented on a health system-wide basis. METHODS Since 2004, Cleveland Clinic has screened CRC specimens with MSI/IHC. Between January 2004 and July 2007, MSI/IHC results went only to the colorectal surgeon (approach 1). Between August 2007 and June 2008, colorectal surgeons and a genetic counselor received the MSI/IHC results, and the counselor e-mailed the colorectal surgeon regarding appropriate patients for genetic counseling (GC) referral (approach 2). After July 2008, the colorectal surgeon and counselor received MSI/IHC results, but the counselor contacted the patient to facilitate referral (approach 3). In approaches 2 and 3, patients were presumed to have sporadic CRC if the tumor lacked MLH1 expression and was also BRAF mutated or if the patient was diagnosed at age greater than 72 years and had no cancer family history. RESULTS Abnormal MSI/IHC results occurred in 178 (16%) of 1,108 patients. In approach 1, 21 (55%) of 38 patients with abnormal MSI/IHC were referred for GC, 12 (32%) of 38 underwent GC, and 10 (26%) of 38 underwent genetic testing (GT). In approach 2, nine (82%) of 11 patients were referred for GC, seven (64%) of 11 underwent GC, and five (45%) of 11 underwent GT. In approach 3, 56 (100%) of 56 patients were referred for GC, 40 (71%) of 56 underwent GC, and 37 (66%) of 56 underwent GT. Time from referral to GC was 10-fold quicker in approach 3 than approach 1. CONCLUSION Implementation of universal MSI/IHC with GC/GT, along with effective multidisciplinary communication and plans of responsibility for patient contact, resulted in increased identification of patients with LS.

A trial of calcium and Vitamin D for the prevention of colorectal adenomas

BACKGROUND Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. METHODS We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2×2 factorial design. Women could elect to receive calcium plus random assignment to vitamin D or placebo. Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations, according to the endoscopists recommendation. The primary end point was adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy. RESULTS Participants who were randomly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter, relative to participants given placebo. Overall, 43% of participants had one or more adenomas diagnosed during follow-up. The adjusted risk ratios for recurrent adenomas were 0.99 (95% confidence interval [CI], 0.89 to 1.09) with vitamin D versus no vitamin D, 0.95 (95% CI, 0.85 to 1.06) with calcium versus no calcium, and 0.93 (95% CI, 0.80 to 1.08) with both agents versus neither agent. The findings for advanced adenomas were similar. There were few serious adverse events. CONCLUSIONS Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00153816.).