The "Studded" Rectum: Phenotypic Evidence of MYH-Associated Polyposis.

BACKGROUND: MYH-associated polyposis is a recessively inherited syndrome of colorectal cancer predisposition attributed to biallelic germline mutations in the base excision repair gene MYH. Clinically it overlaps with attenuated familial adenomatous polyposis, sporadic oligopolyposis, serrated polyposis, familial colorectal cancer type X, and Lynch syndrome. There is no specific phenotypic feature of MYH-associated polyposis. We have noticed that a proportion of patients with MYH-associated polyposis presenting for yearly colonoscopy surveillance have rectums that are studded with small hyperplastic polyps. OBJECTIVE: We report this as a possible unique phenotypic feature of the syndrome. DESIGN: This was a descriptive study. SETTINGS: The study was conducted at a department of colorectal surgery in a tertiary referral center. PATIENTS: Patients affected with oligopolyposis or MYH-associated polyposis presenting for endoscopic surveillance and polyp control were included. INTERVENTIONS: Interventions included colonoscopy or proctoscopy with excision or biopsy of mucosal lesions. MAIN OUTCOME MEASURES: The presence of rectal studding was measured. RESULTS: There were 49 patients, 16 with biallelic germline mutations of MYH; 10 of these had rectal studding. A sampling of rectal polyps was biopsied and all were hyperplastic. Five patients with biallelic MYH mutations had no studding, and 1 had not been prospectively examined. The studding was independent of the nature of the MYH mutation(s). The 33 patients other patients included 21 with serrated polyposis, 2 with a germline APC mutation, 1 with a PTEN mutation, 2 with mixed polyposis, 3 with oligoadenomatous polyposis and no germline mutation, and 4 patients with oligoadenomatous polyposis who had not been genetically tested. Only 1 of these (oligoadenomatous polyposis, not tested) had studding. LIMITATIONS: The study was limited by its small number of biallelic MYH mutation carriers. CONCLUSIONS: Rectal studding may be a sign of MYH-associated polyposis and raises questions about the biology of abnormal base excision repair.

Defining the adenoma burden in lynch syndrome.

BACKGROUND: Patients with 10 or more lifetime adenomas are candidates for genetic counseling and testing for polyposis syndromes. Lynch syndrome falls under the umbrella of hereditary nonpolyposis colorectal cancer, and it is assumed that patients with Lynch syndrome do not develop multiple adenomas. OBJECTIVE: The objective of this study was to document the number of adenomas in patients with Lynch syndrome. DESIGN: This was a retrospective review of clinical, colonoscopy, and pathology records of patients with Lynch syndrome in a prospectively maintained hereditary colorectal cancer database. SETTINGS: The study was conducted at a single-institution tertiary care center with specialized practice in hereditary colorectal cancer syndromes. PATIENTS: We included 263 patients with a germline mutation in 1 of the 4 DNA mismatch repair genes. INTERVENTIONS: Colonoscopy and polypectomy were the study interventions. MAIN OUTCOME MEASURES: The lifetime cumulative number of colorectal adenomas and their characteristics were measured. RESULTS: A total of 107 of the 263 patients had 1 or more adenomas. Sixty-one patients had 1 adenoma, 29 (11%) had 2 to 5 adenomas, 6 (2%) had 6 to 9 adenomas, and 11 patients (4%) had 10 or more cumulative adenomas. The maximum number of synchronous adenomas in any individual was 22, and the maximum number of cumulative adenomas in any individual was 24. Twenty-four of the 107 patients with adenomas underwent a total colectomy or proctocolectomy and were excluded from long-term follow-up. In the remaining 83 patients with adenomas, 426 colonoscopies were performed. A total of 220 (54%) were normal or had hyperplastic polyps; 313 adenomas were found in 206 examinations (46%), and 123 (39%) of the adenomas were advanced. LIMITATIONS: There was variability in the interval of colonoscopy surveillance. Some patients had a variant of unknown significance and were separated from those with a deleterious mutation. CONCLUSIONS: Although 10 or more adenomas prompt testing for polyposis syndromes, Lynch syndrome should also be considered in the differential diagnosis.

Prevalence of occult gynecologic malignancy at the time of risk reducing and nonprophylactic surgery in patients with Lynch syndrome.

OBJECTIVE: The primary aim of this study was to determine the prevalence of occult gynecologic malignancy at the time of risk reducing surgery in patients with Lynch Syndrome. A secondary aim was to determine the prevalence of occult gynecologic malignancy at the time of surgery for non-prophylactic indications in patients with Lynch Syndrome. METHODS: A retrospective review of an Inherited Colorectal Cancer Registry found 76 patients with Lynch syndrome (defined by a germline mutation in a DNA mismatch repair gene) or hereditary nonpolyposis colorectal cancer (HNPCC) (defined by Amsterdam criteria) who had undergone hysterectomy and/or salpingo-oophorectomy for a prophylactic or non-prophylactic indication. Indications for surgery and the prevalence of cancer at the time of each operation were reviewed. RESULTS: 24 of 76 patients underwent prophylactic hysterectomy and/or bilateral salpingo-oophorectomy for Lynch syndrome or HNPCC. In 9 of these patients, a benign indication for surgery was also noted. 4 of 24 patients (17%, 95% CI = 5-38%) were noted to have cancer on final pathology. 20 of 76 patients (26%) undergoing operative management for any indication were noted to have occult malignancy on final pathology. CONCLUSIONS: Patients should be counseled about the risks of finding gynecologic cancer at the time of prophylactic or non-prophylactic surgery for Lynch syndrome and HNPCC, and the potential need for additional surgery.

Metachronous serrated neoplasia is uncommon after right colectomy in patients with methylator colon cancers with a high degree of microsatellite instability.

BACKGROUND: Right-sided serrated polyps are precursors to sporadic microsatellite unstable colon cancers via the methylator pathway and have a high rate of synchronous and metachronous lesions. Serrated polyps also occur in Lynch syndrome, where right-sided microsatellite unstable cancers arise from germline mutations in mismatch repair genes. OBJECTIVE: The aim of this study was to compare serrated neoplasia in patients with sporadic and hereditary microsatellite unstable colon cancer and to examine the effect of right colectomy on the risk of metachronous polyps and cancers. DESIGN: This is a retrospective, descriptive, cohort study from database and chart review. SETTING: This study was conducted at a tertiary care hospital with a center for hereditary colorectal cancer. PATIENTS: Patients who had colon cancers with a high degree of microsatellite instability, methylator cancers, and Lynch syndrome cancers, were included. INTERVENTIONS: Interventions included colectomy, surveillance colonoscopy, and polypectomy. MAIN OUTCOME MEASURES: The primary outcomes measured were the incidence and location of metachronous polyps and cancers. RESULTS: Eighty-five patients were included: 47 with methylator cancers and 38 with Lynch syndrome. Median ages at surgery were 75 years (range, 41-90) and 48 years (range, 27-77), p < 0.0001. Forty-six (98%) patients with methylator cancers and 17 (45%) patients with Lynch syndrome underwent a right colectomy, p < 0.0001. Metachronous cancers occurred in 19/60 (32%) of patients with Lynch syndrome and no patients with methylator cancers, p < 0.0001. Thirty-four patients with methylator cancers had colonoscopic follow-up, with a median of 2 colonoscopies per patient over a 32-month follow-up (range, 1-136). Sixty-three percent of patients with Lynch syndrome had colonoscopic follow-up, median of 4 colonoscopies per patient over 102 months (range, 1-462), p < 0.0001. Four (9%) patients with methylator cancers each had 1 metachronous serrated polyp, compared with 10/37 (27%) patients with Lynch syndrome (p = 0.049), whose median number of polyps was 2 (range, 1-8). Characteristics of other associated polyps were similar between cohorts. LIMITATIONS: This study is somewhat limited by potential inherent bias from its retrospective design. Also, a high number of deaths in the CIMP+ cohort could have contributed to the low number of serrated polyps detected on colonoscopy surveillance, but given current understanding of serrated polyp growth, this may truly represent the left colon's tendency not to develop serrated polyps. CONCLUSIONS: Cancers with a high degree of microsatellite instability arise through 2 different molecular mechanisms. Metachronous serrated neoplasia, benign and malignant, following right colectomy in patients with the CpG-island methylator phenotype of colorectal cancer is uncommon. However, the colons of patients with Lynch syndrome are at high risk after segmental colectomy.

Hereditary non-polyposis colorectal cancer/Lynch syndrome in three dimensions.

BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is defined by family history, and Lynch syndrome (LS) is defined genetically. However, universal tumour testing is now increasingly used to screen for patients with defective mismatch repair. This mixing of the results of family history, tumour testing and germline testing produces multiple permutations and combinations that can foster confusion. We wanted to clarify hereditary colorectal cancer using the three dimensions of classification: family history, tumour testing and germline testing. METHODS: Family history (Amsterdam I or II criteria versus not Amsterdam criteria) was used to define patients and families with HNPCC. Tumour testing and germline testing were then performed to sub-classify patients and families. The permutations of these classifications are applied to our registry. RESULTS: There were 234 HNPCC families: 129 had LS of which 55 were three-dimensional Lynch (family history, tumour testing and germline testing), 66 were two-dimensional Lynch and eight were one-dimensional Lynch. A total of 10 families had tumour Lynch (tumours with microsatellite instability or loss of expression of a mismatch repair protein but an Amsterdam-negative family and negative germline testing), five were Lynch like (Amsterdam-positive family, tumours with microsatellite instability or loss of expression of a mismatch repair protein on immunohistochemistry but negative germline testing), 26 were familial colorectal cancer type X and 95 were HNPCC. CONCLUSION: Hereditary colorectal cancer can be confusing. Sorting families in three dimensions can clarify the confusion and may direct further testing and, ultimately, surveillance.