Colorectal Cancer ____________________________________________________________________________
syndrome have been rendered obsolete [88]. Given the limited modalities available to assess unaffected individuals for Lynch syndrome, family history and the use of clinical criteria may be appropriate in identifying those who warrant further genetic evaluation and testing. Surveillance . The differing surveillance approach in persons with Lynch syndrome relative to average-risk persons is dic- tated by the biologic behavior of Lynch syndrome [90]. Lynch syndrome develops earlier than sporadic colorectal cancer, which suggests screening should begin earlier in life. Most Lynch syndrome colorectal cancers occur in the right colon, making sigmoidoscopy alone insufficient. Annual colonoscopic surveillance is recommended [90; 96]. The accelerated progres- sion from normal mucosa to adenoma to cancer suggests a shorter colonoscopy screening interval (i.e., every one to two years). The substantially higher lifetime incidence of colorectal cancer suggests that surveillance should use the most sensitive test available [90]. Patients with Lynch syndrome are at an elevated risk of extra- colonic cancers, especially endometrial and ovarian [90]. While routine screening in women with Lynch syndrome is recommended due to substantially increased risk of endome- trial cancer, routine transvaginal ultrasound screening for endometrial cancer is insensitive, nonspecific, and without benefit in the general population. Interventions . A study randomized 861 Lynch mutation car- riers to daily aspirin 600 mg or placebo. No difference was found at 24 months, but 56-month follow-up found somewhat lower adenoma rate and colorectal cancer risk in the aspirin group. Further analysis and a planned 10-year follow-up found decreased incidence of all Lynch-associated cancers in the aspirin group [54; 55]. Prophylactic surgery is an alternative to annual colorectal cancer and endometrial cancer screening. The high risk of developing metachronous lesions is the basis for prophylactic surgery [104]. The incidence of metachronous colorectal can- cers has been reported to be 16% at 10 years, 41% at 20 years, and 63% at 30 years following segmental colectomy [105]. With the increased incidence of synchronous and metachronous neoplasms, the treatment of choice for a patient with Lynch syndrome with neoplastic lesions in the colon is generally an extended colectomy. The results of a follow-up study help in the selection of surgical approach. In this trial, 382 MMR mutation carriers were followed over time after surgery. During follow- up, metachronous colorectal cancer developed in no patient receiving total or subtotal colectomy compared with 22% of patients receiving segmental colectomy [106; 107]. An impor- tant factor in the decision to offer prophylactic surgery is the ability of the patient to comply with surveillance examinations. Consideration of total or subtotal colectomy should be bal- anced with patient comorbidities, clinical stage of the disease, patient wishes, and surgical expertise. One retrospective study examined data collected on 242 patients with Lynch
syndrome who underwent surgery for a first colon cancer between 1984 and 2009 [108]. Patients underwent either standard segmental colectomy or extended colectomy. Primary outcomes measured were risk of subsequent colorectal cancer, overall and disease-specific survival, and operative mortality. One patient died of postoperative septicemia within 30 days after segmental colectomy. Subtotal colectomy decreased the risk of subsequent colorectal cancer compared with segmental resection. The cumulative risk of subsequent colorectal cancer was 20% in 10 years and 47% within 25 years after standard resection, and 4% and 9% after extended surgery, respec- tively. However, disease-specific and overall survival within 25 years did not differ significantly between the standard and extended surgery groups (82.7% vs. 87.2%) [108]. Although no data have been published showing a survival advantage in extended versus segmental resection for patients with Lynch syndrome, clinicians might consider extensive colectomy to prevent subsequent colorectal cancer in patients with Lynch syndrome [109]. Also, subtotal or total colectomy does not eliminate rectal cancer risk, and the risk of developing rectal cancer following abdominal colectomy is estimated at 12% at
12 years post-surgery [105; 110]. Familial Adenomatous Polyposis
FAP accounts for 1% of all colorectal cancers and involves germline mutations in the tumor suppressor gene APC [91; 97]. Ashkenazi Jews have elevated risk of colorectal cancer due to APC gene mutation, which occurs in 6% to 7% of this population [111]. Other FAP disorder variants include [91; 97]: • Attenuated FAP: APC gene • Turcot syndrome: APC gene, MMR genes • Serrated polyposis syndrome (previously hyperplastic polyposis syndrome): BRAF and KRAS2 genes • MYH -associated polyposis: MYH gene Genetic diagnosis of FAP in pre-symptomatic patients is per- formed with linkage or direct detection of APC mutations by analyzing lymphocyte DNA in a blood sample. Linkage analysis tests blood samples from multiple persons to identify gene carriers in close and ancillary family members [91; 97; 104]. Clinical Features . FAP is caused by parental transmission of mutation in the APC gene, a tumor suppressor or gatekeeper gene that controls cell proliferation. The most common FAP phenotype is development of hundreds to thousands of colorec- tal polyps, with usual onset during adolescence or early adult- hood. Malignancy develops in one or more polyps as early as 20 years of age, and colorectal cancer develops in almost 100% of patients by 40 years of age if the colon is not removed for primary prevention. Other characteristics of FAP can include polyps in the upper gastrointestinal tract; extracolonic mani- festations, such as congenital hypertrophy of retinal pigment epithelium, osteomas and epidermoid cysts, supernumerary teeth, and desmoid formation; and other malignancies, such as thyroid tumors, small bowel cancer, hepatoblastoma, and
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