___________________________________________________________________________ Colorectal Cancer
Clinical Features . Colorectal cancer and extracolonic malignancies are the primary consequences of Lynch syndrome. Colorectal cancer associated with Lynch syndrome is characterized by early age of onset, excess synchronous and metachronous colorectal neoplasm, right-sided dominance (roughly 67%), and extracolonic tumors. The average age of colorectal cancer diagnosis in patients with Lynch syndrome is 44 to 52 years, versus 71 years in sporadic colorectal cancer. MLH1 and MSH2 account for close to 90% of gene mutations, and the lifetime risk of colorectal cancer in MLH1 and MSH2 mutation carriers is 68.7% in men and 52% in women [97]. Risk of extracolonic malignancy is greatest for endometrial cancer. At least one female member in about half of all Lynch syndrome pedigrees is affected, and 50% of women with an MMR gene mutation present with endometrial cancer as first malignancy. Patients with Lynch syndrome have an elevated risk of several other cancers. Risk of extracolonic tumor development by 70 years of age in Lynch syndrome is shown below, with prevalence rate ranges reflecting differences between specific MMR mutations [97]: • Endometrial ( MLH1/MSH2 ): 14% to 54% • Ovarian: 4% to 20% • Urinary tract: 0.2% to 25% • Stomach: 0.2% to 13% • Small bowel: 0.4% to 12% • Brain/central nervous system: 1% to 4%
The 2004 updated Bethesda Guidelines were developed to improve the false-negative rates with Amsterdam II and outline criteria to prompt MSI tumor testing to identify Lynch syndrome. Tumors meeting one or more of these criteria require testing for MSI [95; 97; 102]: • Colorectal cancer diagnosed at 50 years of age or younger • Synchronous or metachronous Lynch-associated cancer present, regardless of age • Colorectal cancer with Lynch-like histology (e.g., tumor infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, medullary growth pattern) in patients younger than 60 years of age • Colorectal cancer in a patient with one or more first- degree relatives with Lynch-associated cancer diagnosed at or before 50 years of age • Colorectal cancer in a patient with two or more first- or second-degree relatives with a Lynch-associated tumor, regardless of age Although more sensitive than Amsterdam II in identifying families with Lynch syndrome, only 15% to 30% of families not meeting Amsterdam II but meeting Bethesda criteria exhibit MSI gene mutation. Thus, Amsterdam II or Bethesda criteria may be used to help identify patients who should receive genetic testing, but they should not be used as diagnostic instruments [95; 103]. Surveillance . The differing surveillance approach in persons with Lynch syndrome relative to average-risk persons is dictated by the biologic behavior of Lynch syndrome [89]. 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 [95]. The accelerated progression 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. Patients with Lynch syndrome are at an elevated risk of extracolonic cancers, especially endometrial and ovarian. While routine screening in women with Lynch syndrome is recommended due to substantially increased risk of endometrial 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 carriers 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 [55; 56].
• Prostate: 9% to 30% • Breast: 5% to 18%
The adenoma-carcinoma sequence of polyp-to-cancer dwell time is an estimated mean 35 months, considerably more rapid than the 10- to 15-year average in sporadic colorectal cancer. This accelerated rate is likely the result of MMR gene dysfunction that creates frequent DNA mismatches in multiple genes to disrupt their normal function [97]. Until recently, Lynch syndrome was termed hereditary nonpolyposis colorectal cancer, a misnomer because polyps are usually present [100]. Diagnosis . Clinical criteria to identify patients with Lynch syndrome were published in 1990 and termed the Amsterdam criteria. These were revised and expanded with the 1999 Amsterdam II criteria, which included extracolonic cancers. The Amsterdam II defines minimum criteria for a clinical diagnosis of Lynch syndrome as at least three relatives with a Lynch-associated cancer (e.g., colorectal cancer, endometrial, small bowel, ureter, renal pelvis) and [95; 101]: • Two or more successive generations affected • One or more relatives diagnosed before 50 years of age (at least one first-degree relative) • FAP excluded • Tumors verified by pathologic examination
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