Guidelines on Genetic Evaluation and Management of Lynch Syndrome

A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer

Francis M Giardiello MD; John I Allen; Jennifer E Axilbund; C Richard Boland; Carol A Burke; Randall W Burt; James M Church; Jason A Dominitz; David A Johnson; Tonya Kaltenbach; Theodore R Levin; David A Lieberman; Douglas J Robertson; Sapna Syngal; Douglas K Rex

Disclosures

Am J Gastroenterol. 2014;109(8):1159-1179. 

In This Article

Lynch Syndrome Management

Screening

Patients with LS are at increased risk for the development of colorectal and extracolonic cancers at early ages. Although there is insufficient evidence to assess the benefit of annual history, physical examination, and patient and family education, expert opinion would recommend this practice starting at 20–25 years old. The use of other screening tests is discussed here.

Colorectal Cancer. CRC prevention in LS families is guided by the distinctive characteristics of these malignancies, including the younger age of presentation, right-sided colon predominance, and rapid polyp growth with shorter dwell time before malignant conversion. Evidence for the effectiveness of colorectal screening in decreasing CRC mortality has been documented in studies by Järvinen et al..[129–131] (Table 9). Persons at-risk for LS who took up colonoscopic surveillance had 65% (P=0.003) fewer deaths from CRC compared with those who refused surveillance. Update of this Finnish study, which analyzed colonoscopic surveillance in LS mutation carriers, found no difference in CRC deaths between mutation carriers and mutation-negative relatives.[131] Dove-Edwin et al. reported the results of a prospective observational study of colonoscopy surveillance of members in HNPCC or LS families revealing a 72% decrease in mortality from CRC in those undergoing screening.[132] In several studies,[32,133–135] more frequent colonoscopy screening (≤2 years) was associated with earlier-stage CRC at diagnosis and less CRC than less frequent colonoscopy. At least every 2–year colonoscopic surveillance of LS patients is supported by the data presented here and the rapid adenoma–carcinoma sequence reported in these patients.

Endometrial Cancer. EC is the second most common cancer occurring in LS. Estimates of the cumulative lifetime risk of EC in LS patients range from 21 to 60%, with variability depending on specific gene mutation; reports of age at diagnosis of this malignancy are clearly a decade or more younger than sporadic EC, but range from 48 to 62 years old.

Due to the worrisome cumulative risk of EC, several annual screening modalities have been proposed, including pelvic examinations, transvaginal ultrasound, endometrial sampling, and CA-125 testing. Few studies of these interventions have been conducted. At present, the literature reports reveal no evidence of survival benefit from endometrial surveillance (Table 11). Decrease in death from EC can be difficult to prove because 75% of LS patients with EC present with stage I disease and have an 88% 5-year survival rate. Investigation of transvaginal ultrasound reveals poor sensitivity and specificity for the diagnosis of EC in this population.[139–141] However, endometrial sampling appears useful in identifying some asymptomatic patients with EC and those with premalignant endometrial lesions[142–144] (Table 11).

Ovarian Cancer. Estimates of the cumulative lifetime risk of ovarian cancer in LS patients ranges from 0.3 to 20%. Currently, no studies on the effectiveness of ovarian screening are available for women in LS families. In patients with hereditary breast cancer from mutation of BRCA1 or BRCA2 at increased risk for ovarian cancer, 1 investigator found transvaginal ultrasound and CA-125 screening not useful.[145]

Prophylactic Hysterectomy and Oophorectomy. As discussed here, patients with LS have substantial risk for uterine and ovarian cancer. One US study showed benefit for prophylactic gynecologic surgery to reduce or eliminate gynecologic cancer[146] (Table 11). Retrospective analysis of 315 women with MMR mutations who did and did not have gynecologic surgery revealed no cancers in the surgical group compared with a 33 and 5.5% rate of uterine and ovarian cancer, respectively, in the nonsurgical group.[146] Cost-effectiveness analysis modeling of gynecologic screening vs prophylactic gynecologic surgery (hysterectomy and bilateral salpingo-oopherectomy) in a theoretical population of 30–year-old women with LS revealed that prophylactic surgery had lower cost and higher quality-adjusted life-years.[147] An additional modeling study evaluated multiple screening and surgical strategies. This investigation concluded that annual screening starting at age 30 years followed by prophylactic surgery at age 40 years was the most effective gynecologic cancer prevention strategy, but incremental benefit over prophylactic surgery at age 40 years alone was attained at substantial cost.[148]

Gastric Cancer. Some studies have estimated the lifetime risk of gastric cancer in LS as high as 13%, but currently this appears to be much lower in North America and Western Europe. A carefully conducted time trend study of gastric cancer found an 8.0%. and 5.3% lifetime risk of this malignancy in males and females with MMR gene mutation, respectively, and lack of familial clustering.[47] The majority of gastric cancers in LS patients appear to be histologically classified as intestinal type[45,47] and, consequently, potentially amenable to endoscopic surveillance.

Data on screening for gastric cancer are lacking. However, Renkonen-Sinisalo et al.[149] reported that precursor lesions for gastrointestinal cancer, including Helicobacter pylori infection, and intestinal metaplasia were seen in 26 and 14%, respectively, of patients with MMR mutations (Table 13).

Small Intestinal Cancer. The lifetime risk for this cancer ranges from 0.4 to 12.0%.[17,28,39,40,44,48] Two large studies of extracolonic cancer in patients with MMR mutations came to opposite conclusions, with lifetime risks of 0.6 and 12%, respectively.[17,48] Another investigation revealed that the majority of small bowel cancers in an LS cohort were located in the duodenum or ileum[150] and within the reach of EGD and colonoscopy with dedicated ileal intubation. There appears to be no evidence of familial clustering of this extracolonic malignancy.[46]

Studies of small bowel screening in LS patients are lacking. However, one screening investigation of 35 gene mutation carriers found that 2 had jejunal adenomas and 1 had a jejunal cancer[151] (Table 13). Six additional patients had capsule endoscopy images of uncertain clinic relevance, prompting additional invasive investigation in 5 patients. A recent publication suggested that routine surveillance of the small bowel in LS was not cost efficient.[46] However this calculation could change with additional literature evidence.

Urinary Cancer. Estimates of the lifetime risk of urinary tract cancer in LS ranges from 0.2 to 25% in men with MSH2 mutations. This includes elevated risk for transitional cell carcinoma of the ureter, renal pelvis, and bladder.[17,28,39,40,44,48,49,152,153] Currently, a dearth of literature on screening for urinary cancer in LS patients exists. One retrospective study evaluating screening for urinary cancer by urine cytology in individuals in HNPCC or LS families found poor sensitivity (29%) in diagnosing cancer in asymptomatic patients and production of many false-positive results requiring invasive investigation[152] (Table 13). Screening studies have not been effective with urine cytology and urinalysis for microscopic hematuria for urinary cancer in the general population and in groups at higher risk for bladder cancer from environmental factors.[154,155] The benefit of ultrasound screening is unknown. In summary, limited data exist to advocate urinary screening. Expert consensus concludes that urinalysis is inexpensive, noninvasive, usually part of a routine physical examination, easily done, and should be considered in LS patients. Future studies could change this consideration.

Pancreatic Cancer. Risk of pancreatic cancer in LS patients was noted to be elevated in 2 cohort studies. In 1 study, the standardized incident ratio for pancreatic cancer was 10.7 (95% confidence interval: 2.7–47.7), with a 10–year cumulative risk of 0.95%,[51] and the other reported a 8.6–fold increase (95% confidence interval: 4.7–15.7), with cumulative risk of 3.7% by age 70 years.[50] In 1 investigation, the risk of pancreatic cancer was not elevated in a cohort in which the pancreatic cancers were validated by dedicated histologic review.[52]

Other Cancers. There are conflicting data about the risk of several extracolonic cancers in patients with LS patients. With regard to prostate cancer, several studies have revealed no significantly increased risk of this malignancy.[42,51] Other investigations draw opposite conclusions, with relative risk ranging from 2.5–to 10–fold and lifetime risk ranging from 9 to 30% by age 70 years.[48,53,59,157] In breast cancer, inconsistent data exist. One large study revealed no increased risk in LS patients.[46] In contrast, a British study of 121 MMR mutation families found an increased risk of breast cancer for positive and obligate MLH1 mutation carriers with a cumulative risk of 18.2% to age 70 years (95% CI: 11.9–24.5), but not for MSH2 carriers.[44] A German and Dutch study found a mild increase in cumulative risk of breast cancer of 14% by age 70 years.[48] In a recent prospective study of patients with MMR mutations an increased cumulative risk of breast cancer of 4.5% during 10 years of observation was noted (standardized incident ratio=3.95; 95% CL: 1.59–8.13).[51]

Treatment

Colectomy. The treatment for patients with colon cancer or premalignant polyps that cannot be removed by colonoscopy is colectomy. The risk of metachronous CRC after partial colectomy is summarized in Table 14. With partial colectomy, a high 10–year cumulative risk of CRC (16%–19%) is reported in several studies, even in those patients undergoing vigilant colonoscopic surveillance.[32–34] and is ingravescent with longer observation. This risk is substantially reduced if a subtotal (anastomosis of the small bowel to sigmoid) or total (ileorectal anastomosis) colectomy is performed (0–3.4%).[32–34] In a Dutch study, no difference in global quality of life was noted between 51 LS patients who underwent partial colectomy, and 53 who underwent subtotal colectomy, although functional outcomes (eg, stool frequency, stool-related aspects, and social impact) were worse after subtotal colectomy than after partial colectomy.[158] Comparison of life expectancy gained performing total colectomy vs hemicolectomy in LS patients at ages 27, 47, and 67 years by Markov modeling was 2.3, 1, and 0.3 years, respectively.[159] These investigators concluded that total colectomy is the preferred treatment in LS, but hemicolectomy might be an option in older patients.

Although most LS CRCs are right sided, up to 20% can occur in the rectum. When this happens surgical decision making needs to include the use of neoadjuvant chemoradiation and consideration of total protocolectomy and ileal pouch-anal anastomosis. This surgical option is commonly performed in familial adenomatous polyposis patients with severe rectal polyposis or cancer. However, familial adenomatous polyposis patients are usually younger than those with LS, in whom this operation would pose a significant challenge to surgical recovery and postoperative quality of life. However, Kalady et al. found a risk of metachronous advanced neoplasia (cancer and severe dysplasia) of 51% in HNPCC patients who had an anterior resection for rectal cancer.[160] Win et al. found the overall risk of cancer to be 24.5% and a cumulative risk to 30 years of 69%.[33] Therefore, total proctocolectomy with ileal pouch-anal anastomosis is an important option to discuss with patients with rectal cancer and LS.

Chemoprevention. Resistant starch and aspirin have been assessed as chemopreventive agents in patients with LS (Table 15). The Colorectal/Adenoma/Carcinoma Prevention Programme 2 (CAPP2) was a randomized placebo-controlled trial with a 2 × 2 design investigating the effect of resistant starch (Novelose) 30 g/d and aspirin 600 mg/d taken up to 4 years on development of colorectal adenoma and cancer.[161] This study randomized 727 participants to starch or placebo and 693 between aspirin and placebo. The use of resistant starch, aspirin, or both had no effect on the incidence of colorectal neoplasia in LS carriers during a mean period of follow-up of 29 months. CAPP2 follow-up analysis of the long-term effect (median follow-up of 52.7 months) of resistant starch again revealed no effect on CRC development.[162]

The CAPP2 investigators also evaluated the long-term effect of 600 mg of aspirin on CRC development.[163] At a mean follow-up of 55.7 months, intention-to-treat analysis of time to first CRC showed a hazard ratio of 0.63 (95% CL: 0.35–1.13; P=0.12). For participants completing 2 years of intervention (258 on aspirin and 250 on placebo) per-protocol analysis yielded a hazard ratio of 0.41 (95% CL: 0.19–0.86; P=0.02). An intention-to-treat analysis of all LS cancers (ie, colorectal, endometrial, ovarian, pancreatic, small bowel, gallbladder, ureter, stomach, kidney, and brain) revealed a protective effect of aspirin vs placebo (hazard ratio=0.65; 95% CL: 0.42–1.00; P=0.05). During the intervention, adverse events did not differ between aspirin and placebo groups.

The chemoprotective effect of aspirin on colorectal and extracolonic cancer noted in the CAPP2 study of LS patients is supported by a recent meta-analysis of randomized trials of daily aspirin use vs no aspirin (primarily in patients with cardiovascular disease) with a mean duration of treatment of 4 years or longer.[164] This study found decreased risk of death from colorectal and extracolonic cancer after 10 to 20 years of follow-up. Of note, the benefit was unrelated to aspirin doses >75 mg/d.

The CAPP2 trial has several limitations. First, ascertainment of the end point, CRC, was not standardized, and more intensive colonoscopic evaluation could have occurred in the aspirin group than in the nonaspirin group because of more frequent adverse effects after intervention. Second, the extracolonic cancers did not undergo molecular evaluation to assess whether they were related to the germline MMR mutation. Also, the dose of daily aspirin utilized in the CAPP2 trial is significantly higher than that noted to be effective (75 mg/d) in CRC chemoprevention in sporadic CRC.

The CAPP3 is underway to establish the optimum dose and duration of aspirin treatment. Although data exist to suggest that aspirin can decrease the risk of colorectal and extracolonic cancer in LS, currently the evidence is not sufficiently robust or mature to make a recommendation for its standard use.[164]

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