Recommendations for rational use of genetic testing for cancer predisposition have been published by several groups (123,124,125,126). They advocate pre- and post-test genetic counseling by trained health care professionals due to the clinical, psychosocial, financial, and ethical issues raised during the testing process. Of concern, a nationwide study of individuals undergoing genetic testing for hereditary CRC revealed major practitioner lapses, including failure to obtain informed consent, misinterpretation of test results (giving false-negative results), and pursuing expensive nonindicated testing (14). The Commission on Cancer has established standards for genetics professionals, including experience and education in cancer genetics and appropriate certification (127).
Components of the counseling session should include the collection of personal and family medical history; education about the disorder; exploration of psychosocial dimensions; informed consent, including cost and risk of genetic discrimination; disclosure of test results; and follow-up, including the ability of the patient to recontact the counselor for future discoveries pertinent to the patient's management. Details of this process can be found in Trimbath and Giardiello (128) and in the American Society of Clinical Oncology Policy Statement on Genetic Testing for Cancer Susceptibility (127).
In the past, several barriers to patient acceptance of germline testing existed, including cost of genetic tests (exceeding $4800 in some cases) and patient concern about genetic discrimination. In recent years, improved insurance coverage and genetic laboratory preauthorization (checking insurance plan for out-of-pocket patient cost before testing) have eroded this barrier. Also, federal legislation, the Genetic Information Nondiscrimination Act of 2008, has eliminated a positive gene test as a health insurance pre-existing condition or factor for employment in most patients. However, currently, no legislation outlaws the use of this information in military personnel or in disability, long-term care, and life insurance procurement.
When the gene mutation causing LS in the pedigree is known, clinically affected patients can have site-specific germline testing to confirm the diagnosis of LS in the patient. A negative test result for the pedigree mutation in a patient with CRC would indicate that the patient does not have LS, but coincidentally developed a sporadic CRC (phenocopy) (Figure 4).
Most often patients are affected with CRC in families meeting Amsterdam criteria or Bethesda guidelines, or with other indications for genetic testing, but no LS gene mutation has been established in the pedigree. In this circumstance, if the patient's CRC tissue is available (required by federal law to be kept for 7 years after procurement), MSI and/or IHC testing can be done on tumor tissue. If microsatellite testing is stable and IHC reveals the presence of all 4 MMR proteins, then LS is essentially excluded and no additional testing is suggested. The interpretation of these results is that the patient has sporadic (noninherited) CRC. But consideration for the diagnosis of FCRCTX should be given in a patient with a family history meeting Amsterdam I criteria (Figure 5).
Conversely, if MSI testing reveals high instability or IHC testing reveals absence of 1 or more MMR proteins, then, in most circumstances, germline testing of the MMR/EPCAM genes is warranted. Specific germline testing can be guided by IHC results (see Table 8). Additional tumor testing for BRAF mutation and/or hypermethylation of the MLH1 promoter should precede genetic testing when concomitant loss of MLH1 and PMS2 proteins is noted (caused by somatic hypermethylation of the MLH1 promoter). Germline testing can result in the following possibilities: a deleterious (pathogenic) mutation of an MMR/EPCAM gene that confirms the diagnosis of LS in the patient and family; no mutation found—an inconclusive finding unless a deleterious mutation is found in other family members; and a variant of unknown significance—an inconclusive finding unless future status of the alteration is determined by the testing laboratory (a variant of unknown significance is a variation in a genetic sequence whose association with disease risk is unknown). In the latter 2 circumstances, when IHC reveals loss of MSH2, MSH6, or PMS 2 protein alone, suspicion of LS should be maintained and the diagnosis of Lynch-like syndrome entertained. When no germline mutation is found in patients with MLH1 protein loss, BRAF and MLH1 promoter testing for hypermethylation can help differentiate between patients with somatic and germline mutations. Epigenetic mutations causing LS are very rare but are characterized by MLH1 promoter methylation in both the tumor and normal tissue.
When tumor tissue of the clinically affected patient is not available, germline testing can be done. If a deleterious mutation is found, then the diagnosis of LS can be confirmed in the patient. If not, then the patient and family members should be treated as per the patient's personal and family history.
Mutation-specific germline testing can be done in the at-risk member when the family mutation is known and render a dichotomous test result. If the gene mutation is found (positive), the individual has LS; if the gene mutation is not found (negative), the person does not have LS (Figure 4).
In this circumstance, first seek a clinically affected family member to genetically test to attempt to identify the family deleterious gene mutation (Figure 6). An affected family member is the most informative individual to test to find the pedigree mutation. Initially, an evaluation of the tumor is preferred to germline genetic testing if tissue is available. Once the deleterious mutation has been determined, the at-risk person can be definitively tested. If no clinically affected family member is available, germline testing of the at-risk person can be done. If a deleterious mutation is found in the unaffected member, then the diagnosis of LS is made. However, receiving results of “no mutation found” or “variant of unknown significance” are inconclusive results and no additional family genetic testing can be done.
Of note, new types of mutations or genetic alterations are continuously being reported, such as the effect of EPCAM deletions on MSH2 expression, or the rare germline epimutations of MLH1. Also, commercial laboratories doing the germline testing might lack sensitive technology for determining genetic rearrangements (in which all of the genetic components are retained), or alterations in the promoters or introns of the DNA MMR genes. Consequently, families with suspicious clinical histories and concurrent evidence of MMR deficiency through tumor testing should be counseled to undergo periodic repeated assessments as new genetic data can emerge that ultimately elucidate the underlying cause of the cancer risk in their families. In addition, the use of genetic panels might uncover patients and families with forms of attenuated polyposis, such as MYH-associated polyposis, attenuated familial adenomatous polyposis, and polymerase proofreading polyposis; there is often blurring of the clinical presentations of these syndromes and LS.
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.
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. (129,130,131). (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 (32,133,134,135), 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.
Screening for CRC by colonoscopy is recommended in persons at risk (first-degree relatives of those affected) or affected with LS every 1 to 2 years, beginning between ages 20–25 years or 2–5 years before the youngest age of diagnosis of CRC in the family if diagnosed before age 25 years. In surveillance of MMR germline mutation-positive patients, consideration should be given to annual colonoscopy. The age of onset and frequency of colonoscopy in this guideline is in agreement with most organizations and authorities (122,131,136,137,138). This guideline is a strong recommendation, with evidence level III, and GRADE moderate-quality evidence (Table 10).
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 (139,140,141). However, endometrial sampling appears useful in identifying some asymptomatic patients with EC and those with premalignant endometrial lesions (142,143,144) (Table 11).
Screening for EC should be offered to women at risk for or affected with LS by pelvic examination and endometrial sampling annually starting at age 30–35 years (Table 10). The strength of evidence for this guideline is expert consensus—level V, GRADE low-quality evidence, and is in concert with other expert opinion (122,137,138).
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).
Screening for ovarian cancer should be offered to women at risk for or affected with LS by transvaginal ultrasound annually starting at age 30–35 years (Table 10). The strength of evidence for this guideline is expert consensus—level V and GRADE low-quality evidence. In the absence of data on this issue, several consensus panels have suggested that transvaginal ultrasound for ovarian cancer is a screening consideration in LS (122,137,138).
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).
Hysterectomy and bilateral salpingo-oophorectomy should be recommended to women with LS who have finished childbearing or at age 40 years (Table 12). Patient considerations in this decision could include differences in uterine cancer risk, depending on MMR gene mutation; morbidity of surgery; and the risk of menopausal symptoms, osteoporosis, and cardiac disease if hormone replacement therapy is not given. The strength of evidence for this guideline is observational study—level IV and GRADE moderate-quality evidence. This recommendation is in agreement with the Mallorca Group (138). The NCCN recommends considering prophylactic surgery after child bearing is completed (122).
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.
Screening for gastric cancer should be considered in persons at risk for or affected with LS by esophagogastroduodenoscopy (EGD) with gastric biopsy of the antrum at age 30–35 years with treatment of H pylori infection when found. Subsequent, surveillance every 2–3 years can be considered based on individual patient risk factors (Table 10). The strength of evidence for this guideline is expert consensus—level V and GRADE low-quality evidence.
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.
Routine screening of the small intestine is not recommended. This guideline is in concert with the Mallorca group (138), which does not recommend routine screening of the small intestine, but suggests attention to investigation of the distal duodenum and ileum during endoscopic studies. The NCCN suggests capsule endoscopy screening can be considered (122) at 2–3 year intervals beginning at age 30–35 years.
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.
Screening for cancer of the urinary tract should be considered for persons at risk for or affected with LS, with urinalysis annually starting at age 30–35 years (Table 10). The strength of evidence for this guideline is expert consensus—level V and GRADE low-quality evidence. The guideline is in concert with the NCCN (122). The Mallorca group (138) does not recommend routine screening for urinary cancers.
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).
Routine screening of the pancreas is not recommended. The benefit of screening for pancreatic cancer with this magnitude of risk is not established. This recommendation is in concert with other societies (122,138). However, an international pancreas consensus panel recommends that MMR gene mutation carriers with 1 affected first degree relative with pancreatic cancer should be considered for screening (156).
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).
Routine screening of the prostate and breast cancer is not recommended beyond what is advised for the general population. This recommendation is in concert with other societies (122,138).
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 (32,33,34). 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%) (32,33,34). 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.
Colectomy with ileorectal anastomosis is the primary treatment of patients affected with LS with colon cancer or colon neoplasia not removable by endoscopy (Table 12). Consideration for less extensive surgery should be given in patients older than 60–65 years of age and those with underlying sphincter dysfunction. This guideline is a strong recommendation with level III evidence and GRADE moderate-quality evidence. The NCCN (122) and Mallorca group (138) both recommend colectomy with ileorectal anastomosis with no deference to patient age.
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).
Growing but not conclusive evidence exists that use of aspirin is beneficial in preventing cancer in LS patients. Treatment of an individual patient with aspirin is a consideration after discussion of patient-specific risks, benefits, and uncertainties of treatment is conducted (Table 12). The strength of evidence for this guideline is evidence obtained from at least 1 randomized controlled trial—level I and GRADE moderate-quality evidence. This approach is endorsed by the Mallorca group (138) and the NCCN (122).
These authors disclose the following: C. Richard Boland and Randall W. Burt are consultants for Myriad Genetic. Jason A. Dominitz received resources in support of this work from the VA Puget Sound Health Care System, Seattle, Washington. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs. David A. Johnson is a clinical investigator for EXACT Sciences, a consultant for Epigenomics, and on the advisory board for Given Imaging. Tonya Kaltenbach is a research grant recipient and consultant for Olympus American Inc. David A. Lieberman is on the advisory board for Given Imaging and Exact Sciences. Douglas J. Robertson is on the advisory board of Given Imaging. Sapna Syngal is an unpaid advisor/collaborator with Myriad genetics and a consultant for Archimedes, Inc. Douglas K. Rex is a consultant for Olympus America, Braintree Laboratories, Ferring Pharmaceuticals, Epigenomics, EXACT Sciences, Given Imaging, received research support from Olympus America; and is on the speaker's bureau for Olympus America and Boston Scientific. The remaining authors disclose no conflicts.
This guideline was reviewed and approved by governing boards of the American College of Gastroenterology, the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the American Society of Colon and Rectal Surgeons.
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