This is a focused update highlighting the most current NCCN Guidelines for diagnosis and management of Lynch syndrome. Lynch syndrome is the most common cause of hereditary colorectal cancer, usually resulting from a germline mutation in 1 of 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2), or deletions in the EPCAM promoter. Patients with Lynch syndrome are at an increased lifetime risk, compared with the general population, for colorectal cancer, endometrial cancer, and other cancers, including of the stomach and ovary. As of 2016, the panel recommends screening all patients with colorectal cancer for Lynch syndrome and provides recommendations for surveillance for early detection and prevention of Lynch syndrome-associated cancers.

Abstract

This is a focused update highlighting the most current NCCN Guidelines for diagnosis and management of Lynch syndrome. Lynch syndrome is the most common cause of hereditary colorectal cancer, usually resulting from a germline mutation in 1 of 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2), or deletions in the EPCAM promoter. Patients with Lynch syndrome are at an increased lifetime risk, compared with the general population, for colorectal cancer, endometrial cancer, and other cancers, including of the stomach and ovary. As of 2016, the panel recommends screening all patients with colorectal cancer for Lynch syndrome and provides recommendations for surveillance for early detection and prevention of Lynch syndrome-associated cancers.

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. In 2015, an estimated 93,090 new cases of colon cancer and 39,610 new cases of rectal cancer will have occurred in the United States. During the same year, experts estimate that 49,700 people will die of colon and rectal cancer.1 CRC often occurs sporadically, but familial cancer syndromes are common in this disease. Genetic susceptibility to CRC includes well-defined inherited syndromes such as Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis (FAP), and MutY human homolog (MUTYH)-associated polyposis (MAP). Other entities include Cowden, Bannayan-Riley-Ruvalcaba, Peutz-Jeghers, juvenile polyposis, and serrated polyposis syndromes (SPS).2-4

Criteria for Further Risk Evaluation for High-Risk Syndromes

NCCN criteria for further risk evaluation for hereditary syndromes associated with CRC include a known mutation in the family, personal history of CRC and more than 10 adenomas, personal history of CRC or endometrial cancer and additional risk factors, including:

  • CRC diagnosis at younger than 50 years;

  • High microsatellite instability (MSI) or abnormal immunohistochemistry (IHC)-based staining of one or more DNA mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) within the tumor;

  • Synchronous or metachronous Lynch syndrome-associated cancers;

  • High PREMM[1,2,6] Lynch syndrome prediction model score 5% or higher; or

  • Family history of Lynch syndrome-associated cancers.

NCCN criteria for further risk evaluation among individuals unaffected by cancer include a

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NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2016

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NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2016

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NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2016

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NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2016

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NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2016

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PREMM[1,2,6] score 5% or higher or a family history including the criteria above, polyposis, or manifestations associated with FAP, attenuated FAP, MAP, Peutz-Jeghers syndrome, juvenile polyposis syndrome, serrated polyposis syndrome, or Cowden syndrome (ie, desmoid tumor, multifocal or bilateral congenital hypertrophy of the retinal pigment epithelium, cribriform-morular variant of papillary thyroid cancer, hepatoblastoma, or multiple gastrointestinal hamartomatous polyps). Detailed strategies for screening for Lynch syndrome are provided below; see the NCCN guidelines for detail on follow-up patients meeting risk criteria for other syndromes.

Lynch Syndrome

This update focuses on Lynch syndrome because it is the most common hereditary cause of colorectal cancer, accounting for 2% to 4% of all CRC cases,5-8 and because a consensus is emerging across medical speciality societies and expert groups regarding the best strategies for identifying patients with this condition. Lynch syndrome results from a germline mutation in 1 of 4 DNA MMR genes (MLH1, MSH2, MSH6, or PMS2).9 Additionally, deletions in the EPCAM gene, which lead to hypermethylation of the MSH2 promoter and subsequent MSH2 silencing, cause Lynch syndrome.10,11 Identification of Lynch syndrome is important for both individuals with cancer, because of high personal risk for metachronous Lynch syndrome cancers (ie, endometrial cancer after colorectal cancer or vice versa, or second colorectal cancer), and for their families because of autosomal dominant inheritance and potentially high penetrance. After identification of Lynch syndrome, surveillance (particularly for first or metachronous CRC) offers an opportunity for early detection and perhaps even prevention of cancer among mutation carriers. Further, cancer site-specific evaluation and heightened attention to symptoms is also advised for other cancers that occur with increased frequency in affected persons, including gastric, ovarian, pancreatic, urethral, brain (glioblastoma), and small intestinal cancers, as well as sebaceous gland adenomatous polyps and keratoacanthomas.

Definitive Testing in the Setting of Known Lynch Syndrome Mutation

When a known MMR or EPCAM mutation exists in the family, the individual should be tested for the familial mutation. If the test is positive or if testing is not performed for any reason, the individual should follow surveillance for Lynch syndrome outlined subsequently. Individuals who test negative for the familial mutation are considered to be at average risk, not zero risk, for CRC and should follow guidelines for average risk screening.

Strategies for Screening for Lynch Syndrome in Absence of Known Mutation: The traditional approach to identifying individuals at risk for Lynch syndrome has generally employed a 2-step screening process. First, patients meeting clinical criteria based on family history, personal history of cancer, and/or pathologic characteristics are identified, followed by additional application of screening with a molecular test. Commonly employed clinical criteria include Amsterdam II criteria, Bethesda Guidelines, and risk prediction models.

Amsterdam II criteria outline increased risk for Lynch syndrome in a family with a proband affected by CRC or any other Lynch syndrome–associated cancer (ie, endometrial, small bowel, ureter, or renal-pelvic cancers), and 3 relatives with a Lynch syndrome–associated cancer provided the following family criteria are met:

  • One relative is a first-degree relative of the other 2;

  • At least 2 successive generations are affected;

  • At least 1 Lynch syndrome associated cancer was diagnosed before age 50 years.

Additionally, Amsterdam II criteria stipulate that FAP should be excluded and tumors should be verified through pathologic examination.12 Approximately 50% of families meeting the Amsterdam II criteria have a mutation in an MMR gene.13 These criteria are very stringent, however, and miss as many as 68% of patients with Lynch syndrome.14

Bethesda guidelines were later developed and updated to provide broader clinical criteria for Lynch syndrome screening.15 Updated Bethesda criteria16 are:

  • CRC diagnosed in a patient younger than 50 years;

  • Synchronous, metachronous, colorectal, or other tumor associated with Lynch syndrome;

  • CRC tumor has MSI-H histology (ie, presence of tumor-infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern) in a patient younger than 60 years; and

  • CRC in a patient with a family history of cancer diagnosed earlier than age 50 and associated with Lynch syndrome. If more than one relative was diagnosed with a Lynch syndrome-associated cancer, then the age criterion is not needed.

One study reported that MLH1 and MSH2 mutations were detected in 65% of patients with MSI of colon cancer tissue who met the Bethesda criteria.17 Another study reported on the accuracy of the revised Bethesda criteria, concluding that the guidelines were useful for identifying patients who should undergo further testing.18 Patients fulfilling the revised Bethesda criteria had an odds ratio for carrying a germline mutation in MLH1 or MSH2 of 33.3 (95% CI, 4.3–250; P=.001). Still, a considerable number of patients with Lynch syndrome do not meet even the revised Bethesda guidelines.7

Statistical models that predict risk for carrying a mutation in a DNA MMR gene are an additional commonly applied clinical approach to identifying individuals at risk for Lynch syndrome.14,1921 These models give probabilities of mutations or of the development of future cancers based on family and personal history. The PREMM[1,2,6] model can be used online (http://premm.dfci.harvard.edu/) and the MMR predict model is also available for online use (http://hnpccpredict.hgu.mrc.ac.uk/). MMRpro is also available for free download (http://www4.utsouthwestern.edu/breasthealth/cagene/).

Overall, based on clinical criteria, the panel recommends additional evaluation for Lynch syndrome for individuals who 1) meet the revised Bethesda guidelines or Amsterdam II criteria; 2) are diagnosed with endometrial cancer before age 50 years (given the heightened risk of endometrial cancer in women with Lynch syndrome)22,23; or 3) have known Lynch syndrome in the family. For individuals meeting one or more of the first 2 criteria, the panel recommends genetic testing or additional screening of tumor tissue (if available) for MSI or for absent expression of one or more of the 4 DNA MMR proteins via IHC (described in detail in subsequent sections).

A problem with nearly all clinically based criteria for identifying individuals with Lynch syndrome is suboptimal sensitivity. This has led several groups to study an alternative strategy, referred to as “universal screening,” in which all individuals newly diagnosed with CRC undergo either MSI or IHC testing for absence of one of the 4 DNA MMR proteins. This approach provides a sensitivity of 100% (95% CI, 99.3%–100%) and a specificity of 93.0% (95% CI, 92.0%–93.7%) for identifying individuals with Lynch syndrome.24 An alternative approach is to test all patients with CRC diagnosed before age 70 years and patients diagnosed at older ages who meet the Bethesda guidelines.24 This approach gave a sensitivity of 95.1% (95% CI, 89.8%–99.0%) and a specificity of 95.5% (95% CI, 94.7%–96.1%). This alternative approach had improved sensitivity compared with the revised Bethesda criteria, and improved specificity compared with universal screening regardless of age.

The cost-effectiveness of universal screening has been established and has been endorsed by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group at the CDC, the US Multi-Society Task Force on Colorectal Cancer, and the European Society for Medical Oncology.2529

Routine Tumor Testing Criteria for Lynch Syndrome: As of 2016, the panel recommends universal screening of all patients with CRCs, to maximize sensitivity for Lynch syndrome detection and simplify care processes. Additionally, because research has shown high sensitivity of a universal testing approach for identifying women with endometrial cancer due to Lynch syndrome, in 2016 the panel also endorses universal screening of all endometrial tumors.30 The panel emphasizes that great care must be taken in implementing system-level universal testing to avoid loss to follow-up of patients with abnormal tests and to avoid misinterpretation of the molecular screening tests. The panel accordingly recommends that an infrastructure needs to be in place to handle the screening results.31 The panel concluded that counseling by an individual with expertise in genetics is not required prior to routine tumor testing, but strongly recommends follow-up with a provider with expertise in genetics after a positive screen (see subsequent sections).

Initial Tumor Testing Methodologies: Screening for Lynch syndrome currently requires performance of 1 of 2 molecular tests, either after the aforementioned clinical criteria are met or as part of universal screening strategies with either 1) IHC analysis for MMR protein expression; or 2) analysis for MSI, which results from MMR deficiency.32 Greater than 90% of Lynch syndrome tumors are MSI-H and/or lack expression of at least one of the MMR proteins by IHC.

IHC analysis has the advantage of predicting which gene is most likely to be mutated (the gene for the affected protein or its corresponding dimer partner) and thus the first candidate(s) for germline sequencing.32 Interpretation of IHC test reports can sometimes be confusing; when “positive” IHC is reported, care should be taken to ensure that “positive” means abnormal absence of MMR protein expression, as opposed to normal presence of expression.

MSI testing panels may consist of mononucleotide and dinucleotide markers.33 In a study including 1,058 patients with CRC, detection of MMR deficiency using a panel that included both mononucleotide and dinucleotide markers (BAT26, BAT25, D5S346, D2S123, and D17S250) was compared with that of a panel including only mononucleotide markers (BAT26, BAT25, NR21, NR22, and NR24).34 Sensitivity and positive predictive value of the panel including only mononucleotide markers (95.8% and 88.5%, respectively) were better, compared with the panel including both mononucleotide and dinucleotide markers (76.5% and 65.0%, respectively).

Some studies have shown that both IHC and MSI are cost-effective and useful for determining high-risk patients who may have MLH1, MSH2, and MSH6 germline mutations.27,35,36 However, conclusive data are not yet available that establish which strategy is optimal.9,18,3740 A review showed that the sensitivities of MSI and IHC testing are 77% to 89% and 83%, respectively; specificities are 90% and 89%, respectively.27 An analysis of 5,591 unrelated CRC probands undergoing both MSI and IHC testing showed a concordance rate of 97.5%.24 Some experts advocate for using both methods when possible.41 However, the panel recommends using only one test initially. If normal results are found and Lynch syndrome is strongly suspected, then the other test may be performed.

Follow-up Testing of Individuals with Increased Risk Based on Screening: If abnormal MSI or IHC for one of the DNA MMR proteins is identified within a colorectal or endometrial cancer, then a differential diagnosis must be considered (see LS-A 2 of 3, page 1020). For example, 10% to 15% of colorectal cancers have MSI or abnormal IHC (particularly in the case of absent MLH1 expression) due to sporadic development of cancer, rather than an underlying inherited (germline) genetic mutation. The table on LS-A 2 of 3 (see page 1020) in the NCCN Guidelines identifies a range of test result scenarios, the differential diagnosis, and recommended follow-up. In some scenarios, such as with absent MSH2 expression by IHC, follow up germline testing for indicated genes is directly recommended. In other scenarios, additional testing of tumor tissue is recommended. For example, for the common scenario of absent MLH1 expression by IHC, the panel recommends additional tumor testing for presence of MLH1 hypermethylation and/or BRAF V600E mutation, either of which would be consistent with sporadic, rather than Lynch syndrome associated, cancer.29,32,42,43

Where genetic testing is recommended (see LS-A 2 of 3, page 1020), the panel recommends consultation with an individual with expertise in genetics, and germline testing to exclude presence of Lynch-associated mutations. The approach to mutation testing is evolving. Previously, a sequential approach in which 1 or 2 genes were sequenced guided by either disease prevalence or IHC results, followed by additional testing of other genes, was used. Recognition of scenarios in which IHC results were not available also allowed for syndrome-specific testing of the panel of genes that cause Lynch syndrome (MLH1, MSH2, MSH6, PMS2, and EPCAM) simultaneously. Reductions in cost of sequencing and recognition that some patients meeting Lynch syndrome testing criteria may have germline mutations not associated with Lynch syndrome have led to growing use of so called “multigene” panels in clinical practice. These test not only for Lynch syndrome–associated genes, but also additional mutations. As of 2016, the panel recommends that any of these 3 approaches may be employed as follow-up and has provided new guidance on the potential role, strengths, and limitations of multigene panels in the evaluation of Lynch syndrome, as well as other hereditary cancer syndromes.

Follow-up of Genetic Test Results: If a deleterious mutation is found, the panel recommends that Lynch syndrome management guidelines be followed (see LS-4, page 1016).

If no deleterious mutation is found, clinicians are advised to confirm that testing for large rearrangements and deletions of MMR genes were performed by the lab test provider. If still no deleterious mutation is found or a variant of uncertain significance is identified, the panel recommends tailored surveillance based on individual and family risk assessment. Notably, some individuals with abnormal MSI and/or IHC tumor results and no germline mutation detected in the corresponding gene(s) may still have undetected Lynch syndrome. At this time, no consensus has been reached as to whether these patients (sometimes referred to as having “Lynch-like syndrome”) should be managed as having Lynch syndrome or managed based on personal/family history. Growing evidence suggests a subset of these individuals may have double somatic mutations/changes in the MMR genes.44 Although the efficacy of the approach has not yet been proven, genetic testing of the corresponding gene(s) could be performed on tumor DNA to assess for somatic mutations. Individuals found to have double somatic mutations/changes in the MMR genes may not have Lynch syndrome, but double somatic mutations might also be due to non-Lynch germline mutations. Thus, management should be based on personal/family history until further research on Lynch-like syndrome emerges. Additionally, germline testing may be normal despite a strong family history (ie, Amsterdam criteria) or additional features of hereditary cancer syndromes (multiple colon polyps) being present. In these cases, additional testing may be warranted in the proband (such as expanded multigene testing), or tumor testing in an affected family member could be considered due to the possibility of a phenocopy.

Newly Identified Lynch Syndrome

When a mutation is found in the family, it offers an opportunity to provide predictive testing for at-risk family members. An at-risk family member can be defined as a first-degree relative of an affected individual or proband. If a first-degree relative is unavailable or unwilling to be tested, more distant relatives should be offered testing for the known family mutation.

There are many other issues involved in the process of genetic counseling for individuals for pre-symptomatic testing for cancer susceptibility. Some individuals elect not to undergo testing, and it is important to counsel these individuals so they continue with increased surveillance.

Surveillance for Patients with Lynch Syndrome

The NCCN Panel carefully considered surveillance schemes for individuals with Lynch syndrome. Compared with the general population, these patients are at increased lifetime risk for CRC (52%–82% vs 5.5%), endometrial cancer (16%–60% vs 2.7%), and other cancers, including of the stomach and ovary.22,23,4548 Within the population of Lynch syndrome carriers, risk may vary by specific type of DNA MMR gene mutation. For example, individuals with MSH6 and PMS2 mutations have a 10% to 22% risk for colon cancer up to age 70, while those with MLH1 and MSH2 mutations have a 40% to 80% risk. As of 2016, the panel recognizes that controversy continues regarding whether mutation-specific risks should guide differential management.49 The panel's current approach is to offer uniform recommendations for cancer surveillance and prevention, recognizing that, in some clinical scenarios, delaying initiation of surveillance (eg, later starting age for colonoscopy surveillance among PMS2 carriers) may be appropriate, pending availability of large cohort studies of risk among specific mutation carriers.

Existing data on screening refer primarily to colon and endometrial cancers. More data are needed to evaluate the risk and benefits of extracolonic and extraendometrial cancer screening, and recommendations are based mainly on expert opinion.

Colon Cancer Surveillance: If Lynch syndrome is confirmed, colonoscopy is advised to start between the ages of 20 to 25 or 2 to 5 years younger than the youngest diagnosis age in the family, whichever comes first, and should be repeated every 1 to 2 years. This recommendation is based on a systematic review of data between 1996 and 2006 on the reduction in cancer incidence and mortality by colonoscopy50 and is consistent with recommendations made by the US Multi-Society Task Force on Colorectal Cancer, the European Society for Medical Oncology, ASCO, the American Gastroenterological Association, and the American College of Gastroenterology.28,29,42,43,51

However, as mentioned previously, there is still some uncertainty regarding the best age to initiate colonoscopic surveillance. For example, the results of a meta-analysis in which CRC risk in 1,114 Lynch syndrome families (MLH1 and MSH2 mutation carriers) was examined showed that 5-year CRC risk for those ages 20 to 29 is about 1%, with the risk for those ages 30 to 39 being 3% to 5%, with greater risk in men.52 The investigators argued that annual colonoscopy in patients ages 25 to 29 may be an overly aggressive recommendation that is not cost effective (ie, 155 men and 217 women in this age group would need to be screened to prevent one CRC death). However, the panel concluded that more evidence was needed to understand the best age to start screening.

Chromoendoscopy is a relatively new technique in which dye spray is used to enhance visualization and that may be used during colonoscopy. A systematic review of 4 studies indicated that chromoendoscopy is a promising technique for improving detection of lesions and flat adenomas in patients with Lynch syndrome.53 Only one of these studies was a prospective randomized trial, however, and this trial was limited by a small sample of patients who had already undergone colonoscopy and inadequate statistical power to detect clinically meaningful effects.54 Chromoendoscopy may be considered for patients with Lynch syndrome, but larger prospective randomized trials are needed to better understand its role.

Endometrial and Ovarian Cancer Surveillance: Women with Lynch syndrome are at heightened risk for endometrial and ovarian cancers (up to 60% and 24%, respectively).22,23,47,50 Education that enhances recognition of relevant symptoms (ie, dysfunctional uterine bleeding) is advised. Total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) is an option that may be considered for risk reduction in women who have completed child-bearing and carry a MLH1, MSH2, EPCAM, PMS2, or MSH6 mutation.42,51,5558 There is no clear evidence to support routine screening for gynecologic cancers. Annual endometrial sampling may be considered, but the benefit is uncertain.55,5862 Routine transvaginal ultrasound and serum CA-125 testing are not endorsed because they have not been shown to be sufficiently sensitive or specific,55,5963 but the panel recognized that there may be circumstances in which the clinician may find these tests helpful. An observational study showed that hormonal contraceptive use is associated with lower risk of endometrial cancer in carriers of MMR mutations (hazard ratio [HR], 0.39; 95% CI, 0.23—0.64, P<.001).64 However, prospective data are needed before hormonal contraceptives are recommended for prevention of gynecologic cancers in patients with Lynch syndrome.

Surveillance for Other Cancers: The lifetime risk for gastric cancer varies widely between individuals with Lynch syndrome in different populations, from 2% to 4% in the Netherlands to 30% in Korea.50,65 Most cases occur after age 40, and males have a stronger predisposition. Lynch syndrome is also associated with a 3% to 6% risk for small bowel cancer.22,46,6669 There is no clear evidence to support screening for gastric, duodenal, and small bowel cancer in patients with Lynch syndrome.70 For selected individuals or families or those of Asian descent with MLH1, MSH2, or EPCAM mutations, physicians may consider upper esophagogastroduodenoscopy (EGD) extended to the distal duodenum or into the jejunum every 3 to 5 years starting at age 30 to 35.71 Infection with Helicobacter pylori (H. pylori) is thought to be a cause of gastric cancer.72,73 Given the increased risk of gastric cancer in patients with Lynch syndrome, testing and treating for H. pylori should be considered. This is consistent with recommendations by ASCO and the European Society for Medical Oncology.28,42

Risk of urinary tract cancer to age 70 in patients with Lynch syndrome is 1% to 6.7%,23,74 with greater risk among carriers of MSH2 mutations (6.9%), relative to MLH1 (2.9%) and MSH6 (1.7%) mutation carriers.74 Because of this risk, annual urinalysis starting at age 30 to 35 years may also be considered to screen for urothelial cancers in carriers of MLH1, MSH2, or EPCAM mutations, given the relative ease and low cost compared with other tests.75 Risk for pancreatic and brain cancer is also elevated in patients with Lynch syndrome.23,4648 However, no effective screening techniques have been identified for pancreatic cancer; therefore, no screening recommendation is possible at this time. Annual physical and neurologic examination starting at age 25 to 30 years may be considered for central nervous system cancer, but data to support this practice are lacking.

In addition, there have been suggestions of an increased risk for breast cancer in the Lynch syndrome population76,77; however, there is insufficient evidence to support increased screening above average-risk breast cancer screening recommendations.42,51 A study of 188 men with Lynch syndrome also showed a 5-fold increase in risk of prostate cancer.78 However, there is insufficient evidence to support prostate cancer screening among males with Lynch syndrome.42,51

Lynch Syndrome Surveillance Findings and Follow-up: If pathologic findings are noted, continued surveillance is recommended. If the patient is not a candidate for routine surveillance, subtotal colectomy may be considered, although in general, extended surgery is limited to patients after CRC diagnosis. After subtotal colectomy, endoscopic surveillance of the rectum is required, at similar intervals as described previously.

Patients with confirmed adenocarcinoma should be treated following the appropriate NCCN Treatment Guidelines (available at www.NCCN.org).

For patients with adenomatous polyps, recommendations include endoscopic polypectomy with a follow-up colonoscopy every 1 to 2 years. This option depends on the location and characteristics of the polyp, the surgical risk, and patient preference. If an adenomatous polyp cannot be completely resected endoscopically, then segmental or extended colectomy may be performed. Postcolectomy patients should be followed up with lower endoscopic exams every 1 to 2 years.

Because surgical management is evolving, the option of segmental or extended segmental colectomy for patients with confirmed adenocarcinoma or adenomatous polyps is based on individual considerations and discussion of risks. For example, the US Multi-Society Task Force on Colorectal Cancer recommends that surgery in those older than 60 to 65 years and those with underlying sphincter dysfunction should potentially be less extensive.29 Practically, a patient who is unable or unlikely to comply with frequent colonoscopy should be considered for more extensive colectomy, especially if young. Surgical principles for polyps are similarly controversial.

Reproductive Options: Patients of reproductive age should be advised regarding their options for prenatal diagnosis and assisted reproduction, including preimplantation genetic diagnosis. This discussion should include known risks, limitations, and benefits of these technologies. If both partners are a carrier of mutation(s) in the same MMR gene or EPCAM (eg, if both partners carry a mutation in the PMS2 gene), then they should also be advised about the risk of constitutional MMR deficiency syndrome (CMMRD syndrome), a rare recessive syndrome.79

Chemoprevention in Lynch Syndrome: In the randomized CAPP2 trial, 861 participants with Lynch syndrome took either daily aspirin (600 mg) or placebo for up to 4 years; the primary endpoint was the development of CRC.80 After a mean follow-up of 55.7 months, participants taking daily aspirin for at least 2 years had a 63% reduction in the incidence of CRC (incidence rate ratio [IRR], 0.37; 95% CI, 0.18–0.78; P=.008). These participants also saw protection from all Lynch syndrome cancers (IRR, 0.42; 95% CI, 0.25–0.72; P=.001). No protection was seen for participants who completed less than 2 years of the intervention. Subgroup analyses from this trial showed that the association between obesity and CRC in patients with Lynch syndrome may be attenuated by taking daily aspirin.81 However, limitations of the CAPP2 trial highlight the need for larger and long-term randomized trials in this area.82,83 In an observational study including 1,858 patients from the Colon Cancer Family Registry who have Lynch syndrome, aspirin use was associated with reduced risk of CRC, for both patients who took aspirin for 5 or more years (HR, 0.25; 95% CI, 0.10–0.62; P=.003) and those who took it for between 1 month and 4.9 years (HR, 0.49; 95% CI, 0.27–0.90; P=.02), compared with those who took aspirin for less than 1 month.84

At this time, the panel suggests that aspirin may be used to prevent cancer in patients with Lynch syndrome, but it is emphasized that the optimal dose and duration of therapy are currently unknown. The CAPP2 trial used a dose of 600 mg per day,80 although many clinicians who prescribe daily aspirin as chemoprevention in patients with Lynch syndrome use a lower dose. The CAPP3 randomized double-blind trial is currently examining the effects of low, moderate, and high doses of daily aspirin on Lynch syndrome–associated cancer incidence (NCT02497820), but results are not yet available. The panel's recommendation to consider aspirin for chemoprevention is consistent with the stance of the American Gastroenterological Association.43 The American College of Gastroenterology does not recommend standard use of aspirin for chemo-prevention given the lack of evidence regarding its impact on CRC risk.51

Conclusions

Progress has been made in the evidence base surrounding risk for cancer, screening, and surveillance for Lynch syndrome. In particular, the panel strongly recommends screening for Lynch syndrome in all patients with primary colon and rectal cancers, to identify cancer survivors and families who may benefit from personalized cancer surveillance. Lynch syndrome may serve as a paradigm for the potential opportunities and challenges of implementing personalized cancer prevention, screening, and surveillance in usual practice.

Indivdual Disclosures of the NCCN Genetic/Familial High-Risk Assessment: Colorectal Panel

T1

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    BonadonaVBonaitiBOlschwangS. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA2011;305:23042310.

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    KohlmannWGruberS. Lynch Syndrome. GeneReviews at GeneTests: Medical Genetics Information Resource2014.

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    MoreiraLBalaguerFLindorN. Identification of Lynch syndrome among patients with colorectal cancer. JAMA2012;308:15551565.

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    Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med2009;11:3541.

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    LadabaumUWangGTerdimanJ. Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med2011;155:6979.

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    PalomakiGEMcClainMRMelilloS. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med2009;11:4265.

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    BalmanaJBalaguerFCervantesAArnoldD. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann Oncol2013;24Suppl 6:vi7380.

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    GiardielloFMAllenJIAxilbundJE. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology2014;147:502526.

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    GoodfellowPJBillingsleyCCLankesHA. Combined microsatellite instability, MLH1 methylation analysis, and immunohistochemistry for Lynch syndrome screening in endometrial cancers from GOG210: an NRG Oncology and Gynecologic Oncology Group study. J Clin Oncol2015;33:43014308.

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    MarquezEGengZPassS. Implementation of routine screening for Lynch syndrome in university and safety-net health system settings: successes and challenges. Genet Med2013;15:925932.

    • Search Google Scholar
    • Export Citation
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    HendriksYMde JongAEMorreauH. Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians. CA Cancer J Clin2006;56:213225.

    • Search Google Scholar
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    BolandCRThibodeauSNHamiltonSR. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res1998;58:52485257.

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    XicolaRMLlorXPonsE. Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors. J Natl Cancer Inst2007;99:244252.

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    CaldesTGodinoJSanchezA. Immunohistochemistry and microsatellite instability testing for selecting MLH1, MSH2 and MSH6 mutation carriers in hereditary non-polyposis colorectal cancer. Oncol Rep2004;12:621629.

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    VasenHFHendriksYde JongAE. Identification of HNPCC by molecular analysis of colorectal and endometrial tumors. Dis Markers2004;20:207213.

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    HampelHFrankelWPanescuJ. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res2006;66:78107817.

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    LindorNMBurgartLJLeontovichO. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol2002;20:10431048.

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    ReyesCMAllenBATerdimanJPWilsonLS. Comparison of selection strategies for genetic testing of patients with hereditary nonpolyposis colorectal carcinoma: effectiveness and cost-effectiveness. Cancer2002;95:18481856.

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    PinoMSChungDC. Application of molecular diagnostics for the detection of Lynch syndrome. Expert Rev Mol Diagn2010;10:651665.

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    StoffelEMManguPBGruberSB. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol2015;33:209217.

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    KastrinosFMukherjeeBTayobN. Risk of pancreatic cancer in families with Lynch syndrome. JAMA2009;302:17901795.

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    WinAKLindorNMYoungJP. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst2012;104:13631372.

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    JenkinsMADowtyJGAit OuakrimD. Short-term risk of colorectal cancer in individuals with lynch syndrome: a meta-analysis. J Clin Oncol2015;33:326331.

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    NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2016

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    NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2016

    Version 1.2016, 06-13-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2016

    Version 1.2016, 06-13-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery

    NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2016

    Version 1.2016, 06-13-16 ©2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    PalomakiGEMcClainMRMelilloS. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med2009;11:4265.

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    BalmanaJBalaguerFCervantesAArnoldD. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann Oncol2013;24Suppl 6:vi7380.

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    GiardielloFMAllenJIAxilbundJE. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology2014;147:502526.

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    • Export Citation
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    GoodfellowPJBillingsleyCCLankesHA. Combined microsatellite instability, MLH1 methylation analysis, and immunohistochemistry for Lynch syndrome screening in endometrial cancers from GOG210: an NRG Oncology and Gynecologic Oncology Group study. J Clin Oncol2015;33:43014308.

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    • Export Citation
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    MarquezEGengZPassS. Implementation of routine screening for Lynch syndrome in university and safety-net health system settings: successes and challenges. Genet Med2013;15:925932.

    • Search Google Scholar
    • Export Citation
  • 32.

    HendriksYMde JongAEMorreauH. Diagnostic approach and management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a guide for clinicians. CA Cancer J Clin2006;56:213225.

    • Search Google Scholar
    • Export Citation
  • 33.

    BolandCRThibodeauSNHamiltonSR. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res1998;58:52485257.

    • Search Google Scholar
    • Export Citation
  • 34.

    XicolaRMLlorXPonsE. Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors. J Natl Cancer Inst2007;99:244252.

    • Search Google Scholar
    • Export Citation
  • 35.

    CaldesTGodinoJSanchezA. Immunohistochemistry and microsatellite instability testing for selecting MLH1, MSH2 and MSH6 mutation carriers in hereditary non-polyposis colorectal cancer. Oncol Rep2004;12:621629.

    • Search Google Scholar
    • Export Citation
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    VasenHFHendriksYde JongAE. Identification of HNPCC by molecular analysis of colorectal and endometrial tumors. Dis Markers2004;20:207213.

    • Search Google Scholar
    • Export Citation
  • 37.

    HampelHFrankelWPanescuJ. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res2006;66:78107817.

    • Search Google Scholar
    • Export Citation
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    LindorNMBurgartLJLeontovichO. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol2002;20:10431048.

    • Search Google Scholar
    • Export Citation
  • 39.

    ReyesCMAllenBATerdimanJPWilsonLS. Comparison of selection strategies for genetic testing of patients with hereditary nonpolyposis colorectal carcinoma: effectiveness and cost-effectiveness. Cancer2002;95:18481856.

    • Search Google Scholar
    • Export Citation
  • 40.

    ShiaJKlimstraDSNafaK. Value of immunohistochemical detection of DNA mismatch repair proteins in predicting germline mutation in hereditary colorectal neoplasms. Am J Surg Pathol2005;29:96104.

    • Search Google Scholar
    • Export Citation
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    PinoMSChungDC. Application of molecular diagnostics for the detection of Lynch syndrome. Expert Rev Mol Diagn2010;10:651665.

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    StoffelEMManguPBGruberSB. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol2015;33:209217.

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    • Export Citation
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    RubensteinJHEnnsRHeidelbaughJBarkunA. American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Lynch Syndrome. Gastroenterology2015;149:777782.

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    HaraldsdottirSHampelHTomsicJ. Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations. Gastroenterology2014;147:13081316.e1301.

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    • Export Citation
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    EngelCLoefflerMSteinkeV. Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol2012;30:44094415.

    • Search Google Scholar
    • Export Citation
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    KastrinosFMukherjeeBTayobN. Risk of pancreatic cancer in families with Lynch syndrome. JAMA2009;302:17901795.

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    WatsonPVasenHFMecklinJP. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer2008;123:444449.

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    WinAKYoungJPLindorNM. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol2012;30:958964.

    • Search Google Scholar
    • Export Citation
  • 49.

    WinAKLindorNMYoungJP. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst2012;104:13631372.

    • Search Google Scholar
    • Export Citation
  • 50.

    LindorNMPetersenGMHadleyDW. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA2006;296:15071517.

    • Search Google Scholar
    • Export Citation
  • 51.

    SyngalSBrandREChurchJM. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol2015;110:223262; quiz 263.

    • Search Google Scholar
    • Export Citation
  • 52.

    JenkinsMADowtyJGAit OuakrimD. Short-term risk of colorectal cancer in individuals with lynch syndrome: a meta-analysis. J Clin Oncol2015;33:326331.

    • Search Google Scholar
    • Export Citation
  • 53.

    HaanstraJFKleibeukerJHKoornstraJJ. Role of new endoscopic techniques in Lynch syndrome. Fam Cancer2013;12:267272.

  • 54.

    StoffelEMTurgeonDKStockwellDH. Missed adenomas during colonoscopic surveillance in individuals with Lynch Syndrome (hereditary nonpolyposis colorectal cancer). Cancer Prev Res (Phila)2008;1:470475.

    • Search Google Scholar
    • Export Citation
  • 55.

    ChenLMYangKYLittleSE. Gynecologic cancer prevention in Lynch syndrome/hereditary nonpolyposis colorectal cancer families. Obstet Gynecol2007;110:1825.

    • Search Google Scholar
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