Guidelines on Genetic Evaluation and Management of Lynch Syndrome

NA, Not available.

^aLS-associated tumors include tumor of the colorectum, endometrium, stomach, ovary, pancreas, ureter, renal pelvis, biliary tract, brain, small bowel, sebaceous glands, and kerotoacanthomas.

Note. Adapted from the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. Lynch syndrome. Version 2.2012. Available at: https://www.nccn.org/professionals/physiciangls/PDF/colorectal_screening.pdf. (122).
MSI-L, microsatellite low; MSI, microsatellite high; MMR, mismatch repair genes (ie, MLH1, MSH2, MSH6, PMS2); NA, not available; +, protein present in tissue; −, protein not present in tissue.

EGD, esophagogastroduodenoscopy; GRADE, Grades of Recommendation, Assessment, Development, and Evaluation.

Authors and Disclosures

Francis M Giardiello MD¹, John I Allen², Jennifer E Axilbund¹, C Richard Boland³, Carol A Burke⁴, Randall W Burt⁵, James M Church⁴, Jason A Dominitz^6,7, David A Johnson⁸, Tonya Kaltenbach⁹, Theodore R Levin¹⁰, David A Lieberman¹¹, Douglas J Robertson^12,13, Sapna Syngal^14–16 and Douglas K Rex¹⁷

¹Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; ²Yale University School of Medicine, New Haven, Connecticut, USA; ³Baylor University Medical Center, Dallas, Texas, USA; ⁴Cleveland Clinic, Cleveland, Ohio, USA; ⁵University of Utah, Salt Lake City, Utah, USA; ⁶VA Puget Sound Health Care System, Seattle, Washington, USA; ⁷University of Washington, Seattle, Washington, USA; ⁸Eastern Virginia Medical School, Norfolk, Virginia, USA; ⁹Stanford University, Palo Alto, California, USA; ¹⁰Kaiser Permanente Medical Center, Walnut Creek, California, USA; ¹¹Oregon Health and Science University, Portland, Oregon, USA; ¹²White River Junction VA Medical Center, White River Junction, Vermont, USA; ¹³Geisel School of Medicine at Dartmouth, White River Junction, Vermont, USA; ¹⁴Brigham and Women's Hospital, Boston, Massachusetts, USA; ¹⁵Dana Farber Cancer Institute, Boston, Massachusetts, USA; ¹⁶Harvard Medical School, Boston, Massachusetts, USA; ¹⁷Indiana University School of Medicine, Indianapolis, Indiana, USA

Correspondence
Francis M. Giardiello, MD, 1830 East Monument Street, Room 431, Baltimore, Maryland 21205, USA. E-mail: fgiardi@jhmi.edu

Sidebar 1

Guideline

Testing for MMR deficiency of newly diagnosed CRC should be performed. This can be done for all CRCs, or CRC diagnosed at age 70 years or younger, and in individuals older than 70 years who have a family history concerning for LS. Analysis can be done by IHC testing for the MLH1/MSH2/MSH6/PMS2 proteins and/or testing for MSI. Tumors that demonstrate loss of MLH1 should undergo BRAF testing or analysis of MLH1 promoter hypermethylation (Figure 2). To facilitate surgical planning, tumor testing on suspected CRC should be performed on preoperative biopsy specimens, if possible. This guideline is a strong recommendation, with evidence level III, and GRADE moderate-quality evidence.

Sidebar 2

Guideline

Individuals who have a personal history of a tumor showing evidence of MMR deficiency (without evidence of MLH1 promoter methylation); uterine cancer diagnosed at younger than age 50 years; a known family MMR gene mutation; fulfill Amsterdam criteria or revised Bethesda guidelines; and/or have a personal risk of ≥5% chance of LS based on prediction models should undergo genetic evaluation for LS (Figures 3,4,5,6). This guideline is a strong recommendation, with evidence level III, and GRADE moderate-quality evidence.

Sidebar 3

Guideline

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.^{[122,131,136–138]} This guideline is a strong recommendation, with evidence level III, and GRADE moderate-quality evidence (Table 10).

In carriers of deleterious MSH6 and PMS2 mutations, the risk of CRC is lower and age at diagnosis later^[22,25] than in patients with MLH1 and MSH2 mutations. In these affected individuals, consideration could be given to starting screening at age 30 years in MSH6 and 35 years in PMS2 carriers, unless an early-onset cancer exists in a given family.

Sidebar 4

Guideline

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]}

Sidebar 5

Guideline

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]}

Sidebar 6

Guideline

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]

Sidebar 7

Guideline

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.

This guideline is in concert with that of the NCCN.^[122] The Mallorca group recommends initial screening EGD with biopsy without a recommendation for ongoing surveillance.^[138]

Sidebar 8

Guideline

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.

Sidebar 9

Guideline

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.

Sidebar 10

Guideline

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]

Sidebar 11

Guideline

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]

Sidebar 12

Guideline

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.

Sidebar 13

Guideline

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]