Lynch Syndrome AHS-M2004

Applicable Federal Regulations:

On October 27, 2017 the FDA approved VENTANA MMR IHC Panel for patients diagnosed with colorectal cancer (CRC) to detect mismatch repair (MMR) proteins deficiency as an aid in the identification of probable Lynch syndrome and to detect BRAFV600E protein as an aid to differentiate between sporadic CRC and probable Lynch syndrome.

Genetic testing for Lynch syndrome is considered a laboratory developed test (LDT); developed, validated and performed by individual laboratories.

LDTs are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88).

As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Guidelines and Recommendations

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group

In 2009, the EGAPP Working Group recommended (EGAPP, 2009):

1. Offering genetic testing for Lynch Syndrome to individuals with newly diagnosed colorectal cancer to reduce morbidity and mortality in relatives. However, they do not recommend a specific testing protocol.
2. That individuals with newly diagnosed CRC should be routinely offered counseling and educational materials aimed at informing them and their relatives of the potential benefits and harms associated with genetic testing to identify Lynch Syndrome.

National Comprehensive Cancer Network (NCCN)

The NCCN 2016 guidelines on colorectal carcinoma recommends “universal screening of all colorectal carcinomas to maximize sensitivity for identifying individuals with Lynch syndrome and to simplify care processes.” NCCN also states that an alternate strategy is “to limit screening to individuals with colorectal carcinoma diagnosed <70 years plus those at 70 years or older and meet Bethesda criteria.”(Provenzale et al., 2016)

The NCCN considers those at increased risk for Lynch Syndrome to include those who meet the revised Bethesda guidelines or Amsterdam criteria, those who had endometrial cancer before age 50, those with a known Lynch Syndrome in their family, and those who have a >5% risk of Lynch syndrome on any mutation prediction model (MMRpro, PREMM, or MMRpredict). NCCN recommends that individuals meeting one or more of these criteria warrant “further personalized risk assessment, genetic counseling and often genetic testing and management”. For individuals who meet the Lynch syndrome testing criteria, the following testing strategy is recommended:

1. If there is a known deleterious Lynch syndrome mutation, the individual must be tested for familial mutation
2. If there is no known Lynch syndrome mutation and tumor is available for testing, options include tumor testing with IHC and/or MSI or Lynch syndrome specific genetic testing (4 MMR genes and EPCAM) or multi-gene testing
3. If there is no known Lynch syndrome mutation and no tumor is available or tumor is insufficient, options include Lynch syndrome specific genetic testing (4 MMR genes and EPCAM) or multi-gene testing

The NCCN notes that the revised Bethesda criteria are more sensitive than the Amsterdam criteria in identifying individuals at-risk for Lynch Syndrome, but “up to 50% of patients with LS fail to meet even the revised Bethesda guidelines.”

The NCCN recommends testing in the following sequence:

If the tumor of the affected individual (self or family member) is available, consider initial testing of the tumor with immunohistochemistry (IHC) and/or microsatellite instability (MSI) tests. Results of this testing should guide the choice of which gene(s) should be selected for further testing:

1. If IHC testing is normal for MLH1, MSH2, MSH6, and PMS2, and MSI testing shows low MSS/MSI, then no further testing is necessary.
2. If IHC testing is normal for MLH1, MSH2, MSH6, and PMS2, and MSI testing shows high MSI, consider Lynch syndrome germline testing*. If germline testing is negative, then consider somatic MMR genetic testing.
3. If only MSI testing is performed and shows high MSI, consider IHC testing and additional testing based on IHC results. If IHC testing is not done, consider germline Lynch syndrome genetic testing*.
4. If IHC results are normal for MSH2 and MSH6, and staining is absent for MLH1 and PMS2, consider BRAF methylation studies. If BRAF isn’t performed, or if no BRAF mutation or hypermethylation are found, consider germline Lynch syndrome genetic testing*.
5. If BRAF testing is positive and MLH1 promoter methylation testing is not done, no additional testing is needed unless there was a young age of onset or significant family history; then consider MLH1 epimutation testing and/or germline Lynch syndrome genetic testing*.
6. If BRAF testing is negative and MLH1 promoter methylation testing is positive, no additional testing is necessary unless there was a young age of onset or significant family history; then consider MLH1 epimutation testing and/or germline Lynch syndrome mutation testing*.
7. If IHC results are normal for MSH2 and MSH6, and staining is absent for MLH1 and PMS2, and BRAF mutation and MLH1 promoter methylation testing are negative, consider germline Lynch syndrome genetic testing*. If germline testing is negative, then consider somatic MMR genetic testing.
8. If IHC results are normal for MLH1 and PMS2 and staining is absent for MSH2 and MSH6, consider germline Lynch syndrome genetic testing*. If germline testing is negative, then consider somatic MMR genetic testing.
9. If IHC staining is absent only for PMS2, consider germline Lynch syndrome genetic testing*. If germline testing is negative, then consider somatic MMR genetic testing.
10. If IHC staining is absent only for MSH2, consider germline Lynch syndrome genetic testing*. If germline testing is negative, then consider somatic MMR genetic testing.
11. If IHC staining is absent only for MSH6, consider germline Lynch syndrome genetic testing*. If applicable, consider MSI analysis or repeat IHC testing on non-treated tumor. If germline testing is negative, then consider somatic MMR genetic testing.
12. If IHC staining is absent only for MLH1, consider germline Lynch syndrome genetic testing*. If germline testing of MLH1 is negative, consider BRAF methylation studies. If germline testing is negative, consider somatic MMR genetic testing.
13. If IHC staining is absent for MLH1, MSH2, MSH6 and PMS2, consider germline Lynch syndrome genetic testing*. If germline testing of MLH1 is negative, consider BRAF methylation studies. If germline testing is negative, consider somatic MMR genetic testing.
14. If the tumor is not available for testing or insufficient tumor, and criteria are met, consider testing all 4 MMR genes and EPCAM or multi-gene testing.

The NCCN (2016) also recommends that “prior to germline genetic testing proper pre-test counseling should be done by an individual with expertise in genetics.”(Provenzale et al., 2016)

The NCCN guidelines also mention that next generation sequencing technology allows for the sequencing of multiple genes associated with a specific family cancer phenotype or multiple phenotypes simultaneously. NCCN states “when more than one gene can explain an inherited cancer syndrome, multi-gene testing may be more efficient and cost-effective.” NCCN also recommends “there is a role for multi-gene testing in individuals who have tested negative for a single syndrome, but whose personal and family history remains strongly suggestive of an inherited susceptibility”. Due to several limitations and challenges associated with multi-gene testing, the NCCN panel recommends that “when multi-gene testing is offered, it is done in the context of professional genetic expertise with pre- and post-test counseling being offered” (Provenzale et al., 2016)

The 2017 update (Gupta et al., 2017) adds more clear guidance for the use of multigene testing stating:

“Multigene testing is not recommended when:

• There is an individual from a family with a known mutation and there is no other reason for multigene testing;
• The patient's family history is strongly suggestive of a specific known hereditary syndrome for which single-gene analysis may provide definitive diagnosis; or,
• The patient is diagnosed with CRC with microsatellite instability (MSI) or loss of ≥1 DNA mismatch repair (MMR) proteins.

In these 3 scenarios, syndrome-specific panels may be considered.

Multigene testing may be considered in the following scenarios:

• A patient with a personal or family history that meets criteria for >1 hereditary cancer syndrome (eg, Lynch syndrome and BRCA-related breast and/or ovarian cancer)
• Colonic polyposis with uncertain histology
• Adenomatous or mixed polyposis (specific to APC, MUTYH, POLE, and POLD1)
• Family history does not meet criteria for established testing guidelines but there is suspicion of hereditary cancer, and an appropriate panel is available
• Family history is limited or unknown but patient has concerns about hereditary cancer
• As second-line testing hen first-line testing (eg, syndrome-specific or single-gene) is inconclusive”

It also assessed the “strength of evidence linking mutations in genes newly associated with CRC risk and management recommendations for these genes. These include mutations/alterations in APC (I1307K polymorphism), AXIN2,CHEK2,GREM1 (upstreamduplications), MSH3, MUTYH (monoallelic), NTHL1, POLD1, and POLE. Although research has demonstrated a potential risk for CRC associated with mutations in these genes, the value of including these genes for clinical testing (eg, as part of a multigene panel) remains uncertain…. Nonetheless, the panel recognizes that many testing companies offer panels that include these genes, and that patients are being tested and may need guidance regarding subsequent screening and surveillance.”

American Society of Clinical Oncology (ASCO)

The American Society of Clinical Oncology (ASCO) recommends that “genetic testing only be conducted in the setting of pre- and post-test counseling”(Robson, Storm, Weitzel, Wollins, & Offit, 2010). In 2015, ASCO stated that “identifying inherited mutations in genes such as BRCA1, BRCA2, and the genes associated with Lynch syndrome allows for interventions that can significantly reduce the development of cancer and improve survival. Targeted capture assays employing NGS technology allow for testing many genes simultaneously, including genes that would not necessarily have been tested using the phenotype-directed approach, as well as genes of less clearly established clinical utility” (Robson et al., 2015).According to ASCO, multi-gene panel testing is particularly useful in situations where there are multiple high-penetrance genes associated with a specific cancer, and “one example of such a situation is Lynch syndrome, when the results of immunohistochemical analysis are not available to direct testing”(Robson et al., 2015).

U.S. Multi-Society Task Force on Colorectal Cancer

In 2014, The U.S. Multi-Society Task Force on Colorectal Cancer (Giardiello et al., 2014a):

“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.”Also, “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.”

The sequential genetic testing recommended by the task force aligns with the NCCN recommendations.

American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC)

Referral for cancer genetic consultation is recommended by the ACMG and the NSGC for individuals “with a personal history or first-degree relative with (i) an LS-associated cancer in childhood or (ii) another type of childhood cancer and one or more of the following features: (i) café-au-lait macules, skinfold freckling, Lisch nodules, neurofibromas, tibial pseudoarthrosis, or hypopigmented skin lesions; (ii) family history of LS-associated cancer; (iii) a second primary cancer; (iv) a sibling with a childhood cancer; or (v) consanguineous parents” (Hampel et al., 2005).

ASCP, CAP, AMP, and ASCO

American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and American Society of Clinical Oncology (ASCO) issued guidelines in 2017 stating “BRAF p.V600 mutational analysis should be performed in deficient MMR tumors with loss of MLH1 to evaluate for Lynch Syndrome risk. Presence of a BRAF mutation strongly favors a sporadic pathogenesis. The absence of BRAF mutation does not exclude risk of Lynch syndrome”. In addition, they have added the following recommendation for clinicians: “clinicians should order mismatch repair status testing in patients with colorectal cancers for the identification of patients at high risk for Lynch syndrome and/or prognostic stratification” (Sepulveda et al., 2017).

American College of Gastroenterology (ACG)

In 2015, ACG issued the following practice guidelines for the management of patients with hereditary gastrointestinal cancer syndromes (Syngal et al., 2015):

• All newly diagnosed colorectal cancers should be evaluated for mismatch repair deficiency.
• Analysis may be done by immunohistochemical (IHC) testing for the MLH1/MSH2/MSH6/PMS2 proteins and/or testing for microsatellite instability; tumors that demonstrate loss of MLH1 should undergo BRAF testing or analysis for MLH1 promoter hypermethylation.
• Individuals who have a personal history of a tumor showing evidence of mismatch repair deficiency (and no demonstrated BRAF mutation or hypermethylation of MLH1), a known family mutation associated with LS, or a risk of ≥5% chance of LS based on risk prediction models should undergo genetic evaluation for LS.60
• Genetic testing of patients with suspected LS should include germline mutation genetic testing for the MLH1, MSH2, MSH6, PMS2, and/or EPCAM genes or the altered gene(s) indicated by IHC testing.

American Society of Colon and Rectal Surgeons

The American Society of Colon and Rectal Surgeons (Herzig et al., 2017)published guidelines which recommend (based on 2014 U.S. Multi-Society Task Force on Colorectal Cancer):

Universal testing (tumor testing)

• Testing for MMR deficiency of newly diagnosed CRC should be performed
• This can be done for all CRCs or CRC diagnosed at age ≤70 y and in individuals >70 y 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
• To facilitate surgical planning, tumor testing on suspected CRC should be performed on preoperative biopsy specimens, if possible

Traditional testing (germline testing)

• Individuals who have a personal history of a Lynch syndrome–related tumor showing evidence of MMR deficiency (without evidence of MLH1 promoter methylation)
• Personal history of uterine cancer diagnosed at age <50 y
• A known family MMR gene mutation
• Fulfill Amsterdam criteria or revised Bethesda guidelines
• Have a personal risk of ≥5% chance of LS based on prediction models

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81210, 81288, 81292, 81293, 81294, 81295, 81296, 81297, 81298, 81299, 81300, 81301, 81317, 81318, 81319, 81401, 81403, 81406, 81435, 81436, 88341, 96040

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

Barrow, P., Khan, M., Lalloo, F., Evans, D. G., & Hill, J. (2013). Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br J Surg, 100(13), 1719-1731. doi:10.1002/bjs.9316

Brosens, L. A., Offerhaus, G. J. A., & F, M. G. (2015). Hereditary Colorectal Cancer: Genetics and Screening. Surg Clin North Am, 95(5), 1067-1080. doi:10.1016/j.suc.2015.05.004

Cohen, S. A., Laurino, M., Bowen, D. J., Upton, M. P., Pritchard, C., Hisama, F., . . . Grady, W. M. (2016). Initiation of universal tumor screening for Lynch syndrome in colorectal cancer patients as a model for the implementation of genetic information into clinical oncology practice. Cancer, 122(3), 393-401. doi:10.1002/cncr.29758

EGAPP. (2009). 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 Med, 11(1), 35-41. doi:10.1097/GIM.0b013e31818fa2ff

Giardiello, F. M., Allen, J. I., Axilbund, J. E., Boland, C. R., Burke, C. A., Burt, R. W., . . . Rex, D. K. (2014a). Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc, 80(2), 197-220. doi:10.1016/j.gie.2014.06.006

Giardiello, F. M., Allen, J. I., Axilbund, J. E., Boland, C. R., Burke, C. A., Burt, R. W., . . . Rex, D. K. (2014b). Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology, 147(2), 502-526. doi:10.1053/j.gastro.2014.04.001

Gupta, S., Provenzale, D., Regenbogen, S. E., Hampel, H., Slavin, T. P., Jr., Hall, M. J., . . . Ogba, N. (2017). NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017. J Natl Compr Canc Netw, 15(12), 1465-1475. doi:10.6004/jnccn.2017.0176

Hampel, H., Frankel, W. L., Martin, E., Arnold, M., Khanduja, K., Kuebler, P., . . . de la Chapelle, A. (2005). Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med, 352(18), 1851-1860. doi:10.1056/NEJMoa043146

Herzig, D. O., Buie, W. D., Weiser, M. R., You, Y. N., Rafferty, J. F., Feingold, D., & Steele, S. R. (2017). Clinical Practice Guidelines for the Surgical Treatment of Patients With Lynch Syndrome. Dis Colon Rectum, 60(2), 137-143. doi:10.1097/dcr.0000000000000785

Hunter, J. E., Zepp, J. M., Gilmore, M. J., Davis, J. V., Esterberg, E. J., Muessig, K. R., . . . Goddard, K. A. (2015). Universal tumor screening for Lynch syndrome: Assessment of the perspectives of patients with colorectal cancer regarding benefits and barriers. Cancer, 121(18), 3281-3289. doi:10.1002/cncr.29470

Jansen, M., Menko, F. H., Brosens, L. A., Giardiello, F. M., & Offerhaus, G. J. (2014). Establishing a clinical and molecular diagnosis for hereditary colorectal cancer syndromes: Present tense, future perfect? Gastrointest Endosc, 80(6), 1145-1155. doi:10.1016/j.gie.2014.07.049

Kidambi, T. D., Blanco, A., Myers, M., Conrad, P., Loranger, K., & Terdiman, J. P. (2015). Selective Versus Universal Screening for Lynch Syndrome: A Six-Year Clinical Experience. Dig Dis Sci, 60(8), 2463-2469. doi:10.1007/s10620-014-3234-z

Ligtenberg, M. J., Kuiper, R. P., Chan, T. L., Goossens, M., Hebeda, K. M., Voorendt, M., . . . Hoogerbrugge, N. (2009). Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet, 41(1), 112-117. doi:10.1038/ng.283

Lynch, H. T., Lynch, P. M., Lanspa, S. J., Snyder, C. L., Lynch, J. F., & Boland, C. R. (2009). Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet, 76(1), 1-18. doi:10.1111/j.1399-0004.2009.01230.x

Moreira, L., Balaguer, F., Lindor, N., de la Chapelle, A., Hampel, H., Aaltonen, L. A., . . . Castells, A. (2012). Identification of Lynch syndrome among patients with colorectal cancer. Jama, 308(15), 1555-1565. doi:10.1001/jama.2012.13088

Peltomäki PT, O. G., Vasen HFA. (2010). Lynch syndrome. In C. F. Bosman FT, Hruban RH, Theise ND (Ed.), WHO Classification of Tumours of the Digestive System (4th ed., Vol. 3). Lyon: IARC Press.

Provenzale, D., Gupta, S., Ahnen, D. J., Bray, T., Cannon, J. A., Cooper, G., . . . Darlow, S. (2016). Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw, 14(8), 1010-1030.

Robson, M. E., Bradbury, A. R., Arun, B., Domchek, S. M., Ford, J. M., Hampel, H. L., . . . Lindor, N. M. (2015). American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol, 33(31), 3660-3667. doi:10.1200/jco.2015.63.0996

Robson, M. E., Storm, C. D., Weitzel, J., Wollins, D. S., & Offit, K. (2010). American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol, 28(5), 893-901. doi:10.1200/jco.2009.27.0660

Rumilla, K., Schowalter, K. V., Lindor, N. M., Thomas, B. C., Mensink, K. A., Gallinger, S., . . . Thibodeau, S. N. (2011). Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J Mol Diagn, 13(1), 93-99. doi:10.1016/j.jmoldx.2010.11.011

Sepulveda, A. R., Hamilton, S. R., Allegra, C. J., Grody, W., Cushman-Vokoun, A. M., Funkhouser, W. K., . . . Nowak, J. A. (2017). Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn, 19(2), 187-225. doi:10.1016/j.jmoldx.2016.11.001

Syngal, S., Brand, R. E., Church, J. M., Giardiello, F. M., Hampel, H. L., & Burt, R. W. (2015). ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol, 110(2), 223-262; quiz 263. doi:10.1038/ajg.2014.435

Umar, A., Boland, C. R., Terdiman, J. P., Syngal, S., de la Chapelle, A., Ruschoff, J., . . . Srivastava, S. (2004). Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst, 96(4), 261-268.

Vasen, H. F., Mecklin, J. P., Khan, P. M., & Lynch, H. T. (1991). The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum, 34(5), 424-425.

Vasen, H. F., Watson, P., Mecklin, J. P., & Lynch, H. T. (1999). New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. In Gastroenterology (Vol. 116, pp. 1453-1456). United States.

Win, A. K., Parry, S., Parry, B., Kalady, M. F., Macrae, F. A., Ahnen, D. J., . . . Jenkins, M. A. (2013). Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers. Ann Surg Oncol, 20(6), 1829-1836. doi:10.1245/s10434-012-2858-5

Policy Implementation/Update Information

1/1/2019 New policy developed. BCBSNC will provide coverage for lynch syndrome when it is determined to be medically necessary and criteria are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (lpr)