CAM 169

Lynch Syndrome Testing

Category:Laboratory   Last Reviewed:July 2018
Department(s):Medical Affairs   Next Review:July 2019
Original Date:May 2017    

Description
Lynch syndrome (LS) (also known as hereditary non-polyposis colorectal cancer; HNPCC) is the most common form of hereditary colorectal (CRC) and endometrial cancers (EMC), resulting from an autosomal dominant inactivation of any of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) leading to microsatellite instability (MSI) (Rumilla et al., 2011) and associated with an increased risk of colorectal, endometrial, stomach, small bowel and ovarian cancers (Hunter et al., 2015; Lynch et al., 2009; Moreira et al., 2012).

Background 
Lynch syndrome (LS) is recognized by a hereditary predisposition to colorectal, endometrial and other cancers. It accounts for approximately 1% to 3% of all colorectal cancers and 2% to 5% of endometrial cancers (Hampel et al., 2005). In addition to colorectal and endometrial cancers, patients may present with ovarian, urinary tract, stomach, small bowel, hepatobiliary, sebaceous gland and central nervous system neoplasms (Barrow, Khan, Lalloo, Evans & Hill, 2013).

Inactivation by germline mutations or epigenetic silencing in any of four DNA mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) is known to result in Lynch syndrome (Jansen, Menko, Brosens, Giardiello & Offerhaus, 2014). Mutations of the upstream EPCAM gene, which result in silencing of the MSH2 gene, produce a phenotype very similar to LS (Ligtenberg et al., 2009). Mutations in MLH1 and MSH2 are most common (90%) followed by MSH6 (10%) and PMS2 (6% ) (Jansen et al., 2014).

The lifetime risk of CRC is greatly increased in LS patients, but varies significantly from 10-74%, depending on which MMR gene is inactivated (Brosens, Offerhaus & F, 2015). Average age at CRC diagnosis in LS patients is 44 to 61 years, with tumors primarily arising proximal to the splenic flexure (Giardiello et al., 2014b). There is also a high rate of metachronous CRC (16% at 10 years; 41% at 20 years) in LS patients (Win et al., 2013). The histopathology of LS colorectal cancer is often poorly differentiated, with signet cell histology, abundant extracellular mucin, tumor infiltrating lymphocytes and a lymphoid host response to tumor (Peltomäki PT, 2010). LS patients have improved survival rates compared to similar stage spontaneous CRC (Brosens et al., 2015). Lifetime risk of endometrial cancer is significantly increased to 15 – 71% in women with mutation-specific variability (Giardiello et al., 2014b). Increased lifetime risk has also been observed in urinary, ovarian, stomach, hepatobiliary, small bowel, brain, pancreatic and prostate cancers (Brosens et al., 2015).

Several sets of clinical criteria have been developed to identify patients with LS. In 1990, the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (HNPCC) established criteria (Amsterdam I Criteria) for HNPCC (Vasen, Mecklin, Khan & Lynch, 1991), which were updated to be more sensitive in 1999 (Vasen, Watson, Mecklin & Lynch, 1999). The Revised Bethesda Guidelines are a third set of clinicopathologic criteria developed in 2004 to improve identification of individuals who deserve investigation for LS (Umar et al., 2004).

However, as use of clinical criteria and modeling to identify patients with LS has less than optimal sensitivity and efficiency, universal screening for LS (Cohen et al., 2016; Kidambi et al., 2015) has been recommended (Provenzale et al., 2016). Analysis by immunohistochemical testing for the MLH1/MSH2/MSH6/PMS2 proteins and/or MSI testing are commonly used to screen for LS phenotypes (Syngal et al., 2015). Tumors with loss of MLH1 should undergo analysis to exclude BRAF mutation or MLH1 promoter hypermethylation (Giardiello et al., 2014a). Patients with evidence of LS should be referred for genetic evaluation (EGAPP, 2009; Robson et al., 2015; Sepulveda et al., 2017).

Cancer Risks in Individuals with Lynch Syndrome Age ≤ 70 Years Compared to the General Population (Brosens et al., 2015)

Cancer Type General Population Risk Lynch Syndrome (MLH1 and MSH2 heterozygotes)
Risk Mean Age of Onset
Colon 4.8% 52%-82%

44-61 years

Endometrium

2.7%

25%-60%

48-62 years

Stomach

<1%

6%-13%

56 years

Ovary

1.4%

4%-12%

42.5 years

Hepatobiliary tract

<1%

1.4%-4%

Not reported

Urinary tract

<1%

1%-4%

~55 years
Small bowel

<1%

3%-6%

49 years

Brain/central nervous system

<1%

1%-3%

~50 years
Sebaceous neoplasms

<1%

1%-9%

Not reported

Policy 

  1. In all patients with a known colorectal carcinoma:
    • Genetic counseling is considered MEDICALLY NECESSARY for individuals undergoing Lynch Syndrome testing.
    • Tumor Tissue Testing for Lynch Syndrome with IHC and/or MSI tests, OR Lynch syndrome specific blood genetic testing (4 MMR genes and EPCAM) OR blood multi-gene testing is considered MEDICALLY NECESSARY.
  2. Germline genetic testing for a deleterious mutation in the MMR (MLH1, MSH2, MSH6, and PMS2) or EPCAM gene is considered MEDICALLY NECESSARY in any of the following situations:
    • Patients with microsatellite unstable tumors by MSI/IHC testing
    • All patients with newly diagnosed colorectal carcinoma, to identify individuals with Lynch Syndrome.
    • Endometrial cancer prior to age 60
    • Individual has a 1st degree relative with Lynch syndrome with known MLH1, MSH2, MSH6, PMS2, or EPCAM mutation.
    • Individual has a >5% risk of Lynch Syndrome by any mutation risk model (e.g., MMRpro, PREMM, MMRpredict). Testing affected individuals in the family with a Lynch Syndrome related cancer is preferred.
    • If tumor testing is not feasible and the clinical suspicion of Lynch syndrome remains according to the revised Bethesda criteria
      • Colorectal carcinoma diagnosed in a patient who is younger than 50 years of age; 
      • Presence of synchronous or metachronous colorectal or other Lynch syndrome – related tumors (colorectal, endometrial, gastric, ovarian, pancreas, bladder, ureter and renal pelvis, biliary tract, brain (usually glioblastoma as seen in Turcot syndrome), small intestinal cancers, sebaceous gland adenomas and keratoacanthomas as seen in Muir-Torre syndrome), regardless of age; 
      • Colorectal carcinoma with high microsatellite instability histology diagnosed in a patient less than 60 years old; 
      • Colorectal carcinoma diagnosed in a patient with 1 or more first-degree relatives with a Lynch syndrome-associated tumor, with one of the cancers being diagnosed before 50 years of age;
      • Colorectal carcinoma diagnosed in a patient with 2 or more first- or second-degree relatives with Lynch syndrome-related cancer, regardless of age.
    • Individual meets the Amsterdam II criteria
      • 3 or more relatives with a cancer associated with Lynch Syndrome (colorectal cancer or cancer of the endometrium, small intestine, ureter or renal pelvis);
      • One must be a first-degree relative of the other two;
      • At least two successive generations must be affected;
      • At least one relative with cancer associated with Lynch syndrome should be diagnosed before 50 years of age;
      • Familial adenomatous polyposis should be excluded in cases of colorectal carcinoma;
      • Tumors should be verified whenever possible.
  3. When predictive testing is offered to an individual, the following limitations apply:
    • Testing of the tumor of the affected family member should occur first, if possible, to identify a familial mutation. 
    • When a familial mutation is identified in a tissue specimen of an affected family member, other family members being offered predictive testing for risk assessment should be limited to testing for the known familial mutation, and not for other mutations.
    • When individuals with a family history indicative of a hereditary form of colorectal cancer are counseled and a familial mutation is not known, or the tumor of the affected individual is not available for testing, predictive genetic testing of high risk individuals by testing of all four MMR genes and EPCAM is considered MEDICALLY NECESSARY.
    • Individuals in whom deleterious mutations are found should be counseled on their risk of developing cancer or having a recurrence of cancer, and offered a plan for increased surveillance and intervention, if warranted.
    • Genetic testing for Lynch Syndrome is limited to once per lifetime, unless testing for additional clinically relevant mutations is warranted.
  4. Genetic testing for susceptibility to colorectal cancer is considered INVESTIGATIONAL for all other purposes, including, but not limited to, testing of the general population. 

Policy Gudielines 
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.

* Germline Lynch syndrome genetic testing may include testing of the gene(s) that are indicated (based on plausible eitiologies) by the abnormal tumor test result, or instead, multi-gene testing that includes MLH1, MSH2, MSH6, PMS2, and EPCAM concurrently may be performed.

References 

  1. 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  
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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  
  12. 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
  13. 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
  14. 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.
  15. 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.
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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.
  22. 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.  
  23. 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.
  24. 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  

Coding Section

Code Number

Description

CPT 81210 BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s)
  81288 Prometer methylation analysis for MLH1 gene analysis testing (mutL homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome)
  81292

MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis

  81293

MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants

  81294

MLH1 (mutL homolog 1, colon cancer, non-polyposis type 2) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants

  81295

MSH2 (mutS homolog 2, colon cancer, non-polyposis type 1) (e.g., hereditary non‐polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis

  81296 MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (e.g., hereditary non‐polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants
  81297 MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (e.g.,hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/ deletion variants
  81298 MSH6 (mutS homolog 6 (E. coli)) (e.g, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; fullsequence analysis
  81299 MSH6 (mutS homolog 6 (E. coli)) (eg, hereditary non‐polyposis colorectal cancer, Lynch syndrome) gene analysis; known familialvariants
  81300  MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non‐polyposis colorectal cancer, Lynchsyndrome) gene analysis; duplication/deletion variants
  81301 Microsatellite instability analysis (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (e.g., BAT25, BAT26), includes comparison of neoplastic and  normal tissue, if performed
  81317 PMS2 Genetic Testing (postmeiotic segregation increased 2 (S. cerevisiae)) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
  81318 PMS2 Genetic Testing (postmeiotic segregation increased 2 (S. Cerevisiae)) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants  
  81319 PMS2 Genetic Testing (postmeiotic segregation increased 2 [S. cerevisiae]) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants
  81401 Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant (typically using nonsequencing target variant analysis), or detection of a dynamic mutation disorder/triple repeat
  81403 Molecular pathology procedure, Level 4 (e.g., analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 205 exons)
  81406 Molecular pathology procedure, Level 7 (e.g., analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia
  81435 Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include sequencing of at least 10 genes, including APC, BMPR1A, CDH1, MLH1, MSH2, MSH6, MUTYH, PTEN, SMAD4, and STK11
  81436 Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); duplication/deletion analysis panel, must include analysis of at least 5 genes, including MLH1, MSH2, EPCAM, SMAD4, and STK11
  88341 Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure)
  96040 Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family
  S0265 Genetic counseling, under physician supervision, each 15 minutes
ICD-10-CM  C17 Malignant neoplasm of small intestine
  C18.0,C18.1,C18.2,C18.3,C18.4, C18.5,C18.6,C18.7, C18.8, C18.9, C19 Malignant neoplasm, colon
  C20 Malignant neoplasm of rectum
  C54.1 Malignant neoplasm of endometrium
  C65 Malignant neoplasm of renal pelvis
  C66 Malignant neoplasm of the ureter
  C78.5 Secondary malignant neoplasm of large intestine/rectum
  D07.0 Carcinoma in situ of endometrium
  Z80.0 Family history, malignant neoplasm, digestive organs

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2017 Forward     

07/26/2018 

Annual review, rewriting medical necessity criteria to address the genes being tested in one medical necessity statement rather than breaking them out individually. Removing age criteria for testing. Updating guidelines to reflect the changes in the policy criteria. 

04/19/2018 

Interim review, month of review changed, no other changes 

08/03/2017 

Interim review clarifying medical necessity statement related to patients with 1 or more first degree relatives. Updating guidelines. 

05/01/2017

New Policy 


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