Familial Adenomatous Polyposis and MUTYH-Associated Polyposis AHSM2024

Description of Procedure or Service

Familial adenomatous polyposis (FAP) is characterized by development of adenomatous polyps and an increased risk of colorectal cancer (CRC) caused by an autosomal dominant mutation in the APC (Adenomatous Polyposis Coli) gene (Kinzler & Vogelstein, 1996). Depending on the location of the mutation in the APC gene FAP can present as the more severe classic FAP (CFAP) with hundreds to thousands of polyps developing in the teenage years associated with a significantly increased risk of CRC, or attenuated FAP (AFAP) with fewer polyps, developing later in life and less risk of CRC (Brosens, Offerhaus, & F, 2015; Spirio et al., 1993).

MUTYH-associated polyposis (MAP) results from an autosomal recessive mutation of both alleles of the MUTYH gene (Nielsen, Morreau, Vasen, & Hes, 2011) and is characterized by increased risk of CRC most often with or but can present without development of adenomatous polyps.

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for familial adenomatous polyposis and MUTYH-associated polyposis when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Familial Adenomatous Polyposis and MUTYH-Associated Polyposis is covered

Familial adenomatous polyposis and MUTYH-associated polyposis is considered medically necessary for the following:

1. Genetic counseling is considered medically necessary for individuals being considered for genetic testing for FAP/AFAP and/or MAP:
2. Complete sequencing of the APC gene is considered medically necessary for:
   1. Individuals with a personal history of > 10 adenomatous colon polyps, or
   2. Individuals with a personal history of a desmoid tumor, hepatoblastoma or cribriform-morular variant of papillary thyroid cancer, or multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE), or
   3. Individuals with a family history of FAP, AFAP, or MAP, and the familial mutation is unknown
3. Duplication/deletion analysis of the APC gene is considered medically necessary when:
   1. Sequencing of the APC gene does not reveal deleterious changes, and the clinical suspicion of FAP remains, or
   2. There is a known familial duplication or deletion
4. Testing for known familial mutations in the APC gene is considered medically necessary for first degree relatives of an individual with known FAP.
5. Testing for the two common MUTYH mutations (Y179C and G396D) is considered medically necessary when:
   1. There is a personal history of > 10 adenomatous colon polyps, or
   2. APC gene testing is negative and high clinical suspicion for FAP/AFAP remains
   3. The individual meets the following criteria for serrated polyposis syndrome (SPS) with at least some adenomas
      1. At least 5 serrated polyps proximal to the sigmoid colon with 2 or more of these being greater than 10 mm; or
      2. Greater than 20 serrated polyps of any size, but distributed throughout the colon.
      3. Any number of serrated polyps proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis
   4. The two common mutations are known familial mutations
6. Sequencing of the MUTYH gene is considered medically necessary when:
   1. Testing for the two common mutations (Y179C and G396D) is negative, or only one common mutation is detected, and the clinical suspicion of MAP remains, OR
   2. Testing is being requested in a member with a known familial mutation in MUTYH. This testing should be limited to the known familial mutation.
   3. Testing is being done in unaffected parent when the other parent has MAP
   4. Unaffected parent is not tested, testing for children is indicated
7. Duplication/deletion analysis of the MUTYH gene is considered medically necessary when:
   1. Sequencing of the MUTYH gene does not detect a mutation, and the clinical suspicion of MAP remains, OR
   2. There is a known familial duplication or deletion.
8. Multi-gene testing is considered medically necessary in individuals who meet the APC and MUTYH testing criteria and have no known APC or biallelic mutations.
9. . If a pathogenic mutation has been identified in the index patient, predictive testing for the mutation is considered medically necessary for the first-degree relatives. In typical FAP, family members that are found to carry the mutation is covered to undergo periodic examination of
   • the recto-sigmoid from the early teens, and
   • the upper gastrointestinal tract from age 25–30 years to monitor adenoma development.

When Familial Adenomatous Polyposis and MUTYH-Associated Polyposis is not covered

Familial adenomatous polyposis and MUTYH-associated polyposis is considered not medically necessary for the following:

1. Sequencing of the MUTYH gene in children is considered not medically necessary when one of the parents is unaffected and does not have MUTYH mutation and the other parent has MAP.
2. Multi-gene testing is considered not medically necessary in the following situations:
   • An individual is from a family with a known mutation without any other reason for multi-gene testing
   • Multi-gene testing being used as a first-line testing when the family history is strongly suggestive of a known hereditary syndrome.

Policy Guidelines

Inherited syndromes that express adenomatous polyps and confer a significantly increased risk of CRC include Lynch syndrome, familial adenomatous polyposis (FAP), and MUTYH-associated polyposis (MAP)(Jasperson, Tuohy, Neklason, & Burt, 2010). Lynch Syndrome is discussed in a separate policy (M2004).

Familial adenomatous polyposis (FAP) results from mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Mutant or absent APC results increased transcription of cell proliferation genes regulated through the Wnt/β- catenin pathway (Spoto, Gullo, Carneiro, Montgomery, & Brosens, 2018). The prevalence of FAP is about 1:13,000 (Brosens et al., 2015). More than 300 different mutations have been reported, with the clinical presentation dependent on the location of the mutation in the APC gene (Brosens et al., 2007; Spirio et al., 1993). Mutations in the central part of the gene result in classic FAP characterized by the presence of 100 or more adenomatous colorectal polyps (Jansen, Menko, Brosens, Giardiello, & Offerhaus, 2014; Talley, 2017). When fully developed, patients can have up to thousands of colorectal adenomas and have a 100 percent risk of colorectal cancer (CRC). About 50% of patients developed adenomas by age 15 and 95% by age 35. If left untreated, FAP patients will develop CRC at an average age of 39 (range 35-43 year) (Trimbath & Giardiello, 2002).

In contrast, mutations in either end of the gene predispose to AFAP (Spirio et al., 1993). An attenuated form of FAP is characterized by few colorectal adenomas with a later age of onset and an 80 percent lifetime risk of CRC. The diagnosis should be considered in patients 40-50 year old with 10-100 adenomas cumulatively. Patients with AFAP have a 70% lifetime risk of CRC, about 12 years later than in classic FAP (Jasperson et al., 2010; Trimbath & Giardiello, 2002).

Patients with FAP are also at risk for several extracolonic malignancies. (Talley, 2017)

MUTYH-associated polyposis is caused by biallelic mutations in the MUTYH gene base excision repair gene whose protein repairs oxidative damage to the DNA (Sieber et al., 2003). Failure of base excision repair results in transversions in multiple genes, including the APC and KRAS genes(S. S. Grover, Elena., 2017). More than 100 unique MUTYH gene mutations have been reported, however the target genes that are mutated as a consequence of oxidative damage most strongly influence the polyposis phenotype (Boparai et al., 2008).

MUTYH-associated polyposis is usually characterized by development of between 10 to 100 colorectal polyps by the fifth or sixth decade (S. Grover et al., 2012; Sieber et al., 2003). However, MUTYH mutations have been identified in colorectal cancer (CRC) with few or no colorectal polyps(Balaguer et al., 2007; Wang et al., 2004). Adenomas are the predominant polyp type in patients with MUTYH-associated polyposis, however multiple hyperplastic and/or sessile serrated polyps have been reported in some patients.

Guidelines have been established by several organizations to reduce morbidity and mortality from hereditary forms of polyposis and resulting colorectal cancer by identifying individuals at risk and implementing a highly targeted program of cancer surveillance and management guided by the causative mutations identified(Hampel, Bennett, Buchanan, Pearlman, & Wiesner, 2015; Hegde, Ferber, Mao, Samowitz, & Ganguly, 2014; Provenzale et al., 2016; Syngal et al., 2015).

Ciavarella et al (Ciavarella et al., 2018)investigated genetic causes of unexplained adenomatous polyposis in 8 cases of polyposis with no causative germline variant in APD or MUTYH. They identified APC mosaicism in 50% of patients. In three cases mosaicism was restricted to the colon, while in one it also extended to the duodenum and saliva. One patient without APC mosaicism, carrying an APC inframe deletion of uncertain significance, was found to harbor rare germline variants in OGG1, POLQ, and EXO1 genes. They concluded that restrictive selection criteria improved the detection of mosaic APC patients and showed for the first time that an oligogenic inheritance of rare variants might have a cooperative role in sporadic colorectal polyposis onset.

National Comprehensive Cancer Network (NCCN)

The NCCN recommends APC gene testing for individuals with a personal history of >20 adenomas and for individuals with a known deleterious familial mutation. The NCCN recommends testing be considered in individuals with a personal history of a desmoid tumor, hepatoblastoma, cribriformmorular variant of papillary thyroid cancer, multifocal/bilateral CHRPE, or 10-20 adenomas(Gupta et al., 2017; NCCN, 2017).

NCCN recommends MUTYH genetic testing for individuals with a personal history of >20 adenomas and known deleterious MUTYH mutations in family. The NCCN recommends testing be considered in with a personal history of 10-20 adenomas or individuals meetings criteria for serrated polyposis syndrome with at least some adenomas (NCCN, 2017; Provenzale et al., 2016).

When there is no known familial mutation, NCCN recommends polyposis syndrome specific testing(when colonic polyposis is present in a single person with a negative family history consider testing for a de novo APC mutation; if negative follow with testing of MUTYH. When there are known familial mutations in either the APC or MUTYH genes, NCCN recommends testing for those mutations instead of full gene sequencing) or Multi Gene Testing(NCCN, 2017).

Siblings of individuals affected with MAP and children of individuals with MAP are recommended to have biallelic testing for the familial mutations. If one mutation is found, then sequencing of the entire gene is recommended. Also, sequencing of the MUTYH gene may be considered for the unaffected parent, and if that sequencing does not reveal any deleterious mutations, then the NCCN indicates that genetic testing of the children is not considered necessary(NCCN, 2017).

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 “examples of clinical scenarios for which multi-gene testing should be considered include adenomatous polyposis (APC, MUTYH, POLE, POLD1)” NCCN also states “when more than one gene can explain an inherited cancer syndrome, multi-gene testing may be more efficient and cost-effective.” NCCN 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”(Gupta et al., 2017).

NCCN recommendations are in agreement with those by ASCO, which issued an updated statement regarding genetic testing in 2015(Robson et al., 2015).

American College of Gastroenterology (ACG)

The ACG recommends that “individuals who have a personal history of >10 cumulative colorectal adenomas, a family history of one of the adenomatous polyposis syndromes, or a history of adenomas and FAP-type extracolonic manifestations (duodenal/ampullary adenomas, desmoid tumors (abdominal>peripheral), papillary thyroid cancer, congenital hypertrophy of the retinal pigment epithelium ((CHRPE), epidermal cysts, osteomas) should undergo assessment for the adenomatous polyposis syndromes. Genetic testing of patients with suspected adenomatous polyposis syndromes should include APC and MUTYH gene mutation analysis”(Syngal et al., 2015).

ACG further states “failure to identify a mutation in an index case does not rule out the diagnosis of adenomatous polyposis, as mutations cannot be found in all families. If testing is negative, and clinical suspicion remains high, testing for other possible underlying genes should be considered. Failure to find a mutation means that all close relatives must still be screened as if they have FAP. Finding a mutation confirms the diagnosis of adenomatous polyposis and allows relatives to be tested with a high degree of accuracy. Once an affected patient has been genotyped, all at-risk relatives can be screened for the mutation”(Syngal et al., 2015).

American College of Medical Genetics and Genomics (ACMG)

ACMG recommends testing for APC mutations in individuals with “10 or more polyps with autosomal dominant inheritance, and for at-risk family members of individuals with known familial mutations, and in individuals with congenital hypertrophy of retinal pigment epithelium, osteomas, supernumerary teeth, odontomas, desmoids, epidermoid cysts, duodenal and other small-bowel adenomas, gastric fundic gland polyp” (Hegde et al., 2014). It also recommended that “FAP testing be performed using full sequencing of the APC gene. If no mutation is detected, then testing for large gene rearrangements should be performed”(Hegde et al., 2014).

ACMG recommends considering testing for AFAP in individuals with presence of less than 100 adenomas, on average 30 polyps. They note that individuals with 100 or more polyps occurring at ages between 35-40 years or older may be found to have AFAP. According to ACMG, frequent right-sided distribution of polyps is usually noted in these individuals and adenomas and cancers at an age older than that for classic FAP and other GI manifestations are found (Hegde et al., 2014).

ACMG recommends MUTYH gene testing for individuals with colorectal cancer diagnosed at less than 40 years of age, the presence of 10 – 100 adenomatous polyps in the absence of APC gene mutation, and a family history of colon cancer consistent with an autosomal recessive inheritance including colon cancers with or without polyps (Hegde et al., 2014). ACMG indicates that MUTYH testing should begin with testing for the two common mutations, and if none or one mutation is identified, then full sequencing of the MUTYH gene should be considered (Hegde et al., 2014). The ACMG also recommends that testing of the MUTYH gene should also be offered to at-risk family members.

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

ACMG and NSGC recommend that referral for genetic counseling should be considered for “any individual with a personal history of or first-degree relative with (i) a total of ≥10 adenomatous colon polyps with or without a colorectal or other FAP-associated cancer; (ii) a cribriform morular variant of papillary thyroid cancer; (iii) a desmoid tumor; or (iv) hepatoblastoma diagnosed before age 5” (Hampel et al., 2015).

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: 81201, 81202, 81203, 81406, 96040, S0265