National Medical Policy

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1 National Medical Policy Subject: Genetic Testing for Familial Adenomatous Polyposis Policy Number: NMP480 Effective Date*: May 2004 Updated: September 2017 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State s Medicaid manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies guidelines The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* X Other MLN Matters Number: MM Healthcare Common Procedure Coding System (HCPCS) Codes Subject to and Excluded from Clinical Laboratory Improvement Amendments (CLIA) Edits: and-education/medicare-learning-network- MLN/MLNMattersArticles/downloads/MM8162.pdf None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Genetic Testing FAP Sep 17 1

2 Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement Health Net, Inc. considers any of the following medically necessary: 1. Genetic testing* for familial adenomatous polyposis (FAP), also known as adenomatous polyposis coli (APC), and attenuated FAP (AFAP) for any of the following: Confirm the diagnosis of familial adenomatous polyposis with > 10 cumulative colorectal adenomas; or Provide presymptomatic diagnosis of individuals 10 years of age or older at risk for FAP (first-degree relatives of those affected); or Confirm the diagnosis of attenuated familial adenomatous polyposis in those with > 10 cumulative colorectal adenomas; or First-degree relatives (10 years of age or older) of patients at risk for attenuated FAP; or Individuals with a personal history of desmoid tumor. *Note: Genetic testing of APC and/or MUTYH is important to differentiate between FAP/AFAP from MutY human homolog (MUTYH) -associated polyposis (MAP) and colonic polyposis of unknown etiology. Note: Although the diagnosis of familial polyposis is usually made by clinical features, genetic testing in FAP is considered the standard of care for management of this disorder. Testing can provide helpful information to the atrisk family members. With thorough genetic analysis, mutations can be found in 90% of families if the testing can be provided by an affected family member. Note: If informative genetic testing cannot be done, at-risk members are advised to pursue endoscopic screening with yearly sigmoidoscopy starting at 12 years old, and reducing screening frequency with each subsequent decade. After age 50, patients are advised to follow the American Gastroenterology Association guidelines for screening average-risk patients. 2. Microsatellite instability (MSI) testing for any of the following: (see National Medical Policy on Genetic Testing for Hereditary Nonpolyposis Colorectal Cancer) Affected individuals in families meeting Amsterdam criteria; or Affected individuals meeting Bethesda criteria modified. Genetic Testing FAP Sep 17 2

3 3. DNA mismatch repair (MMR) gene testing (hmsh2, hmlh1) for any of the following: Patients with MSI-high tumor test result; or Affected individuals in families meeting any of the first 3 criteria of the Bethesda criteria modified or tumor tissue not available; or First-degree adult relatives of those with known mutation Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets. ICD-10 Codes C18.0-C18.9 Malignant neoplasm of colon C19 Malignant neoplasm of rectosigmoid junction C21.0-C21.8 Malignant neoplasm of anus and anal canal C75.8 Secondary malignant neoplasm of large intestine and rectum D01.0-D01.3 Carcinoma in situ of other and unspecified digestive system D12.0-D12.9 Benign neoplasm of colon, rectum, anus and anal canal D37.2 Neoplasm of uncertain behavior of small intestine D37.4 Neoplasm of uncertain behavior of colon D37.5 Neoplasm of uncertain behavior of rectum D48.1 Neoplasm of uncertain behavior of connective and other soft tissue (desmoid tumor) D49.0 Neoplasm of unspecified behavior of digestive system K63.5 Polyp of colon Z12.12 Encounter for screening for malignant neoplasm of rectum Z8Ø.0 Family history of malignant neoplasm of digestive organs Z83.71 Family history of colonic polyps Z Personal history of colonic polyps Z87.39 Personal history of other diseases of the musculoskeletal system and connective tissue [desmoid tumor] CPT Codes APC (adenomatous polyposis coli) [e.g., familial adenomatous polyposis (FAP), attenuated FAP gene] analysis, full gene sequence APC (adenomatous polyposis coli) [e.g., familial adenomatous polyposis (FAP), attenuated FAP gene] analysis. Known familial variants APC (adenomatous polyposis coli) [e.g., familial adenomatous polyposis (FAP), attenuated FAP gene] analysis, duplication/deletion variants Molecular pathology procedure, Level 2 (e.g., 2-10 SNP s, 1 methylated variant, or 1 somatic variant (typically using nonsequencing target variant analysis or detection of a dynamic mutation disorder/triplet repeat) (Revised in 2016) Genetic Testing FAP Sep 17 3

4 81406 Molecular pathology procedure, Level 7 (e.g., analysis of exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of exons, cytogenomic array analysis for neoplasia) (Revised in 2016) HCPCS Codes G0104 Colorectal cancer screening;flexible sigmoidoscopy G0105 Colorectal cancer screening; colonoscopy on individual at high risk G0121 Colorectal cancer screening; colonoscopy on individual not meeting criteria for high risk Scientific Rationale - Update September 2015 The American Society of Clinical Oncology (ASCO, 2015) endorsement panel determined that the recommendations of the European Society for Medical Oncology (ESMO) guidelines are clear, thorough, and based on the most relevant scientific evidence for familial risk-colorectal cancer. Approximately 5% to 6% of patient cases of CRC are associated with germline mutations that confer an inherited predisposition for cancer. The possibility of a hereditary cancer syndrome should be assessed for every patient at the time of CRC diagnosis. A diagnosis of Lynch syndrome, familial adenomatous polyposis, or another genetic syndrome can influence clinical management for patients with CRC and their family members. Screening for hereditary cancer syndromes in patients with CRC should include review of personal and family histories and testing of tumors for DNA mismatch repair deficiency and/or microsatellite instability. Formal genetic evaluation is recommended for individuals who meet defined criteria. Scientific Rationale Update September 2015 Desmoid tumors, also referred to as aggressive or desmoid fibromatosis, deep musculoaponeurotic fibromatosis, and formerly termed fibrosarcoma grade I of the desmoid type, are locally aggressive tumors with no known potential for metastasis or dedifferentiation. Although they lack the capacity to establish metastases, desmoids are locally aggressive and have a high rate of recurrence even after complete resection. Tumor-related destruction of vital structures and/or organs can be fatal, particularly when these tumors arise in patients with familial adenomatous polyposis (i.e., FAP, Gardner's syndrome). The development of desmoid tumors in patients with FAP was first described by Gardner in 1951 and is now designated Gardner's syndrome (GS). Desmoid tumors are rare in the general population (i.e., 5 to 6 per million per year), but in FAP affect from 5 to 25 percent of patients. The peak incidence of desmoid occurrence in GS is between 28 and 31 years, although they may occur at any age. The risk of developing a desmoid in a patient with FAP is 852 times that of the general population. The desmoids that arise in patients with FAP have a particular preference for surgical sites (eg, the mesentery or abdominal wall following colectomy, the site of an ileal pouch-anal anastomosis), and prior surgery is a risk factor for the development of desmoids in these families. Desmoids in familial adenomatous polyposis (FAP) arise from APC inactivation and subsequent accumulation of beta-catenin in cells. FAP is caused by mutations in the APC (adenomatous polyposis coli) gene, located on chromosome 5q21-q22. Genetic Testing FAP Sep 17 4

5 Independent predictors of their occurrence include APC gene mutations, 3' of codon 1444, a family history of desmoids, female gender, and the presence of osteomas. When extraintestinal lesions are present in any member of an FAP family, the family has traditionally been said to have GS, since all members of the family segregate the same APC mutation. Desmoids may be the first manifestation of GS. Families have also been reported that exhibit desmoids as the only manifestation of an APC mutation. Desmoid tumors can arise in all musculoaponeurotic structures throughout the body but are most common in the abdomen where they begin as mesenteric plaque like lesions that may progress to mesenteric fibromatosis and finally to desmoid tumors. Approximately one-third of abdominal desmoids cause pain. In a series of 38 patients, the most common presenting feature was small bowel obstruction (58%). GS associated desmoids are histologically indistinguishable from sporadic desmoids, although there may be some differences between fibroblastic growths in GS and sporadic desmoids. A distinctive fibroblastic growth, called Gardner associated fibroma, may be seen in young patients and appears to be the precursor lesion of desmoids in GS. Desmoid tumors in GS are monoclonal growths, implying that they are true neoplasms. Desmoids in FAP also arise from APC inactivation and subsequent accumulation of beta-catenin in cells. In contrast, APC mutations are uncommon in sporadic desmoids, which usually arise from beta-catenin mutations. The molecular events that lead to desmoid tumor formation in patients with APC mutations are incompletely understood. However, increasing evidence points to involvement of the APC gene and beta-catenin, both components of the Wnt signaling pathway, in the molecular pathogenesis of desmoids both in Gardner syndrome as well as in sporadic desmoids. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines on Genetic/Familial High-Risk Assessment: Colorectal, (Version ) notes: APC genetic testing is recommended in a proband to confirm a diagnosis of FAP and allow for mutation-specific testing in other family members. Additionally, knowing the location of the mutation in the APC gene can be helpful for predicting the severity of polyposis, rectal involvement and desmoid tumors. The NCCN APC testing criteria was revised: 1. Personal history of >20 adenomas; 2. Known deleterious APC mutation in family; 3. Consider testing if a personal history of a desmoid tumor, hepatoblastoma, cribriform-morular variant of papillary thyroid cancer, or between adenomas (Category 2A Recommendation). The MUTYH-Associated Polyposis (MAP-3) criteria were also revised: An at-risk family member can be defined as a sibling of an affected individual and/or probabnd. Other individuals in a family may also be at risk of having MUTYH-associated polyposis (MAP) or monoallelic MUTYH mutations Vitellaro et al. (2015) Desmoid tumour (DT) is a main cause of death after prophylactic colectomy in patients with familial adenomatous polyposis (FAP). The Genetic Testing FAP Sep 17 5

6 purpose of this study was to evaluate the impact of prophylactic laparoscopic colectomy on the risk of developing DT in patients with FAP. The database of a single institution was reviewed. Patients with classical FAP with defined genotype who underwent either open or laparoscopic colectomy between 1947 and 2011 were included in the study. The impact of various demographic and clinical features on the risk of developing DT was assessed. A total of 672 patients underwent prophylactic colectomy: 602 by an open and 70 by a laparoscopic approach. With a median (range) follow-up of 132 (0-516) months in the open group and 60 (12-108) months in the laparoscopic group, 98 patients (16.3 %) developed DT after an open procedure compared with three (4 per cent) following laparoscopic surgery. The estimated cumulative risk of developing DT at 5 years after surgery was 13.0 per cent in the open group and 4 per cent in the laparoscopic group (P = 0.042). In multivariable analysis, female sex (hazard ratio (HR) 2.18, 95 per cent confidence interval 1.40 to 3.39), adenomatous polyposis coli mutation distal to codon 1400 (HR 3.85, 1.90 to 7.80), proctocolectomy (HR 1.67, 1.06 to 2.61), open colectomy (HR 6.84, 1.96 to 23.98) and year of surgery (HR 1.04, 1.01 to 1.07) were independent risk factors for the diagnosis of DT after prophylactic surgery. Laparoscopic surgery decreased the risk of DT after prophylactic colectomy in patients with FAP. Scientific Rationale Update September 2013 Per the NCCN, A clinical diagnosis of classical familial adenomatous polyps (FAP) is based on the presence of > 100 polyps or fewer polyps at younger ages, especially in a patient with a family history of FAP. When fully developed, patients exhibit hundreds to thousands of colonic adenomatous polyps. The lifetime risk for cancer in individuals with classic FAP approaches 100% by the age of 50. Attenuated FAP (AFAP) is a recognized variant of FAP characterized by a later onset of disease and fewer adenomatous polyps, typically 10 to <100. Genetic testing of APC and/or MUTYH is important to differentiate between FAP/AFAP from MUTYH-associated polyposis (MAP) and colonic polyposis of unknown etiology. Genetic testing confirms the diagnosis and allows mutation-specific testing in other family members to clarify their risks. Additionally, identifying the location of an APC mutation can be useful in predicting the general severity of colonic polyposis and the severity of rectal involvement (for FAP) and of extracolonic cancers in affected patients. If a mutation in APC is not found by sequencing, testing for large rearrangements and deletions of the APC gene may also be performed. When a familial mutation is known (i.e., deleterious APC mutation or biallelic MUTYH mutations) genetic testing can be considered for at-risk family members. An at risk family member can be defined as a first-degree of an affected individual and/or proband. If a first degree relative is unavailable or unwilling to be genetically tested, more distant relatives should be offered testing for the known family mutation. Counseling should be provided for at-risk individuals so that they are able to make informed decisions about the implications involved in the genetic testing, as well as the implications involved in the genetic testing as well as the implications in their own management. Kerr et al (2013) reported inactivating APC mutations cause familial adenomatous polyposis, classically characterized by hundreds to thousands of adenomatous colorectal polyps and cancer. Historically, 98% of pathogenic alterations in APC are nonsense or frameshift mutations; however, few reported series have used techniques that test for large deletions or duplications. Splice site mutations are only rarely documented. Investigators reviewed consecutive cases (n = 1591) submitted Genetic Testing FAP Sep 17 6

7 for complete APC gene analysis during a 4-year period. Testing included mutation screening (Sanger sequencing or conformation sensitive gel electrophoresis and protein truncation testing) with reflex confirmation sequencing. Gene deletion or duplication analysis was performed in 1421 cases by multiplex ligation-dependent probe amplification. Testing yielded 411 pathogenic, 20 likely pathogenic, 15 variant of uncertain significance, 140 likely benign, and 1005 negative reports. Identified were 168 novel variants (103 pathogenic, 5 likely pathogenic, 12 variant of uncertain significance, and 48 likely benign). Of the 431 pathogenic or likely pathogenic mutations, frameshift, nonsense, splice site, and large deletion or duplication mutations represented 43%, 42%, 9%, and 6% of cases, respectively. This is the largest report of clinical APC testing experience with concurrent multiplex ligationdependent probe amplification. In addition to nonsense and frameshift mutations, large deletions or duplications and canonical splice site mutations are a significant cause of familial adenomatous polyposis. Investigators concluded despite technological advances, broad allelic, locus, and phenotypic heterogeneity continue to pose challenges for genetic testing of patients with colorectal adenomatous polyposis. Grover et al (2012) sought to determine the prevalence of pathogenic APC and MUTYH mutations in patients with multiple colorectal adenomas who had undergone genetic testing and to compare the prevalence and clinical characteristics of APC and MUTYH mutation carriers. A cross-sectional study was conducted among 8676 individuals who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the 2 most common MUTYH mutations (Y179C and G396D) between 2004 and Individuals with either mutation underwent full MUTYH gene sequencing. APC and MUTYH mutation prevalence was evaluated by polyp burden; the clinical characteristics associated with a pathogenic mutation were evaluated using logistic regression analyses. The main outcome measure was prevalence of pathogenic mutations in APC and MUTYH genes. Colorectal adenomas were reported in 7225 individuals; 1457 with classic polyposis ( 100 adenomas) and 3253 with attenuated polyposis (20-99 adenomas). The prevalence of pathogenic APC and biallelic MUTYH mutations was 95 of 119 (80% [95% CI, 71%-87%]) and 2 of 119 (2% [95% CI, 0.2%-6%]), respectively, among individuals with 1000 or more adenomas, 756 of 1338 (56% [95% CI, 54%- 59%]) and 94 of 1338 (7% [95% CI, 6%-8%]) among those with 100 to 999 adenomas, 326 of 3253 (10% [95% CI, 9%-11%]) and 233 of 3253 (7% [95% CI, 6%-8%]) among those with 20 to 99 adenomas, and 50 of 970 (5% [95% CI, 4%- 7%]) and 37 of 970 (4% [95% CI, 3%-5%]) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses. Investigators concluded among patients with multiple colorectal adenomas, pathogenic APC and MUTYH mutation prevalence varied considerably by adenoma count, including within those with a classic polyposis phenotype. APC mutations predominated in patients with classic polyposis, whereas prevalence of APC and MUTYH mutations was similar in attenuated polyposis. These findings require external validation. Scientific Rationale Update August 2012 MUTYH (muty Homolog (E. coli) is a human gene encoding a DNA glycosylase, MUTYH glycosylase, involved in oxidative DNA damage repair. Mutations in the MUTYH gene cause an autosomal recessive form of familial adenomatous polyposis (also called MUTYH-associated polyposis). Polyps caused by mutated MYH do not appear until adulthood and are less numerous than those found in patients with APC gene mutations. Genetic Testing FAP Sep 17 7

8 If there is a personal history of multiple adenomatous polyps >10 with negative adenomatous polyposis coli (APC) mutation testing, counseling and testing for MUTYH mutations is recommended by the National Comprehensive Cancer Network (2012) Guidelines for Colorectal Screening. This recommendation is a 2A (i.e., Category 2A: based upon lower level evidence, however there is uniform NCCN consensus that the intervention is appropriate). Lynch syndrome is caused by inherited mutations in DNA mismatch repair genes (primarily MSH2, MLH1, MSH6, and PMS2) and is one of the most prevalent inherited cancer syndromes. Several models have been developed to predict the occurrence of Lynch syndrome in high-risk patients and families, but it is not known how these models compare with one another or how they perform for colorectal cancer patients from the general population. We used data from such patients to test the ability of four models: Leiden, MMRpredict, PREMM(1,2), and MMRpro, to distinguish between those who did and did not carry DNA mismatch repair gene mutations Green et al. (2009) studied a consecutive series of 725 patients who were younger than 75 years at colorectal cancer diagnosis and whose DNA mismatch repair gene mutation status was available; 18 of the 725 patients carried such a mutation. For each model, we calculated the risk score, compared the observed number of mutations with the expected number, and determined the receiver operating characteristics. All statistical tests were two-sided. Although all four models overestimated the probability of a mutation (range = 1.2- to 4.3-fold), especially in low-risk patients, they could discriminate between carriers and noncarriers of a mismatch repair mutation. The areas under the receiver operating characteristics curves from the four models ranged from 0.91 to Carriers of mutations in the MSH6 or PMS2 genes had lower risk scores than carriers of MSH2 or MLH1 mutations. For example, the MMRpredict model gave median risk scores of 24% and 94% (P<.015) for MSH6-PMS2 and MSH2-MLH1 mutation carriers, respectively. For the Leiden, MMRpredict, and PREMM (1,2) models, correcting the risk scores for bias introduced by family size improved their power to discriminate between carriers and noncarriers. After correcting for family size, the best model was MMRpredict, which achieved a sensitivity of 94% (95% confidence interval [CI]= 73% to 99%) and a specificity of 91% (95% CI = 88% to 93%) and identified a smaller proportion of patients than the revised Bethesda criteria as those who should undergo additional molecular or immunohistochemical testing (11% vs 50%). MMRpredict was the bestperforming model for identifying colorectal cancer patients who are at high risk of carrying a DNA mismatch repair gene mutation and thus should be screened for Lynch syndrome. Yurgelun et al. (2012) Colorectal cancers associated with Lynch syndrome are characterized by deficient DNA mismatch repair (MMR) function. Thr author s aim was to evaluate the prevalence of microsatellite instability (MSI) and loss of MMR protein expression in Lynch syndrome-associated polyps. Sixty-two colorectal polyps, 37 adenomatous polyps, 23 hyperplastic polyps, and 2 sessile serrated polyps (SSP), from 34 subjects with germline MMR gene mutations were tested for MSI using a single pentaplex PCR for five mononucleotide repeat microsatellite markers, and also for expression of MLH1, MSH2, MSH6, and PMS2 proteins by immunohistochemistry. High-level MSI (MSI-H) was seen in 15 of 37 (41%) adenomatous polyps, one of 23 (4%) hyperplastic polyps, and one of two (50%) SSPs. Loss of MMR protein expression was seen in 18 of 36 (50%) adenomatous polyps, zero of 21 hyperplastic polyps, and zero of two SSPs. Adenomatous polyps 8 mm or larger in size were Genetic Testing FAP Sep 17 8

9 significantly more likely to show MSI-H [OR, 9.98; 95% confidence interval (CI), ; P = 0.02]and deficient MMR protein expression (OR, 3.17; 95% CI, ; P = 0.02) compared with those less than 8 mm in size. All (six of six) adenomatous polyps 10 mm or larger in size showed both MSI-H and loss of MMR protein expression by immunohistochemistry. Our finding that the prevalence of MMR deficiency increases with the size of adenomatous polyps suggests that loss of MMR function is a late event in Lynch syndrome-associated colorectal neoplasia. Although testing large adenomatous polyps may be of value in the diagnostic evaluation of patients with suspected Lynch syndrome, the absence of an MMR-deficient phenotype in an adenoma cannot be considered as a strong evidence against Lynch syndrome, as it is with colorectal carcinomas. Win et al. (2012) completed a prospective study to determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population. The authors followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country, age, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers. Over a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, to 33.27; P<.001), endometrial cancer (SIR, 30.62; 95% CI, to 66.64; P<.001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P<.001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P<.001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P =.001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P =.009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P =.009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P =.001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P =.97). We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives. Another pathway leading from adenomatous polyps, and probably from serrated adenomas, to invasive cancer has also been described, the mismatch repair pathway. This pathway is involved in colorectal cancers (CRCs) arising in association with the inherited condition HNPCC (Lynch syndrome). The key element of this pathway is dysfunction of DNA mismatch repair (MMR) enzymes, resulting from germline mutations in one of several different DNA mismatch repair genes, most commonly MLH1 or MSH2. Cells with deficient DNA repair capacity due to silencing of MMR genes accumulate DNA errors throughout the genome. The biologic "footprint" is the accumulation of abnormalities in short sequences of nucleotide bases that are repeated dozens to hundreds of times within the genome; these are called microsatellites, and the tumors are described as having the phenotype of microsatellite instability (MSI). Besides being the biologic hallmark of HNPCC, MSI is also found in approximately 15 percent of sporadic CRCs. However, in most of these cases, gene silencing is not due to a specific MMR mutation, but to an epigenetic phenomenon, hypermethylation of Genetic Testing FAP Sep 17 9

10 the gene promoter for the MMR enzyme (usually MLH1), which leads to transcriptional silencing of gene expression. Scientific Rationale Update December 2010 Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by a germ-line mutation of the APC gene. Characteristically, affected patients develop multiple adenomas diffusely throughout the colon beginning in their teens. Colorectal cancer is inevitable in patients with FAP if colectomy is not performed. The average age at symptomatic diagnosis ranges from 34 to 45 years of age. However, the average age of colonic adenoma appearance is 16 years and of cancer diagnosis is 39 years. The FAP gene mutation occurs in approximately 1/10,000-1/30,000 live births in the United States, affects both sexes equally, and accounts for up to 1% of colorectal cancers. Syndromes once thought to be distinct from FAP are now recognized to be, in reality, part of the phenotypic spectrum of FAP. Syndromes with a germline mutation in the APC gene include FAP, Gardner syndrome, some families with Turcot syndrome, and attenuated adenomatous polyposis coli (AAPC). Gardner syndrome is characterized by colonic polyposis typical of FAP, along with osteomas (bony growth most commonly on the skull and the mandible), dental abnormalities, and soft tissue tumors. Turcot syndrome is characterized by colonic polyposis typical of FAP, along with central nervous system tumors (medulloblastoma). AAPC is characterized by fewer colonic polyps (average number of polyps, 30-35) as compared to classic FAP. The polyps also tend to develop at a later age (average age, 36 y), and they tend to involve the proximal colonic area. In considering the spectrum of polyposis syndromes, patients with multiple adenomatous polyps most likely have FAP (or one of its variants), AAPC, or MYHassociated polyposis (MAP). If a patient with a suspected polyposis syndrome undergoes genetic testing and does not have an APC gene mutation, MYH gene testing should be performed to assess for MAP, as 10-20% of patients who do not have an APC gene mutation have biallelic MYH gene mutations. The phenotype of MAP is often indistinguishable from FAP or AAPC, with patients having usually polyps but sometimes more than 100. The age of onset of MAP is usually in patients older than 45 years, and patients often present symptomatically, with colorectal carcinoma commonly found at the time of diagnosis. This is in part because there is usually no family history given the autosomal recessive inheritance pattern of MAP. Duodenal polyps can be found in up to one fifth of patients. There is no increased risk of other types of cancers associated with this syndrome. The APC gene is a tumor suppressor gene that is located on band 5q21. Its function is not completely understood but has been shown to play a part in metaphase chromosome alignment. Normal APC protein promotes apoptosis in colonic cells. Its most important function may be to sequester the growth stimulatory effects of b- catenin, a protein that transcriptionally activates growth-associated genes in conjunction with tissue-coding factors. Mutations of the APC gene result in a truncated/nonfunctional protein. The resultant loss of APC function prevents apoptosis and allows b-catenin to accumulate intracellularly and to stimulate cell growth with the consequent development of adenomas. As the clonal expansion of cells that lack APC function Genetic Testing FAP Sep 17 10

11 occurs, their rapid growth increases the possibility for other growth-advantageous genetic events to occur. This causes alterations in the expression of a variety of genes, thereby affecting the proliferation, differentiation, migration, and apoptosis of cells. Ultimately, enough genetic events happen that allow the adenomatous polyps to become malignant in patients with FAP. This process is similar to that which occurs in sporadic adenomas. As a result, APC is considered the gatekeeper of colonic neoplasia. Its mutation/inactivation is the initial step in the development of colorectal cancer in patients with FAP. Germline (ie, inherited) mutations of the APC gene, as is the case with FAP, result in cells containing 1 mutated copy and 1 normal copy of the gene. Patients inherit one mutated APC allele from an affected parent, and adenomas develop as the second allele from the unaffected parent becomes mutated or lost. Consequently, every colonic epithelial cell in patients with FAP has 1 mutated APC allele. Inactivation of the remaining normal copy of the APC gene, by deletion or mutation, completely removes the tumor suppressive function of APC, thus initiating the growth of adenomatous polyps. Inactivation of the second APC allele occurs frequently in the colon, resulting in the development of numerous adenomas. Scientific Rationale Initial Familial adenomatous polyposis (FAP) also referred to as familial juvenile polyposes, and attenuated familial adenomatous polyposis, are cancer predisposition syndromes transmitted in an autosomal dominant fashion. FAP occurs much less frequently than hereditary nonpolyposis colorectal cancer (HNPCC), accounting for less than 1 percent of the total colon cancer risk in the United States. FAP is caused by germline mutations in the adenomatosis polyposis coli (APC) gene, which is located on chromosome 5q21-q22. More than 300 mutations of the APC gene associated with FAP have been described, most of which lead to frame shifts or premature stop codons, resulting in a truncated APC gene product. In patients with FAP, hundreds to thousands of precancerous colonic polyps typically develop in the second or third decade of life. Its attenuated form carries a similarly high risk, but with an older average age of cancer diagnosis of 54 years. Extracolonic manifestations are variably present and include polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retina pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, and associated cancers. In addition to colorectal adenocarcinoma, patients with FAP are at risk for several extracolonic malignancies including: (1) duodenal ampullary carcinoma; (2) follicular or papillary thyroid cancer; (3) childhood hepatoblastoma; (4) gastric carcinoma; and (5) CNS tumors (mostly medulloblastomas). The diagnosis of FAP can be based upon clinical findings. Greater than 100, if not thousands of colorectal adenomatous polyps or fewer than 100 adenomatous polyps and a relative with FAP supports the clinical diagnosis of FAP. Attenuated FAP is considered in an individual with many (< 100) colonic adenomatous polyps or a family history of colon cancer in persons less than age 60 years with multiple adenomatous polyps. These patients have a delayed onset of colorectal cancer (on average delayed by 12 years) compared to those with classic FAP. Molecular genetic testing is most often used in the early diagnosis of at-risk family members and in the confirmation of the diagnosis of FAP in patients with equivocal findings, e.g., with Genetic Testing FAP Sep 17 11

12 fewer than 100 adenomatous polyps. Molecular genetic testing of APC detects up to 95% of disease-causing mutations. A role for genetic testing in FAP is supported by consensus statements from a number of organizations and by expert opinion. A strategy for testing individuals affected with FAP and those at risk for FAP has been proposed in an official guideline issued by the American Gastroenterological Association. Evaluation of individuals at risk for FAP should begin by first testing a known affected family member to determine if there is a detectable mutation. The preferred method is protein truncation testing, which can detect more than 80 percent of the APC mutations. If a mutation is found in an affected family member, then genetic testing of all relatives at risk can provide a true positive or negative result. When an affected family member is not available for evaluation, genetic testing on at-risk family members can provide only positive or inconclusive results. A true negative test resulting in this setting can only be inferred if a mutation is found in another at-risk family member. Other genetic mutations causing such cases are continuing to be uncovered. One of these (a germ-line mutation in a base excision repair gene called MYH) produces a clinical phenotype similar to attenuated or classic FAP. Testing for MYH mutations should be offered to patients with a family history compatible with recessive inheritance who have a phenotype similar to those with classic or attenuated FAP, particularly those who have 15 or more adenomas. For individuals with classic FAP, colectomy is recommended after adenomas emerge; colectomy may be delayed depending on the size and number of adenomatous polyps. For individuals with attenuated FAP, colectomy may be necessary, but it may be deferred until polyps become difficult to control. The types of colectomy are: total colectomy with mucosal proctectomy with ileo-anal pull through and subtotal colectomy with ileorectal anastomosis. Colectomy with permanent ileostomy is rarely needed. Colectomy with ileorectal anastosmosis is often used for individuals with attenuated FAP or in instances in which the rectum is spared of polyps. If total colectomy with ileo-anal pull-through is performed, routine endoscopic surveillance of the ileal pouch every two years is recommended. If subtotal colectomy is performed, surveillance of the remaining rectum is recommended every six to twelve months, depending on the number of polyps that develop. Review History Medical Advisory Council May 11, 2004 April 2006 Update - no changes March 2007 Code Updates April 2007 Update no changes December 2010 Update. Added Medicare Table with link to LCDs. No Revisions. September 2011 Update. Added Revised Medicare Table. No Revisions. August 2012 Update no changes. Added 2012 CPT Codes. September 2013 Update revised criteria regarding confirmation of the diagnosis of AFAP from >20 to >10 cumulative colorectal adenomas. Added NCCN recommendation for testing of APC and/or MUTYH to differentiate between FAP/AFAP from MUTYH-associated polyposis (MAP) and colonic polyposis of unknown etiology. Code updates. September 2014 Update no revisions Genetic Testing FAP Sep 17 12

13 September 2015 September 2016 September 2017 Update Added APC genetic testing as medically necessary for personal history of desmoid tumor. (NCCN, 2015). Codes updated. Update - no revisions. Codes updated. Update no revisions This policy is based on the following evidence-based guidelines: 1. Terdiman JP, Conrad PG, Sleisenger MH. Genetic testing in hereditary colorectal cancer: Indications and procedures. Am J Gastroenterol 1999;94: American Society of Clinical Oncology (2003) Statement on genetic testing for cancer susceptibility. 3. American College of Medical Genetics/American Society of Human Genetics (2000) Joint statement on genetic testing for colon cancer. 4. Ko C, Hyman NH, Standards Committee of The American Society of Colon and Rectal Surgeons. Practice parameter for the detection of colorectal neoplasms: an interim report (revised). Dis Colon Rectum 2006 Mar;49(3): Davila RE, Rajan E, Baron TH, et al. Standards of Practice Committee, American Society for Gastrointestinal. ASGE guideline: colorectal cancer screening and surveillance. Gastrointest Endosc 2006 Apr;63(4): World Gastroenterology Organisation (WGO). Practice guidelines: colorectal cancer screening. Paris (France): World Gastroenterology Organisation (WGO); p. Colorectal Cancer Screening. 7. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Colon Cancer. Version Update Version Update Version Update Version Update Version Hayes. Medical Technology Directory. Genetic Testing for Susceptibility to Familial Adenomatous Polyposis. January 21, Updated February 11, Archived November 12, Hayes. Genetic Test Evaluation Overview. APC-Associated Polyposis Conditions for Familial Adenomatous Polyposis (Familial Polyposis Coli), Gardner Syndrome, Turcot Syndrome, and Attenuated FAP. Updated July 20, Updated August 20, Archived January 8, National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Colorectal Cancer Screening. Version Update Version Update Version. Update Version Update Version Updated V National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Colorectal. Version Update Version Updated V References Update September Stoffel EM, Mangu PB, Gruber SB, et al. 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 Oncol. 2015; 33(2): References Update September Ahnen DJ, Axell L. Clinical manifestations and diagnosis of familial adenomatous polyposis. UpToDate. July 9, Burt Randall W. Gardner syndrome. UpToDate. January 6, Genetic Testing FAP Sep 17 13

14 3. Grandval P, Blayau M, Buisine MP, et al. The UMD-APC database, a model of nation-wide knowledge base: update with data from 3,581 variations. Hum Mutat May;35(5): doi: /humu Epub 2014 Apr Hegde M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014; 16(1): Ravi V, Patel SR, Raut C, et al. Desmoid tumors: Epidemiology, risk factors, molecular pathogenesis, clinical presentation, diagnosis, and local therapy. UpToDate. April 14, Vitellaro M, Sala P, Signoroni S, et al. Risk of desmoid tumours after open and laparoscopic colectomy in patients with familial adenomatous polyposis.. Br J Surg Apr;101(5): doi: /bjs Epub 2014 Feb 3. References Update September Ibrahim A, Barnes DR, Dunlop J, et al. Attenuated familial adenomatous polyposis manifests as autosomal dominant late-onset colorectal cancer. Eur J Hum Genet Feb Kattentidt-Mouravieva AA, den Heijer M, van Kessel I, Wagner A. How harmful is genetic testing for familial adenomatous polyposis (FAP) in young children; the parents' experience. Fam Cancer May Kennedy RD, Potter DD, Moir CR, El-Youssef M. The natural history of familial adenomatous polyposis syndrome: a 24 year review of a single center experience in screening, diagnosis, and outcomes. J Pediatr Surg Jan;49(1):82-6. References Update September Brand R, Nielsen M, Lynch H, Infante E. MUTYH-Associated Polyposis. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; Grover S, Kastrinos F, Steyerberg EW, et al. Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. JAMA Aug 1;308(5): Kerr SE, Thomas CB, Thibodeau SN, et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn Jan;15(1): Poovorawan K, Suksawatamnuay S, Sahakitrungruang C, et al. Colon cancer prevention by detection of APC gene mutation in a family with attenuated familial adenomatous polyposis. Asian Pac J Cancer Prev. 2012;13(10): References Update August American Cancer Society. Colorectal Cancer. Last Medical Review: 3/2/2011. Available at: -cancer-prevention#top 2. Bonis PA, Ahnen DJ, Axell L, et al. Familial adenomatous polyposis and MUTYH associated polyposis: Screening and management of patients and families. UpToDate. June 27, Calver PM, Frucht H. Molecular genetics of colorectal cancer. UpToDate. March 15, Genetic Testing FAP Sep 17 14

15 4. Gjone H, Diseth TH, Fausa O, et al. Familial adenomatous polyposis: mental health, psychosocial functioning and reactions to genetic risk in adolescents. Clin Genet Jan;79(1): Goodenberger M, Lindor NM. Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol Jul;45(6): Green RC, Parfrey PS, Woods MO, et al. Prediction of Lynch syndrome in consecutive patients with colorectal cancer. SOJ Natl Cancer Inst. 2009;101(5): Han SH, Ryu JS, Kim YJ, et al. Mutation analysis of the APC gene in unrelated Korean patients with FAP: four novel mutations with unusual phenotype. Fam Cancer Mar;10(1): Jasperson KW, Burt RW. APC-associated polyposis conditions. Gene Reviews. Funded by NIH. Developed by the University of Washington, Seattle. Initial Posting: December 18, 1998; Last Update: October 27, Updated 3/27/2014. Available at: 9. Kempers MJ, Kuiper RP, Ockeloen CW, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol Jan;12(1): Munos J. Hereditary Colorectal Cancer Workup. October 31, National Cancer Institute (NCI) a. Genetics of colorectal cancer (PDQ). Last Modified: 10/06/ National Cancer Institute (NCI) b. Cancer Genetics Risk Assessment and Counseling (PDQ). Last Modified: 9/27/2011. Available at: Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30(9): Yurgelun MB, Goel A, Hornick JL, et al. Microsatellite instability and DNA mismatch repair protein deficiency in lynch syndrome colorectal polyps. Cancer Prev Res (Phila) 2012; 5:574. References Update September Bonis PA, Ahnen DJ, Axell L. Familial adenomatous polyposis and MYH associated polyposis: Screening and management of patients and families. UpToDate. February 4, Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 2010; 28:893. References Update December Bonis PAL, Ahnen DJ, Axell L. Screening and management strategies for patients and families with familial colon cancer syndromes. April 2, UpToDate. 2. Wehbi M, Griglione NM. Familial Adenomatous Polyposis. December 7, Available at: 3. Dekker E, Boparai KS, Poley JW, et al. High resolution endoscopy and the additional value of chromoendoscopy in the evaluation of duodenal adenomatosis in patients with familial adenomatous polyposis. Endoscopy. Aug 2009;41(8): Wachsmannova-Matelova L, Stevurkova V, Adamcikova Z, et al. Different phenotype manifestation of familial adenomatous polyposis in families with APC mutation at codon Neoplasma. 2009;56(6): Genetic Testing FAP Sep 17 15

16 5. Doxey BW, Kuwada SK, Burt RW. Inherited polyposis syndromes: molecular mechanisms, clinicopathology, and genetic testing. Clin Gastroenterol Hepatol. Jul 2005;3(7): Duncan RE, Gillam L, Savulescu J, et al. The challenge of developmentally appropriate care: predictive genetic testing in young people for familial adenomatous polyposis. Fam Cancer. Sep Nieuwenhuis MH, De Vos Tot Nederveen Cappel W, Botma A, et al. Desmoid tumors in a dutch cohort of patients with familial adenomatous polyposis. Clin Gastroenterol Hepatol. Feb 2008;6(2): Will OC, Hansmann A, Phillips RK, et al. Adrenal incidentaloma in familial adenomatous polyposis: a long-term follow-up study and schema for management. Dis Colon Rectum. Sep 2009;52(9): Ponti G, Losi L, Pellacani G, et al. Wnt pathway, angiogenetic and hormonal markers in sporadic and familial adenomatous polyposis-associated juvenile nasopharyngeal angiofibromas (JNA). Applied Immunohistochemistry & Molecular Morphology. January 25, Available at References Initial 1. Francis M. Giardiello; Jill D. Brensinger; and Gloria M Petersen. AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology Jul;121(1): Young RC: Cancer statistics, 2002: progress or cause for concern? CA Cancer J Clin 2002, 52: Boardman LA: Heritable colorectal cancer syndromes: recognition and preventive management. Gastroenterol Clin North Am 2002, 31: Petersen GM, Slack J, Nakamura Y: Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology 1991, 100: Offerhaus GJ, Giardiello FM, Krush AJ, et al.: The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology 1992, 102: Abraham SC, Nobukawa B, Giardiello FM, et al.: Fundic gland polyps in familial adenomatous polyposis: neoplasms with frequent somatic adenomatous polyposis coli gene alterations. Am J Pathol 2000, 157: Lyons LA, Lewis RA, Strong LC, et al.: A genetic study of Gardner syndrome and congenital hypertrophy of the retinal pigment epithelium. Am J Hum Genet 1988, 42: Shields JA, Shields CL, Eagle RC Jr, et al.: Adenocarcinoma arising from congenital hypertrophy of retinal pigment epithelium. Arch Ophthalmol 2001, 119: Young J, Barker M, Robertson T, et al.: A case of myoepithelial carcinoma displaying biallelic inactivation of the tumour suppressor gene APC in a patient with familial adenomatous polyposis. J Clin Pathol 2002, 55: Grady WM: Genetic testing for high-risk colon cancer patients. Gastroenterology 2003, 124: Sieber OM, Lipton L, Crabtree M, et al.: Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 2003, 348: Maire F, Hammel P, Terris B, et al.: Intraductal papillary and mucinous pancreatic tumour: a new extracolonic tumour in familial adenomatous polyposis. Gut 2002, 51: Genetic Testing FAP Sep 17 16