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There are currently 2 well-defined types of hereditary colorectal cancer, familial adenomatous polyposis (FAP) and Lynch syndrome (formerly, hereditary nonpolyposis colorectal cancer or HNPCC). Lynch syndrome has been implicated in some endometrial cancers as well.

Familial adenomatous polyposis and associated variants
FAP typically develops by age 16 years and can be identified by the appearance of hundreds to thousands of characteristic, precancerous colon polyps. If left untreated, all affected individuals will go on to develop colorectal cancer. The mean age of colon cancer diagnosis in untreated individuals is 39 years. FAP accounts for about 1% of colorectal cancer and may also be associated with osteomas of the jaw, skull, and limbs; sebaceous cysts; and pigmented spots on the retina referred to as congenital hypertrophy of the retinal pigment epithelium (CHRPE). These collective extraintestinal manifestations of FAP are sometimes referred to as Gardner Syndrome. FAP may also be associated with CNS tumors, referred to as Turcot syndrome.

Germline mutations in the adenomatous polyposis coli (APC) gene, located on chromosome 5, are responsible for FAP and are inherited in an autosomal dominant manner. Mutations in the APC gene result in altered protein length in about 80% to 85% of cases of FAP. A specific APC gene mutation (I1307K) has been found in subjects of Ashkenazi Jewish descent that may explain a portion of the familial colorectal cancer occurring in this population.

A subset of FAP patients may have attenuated FAP (AFAP), characterized by 10-99 cumulative colorectal adenomas occurring later in life than in classical FAP, colorectal cancer occurring at an average age of 50-55 years, fewer extraintestinal cancers, but a high lifetime risk of colorectal cancer of about 70% by age 80. Only 30% or fewer of AFAP patients have APC mutations; some of these patients instead have mutations in the MYH gene and are then diagnosed with MYH-associated polyposis (MAP). MAP occurs with a frequency approximately equal to FAP, with some variability among prevalence estimates for both. While clinical features of MAP are similar to FAP or AFAP, a strong multigenerational family history of polyposis is absent. Biallelic MYH mutations are associated with a cumulative colorectal cancer risk of about 80% by age 70, whereas monoallelic MYH mutation-associated risk of colorectal cancer appears to be relatively minimal. Thus, inheritance for high-risk colorectal cancer predisposition is autosomal recessive in contrast to FAP. When relatively few (i.e., between 10 and 99) adenomas are present and family history is unavailable, the differential diagnosis may include both MAP and Lynch syndrome; genetic testing in this situation could include APC, MYH if APC is negative for mutations, and screening for mutations associated with Lynch syndrome.
Genetic testing for APC mutations may be considered for the following types of patients:

• Family members of patients with FAP and a known APC mutation. Those without the specific mutation have not inherited the susceptibility gene and can forego intense surveillance (although they retain the same risk as the general population and should continue an appropriate level of surveillance).
• Patients with a differential diagnosis of attenuated FAP vs. MYH-associated polyposis vs. Lynch syndrome. These patients do not meet the clinical diagnostic criteria for classical FAP, and have few adenomatous colonic polyps.
• Patients with colon cancer with a clinical picture or family history consistent with classical FAP.

Lynch syndrome
Patients with Lynch syndrome have a predisposition to colorectal cancer and other malignancies as a result of an inherited mutation in a DNA mismatch repair (MMR) gene. Lynch syndrome includes those with an existing cancer and those who have not yet developed cancer. The term “HNPCC” originated prior to the discovery of explanatory MMR mutations for many of these patients, and now includes some who are negative for MMR mutations and likely have mutations in as-yet unidentified genes. For purposes of clarity and analysis, the use of Lynch syndrome in place of HNPCC has been recommended in several recent editorials and publications.

Lynch syndrome is estimated to account for 2% to 4% of colorectal cancer and is also associated with an increased risk of other cancers such as endometrial, ovarian, urinary tract, and biliary tract cancer. Lynch syndrome is associated with a risk of developing colorectal cancer of approximately 15% by age 40, and 40% by age 70, although these estimates vary considerably among studies, are likely influenced by selection bias, and are lower for women than for men. Lynch syndrome patients who have colorectal cancer also have an estimated 16% risk of a second primary within 10 years. The risk for other Lynch syndrome-related cancers is about 22% for men and 34% for women by age 70.

Lynch syndrome is associated with any of a large number of possible mutations in 1 of 4 MMR genes, known as MLH1, MSH2, MSH6, and PMS2. About 70% of Lynch syndrome patients have mutations in either MLH1 or MSH2. Testing for MMR gene mutations is often limited to MLH1 and MSH2 and, sometimes, MSH6; clinical testing for PMS2 mutations has only more recently become available. Gene sizes and the difficulty of detecting mutations in these genes make direct sequencing a time- and cost-consuming process. Thus, additional indirect screening methods are needed to determine which patients should precede to direct sequencing for MMR gene mutations. Available screening methods are microsatellite instability (MSI) testing or immunohistochemical (IHC) testing. BRAF testing is an optional screening method that may be used in conjunction with IHC testing for MLH1 to improve efficiency. A methylation analysis of the MLH1 gene can substitute for BRAF testing, but this assay is much more difficult.

Mutations in MMR genes result in a failure of the mismatch repair system to repair errors that occur during the replication of DNA in tumor tissue. Such errors are characterized by the accumulation of alterations in the length of simple, repetitive microsatellite (2 to 5 base repeats) sequences that are distributed throughout the genome (MSI). MSI testing has been standardized in a 2004 publication subsequent to a National Cancer Institute (NCI) workshop and requires the use of 3 or more mononucleotide markers. Methodologic studies have also shown the importance of laser microdissection of the tumor tissue, comparison of tumor and normal cells, and a minimum proportion of tumor in relation to the quality of the test results. While the sensitivity of MSI testing is high, the specificity is low because approximately 10% of sporadic CRC are MSI-positive due to somatic hypermethylation of the MLH1 promoter.

Absent or reduced protein expression may be a consequence of an MMR gene mutation. IHC assays for the expression of MLH1, MSH2, MSH6, and PMS2 can be used to detect loss of expression of these genes and to focus sequencing efforts on a single gene. It is also possible for IHC assays to show loss of expression, and thus indicate the presence of a mutation, when sequencing is negative for a mutation. In such cases, mutations may be in unknown regulatory elements and cannot be detected by sequencing of the protein coding regions. Thus IHC may add additional information.

The BRAF gene is often mutated in colorectal cancer; when a particular BRAF mutation (1799 T>A transversion, also identified as V600E) is present, to date no MLH1 gene mutations have been reported. Therefore, patients negative for MLH1 protein expression by IHC, and therefore potentially positive for an MLH1 mutation, could first be screened for a BRAF mutation. BRAF-positive samples need not be further tested by MLH1 sequencing. MLH1 gene methylation correlates with the presence of BRAF-V600E; as already noted, a methylation analysis of the MLH1 gene can substitute for BRAF testing, but this assay is much more difficult.

Various attempts have been made to identify which patients with colon cancer should undergo testing for MMR mutations, based primarily on family history and related characteristics using criteria such as the Amsterdam II criteria (low sensitivity but high specificity) and the Bethesda guidelines (better sensitivity but poorer specificity). While family history is an important risk factor and should not be discounted in counseling families, it has poor sensitivity and specificity for identifying Lynch syndrome. Based on this and other evidence, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommended testing all patients with colorectal cancer for Lynch syndrome, using a screening strategy based on MSI or IHC (+BRAF) followed by sequencing in screen-positive patients. This recommendation includes genetic testing for the following types of patients:

• Family members of Lynch syndrome patients with a known MMR mutation; family members would be tested only for the family mutation; those testing positive would benefit from early and increased surveillance to prevent future colorectal cancer.
• Patients with a differential diagnosis of Lynch syndrome vs. attenuated FAP vs. MYH-associated polyposis. 
• Lynch syndrome patients. Genetic testing of the proband with colorectal cancer likely benefits the proband where Lynch syndrome is identified and appropriate surveillance for associated malignancies can be initiated and maintained and benefits family members by identifying the family mutation.

Recently, novel deletions have been reported to affect the expression of the MSH2 MMR gene in the absence of a MSH2 gene mutation, and thereby cause Lynch syndrome. In these cases, deletions in EPCAM, the gene for the epithelial cell adhesion molecule are responsible. EPCAM testing has been added to many Lynch syndrome profiles and is conducted only when tumor tissue screening results are MSI-high, and IHC shows a lack of MSH2 expression, but no MSH2 mutation is found by sequencing.

Rare Lynch syndrome patients have been reported without detectable germline MMR mutations although IHC testing demonstrates a loss of expression of one of the MMR proteins. In at least some of these cases, research has identified germline ‘epimutations,’ i.e., methylation of promoter regions that control the expression of the MMR genes. Such methylation may be isolated, or in conjunction with a linked genetic alteration near the affected MMR gene. The germline epimutations may arise de novo, or may be heritable in either Mendelian or non-Mendelian fashion. This is distinct from some cases of MSI-high sporadic colorectal cancer wherein the tumor tissue may show MLH1 promotor methylation and IHC non-expression, but the same is not true of germline cells. Clinical testing for Lynch syndrome-related germline epimutations is not routine but may be helpful in exceptional cases. Epimutations as a cause of Lynch syndrome are described only for informational purposes; no policy statement is made regarding this testing.

Female patients with Lynch syndrome have a predisposition to endometrial cancer. Lynch syndrome is estimated to account for 2% of all endometrial cancers in women and 10% of endometrial cancers in women younger than 50 years of age. Female carriers of the germline mutations MLH1, MSH2, MSH6, and PMS2 have an estimated 40-62% lifetime risk of developing endometrial cancer, as well as a 4-12% lifetime risk of ovarian cancer.

• At-risk relatives (see Policy Guidelines) of patients with FAP and/or a known APC mutation.
• Patients with a differential diagnosis of attenuated FAP vs. MYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.

Genetic testing for APC gene mutations is not medically necessary for colorectal cancer patients with classical FAP.

Genetic testing for MYH gene mutations may be considered medically necessary in the following patients:

• Patients with a differential diagnosis of attenuated FAP vs. MYH-associated polyposis vs. Lynch syndrome and a negative result for APC gene mutations. Family history of no parents or children with FAP is consistent with MYH-associated polyposis (autosomal recessive).

Genetic testing for MMR gene mutations is considered medically necessary in the following patients:

• Patients with colorectal cancer, for the diagnosis of Lynch syndrome (See Policy Guidelines Section).
• Patients with endometrial cancer and one first-degree relative diagnosed with a Lynch-associated cancer (see Policy Guidelines), for the diagnosis of Lynch syndrome.
• At-risk relatives (see Policy Guidelines) of patients with Lynch syndrome with a known MMR mutation.
• Patients with a differential diagnosis of attenuated FAP vs. MYH-associated polyposis vs. Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation.
• Patients without colorectal cancer but with a family history meeting the Amsterdam or Revised Bethesda criteria, when no affected family members have been tested for MMR mutations.

Genetic testing for EPCAM mutations is considered medically necessary in the following patients:

• Patients with colorectal cancer, for the diagnosis of Lynch syndrome (see Policy Guidelines when:
  • Tumor tissue shows a high level of microsatellite instability
  • Tumor tissue shows lack of MSH2 expression by immunohistochemistry
  • Patient is negative for a germline mutation in MSH2
• At-risk relatives (see Policy Guidelines) of patients with Lynch syndrome with a known EPCAM mutation.
• Patients without colorectal cancer but with a family history meeting the Amsterdam or Revised Bethesda criteria, when no affected family members have been tested for MMR mutations, and when sequencing for MMR mutations is negative.

Pre- and post-genetic counseling may be considered medically necessary as an adjunct to the genetic testing itself.

It is recommended that, when possible, initial genetic testing for FAP or Lynch syndrome be performed in an affected family member so that testing in unaffected family members can focus on the mutation found in the affected family member.

In many cases, genetic testing for MYH gene mutations should first target the specific mutations Y165C and G382D, which account for the majority of mutations in Caucasian populations, and subsequently proceed to sequencing only as necessary. In other ethnic populations, however, proceeding directly to sequencing is appropriate.

For patients with colorectal cancer being evaluated for Lynch syndrome, either the microsatellite instability (MSI) test, or the immunohistochemistry (IHC) test with or without BRAF gene mutation testing, should be used as an initial evaluation of tumor tissue prior to MMR gene analysis. Both tests are not necessary. Consideration of proceeding to MMR gene sequencing would depend on results of MSI or IHC testing. IHC testing in particular may help direct which MMR gene likely contains a mutation, if any, and may also provide some additional information if MMR genetic testing is inconclusive.

When indicated, genetic sequencing for MMR gene mutations should begin with MLH1 and MSH2 genes unless otherwise directed by the results of IHC testing. Standard sequencing methods will not detect large deletions or duplications; when MMR gene mutations are expected based on IHC or MSI studies but none are found by standard sequencing, additional testing for large deletions or duplications is appropriate.

The COLARIS® test from Myriad Genetic Laboratories includes sequence analysis of MLH1, MSH2, MSH6 and PMS2; large rearrangement analysis for MLH1 MSH2, PMS2, and MSH6 large deletions/duplications; and analysis for large deletions in the EPCAM gene near MSH2. Note that there may be 2 versions of this test, the COLARIS (excludes PMS2 testing) and COLARIS Update (includes PMS2 testing). Testing is likely done is stages beginning with the most common types of mutations. Individualized tested (e.g., targeted testing for a family mutation) can also be requested.

The COLARIS® AP test from Myriad Genetic Laboratories includes DNA sequencing analysis of the APC and MUTYH genes as well as analysis of large rearrangements in the APC gene that are not detected by DNA sequencing.

Amsterdam II Clinical Criteria (all criteria must be fulfilled):

• 3 or more relatives with an associated cancer (colorectal cancer, or cancer of the endometrium, small intestine, ureter or renal pelvis);
• 1 should be a first-degree relative of the other two;
• 2 or more successive generations affected;
• 1 or more relatives diagnosed before the age of 50 years;
• Familial adenomatous polyposis (FAP) should be excluded in cases of colorectal carcinoma;
• Tumors should be verified by pathologic examination.
• Modifications:
  • EITHER: very small families, which cannot be further expanded, can be considered to have HNPCC with only two colorectal cancers in first-degree relatives if at least two generations have the cancer and at least one case of colorectal cancer was diagnosed by the age of 55 years;
  • OR: in families with two first-degree relatives affected by colorectal cancer, the presence of a third relative with an unusual early-onset neoplasm or endometrial cancer is sufficient.

Revised Bethesda Guidelines (fulfillment of any criterion meets guidelines):

• Colorectal carcinoma (CRC) diagnosed in a patient who is less than 50 years old;
• Presence of synchronous (at the same time) or metachronous (at another time i.e.- a re-occurrence of) CRC or other Lynch syndrome-associated tumors, regardless of age;
• CRC with high microsatellite instability histology diagnosed in a patient less than 60 years old;
• CRC diagnosed in one or more first-degree relatives with a Lynch syndrome-associated tumor, with one of the cancers being diagnosed at less than 50 years of age;
• CRC diagnosed with one or more first-degree relatives with an HNPCC-related tumor (colorectal, endometrial, stomach, ovarian, pancreas, bladder, ureter and renal pelvis, biliary tract, brain [usually glioblastoma as seen in Turcot syndrome], sebaceous bland adenomas and keratoacanthomas in Muir-Torre syndrome, and carcinoma of the small bowel), with one of the cancers being diagnosed at younger than age 50 years, OR CRC diagnosed in 2 or more first- or second-degree relatives with HNPCC-related tumor, regardless of age.

Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

3/22/2007: Reviewed and approved by the Medical Policy Advisory Committee (MPAC)

12/19/2007: Coding updated per the 2008 CPT/HCPCS revisions

9/15/2008: Code reference section updated per the annual ICD-9 updates effective 10-1-2008

12/24/2008: Code reference section updated per the 2009 CPT/HCPCS revisions

04/16/2010:  Policy description, guidelines, and statements rewritten extensively due to new research findings and approaches to this genetic testing. Policy statements changed to indicate that testing the index patient with APC is considered not medically necessary. Intent of other policy statements generally unchanged, although requirement for positive family history no longer required for testing. Added ICD-9 code 154.0.

02/24/2012: Add policy statement regarding medically necessary indication  for testing for EPCAM mutations in patients with colorectal cancer and negative MMR mutations. Policy description and guidelines updated regarding recent research findings and available testing. Added new CPT codes 81292-81294, 81295-81297, 81298-81300, 81301, and 81317-81319 to the Covered Codes table.

01/10/2013:  Updated the policy description and policy guidelines to include criteria regarding Lynch syndrome-related endometrial cancer.  Policy title changed from "Genetic Testing for Inherited Susceptibility to Colon Cancer Including Microsatellite Instability" to "Genetic Testing for Lynch Syndrome and Other Inherited Intestinal Polyposis Syndromes."  Added the following policy statement: Patients with endometrial cancer and one first-degree relative diagnosed with a Lynch-associated cancer for the diagnosis of Lynch syndrome.  Added ICD-9 code 182.0 to the Code Reference section. Added the following new 2013 CPT codes to the Code Reference section: 81201, 81202, and 81203.

The code(s) listed below are ONLY covered if the procedure is performed according to the "Policy" section of this document. 

Covered Codes