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A genetic predisposition to cutaneous malignant melanoma (CMM) is suspected in specific clinical situations: 1) melanoma has been diagnosed in multiple family members; 2) multiple primary melanomas are identified in a single patient; and 3) when there is an early age of onset. A positive family history of melanoma is the most significant risk factor; it is estimated that approximately 10% of melanoma cases report a first-or-second-degree relative with melanoma. While some of the familial risk may be related to shared environmental factors, three (3) main genes involved in CMM susceptibility have been identified. Cyclin-dependent kinase inhibitor 2A (CDKN2A), located on chromosome 9p21 encodes proteins that act as tumor suppressors. Mutations at this site can alter the tumor suppressor function. The second gene, CDK4, is an oncogene located on chromosome 12q13, and has been identified in about six (6) families worldwide. A third gene, not fully characterized, maps to chromosome 1p22.
The incidence of CDKN2A mutations in the general population is very low. For example, it is estimated that in Queensland, Australia, an area with a high incidence of melanoma, only 0.2% of all patients with melanoma will harbor a CDKN2A mutation. Mutations are also infrequent in those with an early age onset or those with multiple primary melanomas. However, the incidence of CDKN2A mutations increases with a positive family history; CDKN2A mutations will be found in 5% of families with first degree relatives, rising 20-40% in kindreds with 3 or more affected first degree relatives. Mutation detection rates in the CDK2NA gene are generally estimated as 20-25% in hereditary CMM, but can vary between 2% and 50% depending on the family history and population studied. Validated clinical risk prediction tools to assess the probability that an affected individual carries a germline CDKN2A mutation are available.
Familial CMM has been described as a family in which either two first-degree relatives are diagnosed with melanoma, or families with three (3) melanoma patients irrespective of the degree of relationship. Others have defined familial CMM as having at least three (3) (first-, second-, or third-degree) affected members or two (2) affected family members in which at least one was diagnosed before age 50, or pancreatic cancer in a first- or second-degree relative, or one member with multiple primary melanomas. No widely accepted guidelines for the management of families with hereditary risk of melanoma exist.
Other malignancies associated with familial CMM, specifically those associated with CDKN2A mutations, have been described. The most pronounced associated malignancy is pancreatic cancer, followed by other gastrointestinal malignancies, breast cancer, brain cancer, lymphoproliferative malignancies, and lung cancer. It is also important to recognize that other cancer susceptibility genes may be involved in these families. In particular, germline BRCA2 gene mutations have been described in families with melanoma and breast cancer, gastrointestinal cancer, pancreatic cancer or prostate cancer.
CMM can occur either with or without a family history of multiple dysplastic nevi. Families with both CMM and multiple dysplastic nevi have been referred to as having familial atypical multiple mole and melanoma syndrome (FAMMM). This syndrome is difficult to define since there is no agreement on a standard phenotype and dysplastic nevi occur in up to 50% of the general population. Atypical or dysplastic nevi are associated with an increased risk for CMM. Initially, the phenotypes of atypical nevi and CMM were thought to cosegregate in FAMMM families leading to the assumption that a single genetic factor was responsible. However, it was subsequently shown that in families with CDKN2A mutations, there were family members with multiple atypical nevi who were non-carriers of the CDKN2A familial mutation. Thus, the nevus phenotype cannot be used to distinguish carriers from non-carriers of CMM susceptibility in these families.
Some common allele(s) are associated with increased susceptibility to CMM but have low to moderate penetrance. One gene of moderate penetrance is the Melanocortin 1 receptor gene (MC1R). Variants in this gene are relatively common and have low penetrance for CMM. This gene is associated with fair complexion, freckles and red hair; all risk factors for CMM. Variants in MC1R also modify the CMM risk in families with CDKN2A mutations.
Melaris® (Myriad Genetics. Salt Lake City, UT) is a commercially available genetic test of the CDKN2A gene.
No U.S. Food and Drug Administration (FDA)‒approved CDKN2A mutation tests were identified. Melaris® and other CDKN2A tests are laboratory-developed tests (LDTs). Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; LDTs must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Melaris® is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, FDA does not require any regulatory review of this test.
POLICYGenetic testing for mutations associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational.
POLICY GUIDELINESInvestigative 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.
POLICY HISTORY5/18/2006: Approved by Medical Policy Advisory Committee (MPAC)
6/20/2007: Policy reviewed, description updated to include FAMMM and hereditary risk for melanoma versus increased susceptibility. Policy statement updated to include hereditary melanoma. "Mutations Associated with Malignant Melanoma Susceptibility" replaced with "Cutaneous Malignant Melanoma" in policy title
8/18/2008: Policy reviewed, no changes
10/21/2010: Policy reviewed; no changes.
12/13/2011: Added “Familial” to the policy title. Replaced "hereditary" with "familial" in the policy statement and throughout the policy.
11/28/2012: Policy reviewed; no changes.
11/28/2012: Policy reviewed; no changes to policy statement. Added CPT code 81404 to the Code Reference section.
12/02/2014: Policy reviewed; description updated. Policy statement unchanged.
12/31/2014: Code Reference section updated to revise the description of the following CPT code: 81404.
07/30/2015: Code Reference section updated for ICD-10.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.44
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.