Genetic Testing for Familial Cutaneous Malignant Melanoma - CAM 257
Skin cancer is the most common form of cancer, arising from the metaplastic transformation from any of the cell types of the skin (Linares, Zakaria,& Nizran, 2015). Melanomas, which develop from the pigment-producing melanocytes, although much less prevalent than non-melanoma skin cancer, are increasing in incidence (Holmes, 2014; Lee & Lian, 2018). Early and accurate diagnosis is essential, as late-stage melanoma is among the most fatal forms of skin cancer (Cockerell et al., 2017). This, however, presents a significant challenge due to the difficulty of interpreting the histopathology of melanoma and the resulting interobserver and intra-observer variability (Elmore et al., 2017; Gerami et al., 2014).
This policy covers testing to assess the genetic risk of familial cutaneous melanoma and diagnostic testing to differentiate melanocytic lesions with indeterminate histopathology. Genetic testing of melanoma tumors for therapy is addressed in CAM 204115 Molecular Panel Testing of Cancers for Diagnosis, Prognosis, and Identification of Targeted Therapy and CAM 20477 Genetic Testing and Genetic Expression Profiling in Patients with Cutaneous Melanoma.
A search on the FDA database on 10/30/2020 with the term “cutaneous melanoma” identified two results; however, both of these tests are non-invasive tools which utilize electrical impedance spectroscopy and light from visible to near-infrared wavelengths to evaluate skin lesions. Additional tests may be considered laboratory developed tests (LDTs); developed, validated and performed by individual laboratories. LDTs are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request. Specifications pertaining to Medicare and Medicaid can be found in Section VII of this policy document.
- Genetic testing of the genes listed below (see Notes 1-3) for inherited forms of melanoma in an affected individual is considered MEDICALLY NECESSARY if the affected individual has two or more first-degree relatives with melanoma or the individual has three or more primary melanomas.
The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.
- Any other genetic testing for inherited forms of cutaneous melanoma is considered NOT MEDICALLY NECESSARY.
NOTE 1: For 5 or more genes being tested on the same platform, such as multi-gene panel next generation sequencing, please refer to CAM 235 Laboratory Guideline Policy.
NOTE 2: For panel testing of assessment of susceptibility to familial cutaneous malignant melanoma, please refer to CAM 265 Genetic Cancer Susceptibility Panels Using Next Generation Sequencing.
NOTE 3: If there is a known familial variant in the patient history, those variant(s) should be tested for first.
Cutaneous melanoma is one of the most aggressive forms of skin cancer due to its potential for metastasis with poor prognosis when not detected and treated at early stages (Leonardi et al., 2018; Soura, Eliades, Shannon, Stratigos & Tsao, 2016b). Unlike other solid tumors, melanoma affects young and middle-aged individuals with a median age at diagnosis of 57 (Leonardi et al., 2018). Melanoma incidence and mortality are on the rise (Chiaravalloti, Jinna, Kerr, Whalen, & Grant-Kels, 2018; Siegel, Miller, & Jemal, 2017), with the lifetime risk of developing cutaneous melanoma estimated to be 1 in 34 for women and 1 in 53 for men (Siegel et al., 2017). But though complex and varied in nature, the main risk factors involved in the pathogenesis of cutaneous melanoma can be narrowed down to exposure to ultraviolet radiation, the accumulation of many common acquired melanocyte nevi, light skin phenotypes, and a family history of melanoma (Rossi et al., 2019).
Ultraviolet (UV) light radiation from sun exposure is a major risk factor for melanoma skin cancer development (Gilchrest, Eller, Geller & Yaar, 1999; Holmes, 2014), directly associated with an increased risk of melanoma (Leonardi et al., 2018; Pennello, Devesa & Gail, 2000). Skin type, number of congenital and acquired melanocytic nevi, genetic susceptibility, and a family history have also been associated with increased risk for melanoma (Bauer & Garbe, 2003; Bevona, Goggins, Quinn, Fullerton, & Tsao, 2003; Hawkes, Truong, & Meyer, 2016). In addition to the total number of nevi, the size and type of nevi are also individually associated with an increased risk of melanoma, as approximately 25% of melanomas originate from an existing nevus (Gandini et al., 2005; Watt, Kotsis & Chung, 2004). Interestingly, a greater number of nevi with a 3mm diameter or larger was recently associated with melanoma death in males but not in females (Li et al., 2019). Early and accurate identification of patients with increased risk of melanoma development is essential to enable risk-tailored surveillance, management of early staged patients with biologically aggressive tumors (Zager et al., 2018), and improvement of patient outcomes (Cockerell et al., 2017).
Genetic Testing for Familial Cutaneous Melanoma
A family history of melanoma is reported by about 10% of melanoma patients (Soura et al., 2016b), and inherited germline mutations reportedly “increase melanoma risk from 4- to > 1000-fold” (Ransohoff et al., 2016). Determining the genetic origin, however, is complicated, as a portion of familial melanoma can be attributed to shared sun exposure experiences in family members with susceptible skin types (Goldstein & Tucker, 2001). The majority of familial cases lack identifiable germ-line mutations in either known susceptibility genes or in genes commonly mutated in sporadic melanoma (Hawkes et al., 2016). Uncommon, but high-risk, alleles have been found to contribute to the hereditary cancer phenotype that includes unilateral lineage, multi-generational, multiple primary lesions, and early onset of disease (Soura et al., 2016b). Additional research has identified a relationship between telomere length and familial melanoma; patients with familial melanoma had longer telomeres compared to patients with sporadic melanoma (Menin et al., 2016). As such, genes such as TERT, which encodes for the catalytic subunit of telomerase, and POT1, a shelterin complex protein, have been implicated in the presence of multiple primary melanomas and early-onset melanoma in a subset of high-density families (Rossi et al., 2019).
Cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4) are the most commonly identified gene mutations in familial forms of melanoma, which can be defined as a family where either two first-degree relatives or three or more melanoma patients on the same side of the family are diagnosed with melanoma. Germline CDKN2A mutations have been identified in approximately 20-40% of familial melanoma cases where three or more family members are affected (Harland et al., 2016; Rossi et al., 2019). CDKN2A encodes several proteins involved in cell cycle regulation, including p16, which inhibits CDK4 (Hussussian et al., 1994; Koh, Enders, Dynlacht, & Harlow, 1995), and p14ARF, which inhibits MDM2 from regulating p53 (Zhang, Xiong & Yarbrough, 1998). Germline CDKN2A mutations in melanoma families are usually missense or nonsense changes that impair the function of the p16 protein, allowing for unchecked cell cycle progression; however, rare mutations in the p14ARF protein have also been reported and result in proteasomal degradation of p53 with subsequent accumulation of DNA damage (Marzuka-Alcala, Gabree & Tsao, 2014). Overall survival is worse in those with a germline CDKN2A mutation than those with sporadic melanoma or familial melanoma with wild-type CDKN2A genes. Germline mutations also predisposed patients to an increased number of malignancies, such as pancreatic and lung cancer (Tsao & McCormick, 2020).
Mutations in CDKN2A/p16 are associated with familial atypical multiple mole-melanoma (FAMMM syndrome), which is characterized by numerous nevi (some atypical), a family history of melanoma, and an increased risk of pancreatic cancer (Goldstein et al., 2007; Lynch & Krush, 1968). Carriers of a FAMMM mutation typically present with cancer at a younger age than non-carriers (Middlebrooks et al., 2019). Mutations in p14ARF are linked to Melanoma-Astrocytoma Syndrome (MAS), a variant of FAMMM characterized by both cutaneous melanomas and nervous system tumors (Randerson-Moor et al., 2001). Inheritance of CDKN2A mutations are autosomal dominant, but these mutations have variable penetrance based on sun exposure patterns and coinheritance of other melanoma-associated variants, conferring a 76% lifetime risk of developing melanoma in the US (Bishop et al., 2002; Cust et al., 2011). Mutations in CDK4 are even less common, but were most often found affecting arginine 24, resulting in a CDK4 protein that is insensitive to inhibition by the p16 protein. No apparent differences exist in the phenotype (e.g., age at diagnosis, number of melanomas) of families carrying either CDKN2A or CDK4 mutations. In aggregate, between 20-45% of familial melanomas are associated with germline mutations in CDKN2A or CDK4 (Goldstein et al., 2007; Nelson & Tsao, 2009).
Other rare mutations have been associated with melanoma. Germline variations in the melanocortin-1 receptor (MC1R) gene alter the risk of melanoma in individuals with and without CDKN2A mutations (Marzuka-Alcala et al., 2014; Pasquali et al., 2015; Wendt et al., 2018). Germline variants in genes that encode for BRCA1-associated protein-1 (BAP1), telomerase reverse transcriptase (TERT), and microphthalmia-associated transcription factor (MITF) have also been added to the list of genes harboring familial melanoma-predisposing mutations (Simone, Valiante, & Silipo, 2017; Soura, Eliades, Shannon, Stratigos, & Tsao, 2016a). These are more often associated with “mixed cancer syndrome,” where melanoma may appear in the context of a more general predisposition for malignancy. The BAP1 tumor syndrome is associated with the appearance of cutaneous melanoma, uveal melanoma, and various internal malignancies (Wiesner et al., 2011). Mutations in the promoter region of TERT, the protein component of telomerase, and in various components of the shelterin complex have been associated with a higher incidence of melanoma and other internal malignancies (Burke et al., 2013; Horn et al., 2013). Mutations in MITF are associated with a higher nevus count, cutaneous malignant melanoma onset before 40 years of age, and non-blue eye color with no association to freckling, skin color, or hair color (Bertolotto et al., 2011; Yokoyama et al., 2011). Xeroderma pigmentosum (XP) is a rare disorder in which patients have a mutation in genes involved in nucleotide excision repair (NER). Patients with mutations in XPC and XPD have an increased risk of melanoma (Paszkowska-Szczur et al., 2013). Lastly, Cowden syndrome, a type of PTEN hamartoma tumor syndrome characterized by the appearance of trichilemmomas, papillomatous papules, mucosal lesions (papules) and palmar-plantar keratosis within the first three decades of life, is associated with a higher risk of melanoma (Bubien et al., 2013; Soura et al., 2016a).
Several proprietary gene panels exist for assessment of familial cutaneous melanoma. For example, the DermTech Pigmented Legion Assay (PLA) leverages their “Smart Sticker” technology to remove cellular material from the stratum corneum, the material of which is then analyzed for over-expression of LINC00518 (long intergenic non-coding RNA 518) and PRAME (preferentially expressed antigen in melanoma), which may be incidental with genomic atypia associated with melanomas (Gerami et al., 2017). Moreover, Invitae offers a 12-gene panel (9 primary genes plus 3 genes with “preliminary evidence for melanoma”), Fulgent offers a 14-gene panel, and GeneDx offers a 9-gene panel (Fulgent, 2020; GeneDx, 2020; Invitae, 2020). These panels may include genes traditionally associated with familial melanoma itself (such as CDKN2A) as well as genes whose variants are not primarily associated with familial melanoma, but confer added risk regardless (Tsao & McCormick, 2020).
Clinical Utility and Validity of Genetic Testing for Familial Cutaneous Melanoma
The frequency of CDKN2A mutations in patients with a single primary melanoma or multiple primary melanoma were 1.2% and 2.9%, respectively (Berwick et al., 2006); however, depending on selection criteria, mutation frequency rates of CDKN2A can range from 5% to 72% (Delaunay et al., 2017) with a family history of melanoma considered the most important risk factor. The established rule of three is used when proposing genetic testing for primary melanomas; it is generally understood that when three or more melanomas or genetically related cancers are identified in the same patient, or in first- and second-degree relatives, the pretest probability is increased above 10% and the cost of genetic screening can be justified (Leachman et al., 2017).
In a study on CDK2NA genetic testing conducted in Sweden between 2015 and 2020, 913 members across 403 families were identified with cutaneous melanoma. Pissa et al. (2021) found that melanoma cases found in families testing positive for pathogenic variants of CDK2NA boasted significantly higher mortality rates, such that families with the variants had 37.6% melanoma cases that died from melanoma as compared to the 10.0% without (p < 0.001), independent of age, sex, and tumor stage. This significant melanoma-specific mortality associated with families with CDK2NA variants is motivation to identify and enroll carrier families in a preventive surveillance program (Pissa et al., 2021). However, a potential confounding variable involves the diagnoses of pancreatic cancers in the subjects in the study; as pathogenic strains of CDK2NA are also associated with cancers other than melanomas, the 129 of the 913 members present a limitation to the specificity of the study as there did not appear to be a clear manner of segregating its influence.
Potjer et al. (2019) have determined that “Germline mutations in the major melanoma susceptibility gene CDKN2A explain genetic predisposition in only 10-40% of melanoma-prone families” and subsequently characterized 488 melanoma cases from non-CDKN2A/CDK4 families to determine other important mutations in familial melanoma. The authors conclude that “multigene panel testing for familial melanoma is appropriate considering the additional 4% diagnostic yield in non-CDKN2A/CDK4 families. Our study shows that BAP1 and MITF are important genes to be included in such a diagnostic test (Potjer et al., 2019).”
Stolarova et al. (2020) analyzed 264 Czech melanoma patients with early onset, double primary tumors or family history by next generation sequencing NGS analysis of 217 genes, and they identified that “mutations in high-to-moderate melanoma risk genes and in other cancer syndrome genes were significantly associated with melanoma risk,” with those genes including CDKN2A, POT1, and ACD for high-to-moderate melanoma risk, and NBN, BRCA1/2, CHEK2, ATM, WRN, and RB1 for other cancer syndrome genes. An increased potential of carrying mutations was found in “patients with double primary melanoma, melanoma and other primary cancer, but not in patients with early age at onset” (Stolarova et al., 2020). CDK2NA was the most frequently mutated gene among those with high-to-moderate risk, and in other studies reviewed by Stolarova et al. (2020), there was an increased risk for pancreatic cancer among families with CDK2NA mutation, and a more established family history.
Leachman et al. (2017) published an updated algorithm for the identification, testing, and management of hereditary melanoma; the rule of three has been incorporated into this algorithm as an indication for genetic testing in multiple melanomas. The researchers state that “Any patient or family that meets the updated rule of threes should be considered a candidate for genetic testing. If melanoma is the only cancer in a pedigree, then to meet the threshold of genetic testing, a pedigree should have three primary melanomas in first- or second-degree relatives in areas with a high melanoma incidence or two primary melanomas in a low-incidence area. This melanoma panel should include BAP1, CDK4, and CDKN2A. Genes for which risk has not been established but for which studies suggest an elevated risk include MITF and POT1 and we recommend including these in the melanoma panel” (Leachman et al., 2017).
Gerami et al. (2017) tested the validity of a two-gene panel based on LINC00518 and PRAME on differentiating melanoma from nonmelanoma in a multicenter study across 28 sites in the United States, Europe, and Australia. In a sample of 398 (87 melanomas and 311 nonmelanomas), it was found that this classification method was able to accurately identify melanomas from nonmelanomas with a sensitivity of 91% and a specificity of 69%. The real-world performance and utility of the proprietary two-gene assay PLA by DermTech was also retrospectively assessed by four US dermatology practices 3 to 6 months after the PLA. In this cohort of 381 patients, 51 tested positive and 330 tested negative, and from this dataset the authors found that the PLA had a high NPV of > 99% and a high sensitivity of 91 – 95%, while also boasting high specificity (69 – 91%). However, it is unclear if the negative samples, as determined by the PLA, will remain so, as “we [the authors] cannot rule out that some PLA(−) lesions may not have been adequately reassessed in the follow-up period and we certainly recommend erring on the side of caution and surgically biopsying a lesion in question if additional risk factors, further clinical suspicion, or patient concern mandate such a step” (Ferris et al., 2018). However, the authors continue to assert that because 100% of the 51 resulted reported to be positive by the PLA were correctly identified and handled by surgical biopsy, at the least “these findings show that clinicians follow the guidance of the test”, though only time will tell if the biopsies stand correct.
The clinical utility of genetic testing for hereditary melanoma families is debatable because CDKN2A status may not impact medical management in patients with melanoma (Gabree, Patel & Rodgers, 2014). This was further confirmed by Tovar-Parra, Gutiérrez-Castañeda, Gil-Quiñones, Nova, and Pulido (2020), who found that CDKN2A polymorphisms p.G101W, p.R24P, p.M53I, and A148T, in a case-control study with 85 cases and 166 controls, were not associated with increased susceptibility to melanoma in the Colombian population, thereby demonstrating the lack of procedures that would need to be taken for those with this mutation. However, testing for CDKN2A mutations with genetic counseling was shown to be perceived as more informative and motivating to patients to adhere to prevention recommendations (Aspinwall et al., 2018). Compared to no-test controls, participants who received test results (carriers and noncarriers) reported feeling significantly more informed and prepared to manage their risk, and carriers reported greater motivation to reduce sun exposure; all groups reported low negative emotions about melanoma risk (Aspinwall et al., 2018). Parents reported high levels of preparedness to manage children's risk regardless of group. Carrier parents reported greater (but moderate) worry about their children's risk than no-test control parents.
Genetic testing for commonly known cutaneous melanoma mutations can be utilized to determine prognosis and overall survival. Aoude et al. (2020) found that “germline mutation status was the most significant biomarker for OS [overall survival]” and “survival outcomes for germline carriers are poor with the current standards of care.” When using BRAF status and tumor mutation burden (TMB) for prognosis of cutaneous melanoma patients, “BRAF V600 wild-type patients had significantly longer PFS [progression-free survival] than the V600 mutant group (p = 0.0317) … For stage III/IV resected patients, TMB was also significantly associated with longer PFS (p = 0.0034)” (Aoude et al., 2020). The greater the number of recognizable mutations, the more targeted attacks against cancerous cells can be made and the better the prognosis.
National Comprehensive Cancer Network (NCCN, 2021)
The NCCN Guidelines for Cutaneous Melanoma recommend to “Consider the use of molecular testing for histologically equivocal lesions,” either with comparative genomic hybridization (CGH) or fluorescence in situ hybridization (FISH) for detecting genetic mutations, though the former may be more sensitive and specific. The NCCN also states that “The use of gene expression profiling (GEP) testing according to specific AJCC-8 melanoma stage (before or after sentinel lymph node biopsy [SLNB]) requires further prospective investigation in large, contemporary data sets of unselected patients. Prognostic GEP testing to differentiate melanomas at low versus high risk for metastasis should not replace pathologic staging procedures. Moreover, since there is a low probability of metastasis in stage I melanoma and higher proportion of false-positive results, GEP testing should not guide clinical decision-making in this subgroup” (NCCN, 2021).
On testing of primary lesions, the NCCN recommends that “mutational analysis for BRAF or multigene testing of the primary lesion is not recommended for patients with cutaneous melanoma who are without evidence of disease (NED), unless required to guide adjuvant or other systemic therapy or consideration of clinical trials”. However, follow-up procedures for stage 0 in situ, IA-IIA NED, and IIB-IV NED melanomas now extends to “Pre-diagnostic genomic patch testing” as they “may also be helpful to guide biopsy decisions” (NCCN, 2021).
Moreover, the NCCN also recommended that a referral should be considered for genetic counseling “for p16/CDKN2A mutation testing in the presence of 3 or more invasive cutaneous melanomas, or a mix of invasive melanoma, pancreatic cancer, and/or astrocytoma diagnoses in an individual or family” and “Testing for other genes that can harbor melanoma-predisposing mutations may be warranted” (NCCN, 2021).
Indications for genetic testing using emerging molecular technologies for diagnosis and prognostication, the NCCN recommended the following:
- “The panel does not recommend BRAF or NGS [next generation sequencing] testing for resected stage I-II cutaneous melanoma unless it will inform clinical trial participation.
- BRAF mutation testing is recommended for patients with stage III at high risk for recurrence for whom BRAF-directed therapy may be an option.
- For initial presentation with stage IV disease or clinical recurrence, obtain tissue to ascertain alterations in BRAF, and in the appropriate clinical setting. KIT from either biopsy of the metastasis (preferred) or archival material if the patient is being considered for targeted therapy. Broader genomic profiling (e.g., larger NGS panels, BRAF non-V600 mutation) is recommended if feasible, especially if the test results might guide future treatment decisions or eligibility for participation in a clinical trial.
- If BRAF single-gene testing was the initial test performed, and is negative, clinicians should strongly consider larger NGS panels to identify other potential genetic targets (e.g., KIT, BRAF non-V600)” (NCCN, 2021).
The American Academy of Dermatology (AAD)
The AAD published guidelines for the care and management of primary cutaneous melanoma. It was stated that “There is insufficient evidence to recommend routine molecular profiling assessment for baseline prognostication. Evidence is lacking that molecular classification should be used to alter patient management outside of current guidelines (eg, NCCN and AAD). The criteria for and the utility of prognostic molecular testing, including GEP, in aiding clinical decision making (e.g., SLNB eligibility, surveillance intensity, and/or therapeutic choice) needs to be evaluated in the context of clinical study or trial (Swetter et al., 2019).” Further, a “C” recommendation was given regarding patient referral for genetic counseling “and possible germline genetic testing for select patients” with potential hereditary cutaneous melanoma (Swetter et al., 2019).
Regarding patients with a family history of invasive cutaneous melanoma (at least three affected members on one side of the family), “Cancer risk counseling by a qualified genetic counselor is recommended” (Swetter et al., 2019).
European Society for Medical Oncology (ESMO)
The ESMO published 2019 guidelines for cutaneous melanoma diagnosis, treatment and follow-up. This article states that “Mutation testing for actionable mutations is mandatory in patients with resectable or unresectable stage III or stage IV [I, A], and is highly recommended in high-risk resected disease stage IIC but not for stage I or stage IIA-IIB. BRAF testing is mandatory [I, A] (Michielin, van Akkooi, Ascierto, Dummer, & Keilholz, 2019b).”
Regarding follow-up, long-term implications and survivorship, the ESMO has stated that “Patients must be aware that family members have an increased melanoma risk [III, B]. There is no recommendation for genetic testing” (Michielin et al., 2019b).
European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization for Research and Treatment of Cancer (EORTC)
The EDF, EADO, and EORTC collaboratively released an interdisciplinary guideline on the diagnostics of melanoma. With regards to genetic testing of cutaneous melanoma, the guidelines suggest that genetic profiling of melanoma tissues using NGS may help in identifying the genetic alterations that are targetable by drugs. For specific stages and in relation to the BRAF V600 mutation, the guidelines recommend mutation testing for cancers stage III and higher. However, “mutational analysis for BRAF of the primary lesion is not recommended for patients with cutaneous melanoma but without evidence of the disease, unless required to guide consideration of clinical trials for adjuvant therapy” (Garbe et al., 2020).
“Mutational analysis is required to determine the BRAFV600 mutation status in patients with distant metastasis or non-resectable regional metastasis to identify those who are eligible to receive treatment with combined BRAF and MEK inhibitors, and in resected high-risk stage III melanoma patients in the adjuvant setting. BRAFV600 mutation testing should be performed on metastatic tissue, either distant or regional, or on primary tumor if sampling of the metastatic tissue is not feasible” (Garbe et al., 2020).
American Joint Committee on Cancer (AJCC) (Gershenwald et al., 2017)
The AJCC did not include any mention of molecular testing in the most recent 8th edition guidance on melanoma staging (Gershenwald et al., 2017).
U.S. Preventive Services Task Force (USPSTF)
The USPSTF examined the utility of visual skin examination for the prevention of melanoma and found that “Only limited evidence was identified for skin cancer screening, particularly regarding potential benefit of skin cancer screening on melanoma mortality” (Wernli et al., 2016). The use of molecular tests in screening for melanoma is not mentioned.
National Cancer Institute
The NCI updated its PDQ cancer information summary on the genetics of skin cancer (NCI, 2002) in June 2018; this was reaffirmed in 2020. It summarizes expert opinion on genetic testing: “Expert opinion regarding testing for germline pathogenic variants of CDKN2A follows two divergent schools of thought. Arguments for genetic testing include the value of identifying a cause of disease for the individual tested, the possibility of improved compliance with prevention protocols in individuals with an identified pathogenic variant, and the reassurance of a negative testing result in individuals in a family carrying a pathogenic variant. However, a negative test result in a family that does not have a known pathogenic variant is uninformative; the genetic cause of disease in these patients must still be identified. It should also be noted that members of families carrying a CDKN2A pathogenic variant who do not carry the variant themselves may remain at increased risk of melanoma. At this time, identification of a CDKN2A pathogenic variant does not affect the clinical management of the affected patient or family members. Close dermatologic follow-up of these people is indicated, regardless of genetic testing result, and pancreatic cancer screening has unclear utility” (NCI, 2020).
In 2021, the NCI points to the NCCN for current guidance on identifying germline pathogenic variants in genes associated with hereditary melanoma: “the NCCN recommends that individuals with three or more invasive cutaneous melanomas or a combination of invasive melanoma, pancreatic cancer, and/or astrocytoma in an individual or family be referred for genetic counseling and discussion of genetic testing for CDKN2A. Recommendation for multigene (panel) testing is in the context of clinical and family history of melanoma with other cancers such as uveal melanoma, astrocytoma, mesothelioma, breast cancer, pancreatic cancer, and renal cancer" (NCI, 2021).
American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) (Hampel, Bennett, Buchanan, Pearlman, & Wiesner, 2015)
Referral for cancer genetic consultation is recommended by the ACMG and the NSCG for the following types of melanomas:
- Hereditary melanoma for “any individual with a personal history of or first-degree relative with (i) three or more melanomas in the same person or (ii) three or more cases of melanoma and/or pancreatic cancer (Hampel et al., 2015).”
- Melanoma-astrocytoma syndrome for “any individual with a personal history of or first-degree relative with (i) melanoma and astrocytoma in the same person or (ii) one case of melanoma and one case of astrocytoma in two first-degree relatives (Hampel et al., 2015).”
- Aoude, L. G., Bonazzi, V. F., Brosda, S., Patel, K., Koufariotis, L. T., Oey, H., . . . Barbour, A. P. (2020). Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients. Sci Rep, 10(1), 17687. doi:10.1038/s41598-020-74956-3
- Aspinwall, L. G., Stump, T. K., Taber, J. M., Drummond, D. M., Kohlmann, W., Champine, M., & Leachman, S. A. (2018). Genetic test reporting of CDKN2A provides informational and motivational benefits for managing melanoma risk. Transl Behav Med, 8(1), 29-43. doi:10.1093/tbm/ibx011
- Bauer, J., & Garbe, C. (2003). Acquired melanocytic nevi as risk factor for melanoma development. A comprehensive review of epidemiological data. Pigment Cell Res, 16(3), 297-306. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12753404
- Bertolotto, C., Lesueur, F., Giuliano, S., Strub, T., de Lichy, M., Bille, K., . . . Bressac-de Paillerets, B. (2011). A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature, 480(7375), 94-98. doi:10.1038/nature10539
- Berwick, M., Orlow, I., Hummer, A. J., Armstrong, B. K., Kricker, A., Marrett, L. D., . . . Group, G. E. M. S. (2006). The prevalence of CDKN2A germ-line mutations and relative risk for cutaneous malignant melanoma: an international population-based study. Cancer Epidemiol Biomarkers Prev, 15(8), 1520-1525. doi:10.1158/1055-9965.EPI-06-0270
- Bevona, C., Goggins, W., Quinn, T., Fullerton, J., & Tsao, H. (2003). Cutaneous melanomas associated with nevi. Arch Dermatol, 139(12), 1620-1624; discussion 1624. doi:10.1001/archderm.139.12.1620
- Bishop, D. T., Demenais, F., Goldstein, A. M., Bergman, W., Bishop, J. N., Bressac-de Paillerets, B., . . . Melanoma Genetics, C. (2002). Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst, 94(12), 894-903. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12072543
- Bubien, V., Bonnet, F., Brouste, V., Hoppe, S., Barouk-Simonet, E., David, A., . . . French Cowden Disease, N. (2013). High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet, 50(4), 255-263. doi:10.1136/jmedgenet-2012-101339
- Burke, L. S., Hyland, P. L., Pfeiffer, R. M., Prescott, J., Wheeler, W., Mirabello, L., . . . Yang, X. R. (2013). Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations. PLoS One, 8(8), e71121. doi:10.1371/journal.pone.0071121
- Chiaravalloti, A. J., Jinna, S., Kerr, P. E., Whalen, J., & Grant-Kels, J. M. (2018). A deep look into thin melanomas: What's new for the clinician and the impact on the patient. Int J Womens Dermatol, 4(3), 119-121. doi:10.1016/j.ijwd.2018.01.003
- Cockerell, C., Tschen, J., Billings, S. D., Evans, B., Brown, K., Rock, C., & Clarke, L. E. (2017). The influence of a gene-expression signature on the treatment of diagnostically challenging melanocytic lesions. Per Med, 14(2), 123-130. doi:10.2217/pme-2016-0097
- Cust, A. E., Harland, M., Makalic, E., Schmidt, D., Dowty, J. G., Aitken, J. F., . . . Jenkins, M. A. (2011). Melanoma risk for CDKN2A mutation carriers who are relatives of population-based case carriers in Australia and the UK. J Med Genet, 48(4), 266-272. doi:10.1136/jmg.2010.086538
- Delaunay, J., Martin, L., Bressac-de Paillerets, B., Duru, G., Ingster, O., & Thomas, L. (2017). Improvement of Genetic Testing for Cutaneous Melanoma in Countries With Low to Moderate Incidence: The Rule of 2 vs the Rule of 3. JAMA Dermatol, 153(11), 1122-1129. doi:10.1001/jamadermatol.2017.2926
- Elmore, J. G., Barnhill, R. L., Elder, D. E., Longton, G. M., Pepe, M. S., Reisch, L. M., . . . Piepkorn, M. W. (2017). Pathologists' diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study. BMJ, 357, j2813. doi:10.1136/bmj.j2813
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|CPT||81167||BRCA2 (BRCA2, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (i.e., detection of large gene rearrangements)|
|81216||BRCA2 (BRCA2, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis|
|81217||BRCA2 (BRCA2, DNA repair associated) (e.g., hereditary breast and ovarian cancer) gene analysis; known familial variant|
|81404||Molecular pathology procedure, Level 5 (e.g., analysis of 2 – 5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6 – 10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)
|81345||TERT (telomerase reverse transcriptase) (e.g., thyroid carcinoma, glioblastoma multiforme) gene analysis, targeted sequence analysis (eg, promoter region)|
|81479||Unlisted molecular pathology procedure
CDK4, MC1R, BAP1, MITF
|ICD-10-CM (effective 10/01/15)||Investigational for all relevant diagnoses|
|All C43 codes||Malignant melanoma|
|Z80.8||Family history of malignant neoplasm of other organs or systems|
|Z85.820||Personal history of malignant melanoma of skin|
|ICD-10-PCS (effective 10/01/15)||Not applicable. No ICD procedure codes for laboratory tests.|
Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.
"Current Procedural Terminology © American Medical Association. All Rights Reserved"
History From 2013 Forward
Interim review to update notes 1 and 2.
Annual review, no change to policy intent. Updating rationale and refrences.
Annual review, adding medical necessity criteria for BRCA2, MITF and TERT. Adding notes 1-3 related to additional testing and policies. Also updating description, references and rationale.
Annual review, updating policy statement to allow for testing with criteria for CDKN2A, CDK4, MC1R and BAP1. No other changes made.
Annual review, no change to policy intent. Updating ICD coding.
Annual review, updating title and rewriting policy verbiage for additional clarity. No change to policy intent.
Interim review to align with Avalon quarterly schedule. Updated category to Laboratory.
Annual review, no change to policy intent.
Interim Review. Updating to add CPT Coding 81445 and 81455.
Annual review, no change to policy intent. Updating background, descriptions, guidelines, rationale and references. Adding appendix 1.
Annual review. Updated description, rationale and references. Added regulatory staus, policy guidelines and coding. No change to policy intent.
Annual review. Updated rationale and references. Also, added benefit applications section.