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Clinical Policy Bulletin:
RET Proto-Oncogene Testing
Number: 0319


Policy

  1. Aetna considers tests for germline point mutations in the RET gene medically necessary for members who meet any of the following high-risk criteria:

    1. Asymptomatic members of well characterized families with defined RET gene mutations; or
    2. Members of families known to be affected by inherited medullary thyroid carcinoma, but not previously evaluated for RET mutations; or

    3. Members who are first-degree relatives of individuals with medullary thyroid carcinoma and germline RET mutations.

  2. Aetna considers diagnostic testing for germline point mutations in the RET gene medically necessary for members with apparently sporadic medullary thyroid carcinoma.

  3. Aetna considers tests for germline point mutations in the RET gene experimental and investigational for all other indications because it s effectiveness for indications other than the ones listed above has not been established.

See CPB 0140 - Genetic Testing for policy on genetic testing for non-member relatives of Aetna members.



Background

Genetic testing for RET germline mutation has shown 100 % sensitivity and specificity for identifying those at risk for developing inherited medullary thyroid cancer (multiple endocrine neoplasia (MEN) 2A, MEN 2B, or familial medullary thyroid carcinoma (FMTC)).  Use of the genetic assay allows earlier and more definitive identification and clinical management of those with a familial risk for medullary thyroid cancer when compared to the existing standard of annual biochemical monitoring.

Medullary thyroid carcinoma is surgically curable if detected before it has spread to regional lymph nodes.  However, lymph node involvement at diagnosis may be found in up to 75 % of patients for whom a thyroid nodule is the first sign of disease.  Thus, there is an emphasis on early detection and intervention in families, which are affected by the familial cancer syndromes of MEN types 2A and 2B and FMTC, which account for 25 % of medullary thyroid cancer.

After genetic counseling, most family members who test positive undergo surgery to remove the thyroid gland.  First-degree relatives of those with MTC that appears to be sporadic in origin also undergo the biochemical test to verify that the patient's tumor is not caused by an inheritable form of this disease.

In summary, RET proto-oncogene tests can be used to identify familial disease-causing RET point mutations in members of families known to be affected by inherited MTC.  For members of families with defined RET point mutations, results of the RET proto-oncogene tests may be used to decide upon prophylactic thyroidectomy or continued monitoring is necessary.  RET proto-oncogene tests may also be used to distinguish sporadic tumors from familial cancers in patients with MTC but without a previous family history of this disease, and in their first-degree relatives if the patient is found to have a germline RET mutation.
 
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
88271
Modifier 0E
ICD-9 codes covered if selection criteria are met:
193 Malignant neoplasm of the thyroid gland
V16.8 Family history of thyroid cancer


The above policy is based on the following references:
  1. Delbridge L, Robinson B. Genetic and biochemical screening for endocrine disease: III. Costs and logistics. World J Surg. 1998;22(12):1212-1217.
  2. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996;276(19):1575-1579.
  3. Goretzki PE, Hoppner W, Dotzenrath C, et al. Genetic and biochemical screening for endocrine disease. World J Surg. 1998;22(12):1202-1207.
  4. Guiffrida D, Gharib H. Current diagnosis and management of medullary thyroid carcinoma. Ann Oncol. 1998;9(7):695-701.
  5. Heshmanti HM, Gharib H, van Heerden JA, et al. Advances and controversies in the diagnosis and management of medullary thyroid carcinoma. Am J Med. 1997;103(1):60-69.
  6. Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367(6461):375-376.
  7. Larimore TC, Wells SA. Cancer of the endocrine system. In: Cancer: Principles and Practice of Oncology. 5th ed. VT DeVita, S Hellman, SA Rosenberg, eds. Philadelphia, PA: Lippincott-Raven Publishers; 1997.
  8. Mulligan LM, Marsh DJ, Robinson BG, et al. Genotype-phenotype correlation in multiple endocrine neoplasia type 2: Report of the International RET Mutation Consortium. J Intern Med. 1995;238(4):343-346.
  9. Frohnauer MK, Decker RA. Update on the MEN 2A c804 RET mutation: Is prophylactic thyroidectomy indicated? Surgery. 2000;128(6):1052-1057; discussion 1057-1058.
  10. Le HN, Norton JA. Perspective on RET proto-oncogene and thyroid cancer. Cancer J. 2000;6(2):50-57.
  11. Phay JE, Moley JF, Lairmore TC. Multiple endocrine neoplasias. Semin Surg Oncol. 2000;18(4):324-332.
  12. Rodriguez GJ, Balsalobre MD, Pomares F, et al. Prophylactic thyroidectomy in MEN 2A syndrome: Experience in a single center. J Am Coll Surg. 2002;195(2):159-166.
  13. Frilling A, Weber F, Tecklenborg C, Broelsch CE. Prophylactic thyroidectomy in multiple endocrine neoplasia: The impact of molecular mechanisms of RET proto-oncogene. Langenbecks Arch Surg. 2003;388(1):17-26.
  14. Thyroid Carcinoma Task Force. AACE/AAES medical/surgical guidelines for clinical practice: Management of thyroid carcinoma. American Association of Clinical Endocrinologists. American College of Endocrinology. Endocr Pract. 2001;7(3):202-220.
  15. National Academy of Clinical Biochemistry (NACB). NACB: Laboratory support for the diagnosis and monitoring of thyroid disease. Laboratory Medicine Practice Guidelines. Washington, DC: NACB; 2002.
  16. Trepanier A, Ahrens M, McKinnon W, et al. Genetic cancer risk assessment and counseling: Recommendations of the National Society of Genetic Counselors. J Genet Counsel. 2004;13(2):83-114.
  17. Jindrichova S, Vcelak J, Vlcek P, et al. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol. 2004;183(2):257-265.
  18. Kouvaraki MA, Shapiro SE, Perrier ND, et al. RET proto-oncogene: A review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15(6):531-544.
  19. Ogilvie JB, Kebebew E. Indication and timing of thyroid surgery for patients with hereditary medullary thyroid cancer syndromes. J Natl Compr Canc Netw. 2006;4(2):139-147.
  20. DeLellis RA. Pathology and genetics of thyroid carcinoma. J Surg Oncol. 2006;94(8):662-669.
  21. Isabel M. Martinez Ferez, Roman Villegas Portero. Analysis of RET mutations to perform prophylactic thyroidectomy in individuals at risk for medullary thyroid cancer [summary]. AETSA 2006/09. Sevilla, Spain; Andalusian Agency for Health Technology Assessment (AETSA); 2007.
  22. Vestergaard P, Vestergaard EM, Brockstedt H, Christiansen P. Codon Y791F mutations in a large kindred: Is prophylactic thyroidectomy always indicated? World J Surg. 2007;31(5):996-1001; discussion 1002-1004.
  23. Moore SW, Appfelstaedt J, Zaahl MG. Familial medullary carcinoma prevention, risk evaluation, and RET in children of families with MEN2. J Pediatr Surg. 2007;42(2):326-332.
  24. Moore SW, Zaahl MG. Multiple endocrine neoplasia syndromes, children, Hirschsprung's disease and RET. Pediatr Surg Int. 2008;24(5):521-530.
  25. Fialkowski EA, DeBenedetti MK, Moley JF, Bachrach B. RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine neoplasia 2A kindreds. J Pediatr Surg. 2008;43(1):188-190.
  26. American Thyroid Association Guidelines Task Force; Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: Management guidelines of the American
    Thyroid Association. Thyroid. 2009;19(6):565-612.
  27. Frank-Raue K, Rondot S, Raue F. Molecular genetics and phenomics of RET mutations: Impact on prognosis of MTC. Mol Cell Endocrinol. 2010;322(1-2):2-7.
  28. Konstantinou E, Theodoros MS, Theofanis F, et al. Preventive thyroidectomy in patients with hereditary medullary thyroid carcinoma found heterozygote for mutant RET proto-oncogene. Pediatr Endocrinol Rev. 2010;8(2):108-113.


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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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