Clinical Policy Bulletin: RET Proto-Oncogene Testing
Aetna considers tests for germline point mutations in the RET gene medically necessary for members who meet any of the following high-risk criteria:
Asymptomatic members of well characterized families with defined RET gene mutations; or
Members of families known to be affected by inherited medullary thyroid carcinoma, but not previously evaluated for RET mutations; or
Members who are first-degree relatives of individuals with medullary thyroid carcinoma and germline RET mutations; or
Members with Hirschsprung disease.
Aetna considers diagnostic testing for germline point mutations in the RET gene medically necessary for members with apparently sporadic medullary thyroid carcinoma.
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.
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.
Fialkowski et al (2008) stated that multiple endocrine neoplasia type2A (MEN 2A) is a genetic syndrome manifesting as MTC, hyper-parathyroidism, and pheochromocytoma. Multiple endocrine neoplasia 2A results from mutations in the RET proto-oncogene. Hirschsprung disease (HD) is a rare manifestation of MEN 2A and has been described in known MEN 2A families. These investigators described 2 MEN 2A families that were only identified after the diagnosis of HD. Kindred 1: A boy presented in infancy with HD. Genetic screening revealed a C609Y mutation, which is consistent with MEN 2A. Evaluation of his sister, father, and grandmother revealed the same mutation. All 3 had thyroidectomies demonstrating C-cell hyperplasia. The grandmother had a microscopic focus of MTC. Kindred 2: An infant boy and his sister were diagnosed with HD as neonates. Genetic testing demonstrated a C620R gene mutation consistent with MEN 2A. Total thyroidectomies revealed metastatic MTC in the father and C-cell hyperplasia in both children. The authors concluded that HD can be the initial presentation of MEN 2A. They strongly recommend that genetic screening be performed in patients presenting with HD, looking for the known RET mutations associated with MEN 2A. If a mutation consistent with MEN 2A is detected, genetic screening of all first-degree relatives in the kindred is recommended.
In a case report, Pandey et al (2011) emphasized that all patients with a history of HD should consider screening for RET mutations (it should be noted that RET mutations are the predominant but only one of a number of possible causes of HD), as there is a well-established association between HD and MEN 2A. If present, this could facilitate early diagnosis of MEN 2A with resultant thyroidectomy prior to the onset of MTC or at least prior to the development of metastatic disease.
Vaclavikova et al (2012) noted that inactivating germline mutations in the RET proto-oncogene are the major genetic cause of HD. In some cases, HD can be associated with MTC that is commonly caused by activating RET mutations. These investigators performed retrospective and prospective genetic analyses of 157 patients with HD operated on between December 1979 and June 2011; DNA was isolated from peripheral leukocytes. Patients with HD as well as family members were tested for RET mutations by direct sequencing and single-strand conformation polymorphism methods. RET mutations were detected in 16 patients (10 %). Association with MTC was found in 2 families, other 8 families had a mutation with potentially high- risk of MTC development and 4 novel mutations were detected. Total colonic aganglionosis was noted to have a high mutation detection rate (40 %). Three patients underwent total thyroidectomy (2 had clinical manifestation of MTC, 1 C-cell hyperplasia). The authors concluded that these findings showed the benefit of systematic RET mutation screening in HD patients in order to identify the risk of MTC in the preclinical stage of the disease. All patients should be tested for RET mutations at least in exon 10, and now additionally in exon 11 and 13, as well.
An UpToDate review on “Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2” (Lips, 2013) states that “Hirschsprung disease (HD) is characterized by the absence of autonomic ganglion cells within the distal colonic parasympathetic plexus resulting in chronic obstruction and megacolon. In humans, inactivating mutations of the RET proto-oncogene have been associated with HD. HD is a heterogenic disorder, occurring both in a familial and in a sporadic form. In about 50 percent of familial and 15 to 35 percent of sporadic HD patients, mutations in the RET gene are involved. Most HD cases arise from loss of function mutations, RET haploinsufficiency, RET polymorphisms or haplotypes of the RET promotor region. Hirschsprung disease (HD) was found in 50 percent of children in a family with a C620 mutation .... RET proto-oncogene testing in infants presenting with Hirschsprung disease is useful and may identify new multiple endocrine neoplasia 2A kindreds”.
An UpToDate review on “Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging” (Tuttle, 2014) states that “In a patient with negative RET proto-oncogene testing and no family history of MEN2 syndrome, biochemical testing for coexisting tumors is typically not required”.
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. Furthermore, RET proto-oncogene tests are also of clinical value for individuals with Hirschsprung disease.
CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
ICD-9 codes covered if selection criteria are met:
Malignant neoplasm of the thyroid gland
Hirschsprung's disease and other congenital functional disorders of colon
Family history of thyroid cancer
The above policy is based on the following references:
Delbridge L, Robinson B. Genetic and biochemical screening for endocrine disease: III. Costs and logistics. World J Surg. 1998;22(12):1212-1217.
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.
Goretzki PE, Hoppner W, Dotzenrath C, et al. Genetic and biochemical screening for endocrine disease. World J Surg. 1998;22(12):1202-1207.
Guiffrida D, Gharib H. Current diagnosis and management of medullary thyroid carcinoma. Ann Oncol. 1998;9(7):695-701.
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.
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.
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.
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.
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.
Le HN, Norton JA. Perspective on RET proto-oncogene and thyroid cancer. Cancer J. 2000;6(2):50-57.
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.
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.
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.
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.
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.
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.
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.
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.
DeLellis RA. Pathology and genetics of thyroid carcinoma. J Surg Oncol. 2006;94(8):662-669.
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.
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.
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.
Moore SW, Zaahl MG. Multiple endocrine neoplasia syndromes, children, Hirschsprung's disease and RET. Pediatr Surg Int. 2008;24(5):521-530.
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.
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.
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.
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.
Pandey R, Thurow T, de W Marsh R. Hirschsprung disease of the colon, a vaginal mass and medullary thyroid cancer -- a RET oncogene driven problem. J Gastrointest Oncol. 2011;2(4):254-257. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397624/. Accessed March 6, 2013.
Vaclavikova E, Kavalcova L, Skaba R, et al. Hirschsprung's disease and medullary thyroid carcinoma: 15-year experience with molecular genetic screening of the RET proto-oncogene. Pediatr Surg Int. 2012;28(2):123-1288.
Lips CJ. Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed February 2013.
Tuttle RM. Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2014.
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