Genetic Testing for Germline Mutations RET Proto-Oncogene Medullary Carcinoma Thyroid AHS-M2078

Description of Procedure or Service

Medullary thyroid carcinoma (MTC) is an uncommon malignant tumor arising from the calcitoninproducing parafollicular cells (C cells) of thyroid. It accounts for 5–10% of all thyroid cancers, and it mostly occurs as a sporadic entity (sMTC), but a familial pattern (fMTC) is also possible. RET protooncogene germline mutations are crucial for the onset and the progression of fMTC, and the occurrence of single nucleotide polymorphisms could predispose to the sporadic form (Figlioli et al., 2013).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for genetic testing for germline mutations of the RET protooncogene in medullary carcinoma of the thyroid when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Genetic Testing for Germline Mutations RET Proto-Oncogene Medullary Carcinoma Thyroid is covered

Genetic testing for RET proto-oncogene point mutations is considered medically necessary in any of the following situations:

1. Individual is a member of a family with defined RET gene mutations
2. Individual is a member of a family known to be affected by inherited medullary thyroid cancer, but not previously evaluated for RET mutations 
3. As an alternative to annual biochemical testing for C-cell hyperplasia 
4. Individual with apparently sporadic medullary thyroid carcinoma
5. ndividual is a first-degree relative of individuals with sporadic medullary thyroid cancer 

When Genetic Testing for Germline Mutations RET Proto-Oncogene Medullary Carcinoma Thyroid is not covered

Genetic testing for germline point mutations in the RET gene is investigational in all other situations.

Policy Guidelines

Per SEER (Surveillance, Epidemiology, and End Results) data, medullary thyroid carcinoma (MTC) accounts for 1–2% of thyroid cancers in the United States, which is a lower range than the 3-5% often cited, primarily because of the increased incidence of papillary thyroid carcinoma (American Thyroid Association, 2015). Thyroid cancer is traditionally seen as a largely curable disease: thyroidectomy, suppression of thyroid stimulating hormone (TSH), and administration of radioactive iodine confers overall survival rates of 71% at 10 years and 55% at 20 years (Emani V et al, 2016)

Yet these survival rates are only true for the 90% of differentiated thyroid cancers that originate in the follicular cells, comprising papillary, follicular, and Hürthle cell thyroid carcinomas. Medullary thyroid cancer (MTC), which represents approximately 4% of cases, tends to present at late stages and does not respond to TSH suppression or iodine, making it difficult to manage and conferring worse outcomes overall.

MTC originates from calcitonin-secreting neuroendocrine parafollicular or C cells of the thyroid. These cells lack TSH receptors and do not concentrate radioactive iodine. Approximately 50% of patients present with stage III/IV disease and 5-year survival rates range from 73% for patients with stage III disease to 40% for patients with stage IV disease (Machens A et al, 2013).

It is estimated that 20% of MTCs are associated with one of three inherited endocrine syndromes caused by germline mutations of the RET gene (Santoro M and Carlomagno F, 2013). The remaining 80% of MTCs are sporadic, although somatic mutations in RET can be seen in 40% to 50% of sporadic cases. Each of the syndromes can be distinguished by a unique cluster of clinical findings.

Multiple endocrine neoplasia (MEN) 2A is associated with RET mutations in codons 609, 611, 618, and 620 in exon 10, as well as in codon 634 in exon 11. Patients with MEN2A typically have MTC, pheochromocytoma, and primary hyperparathyroidism (PHPT), (Opsahi EM et al, 2016)

MEN2B is associated with RET mutations in codons 918 in exon 16 (> 95% of cases) and codon 883 in exon 15. These patients present with the most aggressive type of MTC. They typically have pheochromocytoma but not PHPT, and, unlike in the other syndromes, also exhibit musculoskeletal abnormalities and other developmental defects.

Finally, familial medullary thyroid cancer (FMTC) is associated with mutations in codons 609, 611, 618, and 620 in exon 10, as well as codon 768 in exon 13 and codon 804 in exon 14. In these patients, MTC is often the only clinical finding, i.e., patients do not necessarily have either pheochromocytoma or PHPT. The diagnosis of FMTC is therefore made after demonstrating MTC in at least 4 family members.

As in MEN2B, the most common mutation in patients with sporadic MTC is in codon 918 in exon 16. Patients with sporadic MTC typically have decreased survival compared with the inherited forms, and often demonstrate lymph node metastases at presentation.

Medullary thyroid cancer (MTC) is a rare tumor (3–5% of all thyroid cancers) arising from the calcitoninproducing parafollicular C cells of the thyroid gland (Wells et al. 2015, Hadoux et al. 2016). MTC occurs either sporadically or (in approximately one-third of cases) in a hereditary form as a component of the type 2 multiple endocrine neoplasia (MEN) syndromes MEN2A and 2B and the related syndrome familial MTC (FMTC) associated with germline RET (rearranged during transfection) mutations (Wells et al. 2015, Hadoux et al. 2016). The RET protooncogene is located on chromosome 10q11.2, encodes a single-pass transmembrane tyrosine kinase receptor, and is known to play a central role in the tumorigenesis of sporadic and hereditary MTC (Wells et al. 2015, Hadoux et al. 2016). While RET germline mutations can be detected in almost 100% of hereditary MTC cases, sporadic MTCs reveal somatic RET mutations in 50–60% of cases (Wells et al. 2015, Hadoux et al. 2016). RET/PTC rearrangements, which were previously believed to be exclusive to PTC, have now been found in some other human cancers, including MTC, but at a very low prevalence (Romei, Ciampi, & Elisei, 2016).

Currently, most patients with either FMTC or MEN2 are identified by genetic testing of at-risk family members. Patients with a positive family history of germline mutation of the RET gene have a 50% chance of inheriting the same mutation. Once identified as genetic carriers, there is a nearly 100% lifetime risk of developing malignancy (Roy et al., 2013).

FMTC

FMTC is similar to MEN2A with a strong predisposition to MTC in various family members without pheochromocytoma or hyperparathyroidism. In FMTC, there must not be any diagnosis of either pheochromocytoma or hyperparathyroidism in >10 carriers, and presentation must be after the age of 50 in multiple family members affected by the disease. Once a family is labeled as FMTC, there is a higher chance of missing a pheochromocytoma because these patients are not screened for the disease. If there is any uncertainty, it is much safer to label the family as MEN2 instead of FMTC (Roy et al., 2013).

Molecular Pathogenesis

MTC in MEN2 is inherited in an autosomal dominant pattern with very high penetrance. The genetic defect in these disorders involves the RET proto-oncogene on chromosome 10q11.2 Currently known RET mutations account for >95% of cases of hereditary MTC.

Medullary thyroid cancer (MTC) is a rare tumor (3–5% of all thyroid cancers) arising from the calcitoninproducing parafollicular C cells of the thyroid gland (Wells et al. 2015, Hadoux et al. 2016). MTC occurs either sporadically or (in approximately one-third of cases) in a hereditary form as a component of the type 2 multiple endocrine neoplasia (MEN) syndromes MEN2A and 2B and the related syndrome familial MTC (FMTC) associated with germline RET (rearranged during transfection) mutations (Wells et al. 2015, Hadoux et al. 2016). The RET protooncogene is located on chromosome 10q11.2, encodes a single-pass transmembrane tyrosine kinase receptor, and is known to play a central role in the tumorigenesis of sporadic and hereditary MTC (Wells et al. 2015, Hadoux et al. 2016). While RET germline mutations can be detected in almost 100% of hereditary MTC cases, sporadic MTCs reveal somatic RET mutations in 50–60% of cases (Wells et al. 2015, Hadoux et al. 2016). 

Understanding of candidate initiating and driving events in oncogenic transformation of thyroidal C cells has been facilitated by the discovery of activating germline mutations of the RET gene in the early 1990s as the genetic basis for hereditary forms of MTC (Wells et al. 2015). RET is located on chromosomal band 10q11.2 and encodes a single-pass transmembrane receptor tyrosine kinase. The RET protein has an extracellular ligand-binding domain composed of a cadherin-like region, and a highly conserved cysteine-rich domain. The intracellular region is composed of two tyrosine kinase domains. Upon ligand binding, the extracellular cysteine-rich domain facilitates receptor dimerization leading to autophosphorylation and tyrosine kinase activation triggering parallel downstream signaling pathway activation including RAS/RAF/MAPK, PI3K/AKT, and JAK-STAT pathways (Mulligan 2014). More than 80 different germline RET mutations have been identified in hereditary MTC. Most are singenucleotide missense mutations resulting in constitutive activation of the RET tyrosine kinase (Wells et al. 2015).

Recently, genetic assays for RET mutations have been used as an alternative to annual biochemical testing for C-cell hyperplasia, in patients with a known family history of MEN 2A, 2B, or FMTC. Annual biochemical screening can be stopped in those patients who test negative for mutations. Patients who test positive may undergo immediate thyroidectomy or postpone thyroidectomy until biochemical tests suggest evolving medullary cancer. Genetic assays have also been used to determine if new cases of medullary thyroid cancer without a family history are truly sporadic in origin. A positive test in this setting should initiate evaluation of family members. In addition, a positive test may prompt screening for pheochromocytoma, a component of MEN 2A and 2B, in the affected patient.

Applicable Federal Regulations

N/A

Guidelines and Recommendations

Currently, most patients with either FMTC or MEN2 are identified by genetic testing of at-risk family members. Patients with a positive family history of germline mutation of the RET gene have a 50% chance of inheriting the same mutation. Once identified as genetic carriers, there is a nearly 100% lifetime risk of developing malignancy.

2009 ATA guidelines for MTC recommend that all patients with C-cell hyperplasia or MTC be offered germline RET testing. It is important to provide appropriate genetic counseling to patients prior to screening for RET mutations. The risks and benefits of genetic testing must be discussed with patients and their families. In addition, once a positive RET mutation is detected, the patient must be carefully advised regarding the risks for other members of the family. Other clinical presentations such as Hirschsprung disease and CLA should also prompt genetic testing for RET mutations (Kloos et al., 2009). Ideally, in the event that a RET mutation is identified, at-risk family members should be offered a prophylactic thyroidectomy prior to the development of MTC. On occasion, a germline RET mutation may not be detected in a family with a clinical diagnosis of MEN2. In these at-risk relatives, periodic screening for MTC should be performed with neck U/S and serum calcitonin levels, screening for pheochromocytoma should be done by measurement of plasma or 24-hour urine metanephrines and normetanephrines, and hyperparathyroidism should be screened with albumin-corrected calcium or ionized calcium and parathyroid hormone levels (Kloos et al., 2009).

Data provide very strong support for the hypothesis that genetic tests for germline point mutations in the RET gene can identify those with an inherited susceptibility for medullary thyroid cancer earlier and more definitively than is possible with biochemical tests. For example, of 365 asymptomatic family members at risk for the inherited disease, 115 tested positive for RET gene mutations. Evidence of disease was subsequently found in all 115 with mutations and in none of the 250 without mutations. Test results affect patient management by prompting thyroidectomy or continued biochemical monitoring in affected patients, and by prompting discontinuation of monitoring in patients who test negative.

NCCN Guidelines for both Medullary Thyroid Carcinoma and Neuroendocrine tumors include screening for Screen for RET protooncogene mutations (exons, 10,11,13-16). Germline mutation should prompt family testing of first-degree relatives and genetic counseling (NCCN, 2017a, 2017b).

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page. 

Scientific Background and Reference Sources

American Thyroid Association Guidelines for management of Medullary Thyroid Carcinoma; Thyroid, 2015 June 25 (6):567-610

E. Modigliani, R. Cohen, J.M. Campos, B. Conte-Devolx, B. Maes, A. Boneu, M. Schlumberger, J.C. Bigorgne, P. Dumontier, L. Leclerc, B. Corcuff, I. Guilhem, Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d’etude des tumeurs a calcitonine, Clin. Endocrinol. (Oxf.) 48 (1998) 265–273.

Bütter A, Gagné J, Al-Jazaeri A, et al. Prophylactic thyroidectomy in pediatric carriers of multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma: Mutation in C620 is associated with Hirschsprung's disease. J Pediatr Surg 2007;42:203-206.

Christine Spitzweg, John C Morris, and Keith C Bible Endocr Relat Cancer June 1, 2016 23 R287-R297 doi: 10.1530/ERC-16-0104

DeLellis RA. Pathology and genetics of thyroid carcinoma. J Surg Oncol. 2006;94(8):662-669.

Donovan DT, Levy ML, Furst EJ, et al. Familial cutaneous lichen amyloidosis in association with multiple endocrine neoplasia type 2A: A new variant. Henry Ford Hosp Med J 1989;37:147-150.

Dottorini ME, Assi A, Sironi M, et al. Multivariate analysis of patients with medullary thyroid carcinoma. Prognostic significance and impact on treatment of clinical and pathologic variables. Cancer 1996;77:1556-1565.

Emani V, Kumar M, Chen AY, Owonikoko TK; Systemic treatment and management approaches for medullary thyroid cancer; Cancer Treat Rev. 2016 Sep 10.50.89-98;

Fialkowski EA, DeBenedetti MK, Moley JF, et al. RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine neoplasia 2A kindreds. J Pediatr Surg 2008;43:188-190.

Figlioli G, Stefano Landi, Cristina Romei, Rossella Ellisei, Federica Gemignani, Medullary Thyroid Carcinoma (MTC) and RET proto-oncogene: Mutation Spectrum in the Familial cases and a metaanalysis of Studies on the sporadic form. Mutation research 752 (2013)36-44.

H. Donis-Keller, S. Dou, D. Chi, K.M. Carlson, K. Toshima, T.C. Lairmore, J.R. Howe, J.F. Moley, P. Goodfellow, S.A. Wells Jr., Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC, Hum. Mol. Genet. 2 (1993) 851–856.

Hadoux J, Pacini F, Tuttle RM & Schlumberger M 2016 Management of advanced medullary thyroid cancer. Lancet. Diabetes & Endocrinology 4 64–71. (doi:10.1016/S2213-8587(15)00337X)

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.

Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: Management guidelines of the American Thyroid Association. Thyroid 2009;19:565-612.

Kouvaraki MA, Shapiro SE, Perrier ND, et al. RET proto-oncogene: A review and update of genotypephenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15(6):531-544.

Machen A, Lorenz K, Dralle H; Progression of Medullary Thyroid Cancer in RET Carriers of ATA class A and C Mutations; J Clin Endocrinol Metab. 2013 Dec 2

Madhuchhanda Roy, Herbert Chen and Rebecca S. Sippel, Current Understanding and Management of Medullary Thyroid Cancer The Oncologist October 2013 vol. 18 no. 10 1093-1100

Moore SW, Zaahl M. Familial associations in medullary thyroid carcinoma with Hirschsprung disease: The role of the RET-C620 “Janus” genetic variation. J Pediatr Surg 2010;45:393-396.

Mulligan LM 2014 RET revisited: expanding the oncogenic portfolio. Nature Reviews. Cancer 14 173– 186. (doi:10.1038/nrc3680)

Mure A, Gicquel C, Abdelmoumene N, et al. Cushing's syndrome in medullary thyroid carcinoma. J Endocrinol Invest 1995;18:180-185. 

National Academy of Clinical Biochemistry (NACB). NACB: Laboratory support for the diagnosis and monitoring of thyroid disease. Washington, DC: NACB; 2002.

NCCN. (2017a). NCCN Clinical Practice Guidelines in Oncology for Neuroendocrine Tumors version 3.2017. 

NCCN. (2017b). NCCN Clinical Practice Guidelines in Oncology for Thyroid Carcinoma Version 2.2017. 

Opsahi EM, Brauckhoff M, Schichting E, Helset K, Svartberg J, Brauckhoff K, et al; A Nationwide study of multiplr endocrine neoplasia type 2A in Norway: prognostic and predictivr factors for the clinical course of medullary thyroid carcinoma; Thyroid 2016 Sep 26(9): 1225-38

O'Riordain DS, O'Brien T, Crotty TB, et al. Multiple endocrine neoplasia type 2B: More than an endocrine disorder. Surgery 1995;118:936-942.

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.

Romei, C., Ciampi, R., & Elisei, R. (2016). A comprehensive overview of the role of the RET protooncogene in thyroid carcinoma. Nat Rev Endocrinol, 12(4), 192-202. doi:10.1038/nrendo.2016.11

Santoro M, Carlomagno F; Central Role of RET in Thyroid Cancer; Cold Spring Harb Perspect Biol, 2013 Dec 1.5(12)

S.L. Hyer, L. Vini, R. A’Hern, C. Harmer, Medullary thyroid cancer: multivariate analysis of prognostic factors influencing survival, Eur. J. Surg. Oncol. 26 (2000) 686–690.

Saad MF, Ordonez NG, Rashid RK, et al. Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine (Baltimore) 1984;63:319-342.

Smallridge RC, Bourne K, Pearson BW, et al. Cushing's syndrome due to medullary thyroid carcinoma: Diagnosis by proopiomelanocortin messenger ribonucleic acid in situ hybridization. J Clin Endocrinol Metab 2003;88:4565-4568.

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.

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.

Verga U, Fugazzola L, Cambiaghi S, et al. Frequent association between MEN 2A and cutaneous lichen amyloidosis. Clin Endocrinol (Oxf) 2003;59:156-161.

Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF & Pacini F, et al. 2015 Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 567–610. (doi:10.1089/thy.2014.0335)

Policy Implementation/Update Information

1/1/2019 New policy developed. BCBSNC will provide coverage for genetic testing for germline mutations RET proto-oncogene medullary carcinoma of the thyroid when it is determined to be medically necessary and criteria are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (lpr)