Coverage Policy Manual
Policy #: 1998054
Category: Laboratory
Initiated: February 1998
Last Review: August 2018
  Genetic Test: Germline Mutations of the RET Protooncogene in Medullary Carcinoma of the Thyroid

Description: Medullary carcinoma of the thyroid is an uncommon type of thyroid cancer that arises from the parafollicular or C cells thyroid, which produce the hormone calcitonin. (Papillary thyroid cancer, arising from the glandular cells, is the most common type of thyroid cancer.) Three distinct but related familial cancer syndromes together are responsible for approximately one-fourth of the incidence of medullary carcinoma of the thyroid; the remaining three-fourths are sporadic. The three inherited syndromes include multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid cancer (FMTC). MEN 2A and MEN 2B differ from each other (and from MEN 1) in the spectrum and frequency of accompanying endocrine malignancies and other disorders. In contrast, FMTC is defined as being in a family with the repeated occurrence of medullary thyroid cancer in the absence of other endocrine malignancies or disorders. MEN 2A, MEN 2B, and FMTC are all dominantly inherited. Point mutations of the germline RET gene, located on chromosome 10, are associated with inheritance of MEN 2A, MEN 2B, or FMTC.

Medullary thyroid cancer is curable surgically 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. Surveillance by annual biochemical monitoring has been used to identify those with the inherited disease before it progresses beyond the earliest stages. The development of invasive medullary thyroid cancer usually is preceded by C-cell hyperplasia, which can be detected by hypersecretion of calcitonin in response to a chemical challenge. 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.

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing for RET proto-oncogene point mutations meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for members with:
    • Family members with defined RET gene mutations;
    • Family members known to be affected by inherited medullary thyroid cancer, but not previously evaluated for RET mutations; and
    • Sporadic medullary thyroid cancer.

Rationale:
The 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.
 
2009 Update
A search of the MEDLINE database was conducted through August 2009.  There was no new published information that would prompt a change in the coverage policy.  
 
2014 Update
A literature search was conducted using the MEDLINE database through July 2014. There was no new literature identified that would prompt a change in the coverage statement.
 
2016 Update
A literature search was conducted using the MEDLINE database through July 2016. There was no new literature identified that would prompt a change in the coverage statement.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2018. No new literature was identified that would prompt a change in the coverage statement.  

CPT/HCPCS:
81403MOLECULAR PATHOLOGY PROCEDURE LEVEL 4
81404MOLECULAR PATHOLOGY PROCEDURE LEVEL 5
81405MOLECULAR PATHOLOGY PROCEDURE LEVEL 6
S3840DNA analysis for germline mutations of the RET proto-oncogene for susceptibility to multiple endocrine neoplasia type 2

References: 1997 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 12.

Carlson KM, Dou S, Chi D, et al.(1994) Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA 1994; 91:1579-83.

Cote GJ, Wohllk N, Evans D, et al.(1995) RET proto-oncogene mutations in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. Clin Endocrinol Metab (Baillieres) 1995; 9:609-30.

Eng C, Clayton D, Schuffenecker I, et al.(1996) The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996; 276:1575-9.

Eng C, Mulligan LM, Smith DP, et al.(1995) A novel point mutation in the tyrosine kinase domain of the RET protooncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. Oncogeneb 1995; 10:509-13.

Eng C, Mulligan LM, Smith DP, et al.(1995) Low frequency at germline mutations in the RET protooncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol 1995; 43:123-7.

Eng C, Mulligan LM, Smith DP, et al.(1995) Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma. Genes; Chromosomes & Cancer 1995; 12:209-12.

Eng C.(1996) Seminars in medicine of the Beth Israel Hospital, Boston. The RET protooncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. NEJM 1996; 335:943-51.

Fink M, Weinhausel A, Niederle B, et al.(1996) Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET protooncogene. Int J Cancer 1996; 69:312-6.

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Maeda S, Namba H, Takamura N, et al.(1995) A single missense mutation in codon 918 of the RET protooncogene in sporadic medullary thyroid carcinomas. Endocrine Journal 1995; 42:245-50.

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Marsh DJ, McDowell D, Hyland VJ, et al.(1996) The identification of false positive responses to the pentagastrin stimulation test in RET mutation negative members of MEN 2A families. Clin Endocrinol 1996; 44:213-220.

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Mulligan LM, Eng C, Healey CS, et al.(1994) Specific mutations of the RET protooncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 1994; 6:70-4.

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Romei C, Elisei R, Pinchera A, et al.(1996) Somatic mutations of the ret protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence. J Clin Endocrinol Metab 1996; 81:1619-22.

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Zedenius J, Larsson C, Bergholm U, et al.(1995) Mutations of codon 918 in the RET protooncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab 1995; 80:3088-90.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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