BlueCross and BlueShield of Montana Medical Policy/Codes
Genetic Testing for Germline Mutations of the RET Proto-Oncogene in Medullary Carcinoma of the Thyroid
Chapter: Genetic Testing
Current Effective Date: October 25, 2013
Original Effective Date: September 01, 2007
Publish Date: October 25, 2013
Revised Dates: December 2011; September 24, 2013
Description

Medullary carcinoma of the thyroid is an uncommon type of thyroid cancer that arises from the parafollicular or C-cells thyroid, which produces 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

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Genetic testing for RET proto-oncogene point mutations may be considered medically necessary in the following:

  • Symptomatic members of families with defined RET gene mutations;
  • Members of families known to be affected by inherited medullary thyroid cancer, but not previously evaluated for RET mutations; or
  • Patients with sporadic medullary thyroid cancer.

Rationale

A 1997 Blue Cross Blue Shield Association (BCBSA) Technology Assessment Center (TEC) Assessment, “Genetic Testing for Germline Mutations of the 'RET' Proto-Oncogene in Medullary Carcinoma of the Thyroid,” (1) concluded that 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.

2010 Update

In their 2010 Thyroid Cancer Guideline, the National Comprehensive Cancer Network (NCCN) states that “about 6% of patients with clinically sporadic MTC [medullary thyroid cancer] carry a germline mutation in RET, which leads to identification of new kindreds with multiple previously undiagnosed affected individuals. Genetic testing for RET proto-oncogene mutations should be encouraged for all newly diagnosed patients with clinically apparent sporadic MTC, and for screening children and adults in known kindreds with inherited forms of MTC; genetic counseling should be considered.” (2)

A search of peer reviewed literature through September 2010 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy.

2013 Update

A search of peer reviewed literature through August 2013 found that recent studies support the coverage position of this policy, and no new clinical trial publications or any additional information was found that would change the coverage position of this medical policy. (3)

American Thyroid Association (ATA)

The ATA has established four MTC risk levels based on correlations between RET genotype and MEN2 phenotype, and has made specific recommendations regarding the ideal timing for prophylactic thyroidectomy. For those with RET variants associated with MEN2B, who have the highest risk for early-onset MTC, thyroidectomy is recommended within the first year of life. For those at the next highest risk level (i.e., those with variants involving RET codon 634), thyroidectomy is recommended in the first 5 years of life. For those with genotypes at the third highest level of risk, thyroidectomy should be considered before 5 years of age, but may be delayed if stringent clinical criteria are met. For those with genotypes in the lowest risk category, thyroidectomy may be delayed after age 5 in the context of normal screening results and a family history consistent with less aggressive MTC (3)

National Comprehensive Cancer Network (NCCN)

In their clinical oncology guideline for thyroid carcinoma, the NCCN recommends that MEN2 gene testing (of RET exons 10, 11, and 13-16) be considered in any patient diagnosed with MTC (NCCN, 2012). Moreover, they recommend genotype-based medical management, with thyroidectomy by age 1 in MEN2B patients and by age 5 in MEN2A patients, consistent with the ATA recommendations above. (3)

Coding

Disclaimer for coding information on Medical Policies

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

ICD-9 Codes

193, 194.0, 194.1, 227.0, 227.1, 252.00-252.08, 258.01-258.03, V16.8, V18.11-V18.19 

ICD-10 Codes

C73, C74.00-C74.92, C75.0, D35.00-D35.02, D35.1, E21.0-E21.5, E31.20-E31.23, Z15.81, Z80.8, Z83.41-Z83.49

Procedural Codes: 81404, 81405, S3840
References
  1. Genetic Testing for Germline Mutations of the 'RET' Proto-Oncogene in Medullary Carcinoma of the Thyroid. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1997 August) 12(12):1-27.
  2. NCCN Clinical Practice Guidelines in Oncology:  Thyroid Carcinoma. National Comprehensive Cancer Network (2010 January 14) v.1.2010. Available at www.nccn.org (accessed 2010 October 14).
  3. Hayes, Inc. Hayes Genetic Test Evaluation Report. Multiple Endocrine Neoplasia Type 2 (MEN2). Landsdale, PA: Hayes, Inc.; July, 2012.
  4. Genetic Testing for Germline Mutations of the RET Proto-Oncogene in Medullary Carcinoma of the Thyroid—Archived. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2003 February) Surgery 2.04.05.
History
December 2011 Updated policy rationale and references. No change in policy statement. Policy archieved by association an not routinely scheduled for review.
October 2013 Policy formatting and language revised.  Policy statement unchanged.  Title changed from "Genetic Testing for Medullary Carcinoma of the Thyroid (RET Proto-Oncogene)" to "Genetic Testing for Germline Mutations of the RET Proto-Oncogene in Medullary Carcinoma of the Thyroid".
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Genetic Testing for Germline Mutations of the RET Proto-Oncogene in Medullary Carcinoma of the Thyroid