Aetna considers tests for germline point mutations in the RET gene medically necessary for members who meet any of the following high-risk criteria:
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.
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.
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:|
|88271||Molecular cytogenetics; DNA probe, each (e.g., FISH)|
|ICD-9 codes covered if selection criteria are met:|
|193||Malignant neoplasm of the thyroid gland|
|751.3||Hirschsprung's disease and other congenital functional disorders of colon|
|V16.8||Family history of thyroid cancer|