Genetic Testing for Medullary Thyroid Carcinoma
DESCRIPTION
Medullary carcinoma of the thyroid is an uncommon type of thyroid cancer. These tumors originate from the parafollicular or C-cells of the thyroid gland, which produce the hormone calcitonin. Together, three distinct but related familial cancer syndromes 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 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 individuals 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. Genetic assays for RET mutations have been used as an alternative to annual biochemical testing for C-cell hyperplasia in individuals with a known family history of MEN 2A, 2B, or FMTC. Annual biochemical screening can be stopped in those individuals who test negative for mutations. Individuals 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
Genetic testing for RET proto-oncogene point mutations for evaluating the risk of developing medullary thyroid cancer is considered medically necessary if medical appropriateness criteria are met. (See Medical Appropriateness below.)
Pre- and post-genetic counseling is considered medically necessary as an adjunct to the genetic testing itself.
See also: Thyroidectomy for the Prevention of Medullary Thyroid Carcinoma
MEDICAL APPROPRIATENESS
Genetic testing for RET proto-oncogene point mutations is considered medically appropriate for an individual with one or more of following indications:
Has no symptoms, but has a family member with defined RET gene mutations; or
Has a family member known to be affected by inherited medullary thyroid cancer, but not previously evaluated for RET mutations; or
Has sporadic medullary thyroid cancer.
ADDITIONAL INFORMATION
Laboratories that conduct genetic testing must comply with the provisions of the Clinical Laboratory Improvement Act (CLIA), which is administered by the Health Care Financing Administration (HCFA) and the Centers for Disease Control and Prevention (CDC).
Genetic counselors must be licensed, certified, or eligible for board certification in their profession, and must have specific training in cancer genetics. They must also be a member of a national genetics society or a national oncology society. (NCI requirements.).
SOURCES
American Association of Clinical Endocrinologists. (2001, June). AACE/AAES medical/surgical guidelines for clinical practice: Management of thyroid carcinoma. Retrieved January 31, 2003 from http://www.aace.com/clin/guidelines/thyroid_carcinoma.pdf.
BlueCross BlueShield Association. Medical Policy Reference Manual. (2:2003). Genetic testing for germline mutations of the RET proto-oncogene in medullary carcinoma of the thyroid (2.04.05). Retrieved September 17, 2007 from BlueWeb. (One article reviewed)
Carreno, M., Girbes, J., Malluguiza, R., Serrano, S., Matias-Guiu, X., Tudela, J., et al. (2001). Usefulness of RET proto-oncogene in the diagnosis of hereditary-type medullary carcinoma of the thyroid. Correlation with surgical findings. Acta Otorrinolaringologica Espanola, 52 (1), 57-63. Abstract retrieved July 10, 2001 from PubMed database.
Eng, C., Clayton, D., Schuffenecker, I., Lenoir, G., Cote, G., Gagel, R. F., 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. Journal of the American Medical Association, 276 (19), 1575-1579. Abstract retrieved April 29, 1999 from PubMed database.
Feldman, G. L., Kambouris, M., Talpos, G. B., Mulligan, L. M., Ponder, B. A., Jackson, C. E. (1994). Clinical value of direct DNA analysis of the RET proto-oncogene in families with multiple endocrine neoplasia type 2A. Surgery, 116 (6), 1042-1047. Abstract retrieved April 29, 1999 from PubMed database.
Fink, M., Weinhusel, A., Niederle, B., Haas, O. A. (1996). Distinction between sporadic and hereditary medullary thyroid carcinoma (MTC) by mutation analysis of the RET proto-oncogene. "Study Group Multiple Endocrine Neoplasia Austria (SMENA)". International Journal of Cancer, 69 (4), 312-316. Abstract retrieved April 29, 1999 from PubMed database.
Frilling, A., Dralle, H., Eng, C., Raue, F., Broelsch C. E. (1995). Presymptomatic DNA screening in families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Surgery, 118 (6), 1099-1103. Abstract retrieved April 29, 1999 from PubMed database.
Hassett, S., Costigan, C., McDermott, M., Fitzgerald, R. J. (2000). Prophylactic thyroidectomy in the treatment of thyroid medullary carcinoma. Age for surgery? European Journal of Pediatric Surgery 10 (5), 334-336. Abstract retrieved July 10, 2001 from PubMed database.
Heshmati, H. M., Gharib, H., Khosla, S., Abu-Lebdeh, H. S., Lindor, N. M. Thibodeau, S. N. (1997). Genetic testing in medullary thyroid carcinoma syndromes: mutation types and clinical significance. Mayo Clinic Proceedings, 72 (5), 430-436. Abstract retrieved April 29, 1999 from PubMed database.
Lips, C. J., Hoppener, J. W., Thijssen, J. H. (2001). Medullary thyroid carcinoma: role of genetic testing and calcitonin measurement. Annals of Clinical Biochemistry, 38 (Pt 3), 168-179. Abstract retrieved July 10, 2001 from PubMed database.
Raue, F. (1998). German medullary thyroid carcinoma/multiple endocrine neoplasia registry. German MTC/MEN Study Group. Medullary Thyroid Carcinoma/Multiple Endocrine Neoplasia Type 2. Langenbecks Archives of Surgery, 383 (5), 334-336. Abstract retrieved April 29, 1999 from PubMed database.
Shirahama, S., Ogura, K., Takami, H., Ito, K., Tohsen, T., Miyauchi, A., et al. (1998). Mutational analysis of the RET proto-oncogene in 71 Japanese patients with medullary thyroid carcinoma. Journal of Human Genetics, 43 (2), 101-106. Abstract retrieved March 5, 1999 from PubMed database.
Skinner, M. A., Wells, S. A. Jr. (1997). Medullary carcinoma of the thyroid gland and the MEN 2 syndromes. Seminars in Pediatric Surgery, 6 (3), 134-140. Abstract retrieved March 5, 1999 from PubMed database.
The Technology Evaluation Center. (1997, August). Genetic testing for germline mutations of the RET proto-oncogene in medullary carcinoma of the thyroid (Vol. 12, No. 12). Chicago: BlueCross BlueShield Association.
Ukkat, J., Lorenz, K., Hinze, R., Thomusch, O., Dralle, H. et al. (2001). Importance of early screening and prophylactic thyroidectomy in asymptomatic nonindex ret germline carriers. World Journal of Surgery, 25 (6), 713-717. Abstract retrieved July 10, 2001 PubMed database.
Wells, S. A. Jr, Chi, D. D., Toshima, K., Dehner, L. P., Coffin, D. M., Dowton, S. B., et al. (1994). Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Annals of Surgery, 220 (3), 237-250. Abstract retrieved April 29, 1999 from PubMed database.
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EFFECTIVE DATE |
11/8/2007 |
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