In English | En español
Questions About Cancer? 1-800-4-CANCER

Genetics of Medullary Thyroid Cancer (PDQ®)

  • Last Modified: 07/25/2012

Page Options

  • Print This Page
  • Print This Document
  • View Entire Document
  • Email This Document


Natural History of Medullary Thyroid Cancer
Hereditary Medullary Thyroid Cancer

 [Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

 [Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

Natural History of Medullary Thyroid Cancer

Thyroid cancer represents approximately 3% of new malignancies occurring annually in the United States, with an estimated 56,460 cancer diagnoses and 1,780 cancer deaths per year.[1] Of these cancer diagnoses, 2% to 3% are medullary thyroid cancer (MTC).[2,3]

MTC arises from the parafollicular calcitonin-secreting cells of the thyroid gland. MTC occurs in sporadic and familial forms and may be preceded by C-cell hyperplasia (CCH), although CCH is a relatively common abnormality in middle-aged adults.[4,5]

Average survival for MTC is lower than that for more common thyroid cancers (e.g., 83% 5-year survival for MTC compared with 90% to 94% 5-year survival for papillary and follicular thyroid cancer).[3,6] Survival is correlated with stage at diagnosis, and decreased survival in MTC can be accounted for in part by a high proportion of late-stage diagnosis.[3,6,7]

In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, familial versus sporadic form, and diagnosis by biochemical screening (i.e., screening for calcitonin elevation) versus symptoms.[7-10]

A Surveillance, Epidemiology, and End Results (SEER) population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95.6% for disease confined to the thyroid gland to 40% for those with distant metastases.[8]

Hereditary Medullary Thyroid Cancer

While the majority of MTC cases are sporadic, approximately 20% to 25% are hereditary because of mutations in the RET (REarranged during Transfection) proto-oncogene.[11-13] Mutations in the RET gene cause multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominant disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 (MEN 1) (OMIM) is an autosomal dominant endocrinopathy that is genetically and clinically distinct from MEN 2; however, the similar nomenclature for MEN 1 and MEN 2 may cause confusion. Of note, there is no increased risk of thyroid cancer for MEN 1.

Historically, MEN 2 has been classified into three subtypes based on the presence or absence of certain endocrine tumors in the individual or family:

  • MEN 2A (OMIM).
  • Familial medullary thyroid carcinoma (FMTC) (OMIM).
  • MEN 2B (OMIM).

All three subtypes impart a high risk of developing MTC. MEN 2A has an increased risk of pheochromocytoma and parathyroid adenoma and/or hyperplasia. MEN 2B has an increased risk of pheochromocytoma and includes additional clinical features such as mucosal neuromas of the lips and tongue, distinctive faces with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and an asthenic Marfanoid body habitus. FMTC has been defined as the presence of at least four individuals with MTC without any other signs or symptoms of pheochromocytoma or hyperparathyroidism in the proband or other family members.[14]

Some families previously classified as FMTC will go on to develop one or more of the MEN 2A-related tumors, suggesting that FMTC is simply a milder variant of MEN 2A. Offspring of affected individuals have a 50% chance of inheriting the gene mutation.

The age of onset of MTC varies in different subtypes of MEN 2. MTC typically occurs in early childhood for MEN 2B, predominantly early adulthood for MEN 2A, and middle age for FMTC.

Germline deoxyribonucleic acid (DNA)-based testing of the RET gene (chromosomal region 10q11.2) identifies disease-causing mutations in more than 95% of individuals with MEN 2A and MEN 2B and in about 88% of individuals with FMTC.[15]


  1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online. Last accessed September 24, 2012. 

  2. Incidence: Thyroid Cancer. Bethesda, Md: National Cancer Institute, SEER, 2004. Available online. Last accessed December 8, 2011. 

  3. Hundahl SA, Fleming ID, Fremgen AM, et al.: A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments] Cancer 83 (12): 2638-48, 1998.  [PUBMED Abstract]

  4. Guyétant S, Rousselet MC, Durigon M, et al.: Sex-related C cell hyperplasia in the normal human thyroid: a quantitative autopsy study. J Clin Endocrinol Metab 82 (1): 42-7, 1997.  [PUBMED Abstract]

  5. LiVolsi VA: C cell hyperplasia/neoplasia. J Clin Endocrinol Metab 82 (1): 39-41, 1997.  [PUBMED Abstract]

  6. Bhattacharyya N: A population-based analysis of survival factors in differentiated and medullary thyroid carcinoma. Otolaryngol Head Neck Surg 128 (1): 115-23, 2003.  [PUBMED Abstract]

  7. Modigliani E, Vasen HM, Raue K, et al.: Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med 238 (4): 363-7, 1995.  [PUBMED Abstract]

  8. Roman S, Lin R, Sosa JA: Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 107 (9): 2134-42, 2006.  [PUBMED Abstract]

  9. Bergholm U, Bergström R, Ekbom A: Long-term follow-up of patients with medullary carcinoma of the thyroid. Cancer 79 (1): 132-8, 1997.  [PUBMED Abstract]

  10. Kebebew E, Ituarte PH, Siperstein AE, et al.: Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 88 (5): 1139-48, 2000.  [PUBMED Abstract]

  11. Elisei R, Romei C, Cosci B, et al.: RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab 92 (12): 4725-9, 2007.  [PUBMED Abstract]

  12. Paszko Z, Sromek M, Czetwertynska M, et al.: The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland. Cancer Invest 25 (8): 742-9, 2007.  [PUBMED Abstract]

  13. Pelizzo MR, Boschin IM, Bernante P, et al.: Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur J Surg Oncol 33 (4): 493-7, 2007.  [PUBMED Abstract]

  14. Eng C: Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. N Engl J Med 335 (13): 943-51, 1996.  [PUBMED Abstract]

  15. Brandi ML, Gagel RF, Angeli A, et al.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86 (12): 5658-71, 2001.  [PUBMED Abstract]