Overview There are 3 main histologic types of thyroid carcinoma: differentiated (including papillary, follicular, and Hürthle), medullary, and anaplastic (aggressive undifferentiated tumor). Of 53,856 patients treated for thyroid carcinoma between 1985 and 1995, 80% had papillary, 11% had follicular, 3% had Hürthle cell, 4% had medullary, and 2% had anaplastic thyroid carcinoma.1 These NCCN guidelines focus on medullary thyroid carcinoma (MTC). Another NCCN guideline addresses papillary, follicular, Hürthle cell, and anaplastic thyroid carcinomas (see NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma [to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org]). MTC derives from the neuroendocrine parafollicular calcitonin-producing (C) cells of the thyroid.2–4 Sporadic MTC accounts for approximately 80% of all cases of the disease. The remaining cases consist of inherited tumor syndromes, such as multiple endocrine neoplasia type 2A (MEN 2A), which is the most common type; MEN 2B; or familial MTC.5,6 Sporadic disease typically presents in the fifth or sixth decade. Familial forms of the disease tend to present at earlier ages.2 Because the C cells are predominantly located in the upper portion of each thyroid lobe, patients with sporadic disease typically present with upper pole thyroid nodules. Metastatic cervical adenopathy appears in approximately 50% of patients at initial presentation. Symptoms of upper aerodigestive tract compression or invasion are reported by up to 15% of patients with sporadic disease.7 Symptoms from distant metastases in the lungs or bones occur in 5% to 10% of patients. The ability of the tumor to...
  • 1.

    Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995 [see comments]. Cancer 1998;83:26382648.

    • Search Google Scholar
    • Export Citation
  • 2.

    Kloos RT, Eng C, Evans DB. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009;19:565612.

  • 3.

    Gagel RF, Hoff AO, Cote GJ. Medullary thyroid carcinoma. In: Braverman LE, Utiger RD, eds. Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text, 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2005:967988.

    • Search Google Scholar
    • Export Citation
  • 4.

    Gagel RF, Cote GJ. Pathogenesis of medullary thyroid carcinoma. In: Fagin JA, ed. Thyroid Cancer. Boston/Dordrecht/London: Kluwer Academic; 1998:85103.

    • Search Google Scholar
    • Export Citation
  • 5.

    Gertner ME, Kebebew E. Multiple endocrine neoplasia type 2. Curr Treat Options Oncol 2004;5:315325.

  • 6.

    Raue F, Frank-Raue K. Multiple endocrine neoplasia type 2: 2007 update. Horm Res 2007;68(Suppl 5):101104.

  • 7.

    Saad MF, Ordonez NG, Rashid RK. Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine (Baltimore) 1984;63:319342.

    • Search Google Scholar
    • Export Citation
  • 8.

    Mazzaferri EL. Thyroid carcinoma: Papillary and follicular. In: Mazzaferri EL, Samaan NA, eds. Endocrine Tumors. Cambridge: Blackwell Scientific Publications; 1993:278333.

    • Search Google Scholar
    • Export Citation
  • 9.

    Hegedus L. Clinical practice. The thyroid nodule. N Engl J Med 2004;351:17641771.

  • 10.

    Cooper DS, Doherty GM, Haugen BR. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006;16:109142.

    • Search Google Scholar
    • Export Citation
  • 11.

    Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas. Prevalence by palpation and ultrasonography. Arch Intern Med 1994;154:18381840.

    • Search Google Scholar
    • Export Citation
  • 12.

    Ron E, Lubin JH, Shore RE. Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiat Res 1995;141:259277.

    • Search Google Scholar
    • Export Citation
  • 13.

    Schneider AB, Bekerman C, Leland J. Thyroid nodules in the follow-up of irradiated individuals: comparison of thyroid ultrasound with scanning and palpation. J Clin Endocrinol Metab 1997;82:40204027.

    • Search Google Scholar
    • Export Citation
  • 14.

    Horner MJ, Ries LA, Krapcho M. SEER Cancer Statistics Review, 1975–2006. Bethesda, MD: National Cancer Institute; 2009. Available at: http://seer.cancer.gov/csr/1975_2006/results_merged/sect_26_thyroid.pdf. Accessed March 15, 2010.

    • Search Google Scholar
    • Export Citation
  • 15.

    Jemal A, Siegel R, Ward E. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225249.

  • 16.

    Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:418428.

    • Search Google Scholar
    • Export Citation
  • 17.

    Layfield LJ, Cibas ES, Gharib H, Mandel SJ. Thyroid aspiration cytology: current status. CA Cancer J Clin 2009;59:99110.

  • 18.

    Frates MC, Benson CB, Charboneau JW. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Radiology 2005;237:794800.

    • Search Google Scholar
    • Export Citation
  • 19.

    Mazzaferri EL. Thyroid cancer in thyroid nodules: finding a needle in the haystack. Am J Med 1992;93:359362.

  • 20.

    Hamming JF, Goslings BM, van Steenis GJ. The value of fine-needle aspiration biopsy in patients with nodular thyroid disease divided into groups of suspicion of malignant neoplasms on clinical grounds. Arch Intern Med 1990;150:113116.

    • Search Google Scholar
    • Export Citation
  • 21.

    Chan BK, Desser TS, McDougall IR. Common and uncommon sonographic features of papillary thyroid carcinoma. J Ultrasound Med 2003;22:10831090.

    • Search Google Scholar
    • Export Citation
  • 22.

    Koike E, Noguchi S, Yamashita H. Ultrasonographic characteristics of thyroid nodules: prediction of malignancy. Arch Surg 2001;136:334337.

  • 23.

    Haymart MR, Repplinger DJ, Leverson GE. Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage. J Clin Endocrinol Metab 2008;93:809814.

    • Search Google Scholar
    • Export Citation
  • 24.

    Henry JF, Denizot A, Puccini M. Early diagnosis of sporadic medullary cancers of the thyroid: value of systematic assay of calcitonin. Presse Med 1996;25:15831588 [in French].

    • Search Google Scholar
    • Export Citation
  • 25.

    Cooper DS, Doherty GM, Haugen BR. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:11671214.

    • Search Google Scholar
    • Export Citation
  • 26.

    Cheung K, Roman SA, Wang TS. Calcitonin measurement in the evaluation of thyroid nodules in the United States: a cost-effectiveness and decision analysis. J Clin Endocrinol Metab 2008;93:21732180.

    • Search Google Scholar
    • Export Citation
  • 27.

    Yeh MW, Demircan O, Ituarte P, Clark OH. False-negative fine-needle aspiration cytology results delay treatment and adversely affect outcome in patients with thyroid carcinoma. Thyroid 2004;14:207215.

    • Search Google Scholar
    • Export Citation
  • 28.

    Asa SL, Bedard YC. Fine-needle aspiration cytology and histopathology. In: Clark OH, Noguchi S, eds. Thyroid Cancer: Diagnosis and Treatment. St Louis: Quality Medical Publishing; 2000:105126.

    • Search Google Scholar
    • Export Citation
  • 29.

    Pacini F, Fontanelli M, Fugazzola L. Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 1994;78:826829.

    • Search Google Scholar
    • Export Citation
  • 30.

    Niccoli P, Wion-Barbot N, Caron P. Interest of routine measurement of serum calcitonin: study in a large series of thyroidectomized patients. The French Medullary Study Group. J Clin Endocrinol Metab 1997;82:338341.

    • Search Google Scholar
    • Export Citation
  • 31.

    Ozgen AG, Hamulu F, Bayraktar F. Evaluation of routine basal serum calcitonin measurement for early diagnosis of medullary thyroid carcinoma in seven hundred seventy-three patients with nodular goiter. Thyroid 1999;9:579582.

    • Search Google Scholar
    • Export Citation
  • 32.

    Horvit PK, Gagel RF. The goitrous patient with an elevated serum calcitonin—what to do? J Clin Endocrinol Metab 1997;82:335337.

  • 33.

    Hodak SP, Burman KD. The calcitonin conundrum—is it time for routine measurement of serum calcitonin in patients with thyroid nodules? J Clin Endocrinol Metab 2004;89:511514.

    • Search Google Scholar
    • Export Citation
  • 34.

    Papi G, Corsello SM, Cioni K. Value of routine measurement of serum calcitonin concentrations in patients with nodular thyroid disease: a multicenter study. J Endocrinol Invest 2006;29:427437.

    • Search Google Scholar
    • Export Citation
  • 35.

    Kouvaraki MA, Shapiro SE, Perrier ND. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid 2005;15:531544.

    • Search Google Scholar
    • Export Citation
  • 36.

    Wohllk N, Cote GJ, Bugalho MM. Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 1996;81:37403745.

    • Search Google Scholar
    • Export Citation
  • 37.

    Elisei R, Romei C, Cosci B. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab 2007;92:47254729.

    • Search Google Scholar
    • Export Citation
  • 38.

    Greene FL, Page DL, Fleming ID, eds. AJCC Cancer Staging Manual, 6th ed. New York: Springer-Verlag; 2002.

  • 39.

    Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual, 7th ed. New York: Springer; 2009.

  • 40.

    Fleming ID, Cooper JS, Henson DE, eds. AJCC Cancer Staging Manual, 5th ed. Philadelphia: Lippincott Williams & Wilkins; 1997.

  • 41.

    Dottorini ME, Assi A, Sironi M. Multivariate analysis of patients with medullary thyroid carcinoma. Prognostic significance and impact on treatment of clinical and pathologic variables. Cancer 1996;77:15561565.

    • Search Google Scholar
    • Export Citation
  • 42.

    Kebebew E, Ituarte PH, Siperstein AE. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000;88:11391148.

    • Search Google Scholar
    • Export Citation
  • 43.

    Samaan NA, Schultz PN, Hickey RC. Medullary thyroid carcinoma: prognosis of familial versus sporadic disease and the role of radiotherapy. J Clin Endocrinol Metab 1988;67:801805.

    • Search Google Scholar
    • Export Citation
  • 44.

    O'Riordain DS, O'Brien T, Weaver AL. Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. Surgery 1994;116:10171023.

    • Search Google Scholar
    • Export Citation
  • 45.

    Lippman SM, Mendelsohn G, Trump DL. The prognostic and biological significance of cellular heterogeneity in medullary thyroid carcinoma: a study of calcitonin, L-dopa decarboxylase, and histaminase. J Clin Endocrinol Metab 1982;54:233240.

    • Search Google Scholar
    • Export Citation
  • 46.

    Mendelsohn G, Wells SA Jr, Baylin SB. Relationship of tissue carcinoembryonic antigen and calcitonin to tumor virulence in medullary thyroid carcinoma. An immunohistochemical study in early, localized, and virulent disseminated stages of disease. Cancer 1984;54:657662.

    • Search Google Scholar
    • Export Citation
  • 47.

    Byar DP, Green SB, Dor P. A prognostic index for thyroid carcinoma. A study of the E.O.R.T.C. Thyroid Cancer Cooperative Group. Eur J Cancer 1979;15:10331041.

    • Search Google Scholar
    • Export Citation
  • 48.

    Szinnai G, Meier C, Komminoth P, Zumsteg UW. Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis. Pediatrics 2003;111:E132139.

    • Search Google Scholar
    • Export Citation
  • 49.

    Romei C, Elisei R, Pinchera A. 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;81:16191622.

    • Search Google Scholar
    • Export Citation
  • 50.

    Eng C, Clayton D, Schuffenecker I. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996;276:15751579.

    • Search Google Scholar
    • Export Citation
  • 51.

    Machens A, Dralle H. Genotype-phenotype based surgical concept of hereditary medullary thyroid carcinoma. World J Surg 2007;31:957968.

  • 52.

    Learoyd DL, Gosnell J, Elston MS. Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol (Oxf) 2005;63:636641.

    • Search Google Scholar
    • Export Citation
  • 53.

    Brandi ML, Gagel RF, Angeli A. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:56585671.

  • 54.

    Machens A, Niccoli-Sire P, Hoegel J. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 2003;349:15171525.

  • 55.

    Skinner MA, Moley JA, Dilley WG. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 2005;353:11051113.

  • 56.

    Burge MR, Zeise TM, Johnsen MW. Risks of complication following thyroidectomy. J Gen Intern Med 1998;13:2431.

  • 57.

    Miccoli P, Antonelli A & Spinelli C L. Completion total thyroidectomy in children with thyroid cancer secondary to the Chernobyl accident. Arch Surg 1998;133:8993.

    • Search Google Scholar
    • Export Citation
  • 58.

    Dralle H, Gimm O, Simon D. Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World J Surg 1998;22:744750; discussion 750–741.

    • Search Google Scholar
    • Export Citation
  • 59.

    Udelsman R, Lakatos E, Ladenson P. Optimal surgery for papillary thyroid carcinoma. World J Surg 1996;20:8893.

  • 60.

    Pattou F, Combemale F, Fabre S. Hypocalcemia following thyroid surgery: incidence and prediction of outcome. World J Surg 1998;22:718724.

  • 61.

    Sosa JA, Bowman HM, Tielsch JM. The importance of surgeon experience for clinical and economic outcomes from thyroidectomy. Ann Surg 1998;228:320330.

    • Search Google Scholar
    • Export Citation
  • 62.

    Brierley J, Tsang R, Simpson WJ. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid 1996;6:305310.

    • Search Google Scholar
    • Export Citation
  • 63.

    Brierley J, Maxon HR. Radioiodine and external radiation therapy in the treatment of thyroid cancer. In: Fagin JA, ed. Thyroid Cancer. Boston/Dordrecht/London: Kluwer Academic; 1998:285317.

    • Search Google Scholar
    • Export Citation
  • 64.

    van Heerden JA, Grant CS, Gharib H. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 1990;212:395400; discussion 400–391.

    • Search Google Scholar
    • Export Citation
  • 65.

    Scopsi L, Sampietro G, Boracchi P. Multivariate analysis of prognostic factors in sporadic medullary carcinoma of the thyroid. A retrospective study of 109 consecutive patients. Cancer 1996;78:21732183.

    • Search Google Scholar
    • Export Citation
  • 66.

    Tisell LE, Hansson G, Jansson S, Salander H. Reoperation in the treatment of asymptomatic metastasizing medullary thyroid carcinoma. Surgery 1986;99:6066.

    • Search Google Scholar
    • Export Citation
  • 67.

    Moley JF, Debenedetti MK, Dilley WG. Surgical management of patients with persistent or recurrent medullary thyroid cancer. J Intern Med 1998;243:521526.

    • Search Google Scholar
    • Export Citation
  • 68.

    Fleming JB, Lee JE, Bouvet M. Surgical strategy for the treatment of medullary thyroid carcinoma. Ann Surg 1999;230:697707.

  • 69.

    Kober F, Hermann M, Handler A, Krotla G. Effect of sorafenib in symptomatic metastatic medullary thyroid cancer [abstract]. J Clin Oncol 2007;25(Suppl 1):Abstract 14065.

    • Search Google Scholar
    • Export Citation
  • 70.

    Kelleher FC, McDermott R. Response to sunitinib in medullary thyroid cancer. Ann Intern Med 2008;148:567.

  • 71.

    Sherman SI. Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers. J Clin Endocrinol Metab 2009;94:14931499.

    • Search Google Scholar
    • Export Citation
  • 72.

    Schlumberger M, Challeton C, De Vathaire F, Parmentier C. Treatment of distant metastases of differentiated thyroid carcinoma. J Endocrinol Invest 1995;18:170172.

    • Search Google Scholar
    • Export Citation
  • 73.

    Nocera M, Baudin E, Pellegriti G. Treatment of advanced medullary thyroid cancer with an alternating combination of doxorubicin-streptozocin and 5 FU-dacarbazine. Groupe d'Etude des Tumeurs a Calcitonine (GETC). Br J Cancer 2000;83:715718.

    • Search Google Scholar
    • Export Citation
  • 74.

    Schlumberger MJ, Elisei R, Bastholt L. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol 2009;27:37943801.

    • Search Google Scholar
    • Export Citation
  • 75.

    Wells SA Jr, Gosnell JE, Gagel RF. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 2010 ;28 :767772.

    • Search Google Scholar
    • Export Citation
  • 76.

    Hong D, Ye L, Gagel R. Medullary thyroid cancer: targeting the RET kinase pathway with sorafenib/tipifarnib. Mol Cancer Ther 2008;7:10011006.

    • Search Google Scholar
    • Export Citation
  • 77.

    Bugalho MJ, Domingues R, Borges A. A case of advanced medullary thyroid carcinoma successfully treated with sunitinib. Oncologist 2009;14:10831087.

    • Search Google Scholar
    • Export Citation
  • 78.

    Goulart B, Carr L, Martins RG. Phase II study of sunitinib in iodine refractory, well-differentiated thyroid cancer (WDTC) and metastatic medullary thyroid carcinoma (MTC) [abstract]. J Clin Oncol 2008;26(Suppl 1):Abstract 6062.

    • Search Google Scholar
    • Export Citation
  • 79.

    Spector E, Franklin MJ, Truskinovsky AM, Dudek AZ. Sorafenib induces partial response in metastatic medullary thyroid carcinoma. Acta Oncol 2010;49:104106.

    • Search Google Scholar
    • Export Citation
  • 80.

    Salgia R, Sherman S, Hong DS. A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC) [abstract]. J Clin Oncol 2008;26(Suppl 1):Abstract 3522.

    • Search Google Scholar
    • Export Citation
  • 81.

    Sugawara M, Geffner DL, Martinez D, Hershman JM. Novel treatment of medullary thyroid cancer. Curr Opin Endocrinol Diabetes Obes 2009;16:367372.

    • Search Google Scholar
    • Export Citation
  • 82.

    Santarpia L, Ye L, Gagel RF. Beyond RET: potential therapeutic approaches for advanced and metastatic medullary thyroid carcinoma. J Intern Med 2009;266:99113.

    • Search Google Scholar
    • Export Citation
  • 83.

    Cakir M, Grossman AB. Medullary thyroid cancer: molecular biology and novel molecular therapies. Neuroendocrinology 2009;90:323348.

  • 84.

    Cerrato A, De Falco V, Santoro M. Molecular genetics of medullary thyroid carcinoma: the quest for novel therapeutic targets. J Mol Endocrinol 2009;43:143155.

    • Search Google Scholar
    • Export Citation
  • 85.

    Chatal JF, Campion L, Kraeber-Bodere F. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group. J Clin Oncol 2006;24:17051711.

    • Search Google Scholar
    • Export Citation
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