Medullary thyroid cancer: Treatment and prognosis
- R Michael Tuttle, MD
R Michael Tuttle, MD
- Professor of Medicine
- Memorial Sloan Kettering Cancer Center
- Section Editors
- David S Cooper, MD
David S Cooper, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Pituitary Disease; Thyroid Disease
- Professor of Medicine and International Health
- Johns Hopkins University School of Medicine
- Douglas S Ross, MD
Douglas S Ross, MD
- Section Editor — Thyroid Disease
- Professor of Medicine
- Harvard Medical School
Patients with medullary thyroid cancer (MTC) can be cured only by complete resection of the thyroid tumor and any local and regional metastases. For patients with residual or recurrent disease after primary surgery or for those with distant metastases, the most appropriate treatment (surgery, chemotherapy, or radiotherapy) is less clear.
This topic review will discuss the role of surgery as primary therapy and the approaches to treating patients with persistent or recurrent MTC after surgery. The approach outlined below is largely in agreement with American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) guidelines [1,2]. Recommendations for the timing of thyroidectomy in children with RET mutations and the role of chemotherapy in the treatment of MTC are reviewed elsewhere. (See "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Preventative surgery' and "Medullary thyroid cancer: Chemotherapy and immunotherapy".)
Newly diagnosed patients with medullary thyroid cancer (MTC) should be staged both biochemically and radiologically (algorithm 1). This evaluation is reviewed briefly below and in more detail elsewhere. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging", section on 'Evaluation'.)
The following tests should be performed:
●Measurement of serum calcitonin and carcinoembryonic antigen (CEA) to determine whether they are produced by the tumor, and if so, as a baseline for comparison with results obtained after surgery. Among patients with either sporadic or familial tumors, those with higher preoperative serum calcitonin concentrations have larger tumors and are less likely to have normal serum concentrations after surgery than those with lower preoperative values .
- National Comprehensive Cancer Network (NCCN) - Guidelines http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on July 26, 2012).
- Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25:567.
- Cohen R, Campos JM, Salaün C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d'Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab 2000; 85:919.
- Machens A, Dralle H. Biomarker-based risk stratification for previously untreated medullary thyroid cancer. J Clin Endocrinol Metab 2010; 95:2655.
- Scollo C, Baudin E, Travagli JP, et al. Rationale for central and bilateral lymph node dissection in sporadic and hereditary medullary thyroid cancer. J Clin Endocrinol Metab 2003; 88:2070.
- Machens A, Hauptmann S, Dralle H. Prediction of lateral lymph node metastases in medullary thyroid cancer. Br J Surg 2008; 95:586.
- Kebebew E, Ituarte PH, Siperstein AE, et al. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000; 88:1139.
- Duh QY, Sancho JJ, Greenspan FS, et al. Medullary thyroid carcinoma. The need for early diagnosis and total thyroidectomy. Arch Surg 1989; 124:1206.
- Fleming JB, Lee JE, Bouvet M, et al. Surgical strategy for the treatment of medullary thyroid carcinoma. Ann Surg 1999; 230:697.
- Witt RL. What is the treatment of the lateral neck in clinically localized sporadic medullary thyroid cancer? Laryngoscope 2010; 120:1286.
- Giraudet AL, Vanel D, Leboulleux S, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab 2007; 92:4185.
- Saad MF, Guido JJ, Samaan NA. Radioactive iodine in the treatment of medullary carcinoma of the thyroid. J Clin Endocrinol Metab 1983; 57:124.
- Zedenius J, Larsson C, Bergholm U, et al. Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab 1995; 80:3088.
- Romei C, Elisei R, Pinchera A, et al. 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; 81:1619.
- Elisei R, Cosci B, Romei C, et al. Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab 2008; 93:682.
- Marsh DJ, Learoyd DL, Andrew SD, et al. Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf) 1996; 44:249.
- Lindsey SC, Ganly I, Palmer F, Tuttle RM. Response to initial therapy predicts clinical outcomes in medullary thyroid cancer. Thyroid 2015; 25:242.
- Engelbach M, Görges R, Forst T, et al. Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements. J Clin Endocrinol Metab 2000; 85:1890.
- Tuttle RM, Ganly I. Risk stratification in medullary thyroid cancer: moving beyond static anatomic staging. Oral Oncol 2013; 49:695.
- Yang JH, Lindsey SC, Camacho CP, et al. Integration of a postoperative calcitonin measurement into an anatomical staging system improves initial risk stratification in medullary thyroid cancer. Clin Endocrinol (Oxf) 2015; 83:938.
- Modigliani E, Cohen R, Campos JM, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'étude des tumeurs à calcitonine. Clin Endocrinol (Oxf) 1998; 48:265.
- Stepanas AV, Samaan NA, Hill CS Jr, Hickey RC. Medullary thyroid carcinoma: importance of serial serum calcitonin measurement. Cancer 1979; 43:825.
- Faggiano A, Milone F, Ramundo V, et al. A decrease of calcitonin serum concentrations less than 50 percent 30 minutes after thyroid surgery suggests incomplete C-cell tumor tissue removal. J Clin Endocrinol Metab 2010; 95:E32.
- Fugazzola L, Pinchera A, Luchetti F, et al. Disappearance rate of serum calcitonin after total thyroidectomy for medullary thyroid carcinoma. Int J Biol Markers 1994; 9:21.
- Girelli ME, Dotto S, Nacamulli D, et al. Prognostic value of early postoperative calcitonin level in medullary thyroid carcinoma. Tumori 1994; 80:113.
- Brauckhoff M, Gimm O, Brauckhoff K, et al. Calcitonin kinetics in the early postoperative period of medullary thyroid carcinoma. Langenbecks Arch Surg 2001; 386:434.
- Ismailov SI, Piulatova NR. Postoperative calcitonin study in medullary thyroid carcinoma. Endocr Relat Cancer 2004; 11:357.
- Jackson CE, Talpos GB, Kambouris A, et al. The clinical course after definitive operation for medullary thyroid carcinoma. Surgery 1983; 94:995.
- Wells SA Jr, Dilley WG, Farndon JA, et al. Early diagnosis and treatment of medullary thyroid carcinoma. Arch Intern Med 1985; 145:1248.
- Scopsi L, Sampietro G, Boracchi P, et al. Multivariate analysis of prognostic factors in sporadic medullary carcinoma of the thyroid. A retrospective study of 109 consecutive patients. Cancer 1996; 78:2173.
- Dottorini ME, Assi A, Sironi M, et al. Multivariate analysis of patients with medullary thyroid carcinoma. Prognostic significance and impact on treatment of clinical and pathologic variables. Cancer 1996; 77:1556.
- 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 2007; 33:493.
- Barbet J, Campion L, Kraeber-Bodéré F, et al. Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab 2005; 90:6077.
- Laure Giraudet A, Al Ghulzan A, Aupérin A, et al. Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol 2008; 158:239.
- Ong SC, Schöder H, Patel SG, et al. Diagnostic accuracy of 18F-FDG PET in restaging patients with medullary thyroid carcinoma and elevated calcitonin levels. J Nucl Med 2007; 48:501.
- Berná L, Cabezas R, Mora J, et al. 111In-octreotide and 99mTc(V)-dimercaptosuccinic acid studies in the imaging of recurrent medullary thyroid carcinoma. J Endocrinol 1995; 144:339.
- Udelsman R, Ball D, Baylin SB, et al. Preoperative localization of occult medullary carcinoma of the thyroid gland with single-photon emission tomography dimercaptosuccinic acid. Surgery 1993; 114:1083.
- Gotthardt M, Béhé MP, Beuter D, et al. Improved tumour detection by gastrin receptor scintigraphy in patients with metastasised medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging 2006; 33:1273.
- Abdelmoumene N, Schlumberger M, Gardet P, et al. Selective venous sampling catheterisation for localisation of persisting medullary thyroid carcinoma. Br J Cancer 1994; 69:1141.
- van Heerden JA, Grant CS, Gharib H, et al. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 1990; 212:395.
- Brierley J, Tsang R, Simpson WJ, et al. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid 1996; 6:305.
- Fersht N, Vini L, A'Hern R, Harmer C. The role of radiotherapy in the management of elevated calcitonin after surgery for medullary thyroid cancer. Thyroid 2001; 11:1161.
- Baudry C, Paepegaey AC, Groussin L. Reversal of Cushing's syndrome by vandetanib in medullary thyroid carcinoma. N Engl J Med 2013; 369:584.
- Fox E, Widemann BC, Chuk MK, et al. Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin Cancer Res 2013; 19:4239.
- Saad MF, Ordonez NG, Rashid RK, et al. Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine (Baltimore) 1984; 63:319.
- de Groot JW, Plukker JT, Wolffenbuttel BH, et al. Determinants of life expectancy in medullary thyroid cancer: age does not matter. Clin Endocrinol (Oxf) 2006; 65:729.
- Ho AS, Wang L, Palmer FL, et al. Postoperative Nomogram for Predicting Cancer-Specific Mortality in Medullary Thyroid Cancer. Ann Surg Oncol 2015; 22:2700.
- Momesso DP, Tuttle RM. Update on differentiated thyroid cancer staging. Endocrinol Metab Clin North Am 2014; 43:401.
- O'Riordain DS, O'Brien T, Weaver AL, et al. Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. Surgery 1994; 116:1017.
- 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; 67:801.
- Lippman SM, Mendelsohn G, Trump DL, et al. 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; 54:233.
- Faggiano A, Talbot M, Lacroix L, et al. Differential expression of galectin-3 in medullary thyroid carcinoma and C-cell hyperplasia. Clin Endocrinol (Oxf) 2002; 57:813.
- 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; 54:657.
- Machens A, Ukkat J, Hauptmann S, Dralle H. Abnormal carcinoembryonic antigen levels and medullary thyroid cancer progression: a multivariate analysis. Arch Surg 2007; 142:289.
- Machens A, Hauptmann S, Dralle H. Medullary thyroid cancer responsiveness to pentagastrin stimulation: an early surrogate parameter of tumor dissemination? J Clin Endocrinol Metab 2008; 93:2234.
- Walter MA, Meier C, Radimerski T, et al. Procalcitonin levels predict clinical course and progression-free survival in patients with medullary thyroid cancer. Cancer 2010; 116:31.
- PREOPERATIVE EVALUATION
- SURGICAL APPROACH
- MTC confined to the neck
- Locally advanced or metastatic MTC
- MTC diagnosed after lobectomy
- POSTOPERATIVE MANAGEMENT
- Monitor for postoperative complications
- Thyroxine therapy
- Assessment of tumor samples for somatic mutations
- SUBSEQUENT MANAGEMENT
- Serum calcitonin and CEA measurement
- - Undetectable calcitonin and normal CEA
- - Persistent hypercalcitoninemia
- Management of persistent/recurrent disease
- - Small volume, asymptomatic
- - Large volume or symptomatic
- - Palliation of the symptoms associated with hormonal excess
- SUMMARY AND RECOMMENDATIONS