Approach to therapy in multiple endocrine neoplasia type 2
- Cornelis J Lips, MD, PhD
Cornelis J Lips, MD, PhD
- Professor of Endocrinology and Metabolism
- Department of Internal Medicine
- University Medical Center Utrecht, The Netherlands
- Douglas W Ball, MD
Douglas W Ball, MD
- Associate Professor of Medicine and Oncology
- Johns Hopkins University School of Medicine
Multiple endocrine neoplasia type 2 (MEN2) is subclassified into two distinct syndromes: types 2A (MEN2A) and 2B (MEN2B) (table 1). Affected patients have germline mutations in the RET proto-oncogene.
●MEN2A is a heritable predisposition to medullary thyroid cancer (MTC), pheochromocytoma, and primary parathyroid hyperplasia. There are four variants of MEN2A.
●MEN2B shares the inherited predisposition to MTC and pheochromocytoma found in MEN2A, but there is no parathyroid gland involvement. Patients with MEN2B tend to have, in addition, mucosal neuromas, intestinal ganglioneuromas, and a Marfanoid habitus.
In both syndromes, there is an occurrence of multicentric tumor formation in all organs where the RET proto-oncogene is expressed. This topic will review the therapy of these endocrine tumor syndromes. The classification, genetics, clinical features, diagnosis, and evaluation of MEN2 are discussed separately. (See "Classification and genetics of multiple endocrine neoplasia type 2" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)
Treatment of sporadic MTC is also discussed in more detail elsewhere. (See "Medullary thyroid cancer: Treatment and prognosis".)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- 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.
- Raue F, Frank-Raue K, Grauer A. Multiple endocrine neoplasia type 2. Clinical features and screening. Endocrinol Metab Clin North Am 1994; 23:137.
- American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009; 19:565.
- Gagel RF, Robinson MF, Donovan DT, Alford BR. Clinical review 44: Medullary thyroid carcinoma: recent progress. J Clin Endocrinol Metab 1993; 76:809.
- Wells SA Jr, Dilley WG, Farndon JA, et al. Early diagnosis and treatment of medullary thyroid carcinoma. Arch Intern Med 1985; 145:1248.
- O'Riordain DS, O'Brien T, Crotty TB, et al. Multiple endocrine neoplasia type 2B: more than an endocrine disorder. Surgery 1995; 118:936.
- 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.
- Cupisti K, Wolf A, Raffel A, et al. Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution's experience over 20 years. Ann Surg 2007; 246:815.
- 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.
- Miccoli P, Minuto MN, Ugolini C, et al. Clinically unpredictable prognostic factors in the outcome of medullary thyroid cancer. Endocr Relat Cancer 2007; 14:1099.
- Baloch ZW, LiVolsi VA. Prognostic factors in well-differentiated follicular-derived carcinoma and medullary thyroid carcinoma. Thyroid 2001; 11:637.
- Rohmer V, Vidal-Trecan G, Bourdelot A, et al. Prognostic factors of disease-free survival after thyroidectomy in 170 young patients with a RET germline mutation: a multicenter study of the Groupe Francais d'Etude des Tumeurs Endocrines. J Clin Endocrinol Metab 2011; 96:E509.
- Niccoli-Sire P, Murat A, Rohmer V, et al. When should thyroidectomy be performed in familial medullary thyroid carcinoma gene carriers with non-cysteine RET mutations? Surgery 2003; 134:1029.
- Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab 2005; 90:2029.
- Frank-Raue K, Rondot S, Raue F. Molecular genetics and phenomics of RET mutations: Impact on prognosis of MTC. Mol Cell Endocrinol 2010; 322:2.
- Skinner MA, Moley JA, Dilley WG, et al. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 2005; 353:1105.
- Marini F, Falchetti A, Del Monte F, et al. Multiple endocrine neoplasia type 2. Orphanet J Rare Dis 2006; 1:45.
- Machens A, Dralle H. Genotype-phenotype based surgical concept of hereditary medullary thyroid carcinoma. World J Surg 2007; 31:957.
- Machens A, Ukkat J, Brauckhoff M, et al. Advances in the management of hereditary medullary thyroid cancer. J Intern Med 2005; 257:50.
- Gimm O, Marsh DJ, Andrew SD, et al. Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab 1997; 82:3902.
- Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene 1997; 15:1213.
- Cranston AN, Carniti C, Oakhill K, et al. RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res 2006; 66:10179.
- Miyauchi A, Futami H, Hai N, et al. Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res 1999; 90:1.
- Kameyama K, Okinaga H, Takami H. RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan. Biomed Pharmacother 2004; 58:345.
- Iwashita T, Murakami H, Kurokawa K, et al. A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun 2000; 268:804.
- Menko FH, van der Luijt RB, de Valk IA, et al. Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. J Clin Endocrinol Metab 2002; 87:393.
- Duh QY, Sancho JJ, Greenspan FS, et al. Medullary thyroid carcinoma. The need for early diagnosis and total thyroidectomy. Arch Surg 1989; 124:1206.
- Lips CJ, Höppener JW, Van Nesselrooij BP, Van der Luijt RB. Counselling in multiple endocrine neoplasia syndromes: from individual experience to general guidelines. J Intern Med 2005; 257:69.
- Yip L, Cote GJ, Shapiro SE, et al. Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg 2003; 138:409.
- Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 2003; 349:1517.
- Cote GJ, Gagel RF. Lessons learned from the management of a rare genetic cancer. N Engl J Med 2003; 349:1566.
- Lesueur F, Cebrian A, Cranston A, et al. Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. J Clin Endocrinol Metab 2005; 90:3454.
- Learoyd DL, Gosnell J, Elston MS, et al. Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol (Oxf) 2005; 63:636.
- Lombardo F, Baudin E, Chiefari E, et al. Familial medullary thyroid carcinoma: clinical variability and low aggressiveness associated with RET mutation at codon 804. J Clin Endocrinol Metab 2002; 87:1674.
- Webb TA, Sheps SG, Carney JA. Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2. Am J Surg Pathol 1980; 4:121.
- Evans DB, Lee JE, Merrell RC, Hickey RC. Adrenal medullary disease in multiple endocrine neoplasia type 2. Appropriate management. Endocrinol Metab Clin North Am 1994; 23:167.
- Utiger RD. Medullary thyroid carcinoma, genes, and the prevention of cancer. N Engl J Med 1994; 331:870.
- Jansson S, Tisell LE, Fjälling M, et al. Early diagnosis of and surgical strategy for adrenal medullary disease in MEN II gene carriers. Surgery 1988; 103:11.
- Lips KJ, Van der Sluys Veer J, Struyvenberg A, et al. Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome). Am J Med 1981; 70:1051.
- Herfarth KK, Bartsch D, Doherty GM, et al. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery 1996; 120:966.
- Gagel RF, Tashjian AH Jr, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 1988; 318:478.
- Scholten A, Schreinemakers JM, Pieterman CR, et al. Evolution of surgical treatment of primary hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Endocr Pract 2011; 17:7.
- Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab 2014; 99:3561.
- O'Riordain DS, O'Brien T, Grant CS, et al. Surgical management of primary hyperparathyroidism in multiple endocrine neoplasia types 1 and 2. Surgery 1993; 114:1031.
- Wells SA Jr, Donis-Keller H. Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes. Endocrinol Metab Clin North Am 1994; 23:215.
- MEDULLARY THYROID CANCER
- Established disease
- - Preoperative evaluation
- - Thyroidectomy
- - Postoperative management
- - Management of residual or recurrent disease
- Preventive surgery
- - Timing of surgery
- - Surgical approach
- Surgical approach
- PRIMARY HYPERPARATHYROIDISM
- Management of asymptomatic disease
- Symptomatic disease
- Preoperative localization
- Surgical approach
- Medical therapy
- OTHER ASSOCIATED DISEASES
- SUMMARY AND RECOMMENDATIONS