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Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment (PDQ®)

Health Professional Version

.

Published online: October 17, 2024.

Created: .

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric multiple endocrine neoplasia (MEN) syndromes. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

General Information About Childhood Multiple Endocrine Neoplasia (MEN) Syndromes

MEN syndromes are familial disorders characterized by neoplastic changes that affect multiple endocrine organs.[1] Changes may include hyperplasia, benign adenomas, and carcinomas.

There are three types of MEN syndromes:

  • Type 1.
  • Type 2, which includes the following two subtypes:
    -

    Type 2A (includes familial medullary thyroid carcinoma).

    -

    Type 2B.

  • Type 4 (also called MENX).

For more information about MEN syndromes, see Genetics of Endocrine and Neuroendocrine Neoplasias.

References

  1. de Krijger RR: Endocrine tumor syndromes in infancy and childhood. Endocr Pathol 15 (3): 223-6, 2004. [PubMed: 15640547]

Clinical Presentation, Molecular Features, and Diagnostic Evaluation

The main clinical features and genetic alterations of the multiple endocrine neoplasia (MEN) syndromes are shown in Table 1.

Table 1. Multiple Endocrine Neoplasia (MEN) Syndromes With Associated Clinical Features and Genetic Alterations

SyndromeClinical Features/TumorsGenetic Alterations
MEN type 1 (Wermer syndrome) [1] Parathyroid 11q13 (MEN1 gene)
Pancreatic islets: Gastrinoma11q13 (MEN1 gene)
Insulinoma
Glucagonoma
VIPoma
Pituitary: Prolactinoma11q13 (MEN1 gene)
Somatotropinoma
Corticotropinoma
Other associated tumors (less common): Carcinoid—bronchial and thymic11q13 (MEN1 gene)
Adrenocortical
Lipoma
Angiofibroma
Collagenoma
MEN type 2A (Sipple syndrome) Medullary thyroid carcinoma 10q11.2 (RET gene)
Pheochromocytoma
Parathyroid gland
MEN type 2B Medullary thyroid carcinoma 10q11.2 (RET gene)
Pheochromocytoma
Mucosal neuromas
Intestinal ganglioneuromatosis
Marfanoid habitus
MEN type 4 Parathyroid gland 12p13 (CDKN1B)
Anterior pituitary tumors
Neuroendocrine tumors

MEN Type 1 (MEN1) Syndrome (Wermer Syndrome)

MEN1 syndrome is an autosomal dominant disorder characterized by the presence of tumors in the parathyroid, pancreatic islet cells, and anterior pituitary. Diagnosis of this syndrome should be considered when two endocrine tumors listed in Table 1 are present.

Clinical practice guidelines recommend that screening for patients with MEN1 syndrome begins by age 5 years and continues throughout life. The tests for screening are age specific and may include yearly serum calcium, parathyroid hormone, gastrin, glucagon, secretin, proinsulin, chromogranin A, prolactin, and IGF-1. Radiological screening should include magnetic resonance imaging of the brain and computed tomography of the abdomen every 1 to 3 years.[2-4]

One study documented the initial presentation of MEN1 syndrome occurring before age 21 years in 160 patients.[5] Of note, most patients had familial MEN1 syndrome and were monitored using an international screening protocol. Patients had the following symptoms and conditions:

  • Primary hyperparathyroidism, the most common symptom, was found in 75% of patients, usually only in those with biological abnormalities. Primary hyperparathyroidism diagnosed outside of a screening program is extremely rare, most often presents with nephrolithiasis, and should lead the clinician to suspect MEN1.[5,6]
  • Pituitary adenomas were discovered in 34% of patients, occurred mainly in females older than 10 years, and were often symptomatic.[5]
  • Pancreatic neuroendocrine tumors were found in 23% of patients. Specific diagnoses included insulinoma, nonsecreting pancreatic tumor, and Zollinger-Ellison syndrome. The first case of insulinoma occurred before age 5 years.[5]
  • Malignant tumors were found in four patients (two adrenal carcinomas, one gastrinoma, and one thymic carcinoma). The patient with thymic carcinoma died before age 21 years of rapidly progressive disease.

Germline MEN1 pathogenic variants are found in 70% to 90% of patients. However, this gene is frequently inactivated in sporadic tumors.[7] Variant testing is combined with clinical screening for patients and family members with proven at-risk MEN1 syndrome.[8]

MEN Type 2A (MEN2A) and MEN Type 2B (MEN2B) Syndromes

A germline activating pathogenic variant in the RET oncogene (a receptor tyrosine kinase) is responsible for the uncontrolled growth of cells in medullary thyroid carcinoma associated with MEN2A and MEN2B syndromes.[9-11] Table 2 describes the clinical features of these syndromes.

MEN2A

MEN2A is characterized by the presence of two or more endocrine tumors (see Table 1) in an individual or in close relatives.[12] RET variants in these patients are usually confined to exons 10 and 11.

  • Familial medullary thyroid carcinoma: This carcinoma is diagnosed in families with medullary thyroid carcinoma in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. RET variants in exons 10, 11, 13, and 14 account for most cases.
    The most recent literature suggests that this entity should not be identified as a form of hereditary medullary thyroid carcinoma that is separate from MEN2A and MEN2B. Familial medullary thyroid carcinoma should be recognized as a variant of MEN2A, to include families with only medullary thyroid cancer who meet the original criteria for familial disease. The original criteria include families of at least two generations with at least two, but less than ten, patients with germline RET pathogenic variants; small families in which two or fewer members in a single generation have germline RET pathogenic variants; and single individuals with a germline RET pathogenic variant.[13,14]

In a small percentage of cases, Hirschsprung disease has been associated with the development of neuroendocrine tumors such as medullary thyroid carcinoma. Germline RET inactivating pathogenic variants have been detected in up to 50% of patients with familial Hirschsprung disease and less often in the sporadic form.[15-17] Cosegregation of Hirschsprung disease and medullary thyroid carcinoma phenotype is infrequently reported, but these individuals usually have a variant in RET exon 10. Patients with Hirschsprung disease are screened for variants in RET exon 10. If such a variant is discovered, a prophylactic thyroidectomy should be considered.[17-19]

MEN2B

MEN2B is characterized by medullary thyroid carcinomas, parathyroid hyperplasias, adenomas, pheochromocytomas, mucosal neuromas, and ganglioneuromas.[12,20,21] The medullary thyroid carcinomas that develop in these patients are extremely aggressive. More than 95% of variants in these patients are confined to codon 918 in exon 16, causing receptor autophosphorylation and activation.[22] Patients also have medullated corneal nerve fibers, distinctive faces with enlarged lips, and an asthenic Marfanoid habitus.

A pentagastrin stimulation test can be used to detect medullary thyroid carcinoma in these patients. However, patient management is driven primarily by the results of genetic analysis for RET variants.[14,22]

A review of 38 patients with genetically confirmed MEN2B at the National Institutes of Health identified eight patients who developed pheochromocytoma in the course of follow-up.[23] Pheochromocytoma was diagnosed at a mean age of 15.2 years (± 4.6 years; range, 10–25 years) and at a mean period of 4 years (± 3.3 years) after MEN2B diagnosis. Only one patient was diagnosed with pheochromocytoma as the initial manifestation of MEN2B after she presented with hypertension and secondary amenorrhea. The youngest patient diagnosed with pheochromocytoma in this cohort was an asymptomatic child aged 10 years. The authors of this study believe that the current guidelines to begin screening for pheochromocytoma at age 11 years are appropriate.

A retrospective analysis identified 167 children with RET variants who underwent prophylactic thyroidectomy. This group included 109 patients without a concomitant central node dissection and 58 patients with a concomitant central node dissection. Children were classified into risk groups by their specific type of RET variant.[24]

  • In the highest-risk category, medullary thyroid carcinoma was found in five of six children (83%) aged 3 years or younger.
  • In the high-risk category, medullary thyroid carcinoma was present in 6 of 20 children (30%) aged 3 years or younger, 16 of 36 children (44%) aged 4 to 6 years, and 11 of 16 children (69%) aged 7 to 12 years (P = .081).
  • In the moderate-risk category, medullary thyroid carcinoma was seen in 1 of 9 children (11%) aged 3 years or younger, 1 of 26 children (4%) aged 4 to 6 years, 3 of 26 children (12%) aged 7 to 12 years, and 7 of 16 children (44%) aged 13 to 18 years (P = .006).

For more information, see Table 1 in Childhood Thyroid Cancer Treatment.

Guidelines for genetic testing of patients suspected of having MEN2 syndrome and the correlations between the type of variant and the risk levels of aggressiveness of medullary thyroid cancer have been published.[14,25]

Table 2. Clinical Features of Multiple Endocrine Neoplasia Type 2 (MEN2) Syndromesa

MEN2 SubtypeMedullary Thyroid CarcinomaPheochromocytomaParathyroid Disease
MEN2A95%50%20% to 30%
MEN2B100%50%Uncommon

aSources: de Krijger,[26] Waguespack et al.,[14] Brauckhoff et al.,[21] and Eng et al.[16]

MEN Type 4 (MEN4) Syndrome

MEN4 is a rare variant of MEN syndrome, originally described in patients who had the MEN1 syndrome phenotype but did not have a variant in the MEN1 gene.[27] Further investigation discovered a variant in the CDKN1B gene. The clinical phenotype is essentially the same as MEN1 syndrome, but patients have fewer neuroendocrine tumors.[28] This syndrome occurs almost exclusively in adults. However, in a study of children with Cushing disease who had corticotropinomas, five patients (2.6%) had variants in the CDKN1B gene. These patients were aged 9 to 12 years at the time of Cushing disease onset.[29] They had none of the other findings of MEN4 syndrome. However, the authors postulate that because of their young age, these patients may be at risk of developing additional neoplasms in the future.

References

  1. Thakker RV: Multiple endocrine neoplasia--syndromes of the twentieth century. J Clin Endocrinol Metab 83 (8): 2617-20, 1998. [PubMed: 9709920]
  2. Thakker RV: Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab 24 (3): 355-70, 2010. [PubMed: 20833329]
  3. Vannucci L, Marini F, Giusti F, et al.: MEN1 in children and adolescents: Data from patients of a regional referral center for hereditary endocrine tumors. Endocrine 59 (2): 438-448, 2018. [PubMed: 28530019]
  4. Thakker RV, Newey PJ, Walls GV, et al.: Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97 (9): 2990-3011, 2012. [PubMed: 22723327]
  5. Goudet P, Dalac A, Le Bras M, et al.: MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines. J Clin Endocrinol Metab 100 (4): 1568-77, 2015. [PubMed: 25594862]
  6. Romero Arenas MA, Morris LF, Rich TA, et al.: Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism. J Pediatr Surg 49 (4): 546-50, 2014. [PubMed: 24726110]
  7. Farnebo F, Teh BT, Kytölä S, et al.: Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab 83 (8): 2627-30, 1998. [PubMed: 9709922]
  8. Field M, Shanley S, Kirk J: Inherited cancer susceptibility syndromes in paediatric practice. J Paediatr Child Health 43 (4): 219-29, 2007. [PubMed: 17444822]
  9. Sanso GE, Domene HM, Garcia R, et al.: Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers. Cancer 94 (2): 323-30, 2002. [PubMed: 11900218]
  10. Alsanea O, Clark OH: Familial thyroid cancer. Curr Opin Oncol 13 (1): 44-51, 2001. [PubMed: 11148685]
  11. Fitze G: Management of patients with hereditary medullary thyroid carcinoma. Eur J Pediatr Surg 14 (6): 375-83, 2004. [PubMed: 15630638]
  12. Puñales MK, da Rocha AP, Meotti C, et al.: Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid 18 (12): 1261-8, 2008. [PubMed: 18991485]
  13. Wells SA, Asa SL, Dralle H, et al.: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 (6): 567-610, 2015. [PMC free article: PMC4490627] [PubMed: 25810047]
  14. Waguespack SG, Rich TA, Perrier ND, et al.: Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol 7 (10): 596-607, 2011. [PubMed: 21862994]
  15. Decker RA, Peacock ML, Watson P: Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet 7 (1): 129-34, 1998. [PubMed: 9384613]
  16. Eng C, Clayton D, Schuffenecker I, et al.: The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276 (19): 1575-9, 1996. [PubMed: 8918855]
  17. Fialkowski EA, DeBenedetti MK, Moley JF, et al.: RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine neoplasia 2A kindreds. J Pediatr Surg 43 (1): 188-90, 2008. [PubMed: 18206480]
  18. Skába R, Dvoráková S, Václavíková E, et al.: The risk of medullary thyroid carcinoma in patients with Hirschsprung's disease. Pediatr Surg Int 22 (12): 991-5, 2006. [PubMed: 17021738]
  19. Moore SW, Zaahl MG: Multiple endocrine neoplasia syndromes, children, Hirschsprung's disease and RET. Pediatr Surg Int 24 (5): 521-30, 2008. [PubMed: 18365214]
  20. Skinner MA, DeBenedetti MK, Moley JF, et al.: Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 31 (1): 177-81; discussion 181-2, 1996. [PubMed: 8632274]
  21. Brauckhoff M, Gimm O, Weiss CL, et al.: Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg 28 (12): 1305-11, 2004. [PubMed: 15517484]
  22. Sakorafas GH, Friess H, Peros G: The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy. Endocr Relat Cancer 15 (4): 871-84, 2008. [PubMed: 19015274]
  23. Makri A, Akshintala S, Derse-Anthony C, et al.: Pheochromocytoma in Children and Adolescents With Multiple Endocrine Neoplasia Type 2B. J Clin Endocrinol Metab 104 (1): 7-12, 2019. [PMC free article: PMC6240163] [PubMed: 30113649]
  24. Machens A, Elwerr M, Lorenz K, et al.: Long-term outcome of prophylactic thyroidectomy in children carrying RET germline mutations. Br J Surg 105 (2): e150-e157, 2018. [PubMed: 29341155]
  25. Kloos RT, Eng C, Evans DB, et al.: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19 (6): 565-612, 2009. [PubMed: 19469690]
  26. de Krijger RR: Endocrine tumor syndromes in infancy and childhood. Endocr Pathol 15 (3): 223-6, 2004. [PubMed: 15640547]
  27. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, et al.: Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A 103 (42): 15558-63, 2006. [PMC free article: PMC1622862] [PubMed: 17030811]
  28. Chevalier B, Coppin L, Romanet P, et al.: Beyond MEN1, When to Think About MEN4? Retrospective Study on 5600 Patients in the French Population and Literature Review. J Clin Endocrinol Metab 109 (7): e1482-e1493, 2024. [PubMed: 38288531]
  29. Chasseloup F, Pankratz N, Lane J, et al.: Germline CDKN1B Loss-of-Function Variants Cause Pediatric Cushing's Disease With or Without an MEN4 Phenotype. J Clin Endocrinol Metab 105 (6): 1983-2005, 2020. [PMC free article: PMC7190031] [PubMed: 32232325]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric surgeons.
  • Pathologists.
  • Pediatric radiation oncologists.
  • Pediatric medical oncologists and hematologists.
  • Ophthalmologists.
  • Rehabilitation specialists.
  • Pediatric oncology nurses.
  • Social workers.
  • Child-life professionals.
  • Psychologists.
  • Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3-5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people in the United States. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[7,8] In children and adolescents, the designation of a rare tumor is not uniform among international groups, as follows:

  • A consensus effort between the European Union Joint Action on Rare Cancers and the European Cooperative Study Group for Rare Pediatric Cancers estimated that 11% of all cancers in patients younger than 20 years could be categorized as very rare. This consensus group defined very rare cancers as those with annual incidences of fewer than two cases per 1 million people. However, three additional histologies (thyroid carcinoma, melanoma, and testicular cancer) with incidences of more than two cases per 1 million people were also included in the very rare group due to a lack of knowledge and expertise in the management of these tumors.[9]
  • The Children's Oncology Group defines rare pediatric cancers as those listed in the International Classification of Childhood Cancer subgroup XI, which includes thyroid cancers, melanomas and nonmelanoma skin cancers, and multiple types of carcinomas (e.g., adrenocortical carcinomas, nasopharyngeal carcinomas, and most adult-type carcinomas such as breast cancers and colorectal cancers).[10] These diagnoses account for about 5% of the cancers diagnosed in children aged 0 to 14 years and about 27% of the cancers diagnosed in adolescents aged 15 to 19 years.[4]
    Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers diagnosed in children aged 0 to 14 years and 9.3% of the cancers diagnosed in adolescents aged 15 to 19 years.

These rare cancers are extremely challenging to study because of the relatively few patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the small number of clinical trials for adolescents with rare cancers.

References

  1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PMC free article: PMC2881732] [PubMed: 20404250]
  2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed August 23, 2024.
  3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PMC free article: PMC4136455] [PubMed: 24853691]
  4. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed August 23, 2024.
  5. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed September 5, 2024.
  6. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr. [PubMed: 24488779]
  7. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017. [PubMed: 28687376]
  8. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017. [PubMed: 28542893]
  9. Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019. [PubMed: 30785015]
  10. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children's Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010. [PMC free article: PMC3020699] [PubMed: 20956621]

Treatment of Childhood Multiple Endocrine Neoplasia (MEN) Syndromes

Treatment options for childhood MEN syndromes, according to type, are as follows:

MEN Type 1 (MEN1) Syndrome

The treatment of patients with MEN1 syndrome is based on the type of tumor. The outcomes of patients with MEN1 syndrome are generally good, provided adequate treatment can be obtained for parathyroid, pancreatic, and pituitary tumors.

The standard approach to patients who present with hyperparathyroidism and MEN1 syndrome is genetic testing and treatment with a cervical resection of at least three parathyroid glands and transcervical thymectomy.[1]

For more information, see the Interventions section in Genetics of Endocrine and Neuroendocrine Neoplasias.

MEN Type 2 (MEN2) Syndromes

The management of medullary thyroid cancer in children from families with MEN2 syndromes relies on presymptomatic detection of the RET proto-oncogene variant responsible for the disease.

MEN2A syndrome

For children with MEN2A syndrome, thyroidectomy is commonly performed by approximately age 5 years or older if that is when a RET variant is identified.[2-7] The outcomes for patients with MEN2A syndrome are generally good, although medullary thyroid carcinoma and pheochromocytoma can recur.[8-10]

A retrospective analysis identified 262 patients with MEN2A syndrome.[11] The median age of the cohort was 42 years and ranged from age 6 to 86 years. There was no correlation between the specific RET variant identified and the risk of distant metastasis. Younger age at diagnosis increased the risk of distant metastasis.

Young children who are relatives of patients with MEN2A syndrome undergo genetic testing before the age of 5 years. Carriers undergo total thyroidectomy as described above, with autotransplant of one parathyroid gland by a certain age.[12-15]

MEN2B syndrome

Patients with MEN2B syndrome have worse outcomes than those with MEN2A syndrome, primarily because medullary thyroid carcinoma is more aggressive. Because of the increased severity of medullary thyroid carcinoma in children with MEN2B syndrome and in those with RET variants in codons 883, 918, and 922, it is recommended that these children undergo prophylactic thyroidectomy in infancy.[3,16,17]; [18][Level of evidence C2] This therapy can improve outcomes in patients with MEN2B syndrome.[19] Complete removal of the thyroid gland is recommended because of a high incidence of bilateral disease.

Targeted therapy

Targeted therapy has been used for patients with the RET gene variant and medullary thyroid cancer. Types of targeted therapy include the following:

Vandetanib

Vandetanib is a selective kinase inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor.

A randomized phase III trial included adult patients with unresectable locally advanced or metastatic (hereditary or sporadic) medullary thyroid carcinoma who were treated with either vandetanib or placebo.[20]

  • The study found that vandetanib administration was associated with significant improvements in progression-free survival (PFS), response rate, disease control rates, and biochemical response.

Children with locally advanced or metastatic medullary thyroid carcinoma were treated with vandetanib in a phase I/II trial.[21]

  • Of 16 patients, only the one patient without the M918T RET variant had no response.
  • Of the 15 patients who had tumor responses, seven had partial responses.
  • Three of the 15 patients had subsequent disease recurrences.
  • Eleven of the 16 patients treated with vandetanib remained on therapy at the time of the report.
  • A subsequent follow-up analysis of this cohort plus one additional patient revealed that 10 of the 17 patients achieved partial responses, and an additional 6 individuals had stable disease. The median PFS for these patients was 6.7 years.[22]
Cabozantinib

Cabozantinib is a tyrosine kinase inhibitor (TKI) that targets three relevant pathways in medullary thyroid carcinoma: MET, VEGFR2, and RET.

In a phase I study, cabozantinib demonstrated promising clinical activity in a cohort of heavily pretreated patients with medullary thyroid carcinoma.[23]

A double-blind phase III trial compared cabozantinib with placebo in adults with progressive, metastatic medullary thyroid carcinoma.[24]

  • The estimated PFS was 11.2 months for patients who received cabozantinib and 4 months for patients who received a placebo.
  • At 1 year, 47.3% of patients who were treated with cabozantinib were alive and progression free, compared with 7.2% of patients who received a placebo.
  • Significant adverse effects resulted in dose reductions in 79% of patients and discontinuation of cabozantinib in 16% of patients.
Selpercatinib

Selpercatinib is a RET inhibitor.

A phase I/II trial of selpercatinib therapy included patients with cancers and RET variants. The study enrolled 55 patients with medullary thyroid cancer (age range, 17–84 years) who were previously treated with vandetanib and/or cabozantinib and 88 patients with medullary thyroid cancer (age range, 15–82 years) who were not previously treated with vandetanib or cabozantinib.[25]

  • For the previously treated cohort, 69% of patients achieved objective responses, and the median duration of response had not been reached, with a median follow-up of 14 months.
  • For the cohort who were not previously treated, 73% of patients achieved objective responses, with a median duration of response of 22.0 months.
  • The most common grades 3 to 4 treatment-related adverse events were hypertension (12%), increased alanine aminotransferase (10%) and aspartate aminotransferase (7%), diarrhea (3%), and prolonged QT interval (2%).
  • The U.S. Food and Drug Administration granted traditional approval to selpercatinib for the treatment of adult and pediatric patients aged 2 years and older with advanced or metastatic RET-variant medullary thyroid cancer who require systemic therapy.[26]

References

  1. Romero Arenas MA, Morris LF, Rich TA, et al.: Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism. J Pediatr Surg 49 (4): 546-50, 2014. [PubMed: 24726110]
  2. Skinner MA, Moley JA, Dilley WG, et al.: Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 353 (11): 1105-13, 2005. [PubMed: 16162881]
  3. Skinner MA: Management of hereditary thyroid cancer in children. Surg Oncol 12 (2): 101-4, 2003. [PubMed: 12946481]
  4. Fitze G: Management of patients with hereditary medullary thyroid carcinoma. Eur J Pediatr Surg 14 (6): 375-83, 2004. [PubMed: 15630638]
  5. 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) 63 (6): 636-41, 2005. [PubMed: 16343097]
  6. Guillem JG, Wood WC, Moley JF, et al.: ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes. J Clin Oncol 24 (28): 4642-60, 2006. [PubMed: 17008706]
  7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 2.2019. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2019. Available online with free subscription. Last accessed June 08, 2020. [PubMed: 35948029]
  8. Lallier M, St-Vil D, Giroux M, et al.: Prophylactic thyroidectomy for medullary thyroid carcinoma in gene carriers of MEN2 syndrome. J Pediatr Surg 33 (6): 846-8, 1998. [PubMed: 9660211]
  9. Dralle H, Gimm O, Simon D, et al.: Prophylactic thyroidectomy in 75 children and adolescents with hereditary medullary thyroid carcinoma: German and Austrian experience. World J Surg 22 (7): 744-50; discussion 750-1, 1998. [PubMed: 9606292]
  10. Skinner MA, Wells SA: Medullary carcinoma of the thyroid gland and the MEN 2 syndromes. Semin Pediatr Surg 6 (3): 134-40, 1997. [PubMed: 9263335]
  11. Voss RK, Feng L, Lee JE, et al.: Medullary Thyroid Carcinoma in MEN2A: ATA Moderate- or High-Risk RET Mutations Do Not Predict Disease Aggressiveness. J Clin Endocrinol Metab 102 (8): 2807-2813, 2017. [PMC free article: PMC5546858] [PubMed: 28609830]
  12. Heizmann O, Haecker FM, Zumsteg U, et al.: Presymptomatic thyroidectomy in multiple endocrine neoplasia 2a. Eur J Surg Oncol 32 (1): 98-102, 2006. [PubMed: 16325365]
  13. Frank-Raue K, Buhr H, Dralle H, et al.: Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype. Eur J Endocrinol 155 (2): 229-36, 2006. [PubMed: 16868135]
  14. Piolat C, Dyon JF, Sturm N, et al.: Very early prophylactic thyroid surgery for infants with a mutation of the RET proto-oncogene at codon 634: evaluation of the implementation of international guidelines for MEN type 2 in a single centre. Clin Endocrinol (Oxf) 65 (1): 118-24, 2006. [PubMed: 16817830]
  15. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 1.2018. Fort Washington, Pa: National Comprehensive Cancer Network, 2018. Available online with free subscription. Last accessed July 5, 2018.
  16. Leboulleux S, Travagli JP, Caillou B, et al.: Medullary thyroid carcinoma as part of a multiple endocrine neoplasia type 2B syndrome: influence of the stage on the clinical course. Cancer 94 (1): 44-50, 2002. [PubMed: 11815959]
  17. Sakorafas GH, Friess H, Peros G: The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy. Endocr Relat Cancer 15 (4): 871-84, 2008. [PubMed: 19015274]
  18. Zenaty D, Aigrain Y, Peuchmaur M, et al.: Medullary thyroid carcinoma identified within the first year of life in children with hereditary multiple endocrine neoplasia type 2A (codon 634) and 2B. Eur J Endocrinol 160 (5): 807-13, 2009. [PubMed: 19240193]
  19. Brauckhoff M, Machens A, Lorenz K, et al.: Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: a changing perspective. Ann Surg 259 (4): 800-6, 2014. [PubMed: 23979292]
  20. Wells SA, Robinson BG, Gagel RF, et al.: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30 (2): 134-41, 2012. [PMC free article: PMC3675689] [PubMed: 22025146]
  21. 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 19 (15): 4239-48, 2013. [PMC free article: PMC4274128] [PubMed: 23766359]
  22. Kraft IL, Akshintala S, Zhu Y, et al.: Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib. Clin Cancer Res 24 (4): 753-765, 2018. [PMC free article: PMC5815946] [PubMed: 29187393]
  23. Kurzrock R, Sherman SI, Ball DW, et al.: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29 (19): 2660-6, 2011. [PMC free article: PMC3646303] [PubMed: 21606412]
  24. Elisei R, Schlumberger MJ, Müller SP, et al.: Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 31 (29): 3639-46, 2013. [PMC free article: PMC4164813] [PubMed: 24002501]
  25. Wirth LJ, Sherman E, Robinson B, et al.: Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med 383 (9): 825-835, 2020. [PMC free article: PMC10777663] [PubMed: 32846061]
  26. Eli Lilly and Company: RETEVMO (selpercatinib): Prescribing Information. Indianapolis, Ind: Lilly USA, LLC, 2020. Available online. Last accessed September 28, 2020.

Treatment Options Under Clinical Evaluation for Multiple Endocrine Neoplasia (MEN) Syndromes

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • LIBRETTO-001 (NCT03157128) (Phase I/II Study of LOXO-292 in Patients With Advanced Solid Tumors, RET Fusion–Positive Solid Tumors, and Medullary Thyroid Cancer): This is a phase I/II, open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of selpercatinib (also known as LOXO-292) administered orally to patients with advanced solid tumors, including RET fusion–positive solid tumors, medullary thyroid cancer, and other tumors with RET activation.

Latest Updates to This Summary (10/17/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of pediatric multiple endocrine neoplasia (MEN) syndromes. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment are:

  • Denise Adams, MD (Children's Hospital Boston)
  • Karen J. Marcus, MD, FACR (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • William H. Meyer, MD
  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta - Egleston Campus)
  • D. Williams Parsons, MD, PhD (Texas Children's Hospital)
  • Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
  • Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
  • Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/multiple-endocrine-neoplasia/hp-child-men-syndromes-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 31909948]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Copyright Notice
Bookshelf ID: NBK552292PMID: 31909948

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