Multiple Endocrine Neoplasia
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Multilpe endocrine neoplasia (MEN) are rare fimilial (inherited) conditions affecting the glands of the endocrine system:

MEN I typically affects parathyroid, the pancreas, and the pituitary while MEN IIa and MEN IIb are associated with medullary thyroid carcinoma.

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Endocrine Cancers
Thyroid Cancer

Information Patients and the Public (6 links)


Information for Health Professionals / Researchers (7 links)

See also: Multiple endocrine neoplasia I (11q13)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Tonelli F, Giudici F, Giusti F, et al.
A heterozygous frameshift mutation in exon 1 of CDKN1B gene in a patient affected by MEN4 syndrome.
Eur J Endocrinol. 2014; 171(2):K7-K17 [PubMed] Related Publications
OBJECTIVE: Multiple endocrine neoplasia type 4 (MEN4) is an autosomal dominant disorder that presents with a spectrum of clinical manifestations overlapping with those of MEN1 syndrome. It is caused by inactivating mutations of the CDKN1B gene, encoding for p27(kip1) cyclin-dependent kinase 2 inhibitor, implicated in cell cycle control. Eight mutations of CDKN1B in MEN4 patients have been published so far. The aim of this study was to characterize the molecular basis of a case of MEN1-like syndrome with a neuroendocrine tumor and persistent primary hyperparathyroidism (PHPT).
METHODS: Clinical, biochemical, and genetic evaluation were undertaken in the proband (a 53-year-old Caucasian woman) and in one 34-year-old son. The proband was operated for recurrent PHPT. Sequence analysis of the MEN1 and CDKN1B genes was performed on constitutional and parathyroid tissue DNA. Staining for p27 was carried out in parathyroid tissue.
RESULTS: Neither MEN1 mutations nor large deletions encompassing the MEN1 gene on chromosome 11q13.1 could be detected in the proband. A germline frameshift mutation of CDKN1B (371delCT) was revealed, predicted to generate a truncated p27 (CDKN1B) protein. This mutation was confirmed on somatic DNA from the pathological parathyroid tissue, with the retention of the WT allele.
CONCLUSIONS: We report a germline heterozygote frameshift mutation of the CDKN1B gene in a Caucasian woman with a long clinical history of MEN1-like multiple endocrine tumors, along with the finding of the mutation in her son. This is the first report of positive CDKN1B mutation analysis in a male subject and also the first description of recurrent hyperparathyroidism in MEN4.

Related: Parathyroid Cancer


Castinetti F, Qi XP, Walz MK, et al.
Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study.
Lancet Oncol. 2014; 15(6):648-55 [PubMed] Related Publications
BACKGROUND: The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2.
METHODS: This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy.
FINDINGS: 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0.57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent.
INTERPRETATION: The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications.


Krampitz GW, Norton JA
RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma.
Cancer. 2014; 120(13):1920-31 [PubMed] Related Publications
The rapid technical advances in molecular biology and accelerating improvements in genomic and proteomic diagnostics have led to increasingly personalized strategies for cancer therapy. Such an approach integrates the genomic, proteomic, and molecular information unique to the individual to provide an accurate genetic diagnosis, molecular risk assessment, informed family counseling, therapeutic profiling, and early preventative management that best fits the particular needs of each patient. The discovery of mutations in the RET proto-oncogene resulting in variable onset and severity of multiple endocrine neoplasia type 2 (MEN2) was the first step in developing direct genetic testing for at-risk individuals. Patients with germline RET mutations may undergo risk assessment and appropriate intervention based on specific mutations. Moreover, family members of affected individuals receive counseling based on understanding of the genetic transmission of the disease. Increasingly, clinicians are able to make therapeutic choices guided by an informative biomarker code. Improvements in detection and management of patients with MEN2 resulting from understanding of the RET proto-oncogene are evidence of the benefits of personalized cancer medicine. This review describes the discovery of the RET proto-oncogene, the association between genotype and phenotype, and the role of mutation analysis on diagnosis and treatment of MEN2.

Related: Thyroid Cancer RET


Siqueira DR, Ceolin L, Ferreira CV, et al.
Role of RET genetic variants in MEN2-associated pheochromocytoma.
Eur J Endocrinol. 2014; 170(6):821-8 [PubMed] Related Publications
BACKGROUND: RET polymorphisms have been involved in the clinical presentation and prognosis of multiple endocrine neoplasia type 2 (MEN2)-associated medullary thyroid carcinoma.
OBJECTIVE: To investigate the effect of RET variants on the penetrance of pheochromocytoma (PHEO) in MEN2 patients.
METHODS: The RET variants L769L, S836S, and G691S/S904S were evaluated in a cohort of 153 MEN2 patients attending a tertiary teaching hospital. A comparison of RET variant frequencies between patients with and without PHEO was performed. Kaplan-Meier curves and Cox regression analysis were used to estimate the effect of RET variants on the age-dependent penetrance.
RESULTS: A total of 48 (31.4%) patients presented with MEN2-associated PHEOs. The mean age at diagnosis was 35.5±13.4 years, 60.4% of patients were women, and 92.8% had RET mutations at codon 634. The frequencies of RET polymorphisms were as follows: 20.1% L769L, 4.75% S836S, and 17.3% S904S/G691S. We did not observe any association between the frequencies of L769L, S836S, or S904S/G691S variants and PHEO development (all P>0.05). However, individuals carrying two RET polymorphic alleles had an increased estimated risk of PHEO (2.63; 95% CI, 1.4-5.0; P=0.004) and were younger at diagnosis when compared with those with one or no polymorphism (29.6±6.3 and 39.3±14.4 years respectively; P=0.006). Accordingly, additional analysis using Cox proportional hazard models demonstrated that the presence of two RET variants was associated with an increased risk for early PHEO development (hazard ratio, 5.99 (95% CI, 2.24-16.03); P<0.001).
CONCLUSIONS: RET polymorphic alleles have an additive effect on the estimated risk of age-related PHEO penetrance in MEN2 patients.


Gurung B, Muhammad AB, Hua X
Menin is required for optimal processing of the microRNA let-7a.
J Biol Chem. 2014; 289(14):9902-8 [PubMed] Article available free on PMC after 04/04/2015 Related Publications
Multiple endocrine neoplasia type I (MEN1) is an inherited syndrome that includes susceptibility to pancreatic islet hyperplasia. This syndrome results from mutations in the MEN1 gene, which encodes menin protein. Menin interacts with several transcription factors, including JunD, and inhibits their activities. However, the precise mechanism by which menin suppresses gene expression is not well understood. Here, we show that menin interacts with arsenite-resistant protein 2 (ARS2), a component of the nuclear RNA CAP-binding complex that is crucial for biogenesis of certain miRNAs including let-7a. The levels of primary-let-7a (pri-let-7a) are not affected by menin; however, the levels of mature let-7a are substantially decreased upon Men1 excision. Let-7a targets, including Insr and Irs2, pro-proliferative genes that are crucial for insulin-mediated signaling, are up-regulated in Men1-excised cells. Inhibition of let-7a using anti-miRNA in wild type cells is sufficient to enhance the expression of insulin receptor substrate 2 (IRS2) to levels observed in Men1-excised cells. Depletion of menin does not affect the expression of Drosha and CBP80, but substantially impairs the processing of pri-miRNA to pre-miRNA. Ars2 knockdown decreased let-7a processing in menin-expressing cells but had little impact on let-7a levels in menin-excised cells. As IRS2 is known to mediate insulin signaling and insulin/mitogen-induced cell proliferation, these findings collectively unravel a novel mechanism whereby menin suppresses cell proliferation, at least partly by promoting the processing of certain miRNAs, including let-7a, leading to suppression of Irs2 expression and insulin signaling.

Related: MEN1


Tonelli F, Giudici F, Nesi G, et al.
Biliary tree gastrinomas in multiple endocrine neoplasia type 1 syndrome.
World J Gastroenterol. 2013; 19(45):8312-20 [PubMed] Article available free on PMC after 04/04/2015 Related Publications
AIM: To describe our patients affected with ectopic biliary tree gastrinoma and review the literature on this topic.
METHODS: Between January 1992 and June 2012, 28 patients affected by duodenopancreatic endocrine tumors in multiple endocrine neoplasia type 1 (MEN1) syndrome underwent surgery at our institution. This retrospective review article analyzes our experience regarding seventeen of these patients subjected to duodenopancreatic surgery for Zollinger-Ellison syndrome (ZES). Surgical treatment consisted of duodenopancreatectomy (DP) or total pancreatectomy (TP). Regional lymphadenectomy was always performed. Any hepatic tumoral lesions found were removed during surgery. In MEN1 patients, removal of duodenal lesions can sometimes lead to persistence or recurrence of hypergastrinemia. One possible explanation for this unfavorable outcome could be unrecognized ectopic localization of gastrin-secreting tumors. This study described three cases among the seventeen patients who were found to have an ectopic gastrinoma located in the biliary tree.
RESULTS: Seventeen MEN1 patients affected with ZES were analyzed. The mean age was 40 years. Fifteen patients underwent DP and two TP. On histopathological examination, duodeno pancreatic endocrine tumors were found in all 17 patients. Eighty-one gastrinomas were detected in the first three portions of the duodenum. Only one gastrinoma was found in the pancreas. The mean number of gastrinomas per patient was 5 (range 1-16). Malignancy was established in 12 patients (70.5%) after lymph node, liver and omental metastases were found. Three patients exhibited biliary tree gastrinomas as well as duodenal gastrinoma(s). In two cases, the ectopic gastrinoma was removed at the same time as pancreatic surgery, while in the third case, the biliary tree gastrinoma was resected one year after DP because of recurrence of ZES.
CONCLUSION: These findings suggest the importance of checking for the presence of ectopic gastrinomas in the biliary tree in MEN1 patients undergoing ZES surgery.

Related: Extra-Hepatic Bile duct cancer (cholangiocarcinoma) Cancer of the Pancreas Pancreatic Cancer


Păun DL, Poiană C, Petriş R, et al.
Multiple endocrine neoplasia type 2A: case report.
Chirurgia (Bucur). 2013 Nov-Dec; 108(6):900-3 [PubMed] Related Publications
Multiple endocrine neoplasia type 2A (MEN 2A) is a complex autosomal dominant inherited syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and primary parathyroid hyperplasia. In patients with only one or two clinical features, identification of a germline RET(REarranged in Transfection) mutation or the identification of the clinical features of MEN 2A in other first degree relatives is required to make the diagnosis. We present the case of a family with MEN 2A syndrome confirmed by genetic analysis which identified RET gene mutation in 634 codon in father - DV - aged 48 years and also in daughter DM -aged 20 years. The specific feature in this case is that the index case was the daughter (diagnosed and operated for pheochromocytoma at the age of 19 years), the father being diagnosed later with medullary thyroid carcinoma by mutational screening in all family members. This family supports the phenomenon of anticipation, in which severity increases and the age of onset decreases in successive generations, the syndrome being discovered earlier and with a worse prognostic in the daughter.

Related: Thyroid Cancer RET


Liu W, Han X, Hu Z, et al.
A novel germline mutation of the MEN1 gene caused multiple endocrine neoplasia type 1 in a Chinese young man and 1 year follow-up.
Eur Rev Med Pharmacol Sci. 2013; 17(22):3111-6 [PubMed] Related Publications
BACKGROUND: Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant cancer predisposition syndrome which manifests a variety of endocrine and non-endocrine neoplasms and lesions. Because of its complexity in clinical manifestations, it is always difficult to set up the diagnosis in the early stage of the disease.
AIM: Using genetic diagnosis to identify and describe the process of the disease from the very beginning and followed the treatment result in 1 year.
MATERIALS AND METHODS: In this assay, a Chinese young man aged 31 with parathyroid hyperplasia, suspected gastrinoma and an enlarged pituitary with elevated level of prolactin (PRL) and growth hormone (GH) was admitted to our Department ward. We performed genetic analysis in his family and described a new nonsense mutation at codon 308 in exon 6 of the MEN1 gene, where a cytosine residue was exchanged for guanine residue (TCA > TGA), and a termination condon (S308X) occurred. During the 1 year follow up, typical manifestations emerged in this kindred and further confirmed the diagnosis of familial MEN 1.
CONCLUSIONS: We presented a case of MEN 1 from its early stage and followed the progression. Meanwhile, the mutation in this kindred has not been reported and our finding can contribute to better understanding about this disease.

Related: MEN1


Metzger R, Milas M
Inherited cancer syndromes and the thyroid: an update.
Curr Opin Oncol. 2014; 26(1):51-61 [PubMed] Related Publications
PURPOSE OF REVIEW: Knowledge related to hereditary thyroid cancer syndromes has expanded enormously. This review identifies contributions that have changed approaches to diagnosis and broadened treatment options for patients with hereditary medullary and nonmedullary thyroid cancers related to multiple endocrine neoplasia type 2 (MEN2), Cowden syndrome, and familial adenomatous polyposis (FAP).
RECENT FINDINGS: A new risk-stratification scheme based on type of RET gene mutation informs the age at which prophylactic thyroidectomy and diagnostic screening for MEN-associated endocrine diseases should occur. Two new US Food and Drug Administration-approved targeted medical therapies are now available for medullary thyroid cancer. There is better understanding of more aggressive clinical features and increased lifetime cancer risks for patients with well differentiated thyroid cancers as part of families with and without Cowden syndrome or FAP. This has led to a clearer appreciation for the role and timing of thyroid ultrasound screening in these populations. It has also informed the appropriate extent of thyroid surgery and the circumstances in which prophylactic thyroidectomy is reasonable to consider as part of hereditary syndromes other than MEN2.
SUMMARY: Recognition and early diagnosis of these syndromes allows for comprehensive medical care and may improve thyroid cancer-related outcomes. Ultrasound-based screening programs to detect thyroid disease are advised for patients and family members with hereditary cancer syndromes.

Related: Thyroid Cancer


Del Prete M, Marotta V, Ramundo V, et al.
Impact of cinacalcet hydrochloride in clinical management of primary hyperparathyroidism in multiple endocrine neoplasia type 1.
Minerva Endocrinol. 2013; 38(4):389-94 [PubMed] Related Publications
AIM: Primary hyperparathyroidism (PHPT) is one of main cause of morbidity in patients with multiple endocrine neoplasia type 1 (MEN1). Medical therapy with cinacalcet-hydrochloride may modify the therapeutic strategy of MEN1 related PHPT. We present an experience with cinacalcet-hydrochloride in two patients with MEN1 PHPT.
METHODS: The study included two MEN1 patients belonging to the same family (a 50-year-old woman and her daughter aged 20 years) with PHPT secondary to multiple involvement of parathyroid glands and other MEN1 related tumors. As both patients refused to undergo parathyroid surgery, we decided to start medical treatment with cinacalcet at the dose of 30 mg/day, which was the first treatment for the youngest patient, while the oldest had already been treated with partial parathyroidectomy. Serum concentrations of PTH, calcium and phosphorus, 24-h urine calcium-to-creatinine ratio and renal-threshold-phosphate concentration were evaluated before and after therapy.
RESULTS: Serum calcium and PTH levels were normalized after 1 and 6 months of therapy, respectively, and 60 and 54 months after the beginning of cinacalcet remained normal. Hypercalciuria, hypophosphoremia and renal-threshold-phosphate normalized during therapy with cinacalcet. At ultrasonography, parathyroid nodular lesion remained unchanged. Cinacalcet was well tolerated without occurrence of side effects.
CONCLUSION: Cinacalcet seems to be highly effective in controlling PHPT in patients with MEN1 either in naïve patients or in those with postsurgical recurrence. If cinacalcet will be confirmed to ensure a long-time control of PHPT or even to prevent the development and progression of PHPT, this may led to modify the therapeutic strategy of MEN1 PHPT.


Piver D, Ronot M, Guedj N, et al.
Case 200: Gastric enterochromaffinlike cell tumors in a patient with type 1 multiple endocrine neoplasia.
Radiology. 2013; 269(3):940-4 [PubMed] Related Publications
History A 55-year-old man presented with chronic epigastric pain lasting for about 1 year and without fever or vomiting. The abdomen was soft and tender at physical examination. Laboratory tests revealed unremarkable liver function, normal hemoglobin level, and normal amylase level. White blood cell count was normal, and there was no inflammatory syndrome. The patient's medical history included pancreatic gastrinoma resected by means of left pancreatectomy 31 years before, hyperparathyroidism treated with subtotal parathyroidectomy 24 years before, and a slowly growing lung mass known for 9 years. Esophagogastroduodenoscopy was performed because of a suspected gastroduodenal ulcer. The results showed numerous small (<10 mm) gastric and duodenal ulcers and multiple 10-15-mm polypoid gastric masses. Contrast material-enhanced dual-phase multidetector row computed tomography (CT) of the chest and abdomen was performed with a 64-section CT scanner (LightSpeed VCT; GE Healthcare, Milwaukee, Wis). Technical parameters for CT were as follows: pitch, 0.98; section thickness and reconstruction interval, 1.25 mm; 120 kVp; and variable milliamperage determined by x-, y-, and z-axis dose modulation. After an unenhanced abdominal scan, iobitridol, a nonionic iodinated contrast agent containing 350 mg of iodine per milliliter (Xenetix 350; Guerbet, Aulnay-sousbois, France), was administered intravenously through a 16-18-gauge catheter. A 120-mL dose of the contrast agent was injected via an antecubital vein at a rate of 4 mL/sec. No oral contrast medium was administered. After preliminary unenhanced abdominal scanning, arterial and portal venous phase acquisitions were obtained 45 and 80 seconds after initiation of contrast medium injection.

Related: Stomach Cancer Gastric Cancer


Moriyoshi K, Minamiguchi S, Miyagawa-Hayashino A, et al.
Collision of extensive exocrine and neuroendocrine neoplasms in multiple endocrine neoplasia type 1 revealed by cytogenetic analysis of loss of heterozygosity: a case report.
Pathol Int. 2013; 63(9):469-75 [PubMed] Related Publications
The combination of exocrine and neuroendocrine neoplasms is rarely found in the pancreas. These combined lesions vary from a clonal tumor with mixed differentiation to the incidental co-existence of two or more independent tumors, but the differential diagnosis is sometimes difficult. Here we report a case of multiple endocrine neoplasia type 1 (MEN1) with extensive ductal and neuroendocrine neoplastic changes. These two types of tumors admixed markedly in some parts, which made it difficult to determine the pathological diagnosis based on histological findings. Cytogenetic analysis showed that loss of heterozygosity (LOH) of the MEN1 locus exists in neuroendocrine but not in exocrine neoplasms, indicating that independent mechanisms of tumorigenesis may occur in these two types of tumors. This case shows the usefulness of cytogenetic analysis for the diagnosis of combined tumors of the pancreas. Extensive exocrine neoplastic change, including pancreatic intraepithelial neoplasia (PanIN) in virtually all pancreatic ducts and a focus of intraductal papillary mucinous neoplasm (IPMN) with focal invasion, was a distinguishing feature of the present case. The possible association of ductal tumorigenesis and a MEN1 background is discussed.

Related: Cancer of the Pancreas Pancreatic Cancer


Gonçalves TD, Toledo RA, Sekiya T, et al.
Penetrance of functioning and nonfunctioning pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 in the second decade of life.
J Clin Endocrinol Metab. 2014; 99(1):E89-96 [PubMed] Related Publications
CONTEXT: Data are scarce on the penetrance of multiple endocrine neoplasia type 1 (MEN1)-related nonfunctioning pancreatic neuroendocrine tumors (NF-PETs) and insulinomas in young MEN1 patients. A potential positive correlation between tumor size and malignancy (2-3 cm, 18%; >3 cm, 43%) has greatly influenced the management of MEN1 adults with NF-PETs.
OBJECTIVE: The aim of the study was to estimate the penetrance of NF-PETs, insulinomas, and gastrinomas in young MEN1 carriers.
DESIGN: The data were obtained from a screening program (1996-2012) involving 113 MEN1 patients in a tertiary academic reference center.
PATIENTS: Nineteen MEN1 patients (aged 12-20 y; 16 patients aged 15-20 y and 3 patients aged 12-14 y) were screened for NF-PETs, insulinomas, and gastrinomas.
METHODS: Magnetic resonance imaging/computed tomography and endoscopic ultrasound (EUS) were performed on 10 MEN1 carriers, magnetic resonance imaging/computed tomography was performed on five patients, and four other patients underwent an EUS.
RESULTS: The overall penetrance of PETs during the second decade of life was 42% (8 of 19). All eight PET patients had NF-PETs, and half of those tumors were multicentric. One-fifth of the screened patients (21%; 4 of 19) harbored at least one large tumor (>2.0 cm). Insulinoma was detected in two NF-PET patients (11%) at the initial screening; gastrinoma was not present in any cases. Six of the 11 (54%) screened patients aged 15-20 years who underwent an EUS had NF-PETs. Potential false-positive EUS results were excluded based on EUS-guided biopsy results, the reproducibility of the NF-PET findings, or the observation of increased tumor size during follow-up. Distal pancreatectomy and the nodule enucleation of pancreatic head tumors were conducted on three patients with large tumors (>2.0 cm; T2N0M0) that were classified as grade 1 neuroendocrine tumors (Ki-67<2%).
CONCLUSIONS: Our data demonstrated high penetrance of NF-PETs in 15- to 20-year-old MEN1 patients. The high percentage of the patients presenting consensus criteria for surgery for NF-PET alone or NF-PET/insulinoma suggests a potential benefit for the periodic surveillance of these tumors in this age group.

Related: Cancer of the Pancreas Pancreatic Cancer MEN1


Kurozumi A, Okada Y, Arao T, et al.
Case of multiple endocrine neoplasia 2B with probable ectopic adrenocorticotropic hormone-secreting liver metastasis from medullary thyroid carcinoma.
J UOEH. 2013; 35(3):193-9 [PubMed] Related Publications
A 31 year old woman was diagnosed with multiple endocrine neoplasia (MEN) 2B at 10 years old. Dark pigmentation gradually developed on her skin and her serum adrenocorticotropic hormone (ACTH) was high, suggesting concurrent ectopic ACTH syndrome (EAS). Corticotropin-releasing hormone (CRH) loading test ruled out Cushing's disease and supported the diagnosis of EAS. Multiple low attenuation mass in the liver was observed in a computed tomography (CT) scan, and was suspected as ectopic ACTH-secreting metastatic tumor from medullary thyroid carcinoma (MTC). ACTH production by MTC is relatively rare, particularly in patients with MEN; patients with ectopic ACTH-secreting liver metastatic tumor from MTC in MEN 2B have never been reported previously.

Related: Thyroid Cancer


Roy M, Chen H, Sippel RS
Current understanding and management of medullary thyroid cancer.
Oncologist. 2013; 18(10):1093-100 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
Medullary thyroid cancer (MTC) typically accounts for 3%-4% of all thyroid cancers. Although the majority of MTCs are sporadic, 20% of cases are hereditary. Hereditary MTC can be found in multiple endocrine neoplasia 2A or 2B or as part of familial MTC based on a specific germline mutation in the RET proto-oncogene. This article discusses the current approaches available for the diagnosis, evaluation, and management of patients and their family members with suspected MTC. The disease is predominantly managed surgically and typically requires a total thyroidectomy and lymph node dissection. A review of recent guidelines on the extent and timing of surgical excision is discussed. There are not very many effective systemic treatment options for MTC, but several emerging therapeutic targets have promise.

Related: Thyroid Cancer RET


Thosani S, Ayala-Ramirez M, Palmer L, et al.
The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2.
J Clin Endocrinol Metab. 2013; 98(11):E1813-9 [PubMed] Related Publications
CONTEXT: Pheochromocytoma (PHEO) occurs in 50% of patients with multiple endocrine neoplasia type 2 (MEN2). It is unknown if the presence of PHEO is associated with more aggressive medullary thyroid cancer (MTC).
OBJECTIVE: To present our experience with MEN2 PHEO and evaluate whether PHEO impacts MTC overall survival in patients with RET codon 634 mutations.
DESIGN: We performed a retrospective chart review of MEN2 patients at MD Anderson Cancer Center from 1960 through 2012.
PATIENTS: The study group comprised 85 patients (group 1) with MEN2-associated PHEO. Of these, 59 patients (subgroup 1) with RET codon 634 mutations were compared to 48 patients (group 2) with RET codon 634 mutations, but without MEN2-associated PHEO.
MAIN OUTCOME MEASURES: Of 85 patients with MEN2 and PHEO, 70 had MEN2A and 15 had MEN2B. Median age at PHEO diagnosis was 32 years. The initial manifestation of MEN2 was MTC in 60% of patients, synchronous MTC and PHEO in 34%, and PHEO in 6% of patients. Of patients, 72% had bilateral PHEO, and most tumors were synchronous (82%). Subgroup analysis of MEN2 patients with and without PHEO, who were carriers of RET codon 634, the most common mutation with PHEO, showed no significant differences in the stage of MTC at initial diagnosis. The median follow-up time for patients with PHEO was 249 months and without PHEO was 67 months (P < .01). Survival analyses among RET 634 carriers did not show shorter survival for patients with PHEO. The median survival time for patients with PHEO was 499 months and without PHEO was 444 months (P < .05).
CONCLUSIONS: PHEO in MEN2 patients are usually bilateral and unlikely to be metastatic. Subgroup analysis of patients with RET 634 mutations with and without PHEO showed that PHEO was not associated with a more advanced stage of MTC at diagnosis or a shorter survival.

Related: Thyroid Cancer RET


Shifrin AL, LiVolsi VA, Zheng M, et al.
Neuroendocrine thymic carcinoma metastatic to the parathyroid gland that was reimplanted into the forearm in patient with multiple endocrine neoplasia type 1 syndrome: a challenging management dilemma.
Endocr Pract. 2013 Nov-Dec; 19(6):e163-7 [PubMed] Related Publications
OBJECTIVE: To describe a unique case of a metastatic thymic carcinoma to the hyperplastic parathyroid gland and to present a challenging management dilemma.
METHODS: Our patient is 60-year-old, intellectually disabled man with history of the multiple endocrine neoplasia type 1 (MEN1) syndrome, a surgery in 1985 for hypercalcemia with removal of one parathyroid gland, surgery in 2007 with findings of extensively necrotic well differentiated neuroendocrine carcinoma (carcinoid tumor) of the thymus. In 2012, he presented with persistent hypercalcemia (calcium level 11.7 mg/dL [range, 8.6-10.2]), and a parathyroid hormone (PTH) level of 225 pg/mL (range, 15-65 pg/mL). He underwent a repeat neck exploration with removal of 2 small inferior and a large left superior 4.5 × 2.5 × 1.5 cm parathyroid glands, all of which showed hyperplasia on intraoperative frozen section. A small portion of the superior gland was reimplanted into the patient's forearm. Final pathology showed the presence of a focus of neuroendocrine tumor within the left superior parathyroid gland with immunostain identical to the thymic carcinoma. His postoperative PTH level was 14 pg/mL and calcium 8.5 mg/dL. A positron emission tomography-computed tomography (PET-CT) and octreotide scans revealed an extensive metastatic disease within the lung, mediastinum, and bones.
RESULTS: We decided to leave a portion of the reimplanted parathyroid gland with possible metastatic thymic carcinoid in his forearm because of the presence a widespread metastatic disease and his intellectual disability that would result in noncompliance with calcium replacement in case of permanent hypocalcemia.
CONCLUSION: Metastatic thymic carcinoma to the parathyroid gland has never been reported in the literature. We have described the first case and presented a challenging management dilemma.

Related: Thymoma and Thymic Carcinoma


Asha HS, Seshadri MS, Rajaratnam S
Hypertensive crisis in a patient with thyroid cancer.
Natl Med J India. 2012 Nov-Dec; 25(6):339-40 [PubMed] Related Publications
Phaeochromocytomas may be discovered incidentally when patients present with hypertensive crisis during general anaesthesia. A 49-year-old man underwent thyroidectomy 25 years ago and was diagnosed to have spindle cell carcinoma of the thyroid. He presented with recent onset of hoarseness of voice and was found to have a vocal cord nodule. He developed a hypertensive crisis during surgery. He was subsequently evaluated and found to have bilateral phaeochromocytoma. Further evaluation revealed a RET proto-oncogene mutation at codon 634 consistent with multiple endocrine neoplasia (MEN)-2A.

Related: Thyroid Cancer


Brauckhoff M, Machens A, Lorenz K, et al.
Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: a changing perspective.
Ann Surg. 2014; 259(4):800-6 [PubMed] Related Publications
OBJECTIVE: This investigation aimed at exploring the suitability of nonendocrine manifestations preceding medullary thyroid cancer (MTC) for early diagnosis of multiple endocrine neoplasia type 2B (MEN 2B).
BACKGROUND: MEN 2B patients, running a high risk of metastatic MTC, must be diagnosed early for biochemical cure.
METHODS: Forty-four MEN 2B patients carrying inherited (3 patients) and de novo (41 patients) M918T RET mutations were examined for signs and symptoms prompting MEN 2B.
RESULTS: All 3 patients with inherited mutations were diagnosed before the age of 1 year and cured of their C-cell disease. Among 41 patients with de novo mutations, MEN 2B was diagnosed in 12 patients after recognition of nonendocrine manifestations [intestinal ganglioneuromatosis (6 patients), oral symptoms (5 patients), ocular ("tearless crying") (4 patients), and skeletal stigmata (1 patient) alone or concomitantly]. In the remaining 29 patients with de novo mutations, the diagnosis of MEN 2B was triggered by symptomatic MTC (28 patients) or pheochromocytoma (1 patient). The former patients, being significantly (P < 0.001) younger (means of 5.3 vs 17.6 years) and having lower calcitonin levels (means of 115 vs 25,519 pg/mL), smaller tumors (67% vs 0% were ≤10 mm) and less often extrathyroidal extension (0% vs 81%), lymph node (42% vs 100%), and distant metastases (8% vs 79%), were biochemically cured more often (58% vs 0%).
CONCLUSIONS: MTC is curable in patients with de novo mutations when nonendocrine MEN 2B components are quickly appreciated and surgical intervention is performed before patients turn 4 years old.

Related: Thyroid Cancer RET


de Laat JM, Pieterman CR, Weijmans M, et al.
Low accuracy of tumor markers for diagnosing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 patients.
J Clin Endocrinol Metab. 2013; 98(10):4143-51 [PubMed] Related Publications
CONTEXT: The assessment of tumor markers for diagnosing pancreatic neuroendocrine tumors (pNET) in multiple endocrine neoplasia type 1 (MEN1) patients is advised in the current guidelines but has never been validated for this purpose.
OBJECTIVE: The objective of the study was to assess the diagnostic accuracy of chromogranin A (CgA), pancreatic polypeptide (PP), and glucagon for pNET in MEN1.
DESIGN: This was a diagnostic study.
SETTING: The study was conducted at Dutch university medical centers from 2008 to 2011, representing 90% of the total Dutch MEN1 population.
PATIENTS AND METHODS: Patients for whom data on tumor markers in combination with the reference standard (ie, radiological imaging) were available between 2008 and 2011 were included. The reference standard for the presence of pNET was pathology or detection on magnetic resonance imaging, computed tomography, or endoscopic ultrasound confirmed on subsequent imaging, irrespective of modality at follow-up.
MAIN OUTCOME MEASURES: The area under the receiver-operating characteristic curve (AUC), positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, sensitivity, and specificity were calculated for each marker.
RESULTS: For the analysis of PP, CgA, and glucagon, 73, 81, and 94 patients were available, respectively. The AUC for CgA was 0.48 [95% confidence interval (CI) 0.35-0.61] with a sensitivity 0.33 and a specificity 0.73; the AUC for glucagon was 0.58 (95% CI 0.46-0.70) with a sensitivity 0.43 and a specificity 0.73; and the AUC for PP was 0.64 (95% CI 0.50-0.77) with a sensitivity 0.36 and a specificity 0.74. Age, imaging modality, tumor size, and number did not influence the outcomes.
CONCLUSION: The diagnostic accuracy of the tumor markers CgA, PP, and glucagon for pNET in MEN1 is low.

Related: Cancer of the Pancreas Pancreatic Cancer


Toledo SP, Lourenço DM, Toledo RA
A differential diagnosis of inherited endocrine tumors and their tumor counterparts.
Clinics (Sao Paulo). 2013; 68(7):1039-56 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
Inherited endocrine tumors have been increasingly recognized in clinical practice, although some difficulties still exist in differentiating these conditions from their sporadic endocrine tumor counterparts. Here, we list the 12 main topics that could add helpful information and clues for performing an early differential diagnosis to distinguish between these conditions. The early diagnosis of patients with inherited endocrine tumors may be performed either clinically or by mutation analysis in at-risk individuals. Early detection usually has a large impact in tumor management, allowing preventive clinical or surgical therapy in most cases. Advice for the clinical and surgical management of inherited endocrine tumors is also discussed. In addition, recent clinical and genetic advances for 17 different forms of inherited endocrine tumors are briefly reviewed.

Related: Cancer Screening and Early Detection Cancer of the Pancreas Pancreatic Cancer


Manchester CS
Multiple endocrine neoplasia: the enigma of MEN.
AACN Adv Crit Care. 2013 Jul-Sep; 24(3):304-13 [PubMed] Related Publications
Multiple endocrine neoplasia (MEN) is an array of tumors found in various endocrine glands throughout the human body. A wide spectrum of clinical manifestations accompanies this syndrome. The complexities of the glandular function and subtle development of symptoms can cause the diagnosis to be missed, and individuals with MEN can be an enigma to the care team. Appropriate differential diagnosis and assessment are critical for these individuals to receive optimal care. An interprofessional team of health care providers, including an endocrinologist and an advanced practice endocrine nurse, must work in concert to orchestrate a plan of care across the continuum. Those specialized nurses who encounter individuals with MEN in a critical care setting are positioned to support the patient, the family, and the care team through this maze of multiple endocrinopathies and tumors.


Lee NE, Lee YJ, Yun SH, et al.
A case of Zollinger-Ellison syndrome in multiple endocrine neoplasia type 1 with urolithiasis as the initial presentation.
Korean J Gastroenterol. 2013; 61(6):333-7 [PubMed] Related Publications
Zollinger-Ellison syndrome (ZES) is characterized by gastrinoma and resultant hypergastrinemia, which leads to recurrent peptic ulcers. Because gastrinoma is the most common pancreatic endocrine tumor seen in multiple endocrine neoplasia type I (MEN 1), the possibility of gastrinoma should be investigated carefully when patients exhibit symptoms associated with hormonal changes. Ureteral stones associated with hyperparathyroidism in the early course of MEN 1 are known to be its most common clinical manifestation; appropriate evaluation and close follow-up of patients with hypercalcemic urolithiasis can lead to an early diagnosis of gastrinoma. We report a patient with ZES associated with MEN 1, and urolithiasis as the presenting entity. A 51-year-old man visited the emergency department with recurrent epigastric pain. He had a history of calcium urinary stone 3 years ago, and 2 years later he had 2 operations for multiple jejunal ulcer perforations; these surgeries were 9 months apart. He was taking intermittent courses of antiulcer medication. Multiple peripancreatic nodular masses, a hepatic metastasis, parathyroid hyperplasia, and a pituitary microadenoma were confirmed by multimodal imaging studies. We diagnosed ZES with MEN 1 and performed sequential surgical excision of the gastrinomas and the parathyroid adenoma. The patient received octreotide injection therapy and close follow-up.


Rowland KJ, Chernock RD, Moley JF
Pheochromocytoma in an 8-year-old patient with multiple endocrine neoplasia type 2A: implications for screening.
J Surg Oncol. 2013; 108(4):203-6 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
Childhood pheochromocytoma in the setting of multiple endocrine neoplasia type 2 (MEN2) remains rare and has not been reported under the age of 12. We present an 8-year-old female with known MEN 2A, C634Y RET mutation, diagnosed with a 6 cm pheochromocytoma requiring laparoscopic adrenalectomy. Given this patient's age at diagnosis, screening guidelines should recommend annual screening beginning at age 8 for patients with MEN 2B or MEN 2A codons 630 or 634 RET mutations.

Related: Cancer Screening and Early Detection RET


Qi XP, Zhao JQ, Du ZF, et al.
Prophylactic thyroidectomy for MEN 2-related medullary thyroid carcinoma based on predictive testing for RET proto-oncogene mutation and basal serum calcitonin in China.
Eur J Surg Oncol. 2013; 39(9):1007-12 [PubMed] Related Publications
INTRODUCTION: Early and normative surgery is the only curative method for multiple endocrine neoplasia type 2 (MEN 2)-related medullary thyroid carcinoma (MTC).
AIMS: To study the timing of prophylactic total thyroidectomy (TT) for MEN 2-related MTC with different RET mutations in a Chinese population, and to compare the sensitivity and accuracy of fully-automated chemiluminescence immunoassay (FACLIA) and radioimmunoassay (RIA) for serum calcitonin (Ct).
METHODS: We collected 24 asymptomatic individuals from 8 unrelated Chinese families with MEN 2, and analyzed RET mutation and Ct levels. Then we performed TT on 17 of the 24 individuals, including TT (2/17), TT with bilateral level VI lymph-node dissection (B-LND(VI); 12/17) and TT with B-LND(VI) + modified unilateral/bilateral/local neck dissection (3/17).
RESULTS: Histopathology revealed bilateral/unilateral MTC in 15/17 (88.2%; median diameter, 1.0 cm) and bilateral C-cell hyperplasia in 2/17 (11.8%; p.V292M/R67H/R982C and p.C618Y). Lymph-node metastasis/fibro-adipose tissue invasion (p.C634R) or solely fibro-adipose tissue invasion (p.C634Y) were found in 2/17 (11.8%). Elevated pre-surgical Ct (pre-Ct) was identified by FACLIA in 17/17 (median age, 24.0), while pre-Ct by RIA was found in only 6/15 (P < 0.001). The median follow-up was 22.0 months, during which 16/17 had no abnormality (one p.C634R individual had elevated Ct), and another 7 carriers still had consistently undetectable Ct by FACLIA.
CONCLUSIONS: Our study highlights the importance and feasibility of individualized prophylactic TT for MEN 2-related MTC, based on predictive integrated screening of RET and pre-Ct levels. Besides, we recommend FACLIA to measure Ct for earlier diagnosis, treatment and follow-up monitoring of MTC.

Related: Thyroid Cancer RET


López CL, Langer P, Waldmann J, et al.
Shortness: an unknown phenotype of multiple endocrine neoplasia type 1.
Eur J Endocrinol. 2013; 169(1):133-7 [PubMed] Related Publications
OBJECTIVE: An observation of shortness among the female participants of a regular screening program in multiple endocrine neoplasia type 1 (MEN1) patients has raised the question as to whether shortness represents a phenotype characteristic of the disease.
METHODS: The body height (cm) of genetically confirmed MEN1 patients at the time of diagnosis was compared with the body height of their unaffected relatives (parents, siblings, and children), the midparental body height, and the body height of the age-matched German population. Univariate analysis of the clinical variables was performed using the t-test, Mann–Whitney U test, and ANOVA as appropriate, and multivariate analysis was performed as a logistic regression analysis. P values <0.05 were considered statistically significant.
RESULTS: The mean body height of 22 female MEN1 patients (mean age 33.5 years) was 161 +/- 5 cm and thus significantly lesser than the body heights of their unaffected female relatives (mean 165.5 +/- 7.3 cm, P=0.027) and the age-matched German female population (mean 167 cm, P=0.0001) and mid-parental height (177.5 cm, P<0.0001). The mean body height of 24 male MEN1 patients (mean age 34.8 years) was also lesser (177 +/- 6.5 cm) than the average body height of German males in this age group (180 cm, P=0.031) and tended to be lesser than that of their unaffected male relatives (178.5 +/- 5.8 cm, P=0.0915) and the mid-parental body height (177.5 cm, P=0.124).
CONCLUSIONS: Small body height is a yet unrecognized phenotype characteristic of MEN1 patients, especially in women. The mechanisms behind this phenotypical characteristic warrant further investigation.

Related: MEN1


Versnick M, Popadich A, Sidhu S, et al.
Minimally invasive parathyroidectomy provides a conservative surgical option for multiple endocrine neoplasia type 1-primary hyperparathyroidism.
Surgery. 2013; 154(1):101-5 [PubMed] Related Publications
BACKGROUND: Many authors advocate routine subtotal parathyroidectomy or total parathyroidectomy and autotransplantation for patients with multiple endocrine neoplasia type 1 (MEN1). Many of these patients are young and recurrence may take decades. Four-gland parathyroid exploration carries a higher risk of complication than minimally invasive parathyroidectomy (MIP). The aim of this study was to assess the role of selective removal of only abnormal glands for MEN1 in the era of MIP.
METHODS: For this retrospective, cohort study we collected data on patients undergoing parathyroidectomy for MEN1 from an endocrine surgery database. We reviewed preoperative localization studies, operative findings, histopathology, and clinical outcomes.
RESULTS: Twenty-six patients underwent parathyroidectomy for MEN1-associated hyperparathyroidism over the 23-year study period. Six of 10 (60%) patients in the total parathyroidectomy group and 4 of 10 (40%) patients in the subtotal parathyroidectomy group developed hypocalcemia. The subtotal and total parathyroidectomy groups both had a recurrence rate of 30% with a mean follow-up rate of 106 and 133 months, respectively. The MIP group had no hypocalcemia or recurrence with a mean follow-up of 19 months.
CONCLUSION: MIP with excision of only documented abnormal parathyroid glands provides an acceptable outcome for patients with MEN1, avoiding the potential for permanent hypoparathyroidism in young patients. It is accepted that recurrent disease is inevitable in these patients; however, such recurrence may take decades to occur and may be able to be dealt with by a further focused procedure.


Lee M, Pellegata NS
Multiple endocrine neoplasia syndromes associated with mutation of p27.
J Endocrinol Invest. 2013; 36(9):781-7 [PubMed] Related Publications
Multiple endocrine neoplasias (MEN) are autosomal dominant disorders characterized by the occurrence of tumors in at least two endocrine glands. Until recently, two MEN syndromes were known, i.e. the MEN type 1 (MEN1) and type 2 (MEN2), which are caused by germline mutations in the MEN1 and RET genes, respectively. These two syndromes are characterized by a different tumor spectrum. A few years ago we described a variant of the MEN syndromes, which spontaneously developed in a rat colony and was named MENX. Affected animals consistently develop multiple endocrine tumors, with a spectrum that shares features with both MEN1 and MEN2 human syndromes. Genetic studies identified a germline mutation in the Cdkn1b gene, encoding the p27 cell cycle inhibitor, as the causative mutation for MENX. Capitalizing on these findings, germline mutations in the human homologue, CDKN1B, were searched for and identified in patients with multiple endocrine tumors. As a consequence of this discovery, a novel human MEN syndrome, named MEN4, was recognized, which is caused by heterozygous mutations in p27. These studies identified Cdkn1b/CDKN1B as a novel tumor susceptibility gene for multiple endocrine tumors in both rats and humans. Here we review the characteristics of the MENX and MEN4 syndromes and we briefly address the main function of p27 and how it is affected by MENX- or MEN4-associated mutations.

Related: Parathyroid Cancer Pituitary Tumors


Marx SJ
Multiplicity of hormone-secreting tumors: common themes about cause, expression, and management.
J Clin Endocrinol Metab. 2013; 98(8):3139-48 [PubMed] Article available free on PMC after 01/10/2014 Related Publications
CONTEXT: Multiplicity of hormone-secreting tumors occurs in a substantial portion of hormone-excess states. Multiplicity increases the difficulty of management and drives the selection of special strategies.
EVIDENCE ACQUISITION: This is a synthesis from publications about tumor development and expression, and also about types of clinical strategy for hormone-secreting tumors.
EVIDENCE SYNTHESIS: Comparisons were made between patient groups with solitary tumors vs those with multiple tumors. Major themes with clinical relevance emerged. Usually, tumor multiplicity develops from a genetic susceptibility in all cells of a tissue. This applies to hormone-secreting tumors that begin as either polyclonal (such as in the parathyroids of familial hypocalciuric hypercalcemia) or monoclonal tumors (such as in the parathyroids of multiple endocrine neoplasia type 1 [MEN1]). High penetrance of a hereditary tumor frequently results in bilaterality and in several other types of multiplicity. Managements are better for the hormone excess than for the associated cancers. Management strategies can be categorized broadly as ablation that is total, subtotal, or zero. Examples are discussed for each category, and 1 example of each category is named here: 1) total ablation of the entire tissue with effort to replace ablated functions (for example, in C-cell neoplasia of multiple endocrine neoplasia type 2); 2) subtotal ablation with increased likelihood of persistent disease or recurrent disease (for example, in the parathyroid tumors of MEN1); or 3) no ablation of tissue with or without the use of pharmacotherapy (for example, with blockers for secretion of stomach acid in gastrinomas of MEN1).
CONCLUSIONS: Tumor multiplicity usually arises from defects in all cells of the precursor tissue. Even the optimized managements involve compromises. Still, an understanding of pathophysiology and of therapeutic options should guide optimized management.


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(15):4239-48 [PubMed] Related Publications
PURPOSE: Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC.
EXPERIMENTAL DESIGN: We conducted a phase I/II trial of vandetanib for children (5-12 years) and adolescents (13-18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m(2) administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m(2)/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit.
RESULTS: Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2-52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%-75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects.
CONCLUSION: Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m(2)/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.

Related: Thyroid Cancer RET


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