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Multiple Endocrine Neoplasia

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

  • Multiple endocrine neoplasia 1 (MEN type I) also known as Wermer's syndrome
  • Multiple endocrine neoplasia 2A (MEN type IIa) also known as Sipple Syndrome
  • Multiple endocrine neoplasia 2B (MEN type IIb)
  • Familial medullary thyroid carcinoma, (FMTC) is a similar inherited condition were medullary thyroid carcinoma may occur in several family members, though not necessarily with the other endocrine tumours seen in MEN.
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
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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).

Tran K, Khan S, Taghizadehasl M, et al.
Gallium-68 Dotatate PET/CT is superior to other imaging modalities in the detection of medullary carcinoma of the thyroid in the presence of high serum calcitonin.
Hell J Nucl Med. 2015 Jan-Apr; 18(1):19-24 [PubMed] Related Publications
OBJECTIVE: Medullary carcinoma of the thyroid (MTC) is a rare neuroendocrine tumour (NET) that expresses somatostatin receptors on the cell membrane and secretes calcitonin. Surgery is the primary curative modality but is achieved only when the diagnosis is timely so there is a high rate of persistent and recurrent disease indicated by a rise in the serum calcitonin levels. Successful management of recurrent disease requires accurate localisation with cross sectional and functional imaging. The introduction of gallium-68-Dotatate ((68)Ga-Dotatate) peptides positron emission tomography/computerized tomography (PET/CT) has significantly improved the detection of NET and has been reported as a valuable adjunct in MTC localisation. We retrospectively reviewed our cases of MTC to correlate the detectability of (68)Ga-Dotatate in relation to calcitonin levels and assess suitability of inoperable patients for peptide receptor radionuclide therapy (PRRT).
SUBJECTS AND METHODS: Seven patients (age range 31-66 years, M:F 3:4) with raised calcitonin (mean=7,143pg/mL) were referred for (68)Ga-Dotatate PET/CT scan for localisation of persisting recurrent MTC. Six patients were known to have MTC treated with thyroidectomy and one patient was presenting for the first time. All patients had multiple imaging including ultrasound (US), CT, magnetic resonance imaging (MRI), fluorine-18-fluorodeoxyglucose ((18)F-FDG) PET/CT and iodine-123-metaiodobenzylguanidine ((123)I-MIBG). Positive findings were defined as areas of increased uptake other than the organs of normal distribution and were correlated with results of biopsies, other imaging, long term monitoring of calcitonin and clinical follow up.
RESULTS: In 6/7 patients with very high serum calcitonin (range= 672-37,180, mean=8,320pg/mL) (68)Ga-Dotatate PET/CT confirmed the presence of active disease seen on other modalities or detected hitherto unsuspected lesions. In at least 3 cases, (68)Ga-Dotatate PET/CT showed many more lesions compared to other imaging combined. In 1/7 patient (68)Ga-Dotatate PET/CT was negative in line with a relatively low calcitonin level (80pg/mL) and negative disease on fine needle aspiration.
CONCLUSION: (68)Ga-Dotatate PET/CT is an effective tool for localising metastatic spread of MTC. It appears to be most effective in the presence of higher levels of serum calcitonin, probably in excess of 500pg/mL. The results of our small cohort had an impact on staging and management with the introduction of peptide receptor radionuclide therapy for inoperable disease.

Lodewijk L, Bongers PJ, Kist JW, et al.
Thyroid incidentalomas in patients with multiple endocrine neoplasia type 1.
Eur J Endocrinol. 2015; 172(4):337-42 [PubMed] Related Publications
OBJECTIVE: Currently, little is known about the prevalence of thyroid tumors in multiple endocrine neoplasia type 1 (MEN1) patients and it is unclear whether tumorigenesis of these thyroid tumors is MEN1-related. The aim of the study was to assess the prevalence of thyroid incidentalomas in MEN1 patients compared with nonMEN1 patients and to verify whether thyroid tumorigenesis is MEN1-related.
DESIGN: A cross-sectional study.
METHODS: The study included two groups: patients with MEN1 and a matched non-MEN1 control group without known thyroid disease, who underwent an ultrasound of the neck for the localization of parathyroid adenoma. Ninety-five MEN1 patients underwent ultrasound of the neck and were matched on gender and age with non-MEN1 patients. The prevalence of thyroid incidentalomas described in the ultrasound report was scored. Multinodular goiters, solitary nodes, and cysts were scored as incidentalomas. Presence of nuclear menin expression was evaluated by menin immunostaining of the thyroid tumors.
RESULTS: In the MEN1 group, 43 (45%) patients had a thyroid incidentaloma compared with 48 (51%) in the non-MEN1 group, of which 14 (15%) and 16 (17%), respectively, were solitary nodes. Menin was expressed in the nuclei of all evaluated thyroid tumors.
CONCLUSIONS: MEN1 patients do not have a higher prevalence of thyroid incidentalomas compared with primary hyperparathyroidism patients without the diagnosis of MEN1. Menin was expressed in the thyroid tumors of MEN1 patients.

Vezzosi D, Cardot-Bauters C, Bouscaren N, et al.
Long-term results of the surgical management of insulinoma patients with MEN1: a Groupe d'étude des Tumeurs Endocrines (GTE) retrospective study.
Eur J Endocrinol. 2015; 172(3):309-19 [PubMed] Related Publications
OBJECTIVE: Management of insulinomas in the context of MEN1 remains poorly studied. The aim of this study was to evaluate long-term results of various surgical approaches in a large cohort of insulinoma-MEN1 patients.
DESIGN AND METHODS: Consecutive insulinoma-MEN1 patients operated on for a nonmetastatic insulinoma between 1957 and 2010 were retrospectively selected from the MEN1 database of the French Endocrine Tumor Group. The type of surgery was categorized as distal pancreatectomy (DP), total pancreatectomy/cephalic duodenopancreatectomy (TP/CDP), or enucleation (E). Primary endpoint was time until recurrence of hypoglycemia after initial surgery. Secondary endpoints were post-operative complications.
RESULTS: The study included 73 patients (median age=28 years). Surgical procedures were DP (n=46), TP/CDP (n=9), or E (n=18). After a median post-operative follow-up of 9.0 years (inter-quartile range (IQR): 2.5-16.5 years), 60/73 patients (82.2%) remained hypoglycemia free. E and TP/CDP were associated with a higher risk of recurrent hypoglycemia episodes (unadjusted hazard ratio: 6.18 ((95% CI: 1.54-24.8); P=0.010) for E vs DP and 9.51 ((95% CI: 1.85-48.8); P=0.007) for TP/CDP vs DP. After adjustment for International Union against Cancer pTNM classification, enucleation remained significantly associated with a higher probability of recurrence. Long-term complications had occurred in 20 (43.5%) patients with DP, five (55.6%) with TP/CDP, but in none of the patients who have undergone E (P=0.002).
CONCLUSION: In the French Endocrine database, DP is associated with a lower risk for recurrent hypoglycemia episodes. Due to lower morbidity, E alone might be considered as an alternative.

Valdés N, Navarro E, Mesa J, et al.
RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation.
Eur J Endocrinol. 2015; 172(3):301-7 [PubMed] Related Publications
OBJECTIVE: Specific germline mutations in the RET proto-oncogene are correlated with clinical features in multiple endocrine neoplasia type 2A (MEN2A); however, data are scarce regarding differences in clinical profiles dependent on the type of nucleotide and amino acid substitution at the same codon. We aimed to analyse differences in clinical risk profiles and outcomes among different amino acids encoded by codon 634.
DESIGN: The study was retrospective and multicentric.
METHODS: We collected data included in the Spanish Online National Database from patients with MEN2A carrying a RET proto-oncogene mutation on codon 634. The mean follow-up time was 7.6±6.9 years (1-32).
RESULTS: Patients (n=173) from 49 unrelated families were C634Y carriers, and 26 patients from eight different families had C634R mutation. We found higher penetrance of medullary thyroid carcinoma, phaeochromocytoma and hyperparathyroidism (P<0.001, P=0.007 and P<0.001 respectively) in C634R carriers than in C634Y carriers. The Kaplan-Meier estimate of cumulative lymph node and distant metastases rates showed that these events occurred earlier in patients harbouring the C634R mutation (P<0.001). A multivariate adjusted Cox regression analysis indicated that the C634R mutation was an independent factor for persistent/recurrent disease (hazard ratio, 3.17; 95% CI: 1.66-6.03; P<0.001).
CONCLUSIONS: Our results suggest that there could be clinical differences caused by different amino acid substitutions at codon 634; specifically, the C634R mutation was associated with a more aggressive MEN2A phenotype than the C634Y mutation.

Romero Arenas MA, Fowler RG, San Lucas FA, et al.
Preliminary whole-exome sequencing reveals mutations that imply common tumorigenicity pathways in multiple endocrine neoplasia type 1 patients.
Surgery. 2014; 156(6):1351-7; discussion 1357-8 [PubMed] Related Publications
BACKGROUND: Whole-exome sequencing studies have not established definitive somatic mutation patterns among patients with sporadic hyperparathyroidism (HPT). No sequencing has evaluated multiple endocrine neoplasia type 1 (MEN1)-related HPT. We sought to perform whole-exome sequencing in HPT patients to identify somatic mutations and associated biological pathways and tumorigenic networks.
METHODS: Whole-exome sequencing was performed on blood and tissue from HPT patients (MEN1 and sporadic) and somatic single nucleotide variants (SNVs) were identified. Stop-gain and stop-loss SNVs were analyzed with Ingenuity Pathways Analysis (IPA). Loss of heterozygosity (LOH) was also assessed.
RESULTS: Sequencing was performed on 4 MEN1 and 10 sporadic cases. Eighteen stop-gain/stop-loss SNV mutations were identified in 3 MEN1 patients. One complex network was identified on IPA: Cellular function and maintenance, tumor morphology, and cardiovascular disease (IPA score = 49). A nonsynonymous SNV of TP53 (lysine-to-glutamic acid change at codon 81) identified in a MEN1 patient was suggested to be a driver mutation (Cancer-specific High-throughput Annotation of Somatic Mutations; P = .002). All MEN1 and 3/10 sporadic specimens demonstrated LOH of chromosome 11.
CONCLUSION: Whole-exome sequencing revealed somatic mutations in MEN1 associated with a single tumorigenic network, whereas sporadic pathogenesis seemed to be more diverse. A somatic TP53 mutation was also identified. LOH of chromosome 11 was seen in all MEN1 and 3 of 10 sporadic patients.

MacIntosh RB, Shivapuja PK, Krzemien MB, Lee M
Multiple endocrine neoplasia type 2B: maxillofacial significance in 5 cases.
J Oral Maxillofac Surg. 2014; 72(12):2498.e1-17 [PubMed] Related Publications
PURPOSE: This paper intends to review for the oral and maxillofacial surgery community the MEN abnormalities generally, to emphasize the maxillofacial abnormalities peculiar to the MEN2B variant particularly, and to demonstrate the importance of early recognition of its most important component, medullary thyroid carcinoma.
PATIENTS AND METHODS: The findings in five individuals with confirmed diagnoses of MEN2B are arranged to demonstrate the various manifestations of the disorder, and together represent the largest single group in the oral and maxillofacial surgery literature to date.
RESULTS: Tabulation of the patients' individual findings demonstrates the variants and severity of the disorder, discloses findings not previously emphasized in the literature, and stresses the significance of early recognition of medullary thyroid carcinoma.
CONCLUSION: The evidence in this study group suggests that the oral mucosal lesions are more commonly neurofibromas than neuromas as previously reported, that the characteristic dental central diastemas may occur independent of tongue size or the presence of oral soft tissue lesions, and that the characteristic apertognathia potentially requires surgical correction.

Dy BM, Que FG, Thompson GB, et al.
Metastasectomy of neuroendocrine tumors in patients with multiple endocrine neoplasia type 1.
Am J Surg. 2014; 208(6):1047-53; discussion 1052-3 [PubMed] Related Publications
BACKGROUND: Neuroendocrine (NE) tumors commonly afflict patients with multiple endocrine neoplasia type 1 (MEN1). It is thought that patients with MEN1 have improved survival compared with individuals with analogous lesions. The role of metastasectomy of NE tumors in MEN1 patients is not clearly defined.
METHODS: A review of MEN1 patients undergoing surgery for NE tumors from 1994 to 2010 at a single tertiary care center was performed. Tumor function, the extent of metastasis, R0 resection, and survival were analyzed.
RESULTS: We identified 30 patients who underwent resection including synchronous and metachronous metastasectomy. Synchronous metastases were identified in 19 patients (63%), whereas 11 (37%) had metachronous disease. R0 resection was achieved in 93% of patients. Estimated 10-year survival is 86.4% (95% confidence interval, 60% to 100%) with no factors predictive of overall survival. The disease-free interval at 1, 5, and 10 years was 89%, 50%, and 19%, respectively, with recurrence occurring at a median of 5.4 years (95% confidence interval, 77.7% to 100%). Synchronous metastasis (P = .0072; hazard ratio [HR], 3.4) and nonfunctioning tumors (P = .014; HR, 3.3) were more likely to recur, whereas age (P = .09; HR, 1.5), gender (P = .49; HR, 1.3), and the site of metastasis (P = .81; HR, 1.1) did not influence recurrence.
DISCUSSION: Patients with MEN1 benefit from resection of metastatic NE disease. Despite a high recurrence rate, survival and disease-free interval is favorable vs patients without MEN1.

Korpershoek E, Petri BJ, Post E, et al.
Adrenal medullary hyperplasia is a precursor lesion for pheochromocytoma in MEN2 syndrome.
Neoplasia. 2014; 16(10):868-73 [PubMed] Free Access to Full Article Related Publications
Adrenal medullary hyperplasias (AMHs) are adrenal medullary proliferations with a size < 1 cm, while larger lesions are considered as pheochromocytoma (PCC). This arbitrary distinction has been proposed decades ago, although the biological relationship between AMH and PCC has never been investigated. Both lesions are frequently diagnosed in multiple endocrine neoplasia type 2 (MEN2) patients in whom they are considered as two unrelated clinical entities. In this study, we investigated the molecular relationship between AMH and PCC in MEN2 patients. Molecular aberrations of 19 AMHs and 13 PCCs from 18 MEN2 patients were determined by rearranged during transfection (RET) proto-oncogene mutation analysis and loss of heterozygosity (LOH) analysis for chromosomal regions 1p13, 1p36, 3p, and 3q, genomic areas covering commonly altered regions in RET-related PCC. Identical molecular aberrations were found in all AMHs and PCCs, at similar frequencies. LOH was seen for chromosomes 1p13 in 8 of 18 (44%), 1p36 in 9 of 15 (60%), 3p12-13 in 12 of 18 (67%), and 3q23-24 in 10 of 16 (63%) of AMHs, and for chromosome 1p13 in 13 of 13 (100%), 1p36 in 7 of 11 (64%), 3p12-13 in 4 of 11 (36%), and 3q23-24 in 11 of 12 (92%) of PCCs. Our results indicate that AMHs are not hyperplasias and, in clinical practice, should be regarded as PCCs, which has an impact on diagnosis and treatment of MEN2 patients. We therefore propose to replace the term AMH by micro-PCC to indicate adrenal medullary proliferations of less than 1 cm.

Singh Ospina N, Thompson GB, Lee RA, et al.
Safety and efficacy of percutaneous parathyroid ethanol ablation in patients with recurrent primary hyperparathyroidism and multiple endocrine neoplasia type 1.
J Clin Endocrinol Metab. 2015; 100(1):E87-90 [PubMed] Related Publications
CONTEXT: The most common feature of multiple endocrine neoplasia type 1 (MEN1) is primary hyperparathyroidism (PHP), which occurs in approximately 95% of MEN1 patients. Approximately 40-60% of patients with MEN1 develop recurrent hypercalcemia within 10-12 years after their initial parathyroid surgery and the successful management of recurrent PHP is challenging.
OBJECTIVE: This study sought to evaluate the safety and efficacy of percutaneous ethanol ablation (PEA) for the treatment of recurrent PHP in patients with MEN1. DESIGN, SETTING, PATIENTS, INTERVENTION, OUTCOME MEASURED: We performed an electronic search to identify patients with a billing code for MEN1 who were seen at Mayo Clinic between 1977 and 2013. Patients with recurrent PHP who underwent PEA were identified and their clinical information was collected. We performed t test analyses to compare mean values.
RESULTS: Thirty-seven patients underwent 80 PEA treatments that included 123 sessions of ethanol administration. Twenty-one patients were women (56.8%) and the mean age at diagnosis of PHP was 33.8 years. The mean preprocedure calcium level was 10.7 mg/dl ± 0.57 (SD) and the mean postprocedure calcium level was 9.6 mg/dl ± 0.76 (P < .01). In 14 treatments (18.9%) the postprocedure calcium was greater than 10.1 mg/dl. Postprocedure hypocalcemia occurred in six treatments (8.1%). Normocalcemia was achieved in 54 of the treatment episodes (73%) and the mean duration of normocalcemia was 24.8 months. PEA was safe with transient hoarseness occurring in four of the treatments (5%).
CONCLUSION: The treatment of recurrent PHP in patients with MEN1 represents a challenge that is associated with increased morbidity. PEA is an effective treatment option for achieving normocalcemia in the majority of the patients with MEN1. PEA is associated with low rates of hypocalcemia and no permanent complications.

Yamazaki M, Hanamura T, Ito K, et al.
A newly identified missense mutation in RET codon 666 is associated with the development of medullary thyroid carcinoma.
Endocr J. 2014; 61(11):1141-4 [PubMed] Related Publications
A 38-year-old woman with a thyroid nodule measuring approximately 2 cm was suspected to have medullary thyroid carcinoma (MTC) because of markedly elevated serum calcitonin and carcinoembryonic antigen levels. There were no signs of pheochromocytoma, whereas primary hyperparathyroidism was suspected based on the findings of inappropriate hypersecretion of parathyroid hormone although no parathyroid tumor was detected with imaging studies. RET mutation analysis revealed a novel germline missense mutation in codon 666, c.1997A>G (p.K666R). She underwent total thyroidectomy with lymphadenectomy and simultaneous total parathyroidectomy with autotransplantation of parathyroid tissue. She was given calcium lactate and alfacalcidol to prevent postoperative hypocalcemia. Pathological findings of the thyroid tumor were compatible with MTC, but the resected parathyroid glands were intact. To our knowledge, c.1997A>G (p.K666R) is a new RET mutation. This is a minor variant, but it is significant because of the possible pathogenicity in tumor formation. It is often difficult to determine whether MTC is generated as part of MEN2-related disease or familial MTC when it is a unique manifestation. In addition, it is still unclear whether all missense mutations in this codon reported previously will lead to the same clinical course and prognosis. Further careful observations of clinical presentation are required to determine the clinical features associated with this variant.

Gurkan E, Gurbuz Y, Tarkun I, et al.
Mixed medullary-papillary carcinoma of the thyroid: report of two cases and review of the literature.
Indian J Pathol Microbiol. 2014 Oct-Dec; 57(4):598-602 [PubMed] Related Publications
Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are two distinct types of thyroid carcinoma with considerable difference in terms of cellular origin, histopathological appearance, clinical course and prevalence. The histogenetic origin and possible molecular mechanisms responsible for the development of mixed medullary-papillary carcinoma of the thyroid are still unclear. The most widely accepted hypotheses considering co-occurrence of MTC and PTC are stem cell theory, collision effect theory and hostage theory. Herein we describe two rare cases of mixed medullary-papillary thyroid carcinoma with co-occurrence of MTC and PTC which developed with concomitant MEN 2A and different sites of lymph node metastasis in the first patient, while with atypical clinical presentation in the second patient. In conclusion, co-expression of thyroglobulin, synaptophysin and chromogranin by the papillary component of mixed tumor seems to support stem cell theory in our first case, whereas positive staining for calcitonin but not for thyroglobulin in the medullary component of the tumor along with separation of these two tumors from each other by a normal thyroid tissue seem to indicates the likelihood of collision effect theory in our second case.

Lairmore TC, Govednik CM, Quinn CE, et al.
A randomized, prospective trial of operative treatments for hyperparathyroidism in patients with multiple endocrine neoplasia type 1.
Surgery. 2014; 156(6):1326-34; discussion 1334-5 [PubMed] Related Publications
BACKGROUND: Hyperparathyroidism (HPT) in multiple endocrine neoplasia (MEN) type 1 is associated with multiglandular parathyroid disease. Previous retrospective studies comparing subtotal parathyroidectomy (SP) and total parathyroidectomy with autotransplantation (TP/AT) have not established clearly better outcomes with either procedure.
METHODS: Patients were assigned randomly to either SP or TP/AT and data were collected prospectively. The rates of persistent HPT, recurrent HPT, and postoperative hypoparathyroidism were compared.
RESULTS: The study cohort included 32 patients randomized to receive either SP or TP/AT (mean follow-up, 7.5 ± 5.7 years). The overall rate of recurrent HPT was 19% (6/32). Recurrent HPT occurred in 4 of 17 patients (24%) treated with SP and 2 of 15 patients (13%) treated with TP/AT (P = .66). Permanent hypoparathyroidism occurred in 3 of 32 patients (9%) overall. The rate of permanent hypoparathyroidism was 12% in the SP group (2/17) and 7% in the TP/AT group (1/15). A second operation was performed in 4 of 17 patients initially treated with SP (24%), compared with 1 of 15 patients undergoing TP/AT (7%; P = .34).
CONCLUSION: This randomized trial of SP and TP/AT in patients with MEN 1 failed to show any difference in outcomes when comparing results of SP versus TP/AT. Both procedures are associated with acceptable results, but SP may have advantages in that is involves only 1 surgical incision and avoids an obligate period of transient postoperative hypoparathyroidism.

Roman JW, Logemann NF, Adams E
Incidental angiofibromas prompt a diagnosis of multiple endocrine neoplasia type-1 (MEN-1).
Dermatol Online J. 2014; 20(9) [PubMed] Related Publications
IMPORTANCE: We believe this to be the first documented report of multiple endocrine neoplasia type-1 (MEN-1) in which the diagnosis was suspected based purely on cutaneous findings. The patient was initially referred to the dermatology department for cosmetic concerns and had no overt symptoms, laboratory abnormalities, or known family history of MEN-1.
OBSERVATIONS: The patient is a 28-year-old man who was referred to the dermatology department for evaluation and removal of skins lesions, later confirmed by biopsy to be facial angiofibromas and a truncal collagenoma. This combination of cutaneous findings was suspicious for a genodermatosis and genetic testing subsequently confirmed the diagnosis of MEN-1. The patient was referred for appropriate follow up and surveillance.
CONCLUSIONS AND RELEVANCE: This case highlights the importance of vigilance on the part of dermatologists to be aware of subtle skin findings that may be characteristic of rare disorders and may have gone unrecognized by other providers and the patients themselves. In this respect, dermatologists are in a unique position given their specialized training in the recognition of inherited skin disorders. An early diagnosis of an inherited disorder, especially one with increased risk of malignancy, can allow for appropriate surveillance and potentially alter the course of the disease.

Anik A, Abaci A
Endocrine cancer syndromes: an update.
Minerva Pediatr. 2014; 66(6):533-47 [PubMed] Related Publications
Endocrine neoplasms comprise a variety of benign and malign tumors that arise from the endocrine glands or neuroendocrine tissues. Although most endocrine neoplasms are sporadic, others are secondary to mutations of many known tumor-predisposing genes. Endocrine cancer syndromes, including Multiple Endocrine Neoplasia type 1 (MEN1), Multiple Endocrine Neoplasia type 2 (MEN2A and MEN2B), Multiple Endocrine Neoplasia type 4 (MEN4) syndromes, and inherited syndromes with different endocrine neoplasms (von Hippel-Lindau disease, Carney complex, Neurofibromatosis type 1, others) are heterogeneous group of cancer susceptibility syndromes that affect one or more of the endocrine glands or neuroendocrine tissues. Genetic studies and researches as well as technological possibilities allowed for detection of new endocrine cancer syndromes and genes leading to tumor susceptibility. In addition, early detection of children at risk for endocrine cancer syndromes using molecular analysis methods provided opportunity to regular monitoring of potential malignancies and timely intervention for these cases (e.g. early prophylactic thyroidectomy in MEN2). This review will describe the clinical, genetic, diagnostic and therapeutic options for endocrine cancer syndromes based on the current literature data.

Viola D, Romei C, Elisei R
Medullary thyroid carcinoma in children.
Endocr Dev. 2014; 26:202-13 [PubMed] Related Publications
Medullary thyroid carcinoma (MTC) originates from thyroid parafollicular C cells, and it accounts for 5% of thyroid malignancies. MTC is sporadic in approximately 80% and hereditary in 20% of cases. When hereditary it can be associated with other benign endocrine neoplasias and/or typical nonendocrine diseases, thus configuring the multiple endocrine neoplasia syndromes (type 2, MEN2/familial MTC, FMTC). Sporadic MTC is usually diagnosed in adult life. Children with clinically evident MTC are belonging to MEN2 families, particularly MEN2A and MEN2B. Children belonging to families with FMTC are usually identified by RET genetic screening shortly after birth or during childhood but they likely develop MTC later in adult life. A genotype-phenotype correlation has been observed between RET mutations and MEN2 syndromes. As for adults, the diagnosis of childhood MTC is based on serum calcitonin (Ct) and neck ultrasound with fine-needle aspiration if a thyroid nodule is present. The standard treatment is total thyroidectomy and central neck node dissection but, according to recent evidence, if the basal Ct is <30 pg/ml or following the institutional cutoff the neck node dissection can be avoided. For advanced metastatic cases, vandetanib has been demonstrated to be effective in children as well as adults.

Bartsch DK, Slater EP, Albers M, et al.
Higher risk of aggressive pancreatic neuroendocrine tumors in MEN1 patients with MEN1 mutations affecting the CHES1 interacting MENIN domain.
J Clin Endocrinol Metab. 2014; 99(11):E2387-91 [PubMed] Related Publications
CONTEXT: Sixty to 80% of multiple endocrine neoplasia type 1 (MEN1) patients develop pancreatic neuroendocrine neoplasias (pNENs), which reveal an aggressive behavior in 10%-20% of patients. Causative MEN1 mutations in the interacting domains of the encoded Menin protein directly alter its regulation abilities and may influence the phenotype.
OBJECTIVE: The objective of the study was the evaluation of an association between MEN1 mutations in different interacting domains of Menin and the phenotype of pNENs.
DESIGN: This was a retrospective analysis of a prospectively collected cohort of 71 genetically confirmed MEN1 patients at a tertiary referral center.
MAIN OUTCOME MEASURES: Analysis of patients' characteristics and clinical phenotype of pNENs regarding the mutation type and its location in Menin interacting domains was measured.
RESULTS: Sixty-seven patients (93%) developed pNENs after a median follow-up of 134 months. Patients with mutations leading to loss of interaction (LOI) with the checkpoint kinase 1 (CHES1) interacting domain codons (428-610) compared with patients with mutations resulting in LOI with other domains (eg, JunD, Smad3) had significantly higher rates of functioning pNENs (70% vs 34%), malignant pNENs (59% vs 16%), and aggressive pNENs (37% vs 9%), respectively. Patients with CHES1-LOI also had an increased pNEN-related mortality (20% vs 4.5%). Neither gender, age, nor the ABO blood types were associated with the phenotype of pNENs.
CONCLUSIONS: MEN1 patients with MEN1 mutations leading to CHES1-LOI have a higher risk of malignant pNENs with an aggressive course of disease and disease-related death.

Debelenko LV, Agarwal S, Du Q, et al.
Menin immunoreactivity in secretory granules of human pancreatic islet cells.
Appl Immunohistochem Mol Morphol. 2014 Nov-Dec; 22(10):748-55 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
The protein product of the Multiple Endocrine Neoplasia Type I (MEN1) gene is thought to be involved in predominantly nuclear functions; however, immunohistochemical (IHC) analysis data on cellular localization are conflicting. To further investigate menin expression, we analyzed human pancreas (an MEN1 target organ) using IHC analyses and 6 antibodies raised against full-length menin or its peptides. In 10 normal pancreas specimens, 2 independently raised antibodies showed unexpected cytoplasmic immunoreactivity in peripheral cells in each islet examined (over 100 total across all 10 patients). The staining exhibited a distinct punctate pattern and subsequent immunoelectron microscopy indicated the target antigen was in secretory granules. Exocrine pancreas and pancreatic stroma were not immunoreactive. In MEN1 patients, unaffected islets stained similar to those in normal samples but with a more peripheral location of positive cells, whereas hyperplastic islets and tumorlets showed increased and diffuse cytoplasmic staining, respectively. Endocrine tumors from MEN1 patients were negative for menin, consistent with a 2-hit loss of a tumor suppressor gene. Secretory granule localization of menin in a subset of islet cells suggests a function of the protein unique to a target organ of familial endocrine neoplasia, although the IHC data must be interpreted with some caution because of the possibility of antibody cross-reaction. The identity, cellular trafficking, and role of this putative secretory granule-form of menin warrant additional investigation.

Massironi S, Rossi RE, Ferrero S, et al.
An esophageal gastrointestinal stromal tumor in a patient with MEN1-related pancreatic gastrinoma: an unusual association and review of the literature.
J Cancer Res Ther. 2014 Apr-Jun; 10(2):443-5 [PubMed] Related Publications
Both multiple endocrine neoplasia type 1 (MEN1)-related gastrinomas and gastrointestinal stromal tumors (GISTs) are rare neoplasms, and their association has been rarely reported. We describe an unusual association between a GIST and a MEN1-related gastrinoma. A 44-year-old man had undergone surgical removal of a pancreatic gastrinoma in 2004 and was then administered long-term somatostatin analogs, and diagnosed as having MEN1 syndrome. Following an uneventful follow-up, in April 2009, an upper gastrointestinal tract endoscopy showed esophageal narrowing, with evidence of a 2-cm solid mass on endoscopic ultrasonography. Histology revealed a tumor composed of elongated cells with plump cytoplasm arranged in a storiform pattern. The immunophenotype of the lesion was CD117 and Platelet Derived Growth Factor (PDGF) positive, whereas alpha-1 muscle actin and S-100 protein were negative. Due to morphological and immunohistochemical results, a final diagnosis of esophageal GIST was made. The association between GISTs and MEN1 could be casual, although a single case of the coexistence of a GIST and a MEN1-related gastrinoma has already been reported. A role of the MEN1 gene in the pathogenesis of GISTs could be hypothesized.

Nozières C, Zhang CX, Buffet A, et al.
p.Ala541Thr variant of MEN1 gene: a non deleterious polymorphism or a pathogenic mutation?
Ann Endocrinol (Paris). 2014; 75(3):133-40 [PubMed] Related Publications
CONTEXT: Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant inherited syndrome, related to mutations in the MEN1 gene. Controversial data suggest that the nonsynonymous p.Ala541Thr variant, usually considered as a non-pathogenic polymorphism, may be associated with an increased risk of MEN1-related lesions in carriers.
OBJECTIVE: The aim of this study was to evaluate the pathogenic influence of the p.Ala541Thr variant on clinical and functional outcomes.
PATIENTS AND METHODS: We analysed a series of 55 index patients carrying the p.Ala541Thr variant. Their clinical profile was compared to that of 117 MEN1 patients. The biological impact of the p.Ala541Thr variant on cell growth was additionally investigated on menin-deficient Leydig cell tumour (LCT)10 cells generated from Men1+/Men1- heterozygous knock-out mice, and compared with wild type (WT).
RESULTS: The mean age at first appearance of endocrine lesions was similar in both p.Ala541Thr carriers and MEN1 patients, but no p.Ala541Thr patient had more than one cardinal MEN1 lesion at initial diagnosis. A second MEN1 lesion was diagnosed in 13% of MEN1 patients and in 7% of p.Ala541Thr carriers in the year following preliminary diagnosis. Functional studies on LCT10 cells showed that overexpression of the p.Ala541Thr variant did not inhibit cell growth, which is in direct contrast to results obtained from investigation of WT menin protein.
CONCLUSION: Taken together, these data raise the question of a potential pathogenicity of the p.Ala541Thr missense variant of menin that commonly occurs within the general population. Additional studies are required to investigate whether it may be involved in a low-penetrance MEN1 phenotype.

Coyle D, Friedmacher F, Puri P
The association between Hirschsprung's disease and multiple endocrine neoplasia type 2a: a systematic review.
Pediatr Surg Int. 2014; 30(8):751-6 [PubMed] Related Publications
PURPOSE: The co-occurrence of Hirschsprung's disease (HSCR) and multiple endocrine neoplasia type 2 (MEN2) is a relatively rare event. The basis for this association is the presence of a "Janus" mutation in the RET proto-oncogene--a mutation that acts simultaneously as both a gain-in-function and a loss-of-function mutation. To date, four mutations in the exon 10 region of RET that are known to cause MEN2A have been implicated in this association: C620, C618, C611 and C609. We performed a systematic review of the published literature on this association to determine its incidence, the prevalence and phenotype of HSCR associated with the 4 RET mutations mentioned above.
METHODS: A systematic literature-based search for relevant articles was conducted using three online databases. After exclusion of ineligible publications, we recorded data on all patients with a diagnosis of HSCR or MEN2A with a "Janus" RET mutation, as well as those who carried the mutation but were unaffected. Statistical analysis was performed using SPSS.
RESULTS: The literature search yielded 885 publications, of which 36 articles, incorporating data on 341 individuals, were eligible for inclusion in the final analysis. Co-occurrence of HSCR and MEN2A was recorded in 84 cases (24.6 %). HSCR occurred alone in 64 carriers of a "Janus" mutation (18.8 %) and MEN2A occurred in isolation in 173 cases (50.7 %). Twenty individuals (5.9 %) were found to carry a "Janus" mutation after screening on the basis of family history but were unaffected by either MEN2A or HSCR. The most common mutation recorded was the C620 mutation [114 cases (48.1 %)]. There was a relatively high incidence of long-segment aganglionosis (29.3 %) and total colonic aganglionosis (17.3 %) in this cohort. This trend was particularly notable in those with C620 mutations, only 33 % of whom had short-segment disease.
CONCLUSION: While the overall incidence of HSCR co-occurring with MEN2A is low, both conditions occur with a relatively high frequency in families with a RET mutation at exon 10. The proportion of cases of long-segment HSCR and total colonic aganglionosis is higher than that in the general population with HSCR in those with C620 and C618 mutations. These findings reinforce the importance of RET mutation testing in HSCR when a family history of either HSCR or MEN2 is present. In families with MEN2A and known exon 10 RET mutations, the threshold for investigation for HSCR in those with gastrointestinal symptoms should be very low. High-quality prospective longitudinal studies of large HSCR populations are required to shed greater light on this rare but important phenomenon.

Sovrea AS, Dronca E, Galatâr M, et al.
Diagnostic correlation between RET proto-oncogene mutation, imaging techniques, biochemical markers and morphological examination in MEN2A syndrome: case report and literature review.
Rom J Morphol Embryol. 2014; 55(2):389-400 [PubMed] Related Publications
Multiple endocrine neoplasia type 2 (MEN2) is a rare autosomal dominant monogenic disorder caused mostly by missense mutations in the RET (REarranged during Transfection) proto-oncogene on chromosome 10q11.2. MEN2A represents more than 50% of all MEN2 cases, having a regular pattern with medullary thyroid carcinoma (MTC) incidence of 90-100%, bilateral pheochromocytoma (PCC) incidence of 40-50% and primary hyperparathyroidism (HPT) incidence of 10-25%. Until recently, the diagnosis of MTC was most frequently based on fine-needle aspiration of thyroid nodules, after an ultrasound examination and endocrine evaluation of serum calcitonin levels. Nowadays, RET gene screening (starting with exons 10 and 11) is a mandatory test used for identification of both symptomatic and non-symptomatic MTC carriers or for exclusion of healthy individuals from subsequent periodical clinical/biochemical screening. In this context, and in the idea of PCC preceding MTC, the early detection of germline RET mutations are highly suggestive for hereditary disease. PCC diagnosis is established in classical manner by abdominal ultrasound imaging or computed tomography confirming the presence of adrenal gland masses, elevated plasma metanephrines and normetanephrines values and histopathological examination. Additional HPT diagnosis is acknowledged by serum ionized calcium and parathormone levels. Here we report a hereditary case of MEN2A in a two-generation Romanian family, along with data presenting the importance of correlative plurifactorial diagnostic scheme in this syndrome and a short literature review.

Walls GV
Multiple endocrine neoplasia (MEN) syndromes.
Semin Pediatr Surg. 2014; 23(2):96-101 [PubMed] Related Publications
Multiple endocrine neoplasia (MEN) syndromes are characterised by the combined occurrence of two or more endocrine tumours in a patient. These autosomal dominant conditions occur in four types: MEN1 due to inactivating MEN1 mutations; MEN2A and MEN2B (MEN3) due to activating mutations of RET and MEN4 due to inactivating cyclin-dependent kinase inhibitor 1B (CDKN1B) mutations. Each MEN syndrome exhibits different combinations of pancreatic islet, anterior pituitary, parathyroid, medullary thyroid and adrenal tumours. This article provides an overview of the clinical features, treatments and molecular genetics of each endocrine tumour syndrome.

Longuini VC, Lourenço DM, Sekiya T, et al.
Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations.
Eur J Endocrinol. 2014; 171(3):335-42 [PubMed] Related Publications
OBJECTIVE: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for.
DESIGN: As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals.
METHODS: Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression.
RESULTS: There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR=2.55, P=0.019, CI=1.013-5.76). Among patients who are ≥30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P=0.002, CI=2.88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors.
CONCLUSIONS: Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.

Borzouei S, Mousavi Bahar SH, Fereydouni MA, et al.
Multiple endocrine neoplasia type IIa associated with Cushing's syndrome.
Arch Iran Med. 2014; 17(6):451-4 [PubMed] Related Publications
Multiple Endocrine Neoplasia type IIa (MEN IIa) is an autosomal dominant syndrome characterized by pheochromocytoma, medullary thyroid carcinoma and hyperparathyroidism. Pheochromocytoma occurs in approximately 50% of patients with MEN IIa. This tumor has the capacity to produce ACTH ectopically and manifests as the Cushing syndrome, although it is very rare. We report a 26-year-old woman patient with severe muscle weakness, skin lesions in extremities, hypertension, and new onset diabetes whose laboratory findings included hypokalemia, metabolic alkalosis, high serum level of cortisol, metanephrine, normetanephrine, calcitonin and bilateral adrenal mass in computed tomography as the first clinical manifestations of an ACTH-secreting pheochromocytoma. In the patients with hypertension, new onset diabetes and hypokalemia, the Cushing syndrome and pheochromocytoma should always be ruled out.

de Laat JM, Pieterman CR, van den Broek MF, et al.
Natural course and survival of neuroendocrine tumors of thymus and lung in MEN1 patients.
J Clin Endocrinol Metab. 2014; 99(9):3325-33 [PubMed] Related Publications
CONTEXT: The natural course and survival of neuroendocrine tumors (NETs) of thymus (Th) and lung in multiple endocrine neoplasia type 1 (MEN1) patients are still unknown.
OBJECTIVE: Our objective was to assess prevalence, tumor growth, and survival of Th and lung NETs in an unselected MEN1 population with long-term follow-up.
DESIGN: This was an observational study.
PATIENTS AND METHODS: A longitudinal study was performed using the Dutch national MEN1 database, including >90% of the Dutch MEN1 population >16 years of age. Patients under care of the Dutch University Medical Centers (1990-2011) (n = 323) were included.
MAIN OUTCOME MEASURES: The prevalence and survival of Th and lung NETs were assessed. Linear mixed-models analysis was applied to assess tumor growth with age as a possible confounder and gender, genotype and baseline tumor size as possible effect modifiers.
RESULTS: Th NETs occurred in 3.4% of patients, almost exclusively in males with a 10-year survival of 25% (95% confidence interval = 8%-80%). A thoracic computed tomography scan was available in 188 patients (58.2%). A lung NET was identified in 42 patients (13.0%) with a 10-year survival of 71.1% (95% confidence interval = 51%-100%). Tumor volume of lung NETs increased 17% per year (P < .001) (tumor doubling time 4.5 years). Tumor doubling time in males was 2.5 vs 5.5 years in females (P = .05). Lung NET growth was not associated with genotype or with baseline tumor size (<1 vs ≥1 cm).
CONCLUSION: In MEN1 patients, Th NETs almost exclusively occurred in males and had a very low prevalence and a high mortality. Lung NETs occurred more often than previously thought, had an indolent course, and occurred equally in both sexes. Tumor growth in males was double compared with female patients.

Mejía-Castrejón J, Landa-Ramírez E
Cognitive behavioural therapy for depression in multiple endocrine neoplasia type IIB: a 1-year follow-up.
BMJ Case Rep. 2014; 2014 [PubMed] Related Publications
This case report describes a 24-year-old man diagnosed with multiple endocrine neoplasia type IIB and major depression. Because cognitive behavioural therapy (CBT) has proven effective in the treatment of major depression in the general population and patients with cancer, we decided to adapt and use this therapy and evaluate its impact on major depression and the patient's quality of life. The therapy was conducted individually in 15 sessions that were given over a span of 25 weeks. The data show that therapy was a useful treatment that reduced depression according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria and self-report instruments. CBT also helped improve the patient's quality of life, and it was considered to be an acceptable intervention for the patient, with ongoing positive results 1 year after the last psychotherapy session. CBT is a potential option for treating depression in this population but further research is needed.

Taïeb D, Kebebew E, Castinetti F, et al.
Diagnosis and preoperative imaging of multiple endocrine neoplasia type 2: current status and future directions.
Clin Endocrinol (Oxf). 2014; 81(3):317-28 [PubMed] Related Publications
Multiple endocrine neoplasia type 2 (MEN2) is a rare autosomal dominant syndrome caused by mutations in the RET protooncogene and is characterized by a strong penetrance of medullary thyroid carcinoma (all subtypes) and is often accompanied by pheochromocytoma (MEN2A/2B) and primary hyperparathyroidism (MEN2A). The evaluation and management of MEN2-related tumours is often different from that of sporadic counterparts. This review article provides an overview of clinical manifestations, diagnosis and surgical management of MEN2 patients. This review also presents applications of the most up-to-date imaging modalities to MEN2 patients that are tightly linked to the clinical management and aims to guide physicians towards a rationale for the use of imaging prior to prophylactic thyroidectomy, initial surgery and reoperations for persistent/recurrent disease. This review also concludes that, in the near future, it is expected that these patients will indeed benefit from newly developed positron emission tomography approaches which will target peptide receptors and protein kinases. Identification of MEN2-specific radiopharmaceuticals will also soon arise from molecular profiling studies. Furthermore, subtotal (cortical-sparing) adrenalectomy, which is a valid option in MEN2 for avoiding long-term steroid replacement, will benefit from an accurate estimation through imaging of differential adrenocortical function.

Cavalli T, Giudici F, Nesi G, et al.
Sarcomatoid carcinoma of the kidney in a MEN1 patient: case report and genetic profile.
Endocr J. 2014; 61(8):781-7 [PubMed] Related Publications
Renal tumors are exceedingly rare in Multiple Endocrine Neoplasia type 1 (MEN1), a pleyotropic hereditary cancer disorder affecting the endocrine system. Herein we report a unique case of renal sarcomatoid carcinoma with concomitant ipsilateral non-secreting adrenal adenoma occurring in a young male MEN1 patient, previously operated for hyperparathyroidism and multiple pancreatic neuroendocrine neoplasms. Molecular analysis in the MEN1 locus at 11q13 showed loss of heterozygosity in the adrenal lesion, while kidney cancer was unrelated to MEN1 syndrome.

Singer K, Heiniger N, Thomas I, et al.
Ectopic Cushing syndrome secondary to metastatic medullary thyroid cancer in a child with multiple endocrine neoplasia syndrome type 2B: clues to early diagnosis of the paraneoplastic syndromes.
J Pediatr Endocrinol Metab. 2014; 27(9-10):993-6 [PubMed] Related Publications
We describe a 13-year-old male with multiple endocrine neoplasia syndrome type 2B with medullary thyroid carcinoma who was diagnosed with ectopic adrenocorticotropin-dependent Cushing syndrome. This report highlights the importance of monitoring for paraneoplastic syndrome in MEN and clues to the diagnosis of this complication provided by growth patterns.

Qi XP, Zhang RX, Cao JL, et al.
The rare intracellular RET mutation p.S891A in a Chinese Han family with familial medullary thyroid carcinoma.
J Biosci. 2014; 39(3):505-12 [PubMed] Related Publications
We report intracellular RET mutation in a Han Chinese pedigree with familial medullary thyroid carcinoma (FMTC). Direct sequencing of RET proto-oncogene identified a missense c.2671T greater than G (p.S891A) mutation in 6 of 14 family members. The single nucleotide polymorphisms c. 135A greater than G (p.A45A), IVS4 + 48A greater than G, c. 1296A greater than G (p.A432A), c. 2071G greater than A (p.G691S), c. 2307T greater than G (p.L769L) and a variant c. 833C greater than A (p.T278N) were also found in 6 carriers. Among 5 of the 6 carriers presented medullary thyroid carcinoma (MTC) as an isolated clinical phenotype, with elevated basal serum calcitonin (Ct). Two underwent non-normative thyroidectomy either two or four times without physician awareness or diagnosis of this disease at initial treatment, but with elevated Ct. One with elevated pre-Ct accepted total thyroidectomy (TT) with modified bilateral neck dissection (MBiND), and whose seventh posterior rib MTC metastases was confirmed 5 months after surgery. Moreover, results of two affected individuals with elevated Ct were reduced to normal after TT with MBiND or prophylactic VI compartmental dissection. However, only another carrier with the variant p.T278N had slightly elevated Ct rejected surgery and was strictly monitored. Given these case results, we suggest that screening of RET and pre-surgical Ct levels in the management of MTC patients is essential for earlier diagnosis and more normative initial treatment, that FMTC patients with cervical lymph nodes metastases may be cured by TT with MBiND, and that prophylactic VI compartmental dissection should be avoided when Ct levels are low.

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