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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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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).

Kiernan CM, Grubbs EG
Surgical Management of Multiple Endocrine Neoplasia 1 and Multiple Endocrine Neoplasia 2.
Surg Clin North Am. 2019; 99(4):693-709 [PubMed] Related Publications
This article summarizes the surgical management of tumors associated with multiple endocrine neoplasia 1 (MEN1) and multiple endocrine neoplasia 2 (MEN2) and includes discussion of the preoperative planning, the goals, and extent of surgery, as well as the intraoperative considerations and the management of recurrent disease.
Related: Thyroid Cancer

Twito O, Grozinsky-Glasberg S, Levy S, et al.
Clinico-pathologic and dynamic prognostic factors in sporadic and familial medullary thyroid carcinoma: an Israeli multi-center study.
Eur J Endocrinol. 2019; 181(1):13-21 [PubMed] Related Publications
Objective: Multiple clinical, pathological and biochemical variables, including the response to initial treatment, are associated with medullary thyroid carcinoma (MTC) prognosis. Studies that include separate analyses of familial and sporadic MTC patients followed for long period are scarce. This study evaluated the association between baseline clinico-pathologic variables and response to initial treatment and short- and long-term disease outcomes in sporadic and familial MTC.
Methods: Patients treated for MTC at four tertiary medical centers were retrospectively analyzed. Clinical and pathological data were collected. The outcomes measured included disease persistence 1 year after diagnosis, disease persistence at last follow-up, disease-related mortality (DRM) and all-cause mortality.
Results: The study enrolled 193 patients (mean age: 48.9 ± 18.7, 44.7% males), of whom 18.1% were familial cases. The mean follow-up period was 10.1 ± 9.4 years (8.5 ± 8.1 in sporadic and 16.9 ± 11.6 in familial MTC). Disease persistence 1-year after diagnosis and at last follow-up was detected in 56.1 and 60.4% patients, respectively. All-cause and DRM were 28.5 and 12.6%, respectively. Extra-thyroidal extension (ETE) and distant metastases (DM) were associated with disease persistence at last follow-up. ETE and DM were also significantly associated with DRM. Complete remission 1 year after diagnosis had high correlation with no evidence of disease at last follow-up (Cramer's V measure of association 0.884, P < 0.001) and with 100% disease-specific survival (Cramer's V measure of association 0.38, P < 0.001).
Conclusions: Apart from clinico-pathologic parameters, close correlation was found between 1-year status and long-term prognosis. These results underscore the importance of combining classical and dynamic factors for both sporadic and familial MTC prognostication and treatment decision making.
Related: Thyroid Cancer

Hassan A, Siddique M, Riaz S, et al.
Medullary Thyroid Carcinoma: Prognostic Variables And Tumour Markers Affecting Survival.
J Ayub Med Coll Abbottabad. 2018 Oct-Dec; 30(Suppl 1)(4):S627-S632 [PubMed] Related Publications
Background: Medullary thyroid carcinoma (MTC) is a relatively rare thyroid malignancy and its clinical course varies among patients due to its familial association. A number of prognostic factors have been studied, but the significance of these factors remains controversial. We evaluated the progression free survival (PFS) and overall survival (OS) of MTC and its association with tumour marker rising velocity and serum calcitonin (Ct) doubling time (DT).
Methods: Analysis of 83 (8.7%) consecutive MTC patients registered at a single centre between 1995 and 2015. The impact of tumour respectability, TNM stage, multiple endocrine neoplasia (MEN) syndrome, local recurrence, Ct DT and Ct rising velocity on PFS and OS was analysed. Median follow-up was 4.3 years (range: 1-18 years).
Results: Eighty-three (8.7%) of all thyroid cancers registered at our centre were MTC. Fifty-five males, 28 females. Mean age 39 years [range: 17-72 years]. Twenty-two were unresectable and 61 resectable. Five-year and 10-year OS was 84% and 77% respectively. Of 68 with follow up greater than a year; 20 (29.4%) were cured, 15 (22.1%) had biochemical evidence of disease, three (4.4%) had stable macroscopic disease and 30 (44.1%) had recurrent/progressive disease. Sixteen (23.5%) died. On multivariate analysis, T4 tumour, male gender, nodal and distant metastases, tumour resectibility, Ct DT less than two years and tumour marker rising velocity of greater than 0.05pg/ml/month were poor prognostic factors (pvalue <0.05). Age and association with MEN syndrome had no statistically significant survival impact. Radiotherapy reduced local relapse in patients with nodal disease. Total thyroidectomy with nodal clearance lessened relapses.
Conclusion: Clinical stage and pathological aspects are predictors of disease progression. Persistent biochemical evidence of MTC does not affect OS, however, Ct DT < 2 years and rapid rate of tumour marker rise predict disease progression.
Related: Thyroid Cancer

Selberherr A, Koperek O, Riss P, et al.
Intertumor heterogeneity in 60 pancreatic neuroendocrine tumors associated with multiple endocrine neoplasia type 1.
Orphanet J Rare Dis. 2019; 14(1):54 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patients with multiple endocrine neoplasia type 1 (MEN-1) develop multiple pancreatic neuroendocrine neoplasias (PNENs). Size at diagnosis and growth during follow-up are crucial parameters. According to the WHO 2017, grading is another important parameter. The impact of grading compared to size (WHO 2000) on the clinical course needs to be evaluated.
METHODS: Sixty PNENs of six patients with MEN-1 were retrospectively evaluated.
RESULTS: Fifty-one tumors with a diameter of < 20 mm were graded as G1. Two of 9 tumors with diameters of ≥20 mm were graded as G2. Tumor size of ≥20 mm correlated significantly with higher proliferation (p = 0.000617). Lymph node metastases were documented in two patients with a total of 19 tumors. In one patient, all 13 tumors (diameter: 0.4 to 100 mm) were classified as G1. However, metastases were documented in 9/29 lymph nodes. In the other patient, 5 tumors (3.5 to 20 mm) were classified as G1. The sixth tumor (30 mm) was classified as G2 (Ki-67: 8%). Metastases were revealed in 2/20 lymph nodes.
CONCLUSIONS: Tumor size of ≥20 mm seems to correlate with more aggressive MEN-1 related pancreatic disease, regardless of individual proliferation. Tumors ≥20 mm and tumors graded as G2 should be treated surgically regardless of their size.
Related: Cancer of the Pancreas Pancreatic Cancer

Novruzov F, Mehmetbeyli L, Aliyev JA, et al.
Metastatic Insulinoma Controlled by Targeted Radionuclide Therapy With 177Lu-DOTATATE in a Patient With Solitary Kidney and MEN-1 Syndrome.
Clin Nucl Med. 2019; 44(6):e415-e417 [PubMed] Related Publications
A 54-year-old man with multiple endocrine neoplasia type 1 had previous history of parathyroid surgery and left thyroid lobectomy 5 years earlier, and was referred for recurrent hypoglycemic episodes. Ga-DOTATATE PET/CT had showed multiple lesions in the right lung, liver, and pancreas. Biopsy from pancreas revealed low-grade neuroendocrine neoplasia. After 2 fractions of Lu-DOTATATE therapy, the size of lesions and its activity reduced on the Ga-DOTATATE scan and the hypoglycemic episodes manifested every day have scaled down to 1 time over 1-year follow-up. Herein, we report a case of malignant insulinoma successfully treated with radiolabeled somatostatin receptor therapy using Lu-DOTATATE.

Cristina EV, Alberto F
Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-Jaw tumour, Familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism.
Best Pract Res Clin Endocrinol Metab. 2018; 32(6):861-875 [PubMed] Related Publications
While primary hyperparathyroidism (PHPT) generally represents a common endocrine disorder, being the more frequent cause of hypercalcemia in outpatients, familial forms of PHPT (FPHPT) account for no more than 2-5% of the overall PHPT. In the last decades, many technical progresses in both molecular and biochemical-radiological evaluation have been made, and substantial advancements in understanding these disorders have been reached. Differences both in the pathogenesis and clinical presentation exist among the various hyperparathyroid syndromic forms, and, since FPHPT is frequently associated to other endocrine, proliferative and/or functional disorders, as also non-endocrine tumours, with varying clinical spectrum of occurrence in each syndrome, its early clinically detection for appropriately preventing complications (i.e. kidney and bone disorders) is strictly advised. In this review, the clinical-biochemical features and diagnostic procedures of each FPHPT form will be summarized and a general overview on surgical and pharmacological approaches to FPHPT has been also considered.

Fernando AR, Samarasekera DN, Bulathsinghela RP
Constipation with megacolon in a 36-year-old man: a rare presentation of MEN2B from Sri Lanka.
BMJ Case Rep. 2019; 12(1) [PubMed] Free Access to Full Article Related Publications
Diffuse intestinal ganglioneuromatosis is a rare condition associated with MEN2B. It is also seen in conditions like neurofibromatosis type 1 and Cowden syndrome. This is a report of a patient who underwent total colectomy with end ileostomy creation for a megacolon. He was diagnosed to have diffuse ganglioneuromatosis on histological examination of the resected segment of colon. The definitive management of diffuse ganglioneuromatosis is to resect and anastomose.

Cetani F, Saponaro F, Borsari S, Marcocci C
Familial and Hereditary Forms of Primary Hyperparathyroidism.
Front Horm Res. 2019; 51:40-51 [PubMed] Related Publications
Individuals with a familial predisposition to the development of parathyroid tumors constitute a small minority of all patients with primary hyperparathyroidism (PHPT). These familial syndromes exhibit Mendelian inheritance patterns and the main causative genes in most families have been identified. They include multiple endocrine neoplasia (MEN; types 1, 2A, and 4), hyperparathyroidism-jaw tumor (HPT-JT) syndrome, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia (FHH), and neonatal severe PHPT. Each MEN type is associated with the various combinations of specific tumors. MEN1 is characterized by the occurrence of parathyroid, enteropancreatic, and pituitary tumors; MEN2A is characterized by medullary thyroid carcinoma and pheochromocytoma, and MEN4 is characterized by a pathological spectrum similar to that of MEN1 in association with tumors of the adrenal, kidney, and reproductive organs. HPT-JT is characterized by PHPT, ossifying fibromas of maxillary bones, kidney disease, and uterine neoplasias. The prompt diagnosis of these diseases is of great importance for planning appropriate surveillance of the mutant carriers and correct surgical management. The search for mutation is also useful for the identification of the family members who do not carry the mutation and can avoid unnecessary biochemical and instrumental evaluations. Surgery remains the treatment of choice in all familial forms except FHH.

Wu Y, Gao L, Guo X, et al.
Pituitary adenomas in patients with multiple endocrine neoplasia type 1: a single-center experience in China.
Pituitary. 2019; 22(2):113-123 [PubMed] Related Publications
PURPOSE: To explore the clinical characteristics of pituitary adenomas in patients with MEN1 and to summarize treatment strategies for MEN1 in a Chinese population.
METHODS: We retrospectively analyzed 54 MEN1 patients with pituitary adenomas diagnosed at Peking Union Medical College Hospital from March 2003 to January 2017. Clinical data, laboratory testing results, treatments of involved glands and treatment responses were collected and analyzed.
RESULTS: The mean age at pituitary adenoma diagnosis was 53.9 ± 17.8. The patients initially consulted the Endocrinology, General Surgery and Neurosurgery departments, in descending frequency. The nonfunctioning adenoma, prolactinoma, GH-secreting adenoma, cosecreting adenoma, and ACTH-secreting adenoma subtypes accounted for 48.1%, 27.8%, 9.3%, 9.3% and 5.6% of the cases, respectively. The remission rate for prolactinomas was 46.2% (6/13) treated with bromocriptine. And the remission rates were 87.5% (7/8) and 100% (3/3) for GH-secreting adenomas and ACTH-secreting adenomas respectively achieved by transsphenoidal surgery. Nineteen (35.2%) patients with asymptomatic nonfunctioning pituitary adenomas showed no progression after a 35-month follow-up with close observation. Regarding treatment priority, patients with thymic carcinoid tumors received first-line surgery, 54% of the patients with enteropancreatic tumors had these tumors treated first, and 26% of all patients had their pituitary adenomas treated first. In acromegalic patients, pituitary lesions tended to be treated first (75%, p = 0.002). PHPT and adrenocortical adenomas can be managed with elective surgery.
CONCLUSIONS: The treatment of MEN1 requires cooperation between multidisciplinary teams. Individualized treatment according to the severity of glandular involvement is needed. GH-secreting and ACTH-secreting pituitary adenomas require active treatment, while nonfunctioning pituitary adenomas can be observed closely.
Related: Pituitary Tumors

Yarman S, Tuncer FN, Serbest E
Three Novel MEN1 Variants in AIP-Negative Familial Isolated Pituitary Adenoma Patients.
Pathobiology. 2019; 86(2-3):128-134 [PubMed] Related Publications
OBJECTIVES: Pituitary adenomas (PAs) may rarely occur in well-defined hereditary conditions, like multiple endocrine neoplasia type 1 (MEN1) syndrome and familial isolated pituitary adenoma (FIPA) associated with germline mutations in MEN1 and AIP, respectively. This study aimed to assess MEN1 genetic abnormalities in AIP mutation-negative FIPA patients, not associated with MEN1 components.
METHODS: Among 20 patients evaluated in 13 FIPA families, 12 were previously reported as AIP mutation-negative. In this study, 6 new families with 8 patients were recruited. All patients were subjected to multiplex ligation-dependent probe amplification to detect copy number variations in AIP and MEN1, and AIP sequencing was performed in additional patients. AIP mutation-negative patients were subjected to MEN1 sequencing.
RESULTS: Our cohort revealed only 3 novel heterozygous MEN1 variants including c.1846T>A p.(*616Argext*21), rs778272737:T>C, and rs972128957:C>T in 2 families, with patients diagnosed with Cushing disease, nonfunction al adenoma, and acromegaly, respectively. Among them, c.1846T>A p. (*616Argext*21) is a stop codon read-through, whereas the others are 3'UTR variations. MEN1 variation frequency was detected as 15%.
CONCLUSIONS: MEN1 alterations can be of significance in FIPA patients and screening could be offered to AIP mutation-negative patients without MEN1 features. Further studies are needed to clarify the role of MEN1 in FIPA patients.
Related: Pituitary Tumors

Lee HN, Cho SG, Lee WH
Interventional Management of Subcapsular Hepatic Hematoma with Hepatic Compartment Syndrome After Laparoscopic Adrenalectomy.
Cardiovasc Intervent Radiol. 2019; 42(4):625-628 [PubMed] Related Publications
Hepatic compartment syndrome is an increase in intrahepatic pressure sufficient to cause compromised hepatic perfusion. Early recognition and prompt management are essential for preventing catastrophic consequences including ischemic liver failure and hypovolemic shock. This is the rare case of laparoscopic adrenalectomy resulting in subcapsular hepatic hematoma with hepatic compartment syndrome. Contrast-enhanced computed tomography demonstrated extensive subcapsular hepatic hematoma with collapse of portal vein and inferior vena cava suggesting impending compartment syndrome. Diagnostical catheter angiography of the liver revealed innumerable foci of petechial extravasation from disrupted isolated arteries. Emergent percutaneous catheter decompression and transarterial embolization were successful.

Ionescu MI, Edwin ID, Wilson CH, et al.
Orthotopic Liver Transplantation for Hereditary Hemorrhagic Telangiectasia and MEN Type I Syndrome - Case Report and Review of Literature.
Chirurgia (Bucur). 2018 Nov-Dec; 113(6):837-848 [PubMed] Related Publications

Beijers HJBH, Stikkelbroeck NML, Mensenkamp AR, et al.
Germline and somatic mosaicism in a family with multiple endocrine neoplasia type 1 (MEN1) syndrome.
Eur J Endocrinol. 2019; 180(2):K15-K19 [PubMed] Related Publications
Context Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1 and can be diagnosed based on clinical, familial and/or genetic criteria. We present a family in which we found both germline and somatic mosaicism for MEN1. Family description In our proband, we diagnosed MEN1. The mutation was not detected in her parents (DNA extracted from leucocytes). When her brother was found to harbor the same MEN1 mutation as our proband and, around the same time, their father was diagnosed with a neuroendocrine carcinoma, this tumor was investigated for the MEN1 mutation as well. In the histologic biopsy of this tumor, the same MEN1 mutation was detected as previously found in his children. Re-analysis of his blood using multiplex ligation-dependent probe amplification (MLPA) showed a minimal, but consistently decreased signal for the MEN1-specific MLPA probes. The deletion was confirmed in his son by high-resolution array analysis. Based on the array data, we concluded that the deletion was limited to the MEN1 gene and that the father had both germline and somatic mosaicism for MEN1. Conclusions To our knowledge, this is the first reported family with combined germline and somatic mosaicism for MEN1. This study illustrates that germline mosaicism is important to consider in apparently sporadic de novo MEN1 mutations, because of its particular importance for genetic counseling, specifically when evaluating the risk for family members and when considering the possibility of somatic mosaicism in the parent with germline mosaicism.

Marini F, Giusti F, Brandi ML
Multiple endocrine neoplasia type 1: extensive analysis of a large database of Florentine patients.
Orphanet J Rare Dis. 2018; 13(1):205 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiple endocrine neoplasia (MEN1) is a rare inherited multi-tumour syndrome, affecting specific neuroendocrine organs and non-endocrine tissues with a variable spectrum of over 20 possible different combinations, caused by inactivating heterozygote mutations of the MEN1 gene. Disease onset, penetrance, clinical presentation, course and prognosis are all extremely variable, even among individuals bearing the same causative mutation, which doesn't allow prediction of the individual clinical phenotype (based on the specific result of the genetic test), thus compelling all patients and mutation carriers to undergo a common routine general screening program.
RESULTS: We performed an extensive epidemiological, clinical and genetic analysis of the Florentine MEN1 patient database, which includes 145 MEN1 patients and 20 asymptomatic MEN1 carriers, constantly followed up at the Regional Referral Centre for Inherited Endocrine Tumours of the Tuscany Region, during the last three decades. We reported, here, the results of clinical, epidemiological and genetic descriptive statistics, as well as correlation analyses between tumours and mutation types and localisation. No direct genotype-phenotype correlation was described, but the importance of the genetic testing was confirmed for an early diagnosis and the identification of asymptomatic carriers.
CONCLUSIONS: As with all rare diseases, the possibility to collect and analyse data on a relatively large number of patients is important for increasing our knowledge of the epidemiologic aspects of the disease, and its natural course and prognosis of single manifestations of the syndrome, in order to set up the best diagnostic and therapeutic plans for patients. In this light, the creation and constant updating of large patient databases is fundamental. Results from database study can provide useful epidemiological, clinical and genetic information about MEN1 syndrome, which could help clinicians in the diagnostic and therapeutic management of single MEN1 patients.
Related: Cancer of the Pancreas Pancreatic Cancer Pituitary Tumors Stomach Cancer Gastric Cancer

Febrero B, Rodríguez JM, Ríos A, et al.
Prophylactic thyroidectomy in multiple endocrine neoplasia 2 (MEN2) patients with the C634Y mutation: A long-term follow-up in a large single-center cohort.
Eur J Surg Oncol. 2019; 45(4):625-630 [PubMed] Related Publications
BACKGROUND: Medullary thyroid carcinoma (MTC) is the main cause of death in multiple endocrine neoplasia 2A (MEN2A) patients. It is therefore important to treat this disease at an early stage. The mutation in codon 634 is considered to be associated with an aggressive clinical course, whereas the C634Y mutation may result in a more indolent course. Prophylactic thyroidectomy is performed before thyroid disease occurs. However, controversy surrounds this disease regarding levels of calcitonin (Ct) and age. In this context, few studies have investigated this mutation over a long period.
OBJECTIVE: To analyze a large cohort of patients with the C634Y mutation who received prophylactic thyroidectomy.
MATERIALS AND METHODS: In a group of 110 MEN2 patients, we analyzed those with the C634Y mutation who had received prophylactic thyroidectomy (absence of clinical and radiological thyroid disease) treated in a tertiary referral hospital between 1983 and 2016. MTC is related to age and Ct. Statistical analysis was performed using the χ
RESULTS: Fifty patients with a mean age of 12 ± 9 years were analyzed; 56% of these had MTC (100% stage I). There was no case of hypoparathyroidism or permanent recurrent damage. MTC was associated mainly with age (OR 1.38). One 5-year-old patient presented with MTC. Mean follow-up time was 16 ± 6 years, and no cases of recurrence were observed.
CONCLUSIONS: Performing prophylactic thyroidectomy in patients with the C634Y mutation allows us to cure the disease without causing long-term complications. Our results support the notion that age <5 years should be a criterion for carrying out prophylactic thyroidectomy in these patients.
Related: RET Thyroid Cancer

Carvalho RA, Urtremari B, Jorge AAL, et al.
Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing.
Eur J Endocrinol. 2018; 179(6):391-407 [PubMed] Related Publications
Background Loss-of-function germline MEN1 gene mutations account for 75-95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile. Methods and patients A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS. Results Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected. Conclusions Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.
Related: MEN1

Makri A, Akshintala S, Derse-Anthony C, et al.
Multiple Endocrine Neoplasia Type 2B Presents Early in Childhood but Often Is Undiagnosed for Years.
J Pediatr. 2018; 203:447-449 [PubMed] Free Access to Full Article Related Publications
We describe the presenting symptoms and signs of multiple endocrine neoplasia type 2B in a cohort of children. Improved awareness of the early nonendocrine signs of multiple endocrine neoplasia type 2B could lead to earlier diagnosis before the development of medullary thyroid cancer and possibly its metastasis.
Related: RET Thyroid Cancer

Yadav M, Agrawal V, Pani KC, et al.
C-cell hyperplasia in sporadic and familial medullary thyroid carcinoma.
Indian J Pathol Microbiol. 2018 Oct-Dec; 61(4):485-488 [PubMed] Related Publications
Context: C-cell hyperplasia (CCH) is characterized by increased mass of C-cells and has been identified as a precursor condition for medullary thyroid carcinoma (MTC). Varying proportion of MTCs is associated with CCH in different studies. This could be due to the lack of uniformity of the definitions and techniques used to identify CCH in these studies.
Aims: This study aims to study the occurrence, clinicopathological, and immunohistochemical features of CCH in MTC diagnosed during a 22-year period at a tertiary care center in North India and to review the available literature on CCH.
Materials and Methods: Eighty-seven consecutive cases of MTC were included in the study. Histological evaluation for the presence of CCH and neoplastic CCH was performed. Confirmation of CCH was done by immunohistochemistry for calcitonin and chromogranin. The presence of neoplastic CCH was correlated with clinical factors and prognostic factors.
Results: Of 87 cases of MTC included in the study, 71 (82%) patients were sporadic and 16 (18%) had familial MTC. Neoplastic CCH was seen in 12 (75%) familial and in 9 (13%) sporadic MTC. Patients with familial MTC were more frequently associated with neoplastic CCH than sporadic MTC (P < 0.001), were younger (P < 0.001), and had more often bilateral and multifocal tumors (P < 0.001). However, there was no significant difference in mean survival time and progression-free survival in patients with and without CCH.
Conclusion: CCH, though more common in familial MTC, can also be seen in sporadic tumors. CCH is not associated with patient survival and disease progression.
Related: Thyroid Cancer

Albers MB, Manoharan J, Bollmann C, et al.
Results of Duodenopancreatic Reoperations in Multiple Endocrine Neoplasia Type 1.
World J Surg. 2019; 43(2):552-558 [PubMed] Related Publications
BACKGROUND: To evaluate the outcome of duodenopancreatic reoperations in patients with multiple endocrine neoplasia type 1 (MEN1).
METHODS: MEN1 patients who underwent reoperations for duodenopancreatic neuroendocrine neoplasms (dpNENs) were retrieved from a prospective database and retrospectively analyzed.
RESULTS: Twelve of 101 MEN1 patients underwent up to three reoperations, resulting in a total of 18 reoperations for dpNEN recurrence. Patients initially underwent either formal pancreatic resections (n = 7), enucleations (n = 3), or duodenotomy with lymphadenectomy for either NF-pNEN (seven patients), Zollinger-Ellison syndrome (ZES, three patients), organic hyperinsulinism (one patient) or VIPoma (one patient). Six patients had malignant dpNENs with lymph node (n = 5) and/or liver metastases (n = 2). The indication of reoperations was NF-pNEN (five patients), ZES (five patients), organic hyperinsulinism (one patient), and recurrent VIPoma (one patient). Median time to first reoperation was 67.5 (range 6-251) months. Five patients required a second duodenopancreatic reoperation for 60-384 months after initial surgery, and one patient underwent a third reoperation after 249 months. The rate of complications (Clavien-Dindo ≥3) was 28%. Four patients required completion pancreatectomy. Six patients developed pancreoprivic diabetes. After a median follow-up of 18 (6-34) years after initial surgery, ten of 12 patients are alive, one died of metastatic pancreatic VIPoma, and one died of metastatic thymic NEN.
CONCLUSION: Reoperations are frequently necessary for dpNEN in MEN1 patients, but are not associated with an increased perioperative morbidity in specialized centers. Organ-sparing resections should be preferred as initial duodenopancreatic procedures to maintain pancreatic function and avoid completion pancreatectomy.
Related: Cancer of the Pancreas Pancreatic Cancer

Motazedi B, Rahmani M, Welch JM, Motazedi A
First report of concomitant pheochromocytoma and duodenal neuroendocrine tumour in a sporadic multiple endocrine neoplasia type 1.
BMJ Case Rep. 2018; 2018 [PubMed] Related Publications
A 77-year-old woman was diagnosed with pheochromocytoma followed by adrenalectomy at age 57. Hyperparathyroidism without osteoprosis was diagnosed at age 58. At age 75, Dual Energy X-ray Absoptiometry (DEXA) revealed osteoporosis and sestamibi scan showed a left parathyroid adenoma. Criteria for parathyroidectomy were met, and she underwent parathyroidectomy. Furthermore, she presented with haematochezia at age 75. An abdominal CT demonstrated a mass in the second portion of the duodenum. Additionally, octreoscan revealed somatostatin receptor positive tissue in the duodenum and Gallium 68 dotatate scan also showed a well-differentiated duodenal neuroendocrine tumour (NET). Genetic testing for MEN1, MEN2 and MEN4 was negative. Diagnosis of sporadic MEN1 syndrome was made. The patient underwent resection of the duodenal NET at age 76. She is in good health 21 years after her first presentation of MEN1. In summary, we present the first sporadic case of MEN1 with concomitant pheochromocytoma and duodenal NET which occurred 20 years apart.
Related: Parathyroid Cancer

De Paoli-Iseppi R, Prentice L, Marthick JR, et al.
Multiple endocrine neoplasia type 1: clinical correlates of MEN1 gene methylation.
Pathology. 2018; 50(6):622-628 [PubMed] Related Publications
Multiple endocrine neoplasia type 1 (MEN 1) has marked severity variation between individuals with the same mutation. To investigate any relationship between promoter methylation and clinical features, blood and tissue samples were collected from 16 members of the Tasman 1 MEN 1 kindred carrying a common splice site mutation and 7 patients with sporadic MEN 1. Methylation at 39 CpGs in the MEN1 promoter were assessed in formalin fixed, paraffin embedded parathyroid tissue. Clinical disease severity markers included age at first parathyroid operation, parathyroid hormone level and corrected serum calcium levels. Six patients with sporadic hyperparathyroidism were used for comparison. Minimal methylation was observed in all patients across CpG sites 1-23. In contrast, hypermethylation was observed at CpG sites 24-31 in MEN 1 patients, a pattern not observed in patients with non-MEN 1 parathyroid disease. Mean methylation at sites 24-31 was significantly correlated with age at first parathyroid operation (r = 0.652, p = 0.041). A permutation test, utilising the mean correlation coefficient (r = -0.401) revealed a possible association between relative PHPT severity and methylation score for each significant CpG site (p < 0.103). This novel study reveals evidence supporting a possible association between altered MEN1 promoter methylation and clinical severity of disease.
Related: MEN1

Nagaoka R, Sugitani I, Sanada M, et al.
The Reality of Multiple Endocrine Neoplasia Type 2B Diagnosis: Awareness of Unique Physical Appearance Is Important.
J Nippon Med Sch. 2018; 85(3):178-182 [PubMed] Related Publications
BACKGROUND: Multiple endocrine neoplasia type 2B (MEN2B) is an extremely rare syndrome mainly caused by RET918 germline mutations. MEN2B typically causes medullary thyroid carcinoma (MTC), pheochromocytoma, and unique physical characteristics including mucosal neuroma, distinctive facial appearance, and Marfanoid habitus. Most patients have abdominal symptoms such as bloating, intermittent constipation, and diarrhea. MTC is the most important determinant of mortality in patients with MEN2B. Establishing the diagnosis of MEN2B at a curative stage of MTC is crucial.
CASE PRESENTATION: We have encountered four patients with MEN2B. Two were hereditary cases from the same family, and two were considered de novo cases with phenotypically normal parents. Mean age at diagnosis was 25.5 years (range, 13-39 years). Although all patients had shown mucosal neuroma on the lips and tongue, in addition to gastrointestinal symptoms from infancy, diagnoses were made from symptomatic MTC even for the hereditary patients (our index case was a 14-year-old girl, whose mother was subsequently diagnosed with advanced MTC). Genetic tests for RET mutations revealed the M918T mutation in all patients. Two patients developed pheochromocytoma, two died from distant metastases of MTC, and two received treatment for multiple metastases of MTC (one with vandetanib).
CONCLUSIONS: In our patients with MEN2B, prophylactic or early thyroidectomy could not be performed. The characteristic phenotype associated with MEN2B is almost always seen prior to detection of MTC or pheochromocytoma. Knowledge about the non-endocrine manifestations of MEN2B needs to be shared among pediatricians and gastroenterologists.
Related: RET Thyroid Cancer

Faulkner AL, Swanson E, McLarney TL, et al.
Use of Dexmedetomidine in a Parturient With Multiple Endocrine Neoplasia Type 2A Undergoing Adrenalectomy and Thyroidectomy: A Case Report.
A A Pract. 2019; 12(5):136-140 [PubMed] Related Publications
Dexmedetomidine is a selective α2-agonist, frequently used in perioperative medicine as anesthesia adjunct. The medication carries a Food and Drug Administration pregnancy category C designation and is therefore rarely used for parturients undergoing nonobstetric surgery. We are reporting the use of dexmedetomidine in the anesthetic management of a parturient undergoing minimally invasive unilateral adrenalectomy for pheochromocytoma during the second trimester of pregnancy. Additionally, because of the multiple endocrine neoplasia type 2A constellation with diagnosis of medullary thyroid cancer, the patient underwent a total thyroidectomy 1 week after the adrenalectomy.
Related: Breast cancer in pregnancy Thyroid Cancer

Balsalobre Salmeron M, Rodriguez Gonzalez JM, Ríos A, et al.
Primary hyperparathyroidism associated with MEN 1: Experience in 71 cases.
Cir Esp. 2018; 96(10):627-633 [PubMed] Related Publications
INTRODUCTION: Primary hyperparathyroidism (pHPT) in MEN 1 is characterized by multiglandular disease and early involvement of parathyroid glands at different times. Persistence and recurrence range from 25%-35%. The purpose was: a) to describe the experience and the treatment of patients with pHPT in MEN 1; b) to analyze the variables related with clinical presentation and recurrence.
METHOD: A total of 97 patients with MEN 1 were diagnosed in a tertiary hospital. A retrospective analysis was made in patients with pHPT (n=71).
STUDY VARIABLES: age at diagnosis, mutation, clinical presentation, laboratory tests, surgical technique, and recurrence of HPT.
RESULTS: Mean age was 38 years, and 50 patients were asymptomatic. The surgical technique was: subtotal parathyroidectomy (n=55), resection of three glands (n=7), and resection of less glands (n=9). Transcervical thymectomy was performed in 53 patients. Mean follow-up was 102.9 months. There were 21 recurrences, There were correlations between age at diagnosis and serum calcium levels with the presence of symptoms (P<.0001). There were also correlations between recurrence and surgical technique (P<.03), non-association with thymectomy (P<.0001), and follow-up time (P<.03).
CONCLUSION: Performing genetic and clinical screening allows us to make a diagnosis in the asymptomatic period and to provide early treatment for HPT in MEN 1. The recurrence rate is high, and follow-up time and the surgical technique used are risk factors for recurrence.

Buła G, Truchanowski W, Koziołek H, et al.
A follow-up study of patients with MEN syndromes - five case reports.
Endokrynol Pol. 2018; 69(2):163-167 [PubMed] Related Publications
THE AIM OF THE STUDY: Evaluation of the results of surgical treatment in patients with hyperparathyroidism related to MEN syndrome MATERIALS AND METHODS: The group of three women and two men aged between 17 and 72 years ( av. 38.6) with MEN- related hyperparathyroidism within 419 patients were operated between 2010-2016. MEN1 syndrome was diagnosed in four patients and MEN2 only once. Pre- and postoperative results of PTH levels and serum calcium values were compared.
RESULTS: The mean preoperative serum PTH level was 215,56 pg/ml, whereas calcium concentration was 1.40 mmol/l. Three Patients with MEN1 syndrome had three and two thirds of parathyroid gland taken, and one had a single parathyroid gland excised with biopsy of the rest glands performed. A patient with MEN2 syndrome had one parathyroid gland excised. Postoperatively, we reported decreased secretion of both PTH (a mean serum PTH concentration 6.72 pg/ml), and serum calcium concentration 1.11 mmol/l. One patient (25%) with MEN 1 developed recurrent hyperparathyroidism after five years from the surgery. The patient was reoperated. The rest of the parathyroid gland was removed with an implantation into separated muscle pockets in the anterior forearm muscles.
CONCLUSIONS: 1. MEN syndrome is a rare cause of primary hyperparathyroidism. 2. Subtotal parathyroidectomy helps to bring back a normal calcium metabolism. 3. Recurrence of hyperparathyroidism in patients with MEN syndrome requires total parathyroidectomy with an autotransplantation into the anterior forearm muscles.

Di Meo G, Sgaramella LI, Ferraro V, et al.
Parathyroid carcinoma in multiple endocrine neoplasm type 1 syndrome: case report and systematic literature review.
Clin Exp Med. 2018; 18(4):585-593 [PubMed] Related Publications
The aim of this report was to illustrate a case of parathyroid carcinoma (PC) in a patient with multiple endocrine neoplasia type 1 (MEN1) along with a comprehensive literature review. A 61-year-old man presented with 9-cm PC causing primary hyperparathyroidism (PHPT). His pre-operative corrected calcium and intact PTH serum levels were 2.92 mmol/L and 391.7 pg/mL, respectively. The neoplastic gland was removed in bloc with thyroid and central compartment lymph nodes. A literature review was run by searching PubMed MEDLINE from 1977 to 2018 for studies of all types, in the English language only, using the terms "Parathyroid, carcinoma, Multiple endocrine neoplasia, type 1, (MEN1)." Pathology confirmed PC. Post-operative calcium and PTH levels were normal. A diagnosis of MEN1 was established post-operatively. Seventeen cases of PC in patients with MEN1 have been reported in the literature. 59% of patients were men, and median age at diagnosis was 50 years, with median serum PTH of 379 pg/mL and median serum calcium level of 3.2 mmol/L. The occurrence of PC in the context of MEN1 is extremely rare. Diagnosis and treatment may represent a challenge, so opportune identification or suspicion of malignancy and adoption of correct surgical approach may offer affected patients the best outcome.
Related: Parathyroid Cancer

Liang M, Jiang J, Dai H, et al.
Robotic enucleation for pediatric insulinoma with MEN1 syndrome: a case report and literature review.
BMC Surg. 2018; 18(1):44 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A patient with a rare pediatric insulinoma and MEN1 syndrome was treated by robotic enucleation surgery.
CASE PRESENTATION: We present a case of a 9-year-old girl presenting with repeated loss of consciousness, concomitant with a pale face, palpitations, and convulsions, which had persisted for 2 years and had been aggravated during the previous 2 months. She was previously misdiagnosed with epilepsy in another hospital. We further examined her while she was hospitalized. By combining her medical history and imaging examination and lab test results, a diagnosis of insulinoma was confirmed. Sanger-directed sequencing on a peripheral blood sample revealed an MEN1 gene mutation, indicating pediatric insulinoma with MEN1 syndrome. The patient underwent minimally invasive insulinoma enucleation surgery under the Da Vinci robot-assisted system with intraoperative ultrasound (IOUS) connected. The surgery was successfully completed within 65 min, and the girl recovered well postoperatively and no longer experienced symptoms of hypoglycemia.
CONCLUSION: This is the first report of a case of pediatric insulinoma treated using robotic enucleation. This experience demonstrates the feasibility and safety of combining robotic surgery with the enucleation procedure as an excellent strategy for pediatric insulinoma.
Related: Cancer of the Pancreas Pancreatic Cancer

Al-Salameh A, Baudry C, Cohen R
Update on multiple endocrine neoplasia Type 1 and 2.
Presse Med. 2018; 47(9):722-731 [PubMed] Related Publications
Multiple endocrine neoplasia type 1 is a rare genetic syndrome, characterized by the co-occurrence, in the same individual or in related individuals of the same family, of hyperparathyroidism, duodenopancraetic neuroendocrine tumors, pituitary adenomas, adrenocortical tumors, and neuroendocrine tumors (carcinoids) in the thymus, the bronchi, or the stomach. Multiple endocrine neoplastic type 2 is a rare genetic syndrome, characterized by the familial occurrence of medullary thyroid carcinoma either isolated or associated with pheochromocytoma, primary hyperparathyroidism, or typical features (Marfanoid habitus, mucosal neuromas). Subjects with clinical MEN1 and those who carry a mutation in the MEN1 gene should be offered biochemical and imaging screening in order to detect tumors and evaluate their progression over time. Children with mutation in the RET gene should have prophylactic total thyroidectomy according to the category of aggressiveness of the detected mutation whereas those with clinical MEN2 should be operated on upon diagnosis. In MEN1 patients, special attention should be paid to evaluate the progression duodenopancraetic neuroendocrine tumors because of their malignant potential. Also, thymic neuroendocrine tumors should be detected as soon as possible because they represent the most lethal tumor. In MEN2, calcitonin and carcinoembryonic antigen (CEA) serve as excellent tumor markers for medullary thyroid carcinoma. Their preoperative levels are correlated with tumor size and predict postoperative cure. Moreover, calcitonin or CEA doubling time has important prognostic value. In both MEN syndromes, multidisciplinary approaches are very important in the care of affected patients. Moreover, those patients should be comprehensively informed and enabled to participate in the decision-making procedure. In addition to multidisciplinary approaches, every effort should be made to follow the recommendations and guidelines issued by national (the French Group of Endocrine Tumors) and international groups.

Conemans EB, Lodewijk L, Moelans CB, et al.
DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment.
Eur J Endocrinol. 2018; 179(3):153-160 [PubMed] Related Publications
OBJECTIVE: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs.
DESIGN AND METHODS: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (
RESULTS: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876,
CONCLUSION: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.
Related: Cancer of the Pancreas Pancreatic Cancer VHL

Mongelli MN, Peipert BJ, Goswami S, et al.
Quality of life in multiple endocrine neoplasia type 2A compared with normative and disease populations.
Surgery. 2018; 164(3):546-552 [PubMed] Related Publications
BACKGROUND: Patient-reported outcomes are measured in chronic disease states to inform intervention and management decisions while minimizing negative outcomes. We hypothesized that health-related quality of life in patients with multiple endocrine neoplasia type 2A would be worse than the general US population but similar to other chronic diseases.
METHODS: Adults ≥18 years with multiple endocrine neoplasia type 2A were recruited to complete the Patient-Reported Outcomes Measurement Information System 29-item questionnaire (n = 45). Scores based on the Patient-Reported Outcomes Measurement Information System T-score metric were compared with the general US population and with cohorts with low back pain, cancer, congestive heart failure, chronic obstructive pulmonary disease, major depressive disorder, rheumatoid arthritis, neuroendocrine tumors, primary hyperparathyroidism, and MEN1.
RESULTS: Compared with US normative data, multiple endocrine neoplasia type 2A patients reported worse anxiety (58.2 ± 12.0, P < .0001), depression (55.4 ± 12.0, P < .01), fatigue (61.4 ± 10.8, P < .0001), pain interference (54.0 ± 11.5, P < .05), and sleep disturbance (56.9 ± 2.7, P < .001), as well as significantly lower physical functioning (45.7 ± 9.3, P < .01) and ability to participate in social roles (46.4 ± 9.7, P < .05). Multiple endocrine neoplasia type 2A patients reported greater fatigue than patients with cancer (P < .0001), chronic obstructive pulmonary disease (P = .01), rheumatoid arthritis (P = .0002), neuroendocrine tumors (P = .0007), and primary hyperparathyroidism (P < .0001) but higher physical functioning compared with patients with rheumatoid arthritis (P = .02), low back pain, congestive heart failure, and chronic obstructive pulmonary disease (P < .0001).
CONCLUSIONS: This study is the first to use the Patient-Reported Outcomes Measurement Information System to compare patient-reported outcomes between multiple endocrine neoplasia type 2A and other chronic conditions. Individuals with multiple endocrine neoplasia type 2A reported worse health-related quality of life in all 7 domains compared with US normative data. Multiple endocrine neoplasia type 2A patients reported greater fatigue but greater physical function compared with several other conditions. Prospective longitudinal evaluation of patient-reported outcomes in multiple endocrine neoplasia type 2A should be conducted to identify treatments associated with the highest health-related quality of life.
Related: USA

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