-
Surgical Oncology Clinics of North... Oct 2015Early diagnosis of multiple endocrine neoplasia (MEN) syndromes is critical for optimal clinical outcomes; before the MEN syndromes can be diagnosed, they must be... (Review)
Review
Early diagnosis of multiple endocrine neoplasia (MEN) syndromes is critical for optimal clinical outcomes; before the MEN syndromes can be diagnosed, they must be suspected. Genetic testing for germline alterations in both the MEN type 1 (MEN1) gene and RET proto-oncogene is crucial to identifying those at risk in affected kindreds and directing timely surveillance and surgical therapy to those at greatest risk of potentially life-threatening neoplasia. Pancreatic, thymic, and bronchial neuroendocrine tumors are the leading cause of death in patients with MEN1 and should be aggressively considered by at least biannual computed tomography imaging.
Topics: Disease Management; Genetic Predisposition to Disease; Genetic Testing; Humans; Multiple Endocrine Neoplasia; Proto-Oncogene Mas; Risk Assessment
PubMed: 26363542
DOI: 10.1016/j.soc.2015.06.008 -
Endocrine Reviews Mar 2021Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for... (Review)
Review
Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroendocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.
Topics: Adolescent; Animals; Germ-Line Mutation; Humans; Mice; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Quality of Life; Signal Transduction
PubMed: 33249439
DOI: 10.1210/endrev/bnaa031 -
Neuroendocrinology 2021The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a... (Review)
Review
Multiple Endocrine Neoplasia Type 1 and the Pancreas: Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement.
The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies.
Topics: Consensus; Duodenal Neoplasms; Humans; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms
PubMed: 32971521
DOI: 10.1159/000511791 -
Thyroid : Official Journal of the... Jun 2015The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid... (Review)
Review
INTRODUCTION
The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association.
METHODS
The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document.
RESULTS
The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC.
CONCLUSIONS
The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendations to represent current, rational, and optimal medical practice.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy, Fine-Needle; Carcinoma, Medullary; Carcinoma, Neuroendocrine; Disease Management; Genetic Testing; Hormone Replacement Therapy; Humans; Multiple Endocrine Neoplasia Type 2a; Multiple Endocrine Neoplasia Type 2b; Proto-Oncogene Proteins c-ret; Radiotherapy; Societies, Medical; Thyroid Neoplasms; Thyroidectomy
PubMed: 25810047
DOI: 10.1089/thy.2014.0335 -
Clinical Endocrinology Oct 2022This review provides an overview of novel insights in the clinical management of patients with Multiple Endocrine Neoplasia Type 1, focusing on the last decade since the... (Review)
Review
This review provides an overview of novel insights in the clinical management of patients with Multiple Endocrine Neoplasia Type 1, focusing on the last decade since the last update of the MEN1 guidelines. With regard to Diagnosis: Mutation-negative patients with 2/3 main manifestations have a different clinical course compared to mutation-positive patients. As for primary hyperparathyroidism: subtotal parathyroidectomy is the initial procedure of choice. Current debate centres around the timing of initial parathyroidectomy as well as the controversial topic of unilateral clearance in young patients. For duodenopancreatic neuroendocrine tumours (NETs), the main challenge is accurate and individualized risk stratification to enable personalized surveillance and treatment. Thymus NETs remain one of the most aggressive MEN1-related tumours. Lung NETs are more frequent than previously thought, generally indolent, but rare aggressive cases do occur. Pituitary adenomas are most often prolactinomas and nonfunctioning microadenomas with an excellent prognosis and good response to therapy. Breast cancer is recognized as part of the MEN1 syndrome in women and periodical screening is advised. Clinically relevant manifestations are already seen at the paediatric age and initiating screening in the second decade is advisable. MEN1 has a significant impact on quality of life and US data show a significant financial burden. In conclusion, patient outcomes have improved, but much is still to be achieved. For care tailored to the needs of the individual patient and improving outcomes on an individual basis, studies are now needed to define predictors of tumour behaviour and effects of more individualized interventions.
Topics: Child; Female; Humans; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Pituitary Neoplasms; Quality of Life
PubMed: 35319130
DOI: 10.1111/cen.14727 -
Surgery Today Dec 2023In patients with multiple endocrine neoplasia type 1 syndrome (MEN 1) and Zollinger-Ellison syndrome (ZES), gastrinomas arise from the duodenum, about 60% are multiple,... (Review)
Review
In patients with multiple endocrine neoplasia type 1 syndrome (MEN 1) and Zollinger-Ellison syndrome (ZES), gastrinomas arise from the duodenum, about 60% are multiple, and about 15% of patients have coexisting pancreatic gastrinomas, which can be localized by the selective arterial secretagogue injection test (SASI test). The guidelines (GLs) by the Japanese Neuroendocrine Tumor Society (JNETS) recommend surgical resection for functioning duodenopancreatic neuroendocrine tumors (NETs), including gastrinomas, in patients with MEN1 (Grade A, 100% agreement among members). Conversely, the GLs of the National Comprehensive Cancer Network (NCCN) in the USA recommend observation and treatment with proton pump inhibitors (PPIs) or exploratory surgery for occult gastrinomas. An international Consensus Statement (ICS) from the European Union (EU) also does not recommend resection of gastrinomas in patients with MEN1, despite some surgeons having reported surgery being curative for gastrinomas in MEN1 patients. In this review, we discuss the serious side effects and tumorigenic effects of the prolonged use of PPIs and the safety and curability of surgery, supported by our results of curative surgery for gastrinomas in 20 patients with MEN1 over 30 years. We conclude that surgery should be the first-line treatment for gastrinomas in MEN1 patients.
Topics: Humans; Gastrinoma; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Proton Pump Inhibitors; Zollinger-Ellison Syndrome
PubMed: 36473964
DOI: 10.1007/s00595-022-02627-z -
Pancreas 2017
Topics: Humans; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Outcome Assessment, Health Care; Pancreatic Neoplasms
PubMed: 28426491
DOI: 10.1097/MPA.0000000000000825 -
Molecular and Cellular Endocrinology Apr 2014Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. Four major forms of MEN,... (Review)
Review
Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands within a single patient. Four major forms of MEN, which are autosomal dominant disorders, are recognized and referred to as: MEN type 1 (MEN1), due to menin mutations; MEN2 (previously MEN2A) due to mutations of a tyrosine kinase receptor encoded by the rearranged during transfection (RET) protoncogene; MEN3 (previously MEN2B) due to RET mutations; and MEN4 due to cyclin-dependent kinase inhibitor (CDNK1B) mutations. Each MEN type is associated with the occurrence of specific tumors. Thus, MEN1 is characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumors; MEN2 is characterized by the occurrence of medullary thyroid carcinoma (MTC) in association with phaeochromocytoma and parathyroid tumors; MEN3 is characterized by the occurrence of MTC and phaeochromocytoma in association with a marfanoid habitus, mucosal neuromas, medullated corneal fibers and intestinal autonomic ganglion dysfunction, leading to megacolon; and MEN4, which is also referred to as MENX, is characterized by the occurrence of parathyroid and anterior pituitary tumors in possible association with tumors of the adrenals, kidneys, and reproductive organs. This review will focus on the clinical and molecular details of the MEN1 and MEN4 syndromes. The gene causing MEN1 is located on chromosome 11q13, and encodes a 610 amino-acid protein, menin, which has functions in cell division, genome stability, and transcription regulation. Menin, which acts as scaffold protein, may increase or decrease gene expression by epigenetic regulation of gene expression via histone methylation. Thus, menin by forming a subunit of the mixed lineage leukemia (MLL) complexes that trimethylate histone H3 at lysine 4 (H3K4), facilitates activation of transcriptional activity in target genes such as cyclin-dependent kinase (CDK) inhibitors; and by interacting with the suppressor of variegation 3-9 homolog family protein (SUV39H1) to mediate H3K methylation, thereby silencing transcriptional activity of target genes. MEN1-associated tumors harbor germline and somatic mutations, consistent with Knudson's two-hit hypothesis. Genetic diagnosis to identify individuals with germline MEN1 mutations has facilitated appropriate targeting of clinical, biochemical and radiological screening for this high risk group of patients for whom earlier implementation of treatments can then be considered. MEN4 is caused by heterozygous mutations of CDNK1B which encodes the 196 amino-acid CDK1 p27Kip1, which is activated by H3K4 methylation.
Topics: Humans; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type 1; Proto-Oncogene Proteins
PubMed: 23933118
DOI: 10.1016/j.mce.2013.08.002 -
Genes Sep 2023The aim of this study is to evaluate the predictive role of specific clinical factors for the diagnosis of Multiple Endocrine Neoplasia type-1 (MEN1) and type-4 (MEN4)...
UNLABELLED
The aim of this study is to evaluate the predictive role of specific clinical factors for the diagnosis of Multiple Endocrine Neoplasia type-1 (MEN1) and type-4 (MEN4) in patients with an initial diagnosis of gastrointestinal, bronchial, or thymic neuroendocrine tumor (NET).
METHODS
Patients referred to the NET Unit between June 2021 and December 2022 with a diagnosis of NET and at least one clinical criterion of suspicion for MEN1 and MEN4 underwent molecular analysis of the and genes. Phenotypic criteria were: (1) age ≤ 40 years; (2) NET multifocality; (3) MEN1/4-associated manifestations other than NETs; and (4) endocrine syndrome related to NETs or pituitary/adrenal tumors.
RESULTS
A total of 22 patients were studied. In 18 patients (81.8%), the first-level genetic test was negative (Group A), while four patients (25%) were positive for (Group B). No patient was positive for . In Group A, 10 cases had only one clinical criterion, and three patients met three criteria. In Group B, three patients had three criteria, and one met all criteria.
CONCLUSION
These preliminary data show that a diagnosis of NET in patients with a negative family history is suggestive of MEN1 in the presence of ≥three positive phenotypic criteria, including early age, multifocality, multiple MEN-associated manifestations, and endocrine syndromes. This indication may allow optimization of the diagnosis of MEN in patients with NET.
Topics: Humans; Adult; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pituitary Neoplasms; Genetic Testing; Gastrointestinal Tract
PubMed: 37761922
DOI: 10.3390/genes14091782 -
Deutsche Medizinische Wochenschrift... Sep 2017Multiple endocrine neoplasia type 1 and 2 are hereditary cancer syndromes. They are characterized by the occurrence of many benign and malignant tumor types, in MEN1...
Multiple endocrine neoplasia type 1 and 2 are hereditary cancer syndromes. They are characterized by the occurrence of many benign and malignant tumor types, in MEN1 parathyroid tumors, pituitary tumors, and pancreas tumors, in MEN2 medullary thyroid carcinoma, pheochromocytoma, and parathyroid tumors. The autosomal dominant inherited tumor syndromes are caused by mutations in the MEN1 gene, a tumor suppressor gene, and mutations in the RET gene, an activated oncogene, in MEN2. The clinical expression of the different tumors can vary within and between families, with a good genotype-phenotype correlation in MEN2. Early diagnosis and therapy is possible by using biochemical and imaging screening in the families. Early thyroidectomy in young patients with MEN2 results in a high cure rate of MTC.
Topics: Early Detection of Cancer; Humans; Multiple Endocrine Neoplasia; Mutation; Proto-Oncogene Proteins; Thyroidectomy
PubMed: 28902384
DOI: 10.1055/s-0043-109522