Multiple endocrine neoplasia: an update.

The multiple endocrine neoplasia (MEN) syndromes include MEN1, MEN2 (formerly MEN2A), MEN3 (formerly MEN2B) and the recently identified MEN4. Clinical presentations are varied and often relate to the overproduction of specific hormones. Understanding the genetics of each syndrome assists in determining screening timelines. Treatments for each manifestation are dependent on location, risk of recurrence or malignancy, hormone excess and surgical morbidity. Multidisciplinary management should include geneticists, genetic counsellors, endocrinologists and endocrine surgeons.

Inherited cancer syndromes and the thyroid: an update.

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

[Multiple endocrine neoplasia (MEN)]. / Multiple endokrine Neoplasie (MEN).

CLINICAL ISSUE: Multiple endocrine neoplasia (MEN) types 1 and 2 are hereditary cancer syndromes. They are characterized by the occurrence of many benign and malignant tumor types. STANDARD TREATMENT: Carriers of a MEN1 or RET gene mutation can be identified before manifestation of the disease. Family screening allows the early diagnosis and therapy of gene carriers. TREATMENT INNOVATIONS: Early thyroidectomy in young patients with MEN2 results in a high cure rate of medullary thyroid carcinoma (MTC). Treatment with tyrosine kinase inhibitors (TKI), such as vadetanib and cabozantinib, represents an important new therapeutic option for patients with progressive metastatic MTC. Neuroendocrine tumors (MEN1) are treated surgically and progressive disease is treated with somatostatin or everolimus. DIAGNOSTICS: The most important imaging methods for monitoring of MTC are sonography of the neck and upper abdomen and computed tomography (CT) of the lungs. In cases of MEN1 metastases can be localized by DOTATOC positron emission tomography CT (PET/CT). PERFORMANCE: Using these methods up to 70 % of tumors and metastases can be detected, depending on the localization, size and endocrine activity. Follow-up investigations with CT is an important tool for monitoring changes in tumor mass which are important criteria for decisions concerning TKI therapy. ACHIEVEMENTS: Together with the doubling time of tumor markers, tumor progression monitored by imaging methods or response evaluation criteria In solid tumors (RECIST) are prognostic factors and provide indications for initiating systemic therapy (e.g. TKI) PRACTICAL RECOMMENDATIONS: Patients with MEN syndromes should be treated in specialized centers because of the complexity and rarity.

[Tumor predisposition in endocrinology - from MEN to FIPA]. / Tumorprädisposition in der Endokrinologie ­ von MEN bis FIPA.

Understanding genetic predisposition has a significant impact on the management of patients with endocrine tumours, including therapy, early detection and prevention. These tumours, which develop as part of a familial predisposition, often manifest early in life and frequently affect several endocrine organs. In the following article, both common syndromes, such as multiple endocrine neoplasia (MEN) syndromes, and rare syndromes, such as familial isolated pituitary adenoma (FIPA), are presented based on their indicator diseases.

Medullary thyroid microcarcinoma: a population-level analysis of 310 patients.

BACKGROUND: Medullary thyroid microcarcinomas (microMTCs) are medullary thyroid carcinomas (MTCs) that measure ≤1 cm in size for which there is a paucity of data on incidence, characteristics, and clinical significance. METHODS: Patients who had a diagnosis of microMTC were abstracted from the Surveillance, Epidemiology, and End Results database (1988-2007). The data were analyzed using chi-square tests, t tests, and log-rank tests; multivariate logistic regression was used to identify factors that were associated independently with lymph node metastases. Tests for diagnostic accuracy, including likelihood ratio tests and post-test probability tests, were computed to evaluate the size-specific likelihood of developing lymph node metastases among patients with microMTC. RESULTS: In total, 310 patients had microMTC; its incidence increased during the study period (P(trend) = .033), and microMTC as a proportion of all MTCs increased by 39%. The mean tumor size was 5.7 mm. Thirty-one percent of tumors were multifocal, and 7.8% had extrathyroid extension. Lymph node metastases occurred in nearly 37% of patients who had any lymph nodes removed (65 of 176 patients). Nearly 20% of patients had regional disease, and 5% had distant metastases. The overall 10-year survival rates for patients with localized, regional, and distant disease stages were 96%, 87%, and 50%, respectively (P < .001). After adjustment, extrathyroid extension (odds ratio [OR], 41.9; P < .001) and tumor size (OR, 1.2; P = .008) retained an independent association with lymph node metastases. MTCs that measured ≤5 mm were associated with a probability of lymph node metastases of approximately 23%, and the probability increased for patients who had tumors >5 mm. CONCLUSIONS: The current results indicated that microMTCs have significant rates of poor prognostic features known to impact the survival of patients with MTC. These microcarcinomas are an important clinical entity that requires comprehensive evaluation and surgical management.

MEN syndromes.

MEN1 and MEN2 are rare inherited cancer syndromes which express a variety of endocrine and nonendocrine tumors. The improved knowledge of molecular and clinical physiopathology of MEN syndromes, together with the availability of genetic testing, have led to earlier detection and intervention, with consequent reduction of mortality and morbidity for MEN-associated tumors. Genetic testing has gained a key role in the detection of asymptomatic patients harbouring mutations responsible for these syndrome, and allows institution of early and tailored intervention with a positive impact on the course of disease.

[Sweat gland polyneoplasia with extensive metastases].

The paper describes a case of sweat gland polyneoplasia with extensive metastases in a 47-year-old woman, which is indicative of extreme malignancy of this tumor.

Medullary Thyroid Carcinoma in Children.

The vast majority of medullary thyroid carcinomas (MTC) in children are inherited as part of the multiple endocrine neoplasia (MEN) syndromes MEN2A and MEN2B, and the related variant, familial MTC. Prophylactic surgery in infants and children identified through genetic screening leads to the highest survival in these patients. This article summarizes the current recommendations for screening, treatment, and surveillance of children with MTC to provide a concise clinically relevant review for pediatric practitioners.

Multiple endocrine neoplasia syndromes.

The multiple endocrine neoplasia (MEN) syndromes are rare autosomal-dominant conditions that predispose affected individuals to benign and malignant tumors of the pituitary, thyroid, parathyroids, adrenals, endocrine pancreas, paraganglia, or nonendocrine organs. The classic MEN syndromes include MEN type 1 and MEN type 2. However, several other hereditary conditions should also be considered in the category of MEN: von Hippel-Lindau syndrome, the familial paraganglioma syndromes, Cowden syndrome, Carney complex, and hyperparathyroidism jaw-tumor syndrome. In addition, researchers are becoming aware of other familial endocrine neoplasia syndromes with an unknown genetic basis that might also fall into the category of MEN. This article reviews the clinical features, diagnosis, and surgical management of the various MEN syndromes and genetic risk assessment for patients presenting with one or more endocrine neoplasms.

Medullary Thyroid Carcinoma: Prognostic Variables And Tumour Markers Affecting Survival.

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.

Management of familial hyperparathyroidism syndromes: MEN1, MEN2, MEN4, HPT-Jaw tumour, Familial isolated hyperparathyroidism, FHH, and neonatal severe hyperparathyroidism.

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.

[Multiple endocrine neoplasia]. / Multiple endokrine Neoplasie.

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.

Familial neuroendocrine tumor syndromes: from genetics to clinical practice.

Thanks to recent developments in molecular biology and cancer genetics, genetic testing has become widely available and useful in several kinds of familial tumor syndrome. However, the impact of genetic testing on medical management is not always straightforward. Clinicians have to consider the psychological impact and ethical complexities of communicating hereditary cancer risk information to families. This review notes some points on genetic counseling before and after genetic testing for familial neuroendocrine tumor syndromes.

Oral mucosal stigmata in hereditary-cancer syndromes: From germline mutations to distinctive clinical phenotypes and tailored therapies.

Numerous familial tumor syndromes are associated with distinctive oral mucosal findings, which may make possible an early diagnosis as an efficacious marker for the risk of developing visceral malignancies. In detail, Familial Adenomatous Polyposis (FAP), Gardner syndrome, Peutz-Jeghers syndrome, Cowden Syndrome, Gorlin Syndrome, Lynch/Muir-Torre Syndrome and Multiple Endocrine Neoplasia show specific lesions of the oral mucosa and other distinct clinical and molecular features. The common genetic background of the above mentioned syndromes involve germline mutations in tumor suppressor genes, such as APC, PTEN, PTCH1, STK11, RET, clearly implied in both ectodermal and mesodermal differentiation, being the oral mucosal and dental stigmata frequently associated in the specific clinical phenotypes. The oral and maxillofacial manifestations of these syndromes may become visible several years before the intestinal lesions, constituting a clinical marker that is predictive for the development of intestinal polyps and/or other visceral malignancies. A multidisciplinary approach is therefore necessary for both clinical diagnosis and management of the gene-carriers probands and their family members who have to be referred for genetic testing or have to be investigated for the presence of visceral cancers.

Multiple endocrine neoplasia type 2 and RET: from neoplasia to neurogenesis.

Multiple endocrine neoplasia type 2 (MEN 2) is an inherited cancer syndrome characterised by medullary thyroid carcinoma (MTC), with or without phaeochromocytoma and hyperparathyroidism. MEN 2 is unusual among cancer syndromes as it is caused by activation of a cellular oncogene, RET. Germline mutations in the gene encoding the RET receptor tyrosine kinase are found in the vast majority of MEN 2 patients and somatic RET mutations are found in a subset of sporadic MTC. Further, there are strong associations of RET mutation genotype and disease phenotype in MEN 2 which have led to predictions of tissue specific requirements and sensitivities to RET activity. Our ability to identify genetically, with high accuracy, subjects with MEN 2 has revolutionised our ability to diagnose, predict, and manage this disease. In the past few years, studies of RET and its normal ligand and downstream interactions and the signalling pathways it activates have clarified our understanding of the roles played by RET in normal cell survival, proliferation, and differentiation, as well as in disease. Here, we review the current knowledge of the normal functions of RET and the effects of mutations of this gene in tumorigenesis and in normal development.

Multiple endocrine neoplasia syndromes 1 and 2: manifestations and management in childhood and adolescence.

The identification of the genetic causes of the multiple endocrine neoplasia (MEN) syndromes 1 and 2, and associated genotype-phenotype relationships, has revolutionised the clinical care of affected patients. A genetic diagnosis can be made during infancy and careful clinical surveillance, coupled with early intervention, has the potential to improve both morbidity and mortality. These developments have seen the management of patients with MEN move into the arena of paediatric medicine. In this review article, we consider the genetic causes of MEN together with the clinical manifestations and management of these syndromes.