Hemithyroidectomy versus total thyroidectomy for well differentiated T1-2 N0 thyroid cancer: systematic review and meta-analysis.

BACKGROUND: Evidence for limiting the extent of surgery in patients with low-risk thyroid cancer is lacking. METHODS: A systematic search was performed according to the PRISMA and MOOSE guidelines to assess the effect of total thyroidectomy (TT) with or without radioactive iodine (RAI) treatment versus hemithyroidectomy (HT) on recurrence and overall mortality in patients with differentiated (papillary or follicular) T1-2 N0 thyroid cancer. PubMed, Embase and Cochrane databases were searched, and two authors independently assessed the articles. RESULTS: A total of ten eligible articles were identified. All were observational cohort series, representing a total of 23 134 patients, of which 17 699 were available for meta-analysis. Six studies included patients who had TT followed by RAI treatment. The pooled recurrence rate after TT ± RAI and HT was 2·3 and 2·8 per cent respectively (odds ratio (OR) 1·12, 95 per cent c.i. 0·82 to 1·53; P = 0·48). The pooled 20-year overall survival rate after TT ± RAI was 96·8 per cent, compared with 97·4 per cent for HT (OR 1·30, 0·71 to 2·37; P = 0·40). Overall, higher complication rates were found in the TT ± RAI group. CONCLUSION: Recurrence rates after HT for treatment of well differentiated T1-2 N0 thyroid cancer were similar to those after TT ± RAI, with a lower incidence of treatment-related complications.

ANTECEDENTES: No hay evidencia para limitar la extensión de la cirugía en pacientes con cáncer de tiroides de bajo riesgo. MÉTODOS: Se realizó una búsqueda sistemática siguiendo las recomendaciones PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) y MOOSE (Meta-analysis of Observational Studies in Epidemiology) para evaluar el efecto de la tiroidectomía total (TT) +/− yodo radioactivo (radioactive iodine treatment, RAI) versus hemitiroidectomía (HT) en la recidiva y en la mortalidad global en el cáncer de tiroides diferenciado (papilar/folicular) T1-T2N0. Se realizaron búsquedas en las bases de datos PubMed, Embase y Cochrane, y dos autores evaluaron los artículos de forma independiente. RESULTADOS: Se identificaron un total de 10 artículos de interés. Todos ellos eran estudios de cohortes observacionales, con un total de 23.134 pacientes, de los cuales 17.699 se incluyeron en el metaanálisis. En seis estudios, los pacientes fueron tratados mediante TT seguida de RAI. Las tasas agrupadas de recidiva tras TT +/− RAI y HT fueron 2,3% and 2,8%, respectivamente (razón de oportunidades, odds ratio, OR = 1,12, i.c. del 95% 0,82-1,54, P = 0.48). La supervivencia global a 20 años de TT +/− RAI fue del 96,8% en comparación con el 97,4% para la HT (OR = 1,30, i.c. del 95% 0,71-2,37, P = 0,40). Globalmente, se observaron más complicaciones en el grupo de TT +/− RAI. CONCLUSIÓN: Esta revisión sistemática con metaanálisis demuestra tasas de recidiva similares tras una HT para el tratamiento del cáncer de tiroides T1-2N0 bien diferenciado en comparación con TT +/− RAI, con una menor incidencia de complicaciones relacionadas con el tratamiento.

DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment.

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 (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed. RESULTS: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression. 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.

The penetrance of paraganglioma and pheochromocytoma in SDHB germline mutation carriers.

Germline mutations in succinate dehydrogenase B (SDHB) predispose to hereditary paraganglioma (PGL) syndrome type 4. The risk of developing PGL or pheochromocytoma (PHEO) in SDHB mutation carriers is subject of recent debate. In the present nationwide cohort study of SDHB mutation carriers identified by the clinical genetics centers of the Netherlands, we have calculated the penetrance of SDHB associated tumors using a novel maximum likelihood estimator. This estimator addresses ascertainment bias and missing data on pedigree size and structure. A total of 195 SDHB mutation carriers were included, carrying 27 different SDHB mutations. The 2 most prevalent SDHB mutations were Dutch founder mutations: a deletion in exon 3 (31% of mutation carriers) and the c.423+1G>A mutation (24% of mutation carriers). One hundred and twelve carriers (57%) displayed no physical, radiological or biochemical evidence of PGL or PHEO. Fifty-four patients had a head and neck PGL (28%), 4 patients had a PHEO (2%), 26 patients an extra-adrenal PGL (13%). The overall penetrance of SDHB mutations is estimated to be 21% at age 50 and 42% at age 70 when adequately corrected for ascertainment. These estimates are lower than previously reported penetrance estimates of SDHB-linked cohorts. Similar disease risks are found for different SDHB germline mutations as well as for male and female SDHB mutation carriers.

Expression of p27Kip1 and p18Ink4c in human multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors.

PURPOSE: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27Kip1 and p18Ink4c in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1-related pancreatic neuroendocrine tumor development is not known. METHODS: In this study, we characterized protein expression of p27Kip1 and p18Ink4c in human MEN1-related PanNETs by immunohistochemistry. From the nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 population, MEN1-patients, who underwent pancreatic surgery, were selected. A tissue micro-array was constructed with available paraffin tissue blocks, and PanNETs from 61 MEN1 patients were eligible for analysis. RESULTS: Expression of p27Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18Ink4c (67.3%). No association was found between expression of either p27Kip1 or p18Ink4c and clinic-pathological characteristics. CONCLUSIONS: These findings indicate that loss of p18Ink4c, but not p27Kip1, is a common event in the development of MEN1-related PanNETs. Restoration of p18Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.

Carcinoid heart disease: a guide for screening and timing of surgical intervention.

The cardiac manifestations of a neuroendocrine tumour are referred to as carcinoid heart disease (CaHD) and are associated with a poor prognosis. Surgical intervention is the only proven therapeutic option and may prolong survival and quality of life. No consensus has been reached internationally with regard to screening for CaHD and the optimal timing for surgery. Although limited evidence is available on this matter, a trend towards early surgery and subsequent reduced mortality has been observed. In this review we provide an overview of the current understanding and propose a protocol to guide cardiologists in the screening for CaHD and the timing of referral to a specialised surgical centre.

Thoracic and duodenopancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1: natural history and function of menin in tumorigenesis.

Mutations of the multiple endocrine neoplasia type 1 (MEN1) gene lead to loss of function of its protein product menin. In keeping with its tumor suppressor function in endocrine tissues, the majority of the MEN1-related neuroendocrine tumors (NETs) show loss of heterozygosity (LOH) on chromosome 11q13. In sporadic NETs, MEN1 mutations and LOH are also reported, indicating common pathways in tumor development. Prevalence of thymic NETs (thNETs) and pulmonary carcinoids in MEN1 patients is 2-8%. Pulmonary carcinoids may be underreported and research on natural history is limited, but disease-related mortality is low. thNETs have a high mortality rate. Duodenopancreatic NETs (dpNETs) are multiple, almost universally found at pathology, and associated with precursor lesions. Gastrinomas are usually located in the duodenal submucosa while other dpNETs are predominantly pancreatic. dpNETs are an important determinant of MEN1-related survival, with an estimated 10-year survival of 75%. Survival differs between subtypes and apart from tumor size there are no known prognostic factors. Natural history of nonfunctioning pancreatic NETs needs to be redefined because of increased detection of small tumors. MEN1-related gastrinomas seem to behave similar to their sporadic counterparts, while insulinomas seem to be more aggressive. Investigations into the molecular functions of menin have led to new insights into MEN1-related tumorigenesis. Menin is involved in gene transcription, both as an activator and repressor. It is part of chromatin-modifying protein complexes, indicating involvement of epigenetic pathways in MEN1-related NET development. Future basic and translational research aimed at NETs in large unbiased cohorts will clarify the role of menin in NET tumorigenesis and might lead to new therapeutic options.

Increased prevalence of impaired fasting glucose in MEN1 gene mutation carriers.

OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by parathyroid, gastroenteropancreatic, pituitary and adrenal tumours. Cardiovascular disease has been identified as an important cause of death in MEN1 patients. Menin, the product of the MEN1 gene, is a co-activator for peroxisome proliferator-activated receptor-γ and the vitamin D receptor, which are involved in glucose metabolism. We aimed to compare insulin sensitivity and prevalence of impaired fasting glucose and diabetes mellitus between MEN1 patients and controls. DESIGN: Cross-sectional study. PATIENTS: Sixty-three MEN1 gene mutation carriers (44% men, mean age 41 years) from 22 kindreds and 126 unrelated controls matched for gender, age and BMI. MEASUREMENTS: Fasting glucose levels were categorized and compared using WHO criteria. Homeostasis model assessment (HOMA) was used as a measure of insulin resistance. RESULTS: Homeostasis model assessment was significantly increased in MEN1 patients compared with controls (3·0 ± 2·0 vs 2·0 ± 1·0, P < 0·05). In MEN1 patients, HOMA was associated with BMI, but not with age, calcium and gastrin levels. Using logistic regression analysis, the presence of hyperparathyroidism, pancreatic lesions and various other manifestations was not associated with HOMA. Impaired fasting glucose was more prevalent in MEN1 compared with controls (17%vs 6%, P < 0·05). Three MEN1 patients (5%) compared with four controls (3%) were diabetic (not significant). CONCLUSIONS: Multiple endocrine neoplasia type 1 patients had decreased insulin sensitivity and higher prevalence of impaired fasting glucose compared with controls, which was unrelated to MEN1 manifestations. Impaired glucose metabolism may result in increased risk of cardiovascular disease in MEN1 patients.

Care for patients with multiple endocrine neoplasia type 1: the current evidence base.

Multiple endocrine neoplasia type 1 (MEN1) is a rare disease caused by mutations in the MEN1 gene on chromosome 11. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumours (pNET), pituitary tumours (PIT), adrenal adenomas (ADR) and neuroendocrine tumours (NET) of the stomach, bronchus and thymus. MEN1 is a syndrome with high penetrance and high morbidity. Malignant NETs are the most important cause of MEN1-related death. Since 1997 the diagnosis can be made by genetic screening. MEN1 is a complex syndrome and the endocrine manifestations cannot be viewed upon as coinciding sporadic tumours. Differences in epidemiology and pathology between MEN1-related tumours and their sporadic counterparts show that a unique approach is needed. Therefore the care for MEN1 patients should be provided by a centre of expertise. Early genetic diagnosis and periodic screening are important pillars of care. For primary hyperparathyroidism surgery is the most important treatment modality, with a subtotal parathyroid gland resection as the procedure of choice. In neuroendocrine tumours surgery also is the most important treatment modality. Selective tumour enucleation has no place in the surgical treatment of MEN1-related pNETs; the exact procedure depends on the functionality of the tumour. In MEN1-associated pituitary and adrenal adenomas, watchful waiting and medical therapy play more important roles. In the twenty-first century new developments will impact the care for MEN1 patients. These developments should be critically evaluated in clinical research with the ultimate goal of optimizing the care for MEN1 patients on an evidence base.

Multiple endocrine neoplasia type 1: a chromatin writer's block.

Multiple endocrine neoplasia type 1 (MEN1) is caused by inactivating germ line mutations of the MEN1 tumour suppressor gene. The MEN1 gene product, menin, participates in many cellular processes, including regulation of gene transcription. As part of a protein complex that writes a trimethyl mark on lysine 4 of histone H3 (H3K4me3), menin is involved in activating gene transcription. Several functions of the menin histone methyltransferase complex have been discovered through protein interaction studies. Menin can interact with nuclear receptors and regulate transcription of hormone responsive target genes. Menin regulates transcription of cyclin-dependent kinase inhibitor and Hox genes via the chromatin-associated factor LEDGF. Aberrant expression of menin target genes in tumours in MEN1 patients suggests that loss of writing of the H3K4me3 mark contributes to MEN1 tumourigenesis. At present, drugs are being developed that target chromatin modifications. The identification of compounds that could restore H3K4me3 on menin target genes would provide new therapeutic strategies for MEN1 patients.

[Diverse expression of multiple endocrine neoplasia type 1]. / Pluriforme expressie van multipele endocriene neoplasie type 1.

MEN-1 is an autosomal dominantly inherited disorder, characterised by the occurrence of multiple tumours, particularly in the parathyroid glands, the pancreatic islets, the pituitary gland and the adrenal glands, as well as by neuroendocrine carcinoid tumours. Various clinical manifestations are presented by description of three patients harbouring a MEN1 gene germline mutation. A 44-year-old man had symptoms of hyperparathyroidism and in addition to parathyroid adenomas proved to have tumours in the thymus, adrenal and pituitary glands. A 48-year-old woman from a family with MEN-1 had suffered since her 40th year from headache and heartburn; she appeared to have adenomas in the parathyroid glands and gastrinomas in the pancreas, leading to a Zollinger-Ellison syndrome. One of her relatives, a man aged 29, had suffered from childhood from convulsions due to attacks of hypoglycaemia, and an insulinoma was assessed. In all patients, surgical and/or medical treatment alleviated symptoms. Clearly, the position or nature of the mutations in the MEN1 gene do not correlate with the clinical expression of the disease. Family investigation, DNA analysis and periodic examination improve quality of life and the life expectancy.

[Multiple endocrine neoplasia type 1: recent developments and guidelines for DNA diagnosis and periodic clinical monitoring]. / Multipele endocriene neoplasie type 1: recente ontwikkelingen en richtlijnen voor DNA-diagnostiek en periodiek klinisch onderzoek.

Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominantly inherited disorder, characterised by the occurrence of multiple tumours, particularly in the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands, as well as neuroendocrine carcinoid tumours. Since the identification of the responsible gene in 1997, the diagnosis MEN-1 can be assessed easily, and even presymptomatically, by DNA analysis. An early diagnosis is of importance because through periodic clinical monitoring of (putative) MEN1 gene germline mutation carriers, tumour development can be detected and treated at an early stage. Eligible for DNA analysis are MEN-1 patients and their family members, as well as patients with seemingly sporadic MEN-1 related tumours in whom on clinical grounds carriership of a MEN1 gene germline mutation is suspected. Eligible for periodic clinical monitoring are putative and confirmed carriers of a MEN1 germline mutation from the age of 5.