Multifocality is not associated with worse survival in sporadic pancreatic neuroendocrine tumors.

BACKGROUND AND OBJECTIVES: Pancreatic neuroendocrine tumors (pNETs) in patients with hereditary cancer syndromes are typically multifocal. In contrast, sporadic pNETs are usually unifocal and the incidence of multifocal sporadic pNETs is unknown. The primary aim of this study was to investigate the incidence of multifocality in sporadic pNETs and any associated effect on recurrence risk and survival. METHODS: Patients who underwent resection of pNETs at Mayo Clinic from 2000 to 2019 were identified and clinical data were obtained from medical records. Syndromic disease was defined as pNETs arising in the setting of a hereditary cancer syndrome. Statistical comparisons were made using χ2 , Fisher's exact, and Kruskal-Wallis tests and survival was assessed using the Kaplan-Meier method. RESULTS: Six hundred and sixty-one patients with sporadic pNETs and fifty-nine with syndromic pNETs were identified. Multifocal disease was present in 4.8% of sporadic patients and 84.7% of syndromic patients (p < .001). Within patients with sporadic pNETs, clinicopathologic features and recurrence-free and overall survival were similar between patients with unifocal and multifocal disease. CONCLUSIONS: Multifocal sporadic pNETs are rare and multifocality is not associated with worse survival or increased recurrence risk. Patients with multifocal sporadic pNETs can likely be safely managed with a combination of resection and observation as indicated for each tumor.

Distinct Prognostic Factors in Sporadic and Multiple Endocrine Neoplasia Type 1-Related Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PNET) may develop sporadically or in the context of hereditary syndromes. In patients with multiple endocrine neoplasia type 1 (MEN1), PNET is the leading cause of death. Our aim was to compare the mortality risk in sporadic and MEN1-related PNETs and identify high-risk populations. A retrospective Surveillance, Epidemiology, and End Results database analysis of patients with PNET was used. Patients with MEN1 were defined by syn/metachronous pituitary adenoma. Clinical data were retrieved, and all-cause mortality (ACM) risk was compared in univariate and multivariable analyses. The cohort included 569 patients (46.6% males) with sporadic (n=542) and MEN1-related (n=27) PNETs. Age at diagnosis of MEN1-related PNET was significantly younger than with sporadic PNETs (mean age 49.2±16.7 vs. 61.6±12.7 years, respectively; p < 0.001). Survival analysis showed a trend for a better outcome in patients with MEN1-related vs. sporadic PNET (Log-rank, p=0.09) and in subgroup analysis for patients with advanced disease (p=0.08). Furthermore, among patients followed expectantly, those with MEN1-related PNET had lower ACM risk than their sporadic counterparts (p=0.08). Multivariable analysis demonstrated lower ACM risk in patients diagnosed with MEN1 (hazard ratio 0.35, 95% confidence interval 0.11-1.2, p=0.09), further supporting the trend detected in the univariate analysis. In conclusion, our study demonstrates the distinct clinical profile of patients with MEN1-related PNET compared to sporadic disease and emphasizes the expertise required to accurately manage patients with PNET in this rare context. The cautious decision-making required before embarking on surgical intervention is further emphasized in this robust analysis of a large cancer database.

Uncommon tumors in multiple endocrine neoplasia (MEN) type 1: Do they have a relationship with the prognosis of these patients?

INTRODUCTION: The prognosis of MEN 1 patients is not only determined by pancreatic disease; it is also related to other uncommon tumors. The objective of this study is to analyze the tumors associated with MEN 1 outside the classic triad and to investigate their relationship with mortality. MATERIALS AND METHODS: One hundred and five MEN 1 patients were studied in a tertiary referral hospital (1980-2019). RESULTS: With a follow-up of 11 ± 4 years, seven patients died (8%), four as a consequence MEN syndrome. Thirty-three percent had adrenal gland tumors. One patient died of adrenal cancer. Eight percent presented with a neuroendocrine thoracic neoplasm, and one patient died. Another patient died due to cutaneous T-cell lymphoma. A further patient died because of a gastrinoma with liver metastasis. CONCLUSIONS: To conclude, 75% of MEN-related deaths were the result of an uncommon pathology, and we, therefore, recommend that these tumors should be taken into account in the screening and follow-up of these patients.

Understanding the clinical course of genotype-negative MEN1 patients can inform management strategies.

BACKGROUND: It is unclear whether genotype-negative clinical multiple endocrine neoplasia type 1 patients derive equal benefit from prospective surveillance as genotype-positive patients. METHODS: In this retrospective cohort study, we compared genotype-negative patients with clinical multiple endocrine neoplasia type 1 with genotype-positive index cases. Primary outcome was age-related penetrance of manifestations; secondary outcomes were disease-specific survival and clinical course of endocrine tumors. RESULTS: We included 39 genotype-negative patients with clinical multiple endocrine neoplasia type 1 (Male: 33%) and 63 genotype-positive multiple endocrine neoplasia type 1 index cases (Male: 59%). Genotype-negative patients with clinical multiple endocrine neoplasia type 1 were 65 years old at last follow-up; genotype-positive multiple endocrine neoplasia type 1 index cases were 50 (P < .001). Genotype-negative patients with clinical multiple endocrine neoplasia type 1 were significantly older at their first and second primary manifestation. Only 1 developed a third primary manifestation. No genotype-negative patients with clinical multiple endocrine neoplasia type 1 with primary hyperparathyroidism and a pituitary adenoma developed a duodenopancreatic neuroendocrine tumor. Disease-specific survival was significantly better in genotype-negative patients with clinical multiple endocrine neoplasia type 1. In genotype-negative patients with clinical multiple endocrine neoplasia type 1, primary hyperparathyroidism was single-gland disease in 47% of parathyroidectomies versus 0% in genotype-positive multiple endocrine neoplasia type 1 index cases. In genotype-negative patients with clinical multiple endocrine neoplasia type 1, 17% of duodenopancreatic neuroendocrine tumors were multifocal versus 68% in genotype-positive multiple endocrine neoplasia type 1 index cases. Genotype-negative patients with clinical multiple endocrine neoplasia type 1 had more pituitary macroadenomas, fewer prolactinomas, and more somatotroph adenomas. CONCLUSION: Genotype-negative patients with clinical multiple endocrine neoplasia type 1 have a different clinical course than genotype-positive multiple endocrine neoplasia type 1 index cases. This may support a separate classification and a tailored surveillance regimen. Of the genotype-negative patients with clinical multiple endocrine neoplasia type 1 who had parathyroidectomy, almost half had no evidence of multigland disease and may be potential candidates for a more targeted single-gland approach.

Metastatic Potential and Survival of Duodenal and Pancreatic Tumors in Multiple Endocrine Neoplasia Type 1: A GTE and AFCE Cohort Study (Groupe d'étude des Tumeurs Endocrines and Association Francophone de Chirurgie Endocrinienne).

OBJECTIVE: To assess the distant metastatic potential of duodeno-pancreatic neuroendocrine tumors (DP-NETs) in patients with MEN1, according to functional status and size. SUMMARY BACKGROUND DATA: DP-NETs, with their numerous lesions and endocrine secretion-related symptoms, continue to be a medical challenge; unfortunately they can become aggressive tumors associated with distant metastasis, shortening survival. The survival of patients with large nonfunctional DP-NETs is known to be poor, but the overall contribution of DP-NETs to metastatic spread is poorly known. METHODS: The study population included patients with DP-NETs diagnosed after 1990 and followed in the MEN1 cohort of the Groupe d'étude des Tumeurs Endocrines (GTE). A multistate Markov piecewise constant intensities model was applied to separate the effects of prognostic factors on 1) metastasis, and 2) metastasis-free death or 3) death after appearance of metastases. RESULTS: Among the 603 patients included, 39 had metastasis at diagnosis of DP-NET, 50 developed metastases during follow-up, and 69 died. The Markov model showed that Zollinger-Ellison-related tumors (regardless of tumor size and thymic tumor pejorative impact), large tumors over 2 cm, and age over 40 years were independently associated with an increased risk of metastases. Men, patients over 40 years old and patients with tumors larger than 2 cm, also had an increased risk of death once metastasis appeared. CONCLUSIONS: DP-NETs of 2 cm in size or more, regardless of the associated secretion, should be removed to prevent metastasis and increase survival. Surgery for gastrinoma remains debatable.

One-Year Postoperative Mortality in MEN1 Patients Operated on Gastric and Duodenopancreatic Neuroendocrine Tumors: An AFCE and GTE Cohort Study.

IMPORTANCE: In MEN1 patients with gastric and duodenopancreatic neuroendocrine tumors (GPD-NET), surgery aims to control secretions or to prevent metastatic spread, but after GPD-NET resection, postoperative mortality may be related to the surgery itself or to other associated MEN1 lesions with their own uncontrolled secretions or metastatic behavior. OBJECTIVE: To analyze the causes of death within 1 year following a GPD-NET resection in MEN1 patients. DESIGN: An observational study collecting data from the Groupe d'étude des Tumeurs Endocrines (GTE) database. The analysis considered the time between surgery and death (early deaths [<1 month after surgery] versus delayed deaths [beyond 1 month after surgery]) and the period (before 1990 vs after 1990). Causes of death were classified as related to GDP surgery, related to surgery for other MEN1 lesions or not related to MEN1 causes. SETTING: GTE database which includes 1220 MEN1 patients and 441 GPD-NET resections. PARTICIPANTS: Four hundred and forty-one GPD-NET resections. MAIN OUTCOME MEASURES: The primary end point was postoperative mortality within 1 year after surgery. RESULTS: Twenty-four patients met the inclusion criteria (2%). Median age at death was 50.5 years. Sixteen deaths occurred in the 30-day postoperative period (76%). Among the 8 delayed deaths, 3 occurred as a result of medical complications between 30 and 90 postoperative days. After 1990, mean age at death increased from 48 to 58 years (p = 0.09), deaths related to uncontrolled acid secretion disappeared (p < 0.001) and deaths related to associated MEN1 lesions increased from 8 to 54% (p = 0.16). CONCLUSION: Surgery and uncontrolled secretions remain the two main causes of death in MEN1 patients operated for a GPD-NET tumor. Improving the prognosis of these patients requires a strict evaluation of the secretory syndrome and MEN1 aggressiveness before GDP surgery.

Histologically Proven Bronchial Neuroendocrine Tumors in MEN1: A GTE 51-Case Cohort Study.

OBJECTIVE: To evaluate the natural history of MEN1-related bronchial endocrine tumors (br-NETs) and to determine their histological characteristics, survival and causes of death. br-NETs frequency ranges from 3 to 13% and may reach 32% depending on the number of patients evaluated and on the criteria required for diagnosis. METHODS: The 1023-patient series of symptomatic MEN1 patients followed up in a median of 48.7 [35.5-59.6] years by the Groupe d'étude des Tumeurs Endocrines was analyzed using time-to-event techniques. RESULTS: br-NETs were found in 51 patients (4.8%, [95% CI 3.6-6.2%]) and were discovered by imaging in 86% of cases (CT scan, Octreoscan, Chest X-ray, MRI). Median age at diagnosis was 45 years [28-66]. Histological examination showed 27 (53%) typical carcinoids (TC), 16 (31%) atypical carcinoids (AC), 2 (4%) large cell neuroendocrine carcinomas (LCNEC), 3(6%) small cell neuroendocrine carcinomas (SCLC), 3(6%) TC associated with AC. Overall survival was not different from the rest of the cohort (HR 0.29, [95% CI 0.02-5.14]). AC tended to have a worse prognosis than TC (p = 0.08). Seven deaths were directly related to br-NETs (three AC, three SCLC and one LCNEC). Patients who underwent surgery survived longer (p = 10-4) and were metastasis free, while 8 of 14 non-operated patients were metastatic. There were no operative deaths. CONCLUSIONS: Around 5% of MEN1 patients develop br-NETs. br-NETs do not decrease overall survival in MEN1 patients, but poorly differentiated and aggressive br-NETs can cause death. br-NETs must be screened carefully. A biopsy is essential to operate on patients in time.

Long-term Follow-up of MEN1 Patients Who Do Not Have Initial Surgery for Small ≤2 cm Nonfunctioning Pancreatic Neuroendocrine Tumors, an AFCE and GTE Study: Association Francophone de Chirurgie Endocrinienne & Groupe d'Etude des Tumeurs Endocrines.

OBJECTIVE: To report long-term follow-up of patients with multiple endocrine neoplasia type 1 (MEN1) and nonfunctioning pancreatic neuroendocrine tumors (NF-PET). BACKGROUND: Pancreaticoduodenal tumors occur in almost all patients with MEN1 and are a major cause of death. The natural history and clinical outcome are poorly defined, and management is still controversial for small NF-PET. METHODS: Clinical outcome and tumor progression were analyzed in 46 patients with MEN1 with 2 cm or smaller NF-PET who did not have surgery at the time of initial diagnosis. Survival data were analyzed using the Kaplan-Meier method. RESULTS: Forty-six patients with MEN1 were followed prospectively for 10.7 ±â€Š4.2 (mean ±â€Šstandard deviation) years. One patient was lost to follow-up and 1 died from a cause unrelated to MEN1. Twenty-eight patients had stable disease and 16 showed significant progression of pancreaticoduodenal involvement, indicated by increase in size or number of tumors, development of a hypersecretion syndrome, need for surgery (7 patients), and death from metastatic NF-PET (1 patient). The mean event-free survival was 13.9 ±â€Š1.1 years after NF-PET diagnosis. At last follow-up, none of the living patients who had undergone surgery or follow-up had evidence of metastases on imaging studies. CONCLUSIONS: Our study shows that conservative management for patients with MEN1 with NF-PET of 2 cm or smaller is associated with a low risk of disease-specific mortality. The decision to recommend surgery to prevent tumor spread should be balanced with operative mortality and morbidity, and patients should be informed about the risk-benefit ratio of conservative versus aggressive management when the NF-PET represents an intermediate risk.

Natural History of MEN1 GEP-NET: Single-Center Experience After a Long Follow-Up.

BACKGROUND: The multiple endocrine neoplasia type 1 syndrome (MEN1) natural history is poorly evaluated, and few single-institution experiences about hereditary gastroenteropancreatic neuroendocrine tumors (GEP-NET) are reported. Our purpose is to analyze the role of GEP-NET in MEN1-related death, as well as the behavior of these lesions during follow-up. METHODS: The study population consists of 77 patients diagnosed with MEN1 GEP-NET, regularly followed up since 1990. Extensive clinical data were prospectively recorded. Statistical analysis was performed both on the whole population of 77 patients and on two subgroups including patients who, during the long lasting study period, underwent GEP-NET surgery (50 pts) and who did not (27 pts), respectively. RESULTS: Twenty-five males (32.5%) and 52 females (67.5%) were enrolled. Sixty-four patients had MEN1 family history (83.1%), and genetic mutation was detected in 67 cases (87%). The mean age at GEP-NET diagnosis was 41.4 years (SD = 13.6); 16 patients (20.8%) had GEP-NET diagnosed before age 30 and 12 cases (15.6%) before 1996. The mean interval time between MEN1 diagnosis and GEP-NET detection was 5.7 years (range -11/37; SD = 8.1 years). Overall, the mean follow-up time from MEN1 diagnosis was 15.8 years (SD = 9.7 years) and from GEP-NET diagnosis was 9.6 years (SD = 6.9 years). Gastrinoma was the most frequent functioning GEP-NET and pancreatoduodenectomy the most adopted surgery. GEP-NET progression affected 12 patients within the non-surgical group, while 18 subjects developed progression after surgery. CONCLUSIONS: Our single-center data provide information on epidemiologic, clinical and pathological features of GEP-NET in MEN1 making possible to clarify their natural history.

PROGNOSTIC FACTORS FOR SURVIVAL OF MEN1 PATIENTS WITH DUODENOPANCREATIC TUMORS METASTATIC TO THE LIVER: RESULTS FROM THE DMSG.

OBJECTIVE: Duodenopancreatic neuroendocrine tumors (DP-NETs) develop in a majority of patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Overall survival (OS) and prognostic factors for patients with liver metastases from DP-NETs are not known. METHODS: This was a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population treated between 1990 and 2014. OS was assessed with time to event analysis, and prognostic factors were evaluated. RESULTS: A total of 56% of the MEN1 patients (n = 220) were diagnosed with a DP-NET, of who 34 (15%) developed DP-NET liver metastases. Median age at liver metastases diagnosis was 53 years (range 31-74). Of those patients, 16 patients (47%) had died after a median follow-up of 4 years (range 0.3-12.3). OS at 2, 5, and 10 years were 91%, 65%, and 50%, respectively. A trend towards worse survival was seen in males compared to females (5-year OS 58% versus 75%, P = .07) and also in patients with multiple liver metastases compared to patients with solitary liver metastasis (59 versus 83%, P = .09). CONCLUSION: Despite the fairly indolent course of DP-NET liver metastases in MEN1 patients, half of the population was deceased after 10 years. Sex and tumor load at diagnosis of liver metastases are possible prognostic factors for worse survival. ABBREVIATIONS: DMSG = DutchMEN1 Study Group; D-NET = duodenal neuroendocrine tumor; DP-NET = duodenopancreatic neuroendocrine tumor; HPF = high-power field; Ki67 LI = Ki67 labeling index; MEN1 = multiple endocrine neoplasia type 1; NET = neuroendocrine tumor; OS = overall survival; P-NET = pancreatic neuroendocrine tumor; PPI = proton pump inhibitor; ULN = upper limit of normal; WHO = World Health Organization.

Long-term outcomes in patients with multiple endocrine neoplasia type 1 and pancreaticoduodenal neuroendocrine tumours.

BACKGROUND: In patients with multiple endocrine neoplasia type 1 (MEN-1), pancreaticoduodenal (PD) neuroendocrine tumours (NETs) are associated with early mortality, yet the best treatment strategy remains uncertain. AIM: To assess patient important outcomes (mortality and metastasis) of PD-NETs and predictors of outcomes in patients with MEN-1. METHODS: Retrospective cohort of patients with MEN-1 who attended the Mayo Clinic, Rochester, MN from 1997 to 2014. RESULTS: We identified 287 patients with MEN-1; 199 (69%) patients had 217 PD-NETs. Among those with a PD-NETs, 129 (65%) had surgery of which 90 (70%) had their primary surgery performed at Mayo Clinic. The median postoperative follow-up was 8 years during which 13 (14%) patients died. The mean (±standard deviation) age of death was 51 (±9) years. Tumour size, metastasis at surgery or tumour type were not predictive of mortality, but for every year older at surgery, the odds of metastasis increased by 6%. Surgery was not performed in 70 (35%) patients. Among those who were observed/medically managed without known metastatic disease, mean tumour growth was 0·02 cm/year (range, -0·13-0·4 cm/year). Four patients (7%) died at a median age of 77 (range, 51-89) years. CONCLUSION: PD-NETs are common in patients with MEN-1 and are associated with early mortality even after surgical intervention. Active surveillance is a viable option in nonaggressive PD-NETs, although definitive factors identifying such patients are lacking. Therefore, counselling regarding risks and benefits of current treatment options remains integral to the care of patients with MEN-1.

A novel in-frame deletion in MEN1 (p.Ala416del) causes familial multiple endocrine neoplasia type 1 with an aggressive phenotype and unexpected inheritance pattern.

The present study describes a family with multiple endocrine neoplasia type 1 (MEN1) caused by a previously undescribed in-frame deletion c.1246_1248delGCC (Ala416del) in the MEN1 gene. Evidence for the pathogenic character of this mutation, which triggers an aggressive clinical outcome, is demonstrated. Aggregation analysis in the tested family was strongly suggestive of causality of the detected mutation. This was supported by the analysis of LOH (loss of heterozygosity) in tumor-derived DNA and by computational analysis of the functional and structural implications of the mutation. Different phenotypic characteristics were identified among family members, which is typical for MEN1. Additionally, an unexpected disease inheritance pattern was observed in this kindred, in which either all or none of the siblings of one branch inherited the disease.

Targeting ß-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours.

Inactivating MEN1 mutations are the most common genetic defects present in sporadic and inherited pancreatic neuroendocrine tumours (PNETs). The lack of interventional therapies prompts us to explore the therapeutic approach of targeting ß-catenin signalling in MEN1-mutant PNETs. Here we show the MEN1-encoded scaffold protein menin regulates phosphorylation of ß-catenin. ß-catenin signalling is activated in MEN1-mutant human and mouse PNETs. Conditional knockout of ß-catenin suppresses the tumorigenesis and growth of Men1-deficient PNETs, and significantly prolongs the survival time in mice. Suppression of ß-catenin signalling by genetic ablation or a molecular antagonist inhibits the expression of proproliferative genes in menin-null PNETs and potently improves hyperinsulinemia and hypoglycemia in mice. Blockade of ß-catenin has no adverse effect on physiological function of pancreatic ß-cells. Our data demonstrate that ß-catenin signalling is an effective therapeutic target for MEN1-mutant PNETs. Our findings may contribute to individualized and combined medication treatment for PNETs.

Natural course and survival of neuroendocrine tumors of thymus and lung in MEN1 patients.

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

Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors.

Multiple endocrine neoplasia type 1 (MEN1) is classically characterized by the development of functional or nonfunctional hyperplasia or tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because effective treatments have been developed for the hormone excess state, which was a major cause of death in these patients in the past, coupled with the recognition that nonendocrine tumors increasingly develop late in the disease course, the natural history of the disease has changed. An understanding of the current causes of death is important to tailor treatment for these patients and to help identify prognostic factors; however, it is generally lacking.To add to our understanding, we conducted a detailed analysis of the causes of death and prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with Zollinger-Ellison syndrome (MEN1/ZES patients) and compared our results to those from the pooled literature data of 227 patients with MEN1 with pancreatic endocrine tumors (MEN1/PET patients) reported in case reports or small series, and to 1386 patients reported in large MEN1 literature series. In the NIH series over a mean follow-up of 24.5 years, 24 (23%) patients died (14 MEN1-related and 10 non-MEN1-related deaths). Comparing the causes of death with the results from the 227 patients in the pooled literature series, we found that no patients died of acute complications due to acid hypersecretion, and 8%-14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In the 2 series (the NIH and pooled literature series), two-thirds of patients died from an MEN1-related cause and one-third from a non-MEN1-related cause, which agrees with the mean values reported in 10 large MEN1 series in the literature, although in the literature the causes of death varied widely. In the NIH and pooled literature series, the main causes of MEN1-related deaths were due to the malignant nature of the PETs, followed by the malignant nature of thymic carcinoid tumors. These results differ from the results of a number of the literature series, especially those reported before the 1990s. The causes of non-MEN1-related death for the 2 series, in decreasing frequency, were cardiovascular disease, other nonendocrine tumors > lung diseases, cerebrovascular diseases. The most frequent non-MEN1-related tumor deaths were colorectal, renal > lung > breast, oropharyngeal. Although both overall and disease-related survival are better than in the past (30-yr survival of NIH series: 82% overall, 88% disease-related), the mean age at death was 55 years, which is younger than expected for the general population.Detailed analysis of causes of death correlated with clinical, laboratory, and tumor characteristics of patients in the 2 series allowed identification of a number of prognostic factors. Poor prognostic factors included higher fasting gastrin levels, presence of other functional hormonal syndromes, need for >3 parathyroidectomies, presence of liver metastases or distant metastases, aggressive PET growth, large PETs, or the development of new lesions.The results of this study have helped define the causes of death of MEN1 patients at present, and have enabled us to identify a number of prognostic factors that should be helpful in tailoring treatment for these patients for both short- and long-term management, as well as in directing research efforts to better define the natural history of the disease and the most important factors determining long-term survival at present.

Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study.

Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.

Association of type-O blood with neuroendocrine tumors in multiple endocrine neoplasia type 1.

CONTEXT: The ABO blood type system describes the expression of human blood group antigens found on both erythrocytes and normal tissue throughout the body. We recently reported an association between O blood type and the manifestation of pancreatic neuroendocrine tumors in a cohort of patients with Von Hippel-Lindau syndrome. OBJECTIVE: The aim of the study was to determine whether there is an association of ABO blood type with the development of neuroendocrine tumors in patients with multiple endocrine neoplasia, type 1 (MEN-1). DESIGN: A retrospective analysis of 105 patients with MEN-1 was performed. Demographic, clinical, and biochemical data were analyzed by ABO blood type. Fisher's exact test was used to determine association between ABO blood type and manifestation of neuroendocrine tumor. RESULTS: Demographic and clinical characteristics were similar amongst blood type cohorts. We found an association between O blood type and the manifestation of a primary neuroendocrine tumor of the gastrointestinal tract, lung, pancreas, and thymus in patients with MEN-1 (P = 0.01). Sixteen of 17 (94%) metastatic tumors had type-O blood, compared to 32 of 43 (74%) with a benign tumor who had non-O blood type. CONCLUSIONS: Our findings suggest an association between O blood type and the manifestation of a primary neuroendocrine tumor in patients with MEN-1. Prospective clinical studies are warranted to see whether patient blood type status may be a useful addition to current screening and surveillance practices.

Importance of surveillance for multiple endocrine neoplasia-1 and surgery in patients with sporadic Zollinger-Ellison syndrome.

BACKGROUND & AIMS: Zollinger-Ellison syndrome (ZES) is a rare disorder characterized by gastrin-secreting tumors of the gastrointestinal tract and gastric acid hypersecretion. There is controversy over the best way to manage these patients; we investigated outcomes of patients with different forms of the disease, who did and did not undergo surgery. METHODS: We performed a retrospective chart review of patients with ZES associated with multiple endocrine neoplasia type 1 (MEN-1) (n = 16) and those with sporadic ZES (n = 33) seen at a tertiary care center from August 1994 to January 2012. Cox proportional hazards modeling was used to compare survival times among groups, based on treatment with surgery (n = 34) and the presence of MEN-1 (n = 9 with surgery; n = 7 without surgery). Differences were compared using the unpaired Student t test and the Fisher exact test. RESULTS: Patients with MEN-1 syndrome-associated ZES presented at a younger age than patients with sporadic ZES (34.9 vs 45.7 y, respectively; P < .05) and were diagnosed at a younger age (39.3 vs 49.7 y, respectively; P < .01), yet lived a similar number of years (55.9 vs 55.1 y, respectively; P = .91). None of the patients with MEN-1-associated ZES died of progressive disease, compared with 86% of deaths among patients with sporadic ZES (P < .05). Lymph node involvement, detected during surgery, increased the risk of metastasis to liver (P = .13) and lack of cure by surgery (P = .01). Surgery reduced all-cause mortality (hazard ratio, 0.11; 95% confidence interval, 0.2-0.6; P = .011) and disease-related mortality (hazard ratio, 0.14; 95% confidence interval, 0.2-0.84; P = .032) of patients with sporadic, but not MEN-1 syndrome-associated, ZES. CONCLUSIONS: The presence of MEN-1 is associated with earlier onset and diagnosis of ZES, but a benign clinical course that rarely results in disease-related death; surgery therefore can be deferred for these patients. However, 86% of deaths among patients with sporadic ZES are attributed to disease-related causes, and mortality is reduced by early surgical intervention. Patients with sporadic ZES should undergo surgery soon after diagnosis.