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.
Multiple Endocrine Neoplasia type 1 (MEN1) is diagnosed when two out of the three primary MEN1-associated endocrine tumors occur in a patient. Up to 10-30 % of those patients have no mutation in the ...MEN1 gene. It is unclear if the phenotype and course of the disease of mutation-negative patients is comparable with mutation-positive patients and if these patients have true MEN1. The present study aims to describe and compare the clinical course of MEN1 mutation-negative patients with two out of the three main MEN1 manifestations and mutation-positive patients during long-term follow-up.
This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population.
A total of 293 (90.7 %) mutation-positive and 30 (9.3 %) mutation-negative MEN1 patients were included. Median age of developing the first main MEN1 manifestation was higher in mutation-negative patients (46 vs. 33 years) (P = 0.007). Mutation-negative patients did not develop a third main MEN1 manifestation in the course of follow-up compared to 48.3 % of mutation-positive patients (P < 0.001). Median survival in mutation-positive patients was estimated at 73.0 years (95 % CI, 69.5-76.5) compared to 87.0 years (95 % CI not available) in mutation-negative patients (P = 0.001).
Mutation-positive and mutation-negative MEN1 patients have a different phenotype and clinical course. Mutation-negative patients develop MEN1 manifestations at higher age and have a life expectancy comparable with the general population. The apparent differences in clinical course suggest that MEN1 mutation-negative patients do not have true MEN1, but another MEN1-like syndrome or sporadic co-incidence of two neuro-endocrine tumors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Pancreatic neuroendocrine tumors (pNETs) are highly prevalent in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic disease is an important cause of ...MEN1-related mortality. Especially small nonfunctional (NF) pNETs pose a challenge to the treating physician and more information is needed regarding their natural course. We assessed long-term natural history of small NF-pNETs and its modifiers in the Dutch MEN1 population.
Patients and Methods
Retrospective longitudinal observational cohort study of patients with small (<2 cm) NF-pNETs from the Dutch national MEN1 database, which includes >90% of the Dutch MEN1 population. Modifiers of long-term natural course were analyzed using linear mixed-models analysis.
Results
Growth rate of the 115 included small NF-pNETs from 99 patients was slow (0.4 mm/y; 95% confidence interval, 0.15 to 0.59). Seventy percent of the tumors was stable and a subgroup of 30% of the tumors was growing (1.6 mm/y; 95% confidence interval, 1.1 to 2.0). No differences in clinical characteristics were identified between growing and stable tumors. Within the subgroup of growing tumors, germline missense mutations were significantly associated with accelerated growth compared with nonsense and frameshift mutations.
Conclusion
The majority of small NF-pNETs are stable at long-term follow-up, irrespective of the underlying MEN1 genotype. A subgroup of tumors is slowly growing but cannot be identified on clinical grounds. In this subgroup, tumors with missense mutations exhibited faster growth. Additional events appear necessary for pNETs to progress. Future studies should be aimed at identifying these molecular driving events, which could be used as potential biomarkers.
The size of 115 small NF-pNETs from 99 MEN1 patients was followed over time. Most tumors were stable. In the subgroup of growing tumors a genotype-phenotype correlation was seen.
Duodenopancreatic neuroendocrine tumors (dpNETs) frequently occur in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic dpNET is the primary cause of disease-related mortality. ...There is a need for biomarkers that can identify patients with MEN1-related dpNETs that are at high risk of developing distant metastasis. Polyamines have tumor-promoting roles in several cancer types.
We hypothesized that MEN1-dpNET-related disease progression is associated with elevated levels of circulating polyamines.
Through an international collaboration between The University of Texas MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht, plasma polyamine levels were assessed using mass spectrometry in 84 patients with MEN1 (20 with distant metastatic dpNETs patients and 64 with either indolent dpNETs or no dpNETs controls). A mouse model of MEN1-pNET, Men1fl/flPdx1-CreTg, was used to test time-dependent changes in plasma polyamines associated with disease progression.
A 3-marker plasma polyamine signature (3MP: N-acetylputrescine, acetylspermidine, and diacetylspermidine) distinguished patients with metastatic dpNETs from controls in an initial set of plasmas from the 3 participating centers. The fixed 3MP yielded an area under the curve of 0.84 (95% CI, 0.62-1.00) with 66.7% sensitivity at 95% specificity for distinguishing patients from controls in an independent test set from MDACC. In Men1fl/flPdx1-CreTg mice, the 3MP was elevated early and remained high during disease progression.
Our findings provide a basis for prospective testing of blood-based polyamines as a potential means for monitoring patients with MEN1 for harboring or developing aggressive disease.
Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary endocrine tumor syndrome characterized by the triad of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors ...(pNETs), and pituitary tumors. Patients are confronted with substantial morbidity and are consequently at risk for an impaired quality of life (QOL). Meticulous assessment of QOL and associated factors in a representative population is needed to understand the full spectrum of the burden of the disease. Patients and Methods: A cross-sectional study was performed using the national Dutch MEN1 cohort. Patients with a confirmed MEN1 mutation received the SF-36 Health Related Quality of Life questionnaire and questions regarding sociodemographic and medical history. Results: A total of 227 of 285 (80%) eligible MEN1 patients returned the questionnaires. Health-related QOL scores (HRQOL) in MEN1 patients were significantly lower for the majority of subscales of the SF-36 in comparison with the general Dutch population. The most consistent predictor for HRQOL was employment status, followed by the presence of a pituitary tumor. 16% of patients harboring a pNET and 29% of patients with a pituitary tumor according to the medical records, reported that they were unaware of such a tumor. These subgroups of patients had several significant better QOL scores than patients who were aware of their pNET or pituitary tumors. Conclusion: Patients with MEN1 have an impaired QOL in comparison with the general Dutch population warranting special attention within routine care. For daily practice, physicians should be aware of their patients’ impaired QOL and of the impact of unemployment on QOL.
Nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) are highly prevalent and constitute an important cause of mortality in patients with multiple endocrine neoplasia type 1 (MEN1). Still, the ...optimal age to initiate screening for pNETs is under debate.
The aim of this work is to assess the age of occurrence of clinically relevant NF-pNETs in young MEN1 patients.
Pancreatic imaging data of MEN1 patients were retrieved from the DutchMEN Study Group database. Interval-censored survival methods were used to describe age-related penetrance, compare survival curves, and develop a parametric model for estimating the risk of having clinically relevant NF-pNET at various ages. The primary objective was to assess age at occurrence of clinically relevant NF-pNET (size ≥ 20 mm or rapid growth); secondary objectives were the age at occurrence of NF-pNET of any size and pNET-associated metastasized disease.
Five of 350 patients developed clinically relevant NF-pNETs before age 18 years, 2 of whom subsequently developed lymph node metastases. No differences in clinically relevant NF-pNET-free survival were found for sex, time frame, and type of MEN1 diagnosis or genotype. The estimated ages (median, 95% CI) at a 1%, 2.5%, and 5% risk of having developed a clinically relevant tumor are 9.5 (6.5-12.7), 13.5 (10.2-16.9), and 17.8 years (14.3-21.4), respectively.
Analyses from this population-based cohort indicate that start of surveillance for NF-pNETs with pancreatic imaging at age 13 to 14 years is justified. The psychological and medical burden of screening at a young age should be considered.
Context:
The assessment of tumor markers for diagnosing pancreatic neuroendocrine tumors (pNET) in multiple endocrine neoplasia type 1 (MEN1) patients is advised in the current guidelines but has ...never been validated for this purpose.
Objective:
The objective of the study was to assess the diagnostic accuracy of chromogranin A (CgA), pancreatic polypeptide (PP), and glucagon for pNET in MEN1.
Design:
This was a diagnostic study.
Setting:
The study was conducted at Dutch university medical centers from 2008 to 2011, representing 90% of the total Dutch MEN1 population.
Patients and Methods:
Patients for whom data on tumor markers in combination with the reference standard (ie, radiological imaging) were available between 2008 and 2011 were included. The reference standard for the presence of pNET was pathology or detection on magnetic resonance imaging, computed tomography, or endoscopic ultrasound confirmed on subsequent imaging, irrespective of modality at follow-up.
Main Outcome Measures:
The area under the receiver-operating characteristic curve (AUC), positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, sensitivity, and specificity were calculated for each marker.
Results:
For the analysis of PP, CgA, and glucagon, 73, 81, and 94 patients were available, respectively. The AUC for CgA was 0.48 95% confidence interval (CI) 0.35–0.61 with a sensitivity 0.33 and a specificity 0.73; the AUC for glucagon was 0.58 (95% CI 0.46–0.70) with a sensitivity 0.43 and a specificity 0.73; and the AUC for PP was 0.64 (95% CI 0.50–0.77) with a sensitivity 0.36 and a specificity 0.74. Age, imaging modality, tumor size, and number did not influence the outcomes.
Conclusion:
The diagnostic accuracy of the tumor markers CgA, PP, and glucagon for pNET in MEN1 is low.
Context:
Guidelines advise lifelong radiological followup for asymptomatic pituitary adenomas (PITs) because of the risk for growth and subsequent visual field defects. In the context of multiple ...endocrine neoplasia type 1 (MEN1) an even more comprehensive screening is advised because PITs are presumed to manifest more aggressive behavior. We studied the long-term course of MEN1-related PITs, which may be used as a model for sporadically occurring PITs.
Objective:
The aim of our study is to assess the results of systematic pre-symptomatic PIT screening and subsequent long-term followup of PITs with emphasis on nonfunctioning microadenomas diagnosed by screening.
Patients and Methods:
A cohort study was performed using the Dutch national MEN1 database, including greater than 90% of the Dutch MEN1 population older than 16 years (n = 323).
Main Outcome Measures:
Screening results, natural course, and effects of treatment of PIT were assessed.
Results:
PIT was diagnosed in 123 patients with MEN1 (38.1 %), of whom 66 were diagnosed by MEN1-related screening. Ninety-one percent of the nonfunctioning PIT detected during screening (n = 35), did not require intervention during followup (median, 6.0 y). Three microadenomas showed limited growth but did not progress toward macroadenomas. Both screening-detected and prevalent prolactinomas (n = 52) responded well to treatment with dopamine agonists.
Conclusion:
Systematic presymptomatic screening for PIT in patients with MEN1 predominantly results in detection of nonfunctioning microadenomas. Prolactinoma in patients with MEN1 responded well to medical treatment. Microadenomas grew only occasionally and after many years without clinical consequences. Frequent magnetic resonance imaging followup of nonfunctioning microadenomas in the context of MEN1 and sporadically occurring PITs therefore seems debatable.
Background and objectives
Gastrinomas are the most prevalent functioning neuroendocrine tumors (NET) in multiple endocrine neoplasia type 1 (MEN1). Guidelines suggest medical therapy in most ...patients, but surgery may be considered in a subgroup. Currently, factors to guide management are necessary. This population‐based cohort study assessed prognostic factors of survival in patients with MEN1‐related gastrinomas.
Methods
Patients with MEN1 having gastrinomas were identified in the Dutch MEN1 database from 1990 to 2014 based on fasting serum gastrin (FSG) levels and/or pathology. Predictors of overall survival were assessed using Cox regression.
Results
Sixty‐three patients with gastrinoma (16% of the MEN1 population) were identified. Five‐ and 10‐year overall survival rates were 83% and 65%, respectively. Prognostic factors associated with overall survival were initial FSG levels ≥20x upper limit of normal (ULN) (hazard ratio HR, 6.2 95% confidence interval, 1.7‐23.0), pancreatic NET ≥2 cm (HR 4.5; 1.5‐13.1), synchronous liver metastases (HR 8.9; 2.1‐36.7), gastroduodenoscopy suspicious for gastric NETs (HR 12.7; 1.4‐115.6), and multiple concurrent NETs (HR 5.9; 1.2‐27.7).
Conclusion
Life expectancy of patients with MEN1 gastrinoma is reduced. FSG levels and pancreatic NETs ≥2 cm are prognostic factors. FSG levels might guide surveillance intensity, step‐up to additional diagnostics, or provide arguments in selecting patients who might benefit from surgery.
Objective:
Identifying a germline mutation in the multiple endocrine neoplasia type 1 (MEN1) gene in an index case has consequences for a whole family. Eligible family members should be offered ...genetic counseling and MEN1 mutation testing. Subsequently, clinical screening of mutation carriers according to the guidelines should be initiated. We assessed whether there is a lag time from MEN1 diagnosis of the index case to MEN1 diagnosis of family members. In addition, we determined whether this lag time was associated with an increased morbidity and mortality risk.
Design:
A cohort study was performed using the Dutch MEN1 database, including >90% of the Dutch MEN1 population >16 years of age (n = 393).
Results:
Fifty-eight MEN1 families were identified, of whom 57 were index cases and 247 were non-index cases (n = 304). The median lag time in MEN1 diagnosis of family members was 3.5 (range, 0–30) years. At the time of MEN1 diagnosis, 30 (12.1%) non-index cases had a duodenopancreatic neuroendocrine tumor, of whom 20% had metastases with a mean lag time of 10.9 years, in comparison with 7.1 years without metastases. Twenty-five (10.1%) non-index cases had a pituitary tumor, of whom 80% had a microadenoma and 20% had a macroadenoma, with mean lag times of 7.2 and 10.6 years, respectively. Ninety-five (38.4%) non-index cases had a primary hyperparathyroidism with a mean lag time of 9.5 years in comparison with seven patients without a primary hyperparathyroidism with a mean lag time of 3 years (P = .005). Ten non-index cases died because of a MEN1-related cause that developed during or before the lag time.
Conclusion:
There is a clinically relevant delay in MEN1 diagnosis in families because of a lag time between the diagnosis of an index case and the rest of the family. More emphasis should be placed on the conduct of proper counseling and genetic testing in all eligible family members.
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