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.
OBJECTIVE:To estimate short and long-term morbidity after pancreatic surgery for multiple endocrine neoplasia type 1 (MEN1)-related nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs).
...BACKGROUND:Fifty percent of the MEN1 patients harbor multiple NF-pNETs. The decision to proceed to NF-pNET surgery is a balance between the risk of disease progression versus the risk of surgery-related morbidity. Currently, there are insufficient data on the surgical complications after MEN1 NF-pNET surgery.
METHODS:MEN1 patients diagnosed with a NF-pNET who underwent surgery were selected from the DutchMEN1 study group database, including >90% of the Dutch MEN1 population. Early postoperative complications, new-onset diabetes mellitus, and exocrine pancreatic insufficiency were captured.
RESULTS:Sixty-one patients underwent NF-pNET surgery at 1 of the 8 Dutch academic centers. Patients were young (median age 41 years) with low American Society of Anesthesiologists scores. Median NF-pNET size on imaging was 22 mm (3–157). Thirty-three percent (19/58) of the patients developed major early—Clavien-Dindo grade III to IV—complications mainly consisting International Study Group of Pancreatic Surgery grade B/C pancreatic fistulas. Twenty-three percent of the patients (14/61) developed endocrine or exocrine pancreas insufficiency. The development of major early postoperative complications was independent of the NF-pNET tumor size. Twenty-one percent of the patients (12/58) developed multiple major early complications.
CONCLUSIONS:MEN1 NF-pNET surgery is associated with high rates of major short and long-term complications. Current findings should be taken into account in the shared decision-making process when MEN1 NF-pNET surgery is considered.
Reliable prediction of disease status is a major challenge in managing gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aim of the study was to validate the NETest®, a blood molecular ...genomic analysis, for predicting the course of disease in individual patients compared to chromogranin A (CgA). NETest® score (normal ≤20%) and CgA level (normal <100 µg/L) were measured in 152 GEP-NETs. The median follow-up was 36 (4–56) months. Progression-free survival was blindly assessed (Response Evaluation Criteria in Solid Tumors RECIST version 1.1). Optimal cutoffs (area under the receiver operating characteristic curve AUC), odds ratios, as well as negative and positive predictive values (NPVs/PPVs) were calculated for predicting stable disease (SD) and progressive disease (PD). Of the 152 GEP-NETs, 86% were NETest®-positive and 52% CgA-positive. NETest® AUC was 0.78 versus CgA 0.73 (p = ns). The optimal cutoffs for predicting SD/PD were 33% for the NETest® and 140 µg/L for CgA. Multivariate analyses identified NETest® as the strongest predictor for PD (odds ratio: 5.7 score: 34–79%; 12.6 score: ≥80%) compared to CgA (odds ratio: 3.0), tumor grade (odds ratio: 3.1), or liver metastasis (odds ratio: 7.7). The NETest® NPV for SD was 87% at 12 months. The PPV for PD was 47 and 64% (scores 34–79% and ≥80%, respectively). NETest® metrics were comparable in the watchful waiting, treatment, and no evidence of disease (NED) subgroups. For CgA (>140 ng/mL), NPV and PPV were 83 and 52%. CgA could not predict PD in the watchful waiting or NED subgroups. The NETest® reliably predicted SD and was the strongest predictor of PD. CgA had lower utility. The NETest® anticipates RECIST-defined disease status up to 1 year before imaging alterations are apparent.
Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant inherited condition, causing significant morbidity, and a reduction of life expectancy. A timely and accurate diagnosis of MEN1 ...is paramount to improve disease outcomes. This enables early identification of tumor manifestations allowing timely treatment for reducing morbidity and improving survival. Current management of MEN1 poses two challenges regarding the MEN1 diagnosis: diagnostic delay and the issue of phenocopies. A delay in diagnosis can be caused by a delay in identifying the index case, and by a delay in identifying affected family members of an index case. At present, lag time between diagnosis of MEN1 in index cases and genetic testing of family members was estimated to be 3.5 years. A subsequent delay in diagnosing affected family members was demonstrated to cause potential harm. Non-index cases have been found to develop clinically relevant tumor manifestations during the lag times. Centralized care, monitoring of patients outcomes on a national level and thereby improving awareness of physicians treating MEN1 patients, will contribute to improved care. The second challenge relates to "phenocopies." Phenocopies refers to the 5-25% of clinically diagnosed patients with MEN1in whom no mutation can be found. Up to now, the clinical diagnosis of MEN1 is defined as the simultaneous presence of at least two of the three characteristic tumors (pituitary, parathyroids, or pancreatic islets). These clinically diagnosed patients undergo intensive follow up. Recent insights, however, challenge the validity of this clinical criterion. The most common mutation-negative MEN1 phenotype is the combination of primary hyperparathyroidism and a pituitary adenoma. This phenotype might also be caused by mutations in the
gene, causing the recently described MEN4 syndrome. Moreover, primary hyperparathyroidism and pituitary adenoma are relatively common in the general population. Limiting follow-up in patients with a sporadic co-occurrence of pHPT and PIT could reduce exposure to radiation from imaging, healthcare costs and anxiety.
Introduction: The rarity of neuroendocrine tumors (NETs) and their heterogeneous presentation complicate the identification of risk factors for their development and natural course. Several ...tumor-specific prognostic factors have been identified, but less attention has been given to lifestyle factors as risk and prognostic factors. This review aimed to identify studies on smoking, alcohol use, physical activity, diet, body mass index (BMI), and diabetes and their association with the development and course of gastroenteropancreatic (GEP-) NETs. Methods: The literature was systematically searched for articles on lifestyle factors and NETs available via PubMed and Embase. Study quality was assessed using the Newcastle-Ottawa scale. Results: A total of 25 eligible studies out of 3,021 screened articles were included. Most studies reported on smoking and alcohol, reporting conflicting results. Diet seems to have an influence on NET development, but few studies were published. Articles reporting on BMI were not unanimous on the effect on GEP-NETs. Diabetes was reported as a risk factor for NETs, while a protective effect was observed with metformin use. Conclusion: Different tissues, i.e., the pancreas and small intestine, may respond differently to exposure to alcohol and smoking. Evidence for diet so far is too limited to draw conclusions. Diabetes seems to be an important risk factor for the development of pancreatic NETs with a protective role in disease progression, while BMI is not unequivocally associated with the development and prognosis of NETs. Hence, our findings suggest that lifestyle factors play an important role in NET development as a disease course. Future research should consider lifestyle as an influence on disease progression and treatment response.
Pancreatic neuroendocrine tumors (pNETs) in Von Hippel–Lindau (VHL) disease have a relatively good prognosis. However, a subset of pNETs metastasize and significantly contribute to VHL-related ...mortality. Evidence-based guidelines are needed for timely detection, management and intervention of these tumors. However, the value of several diagnostic tools is controversial, and evidence-based management strategies are lacking. This systematic review aims to update current literature on diagnostic and management strategies of pNETs in VHL and proposes evidence-based recommendations. The databases of PubMed/Medline, Embase and Web of Science were systematically searched to identify relevant studies. Studies were screened independently and cross-checked by two authors to assess eligibility for inclusion. Eighty-four articles were eligible for full text reading, and thirteen were critically appraised using the modified Quality Assessment of Diagnostic Accuracy Studies or modified Quality in Prognostic Studies tool. Six studies assessed the diagnostic value of imaging modalities, five focused on the optimal timing for surgical intervention, and one article studied the growth rate of pNETs. Quality of the available evidence was determined using the Grading of Recommendations, Assessment, Development and Evaluations tool. Studies recommended CT or MRI as the primary screening modalities for pNETs. For detection of metastases, 68Gallium-DOTATATE/TOC PET/CT is advised. For pNETs <2 cm a watch-and-wait approach is recommended, while for pNETs ≥2.5 cm surgical resection is advised. Due to limited data, no strong recommendations on surveillance could be proposed.
Available neuroendocrine biomarkers are considered to have insufficient accuracy to discriminate patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) from healthy controls. Recent ...studies have demonstrated a potential role for circulating neuroendocrine specific transcripts analysis-the NETest-as a more accurate biomarker for NETs compared to available biomarkers. This study was initiated to independently validate the discriminative value of the NETest as well as the association between tumor characteristics and NETest score.
Whole blood samples from 140 consecutive GEP-NET patients and 113 healthy volunteers were collected. Laboratory investigators were blinded to the origin of the samples. NETest results and chromogranin A (CgA) levels were compared with clinical information including radiological imaging to evaluate the association with tumor characteristics.
The median NETest score in NET patients was 33 vs. 13% in controls (
< 0.0001). The NETest did not correlate with age, gender, tumor location, grade, load, or stage. Using the cut-off of 14% NETest sensitivity and specificity were 93 and 56%, respectively, with an AUC of 0.87. The optimal cut-off for the NETest in our population was 20%, with sensitivity 89% and specificity 72%. The upper limit of normal for CgA was established as 100 μg/l. Sensitivity and specificity of CgA were 56 and 83% with an AUC of 0.76. CgA correlated with age (rs = 0.388,
< 0.001) and tumor load (rs = 0.458,
< 0.001).
The low specificity of the NETest precludes its use as a screening test for GEP-NETs. The superior sensitivity of the NETest over CgA (93 vs. 56%;
< 0.001), irrespective of the stage of the disease, emphasize its potential as a marker of disease presence in follow up as well as an indicator for residual disease after surgery.
We aimed to investigate the postoperative trend in blood pressure (BP)-related outcomes BP and antihypertensive (AHT) drug use during the year following adrenalectomy for primary aldosteronism (PA) ...to determine the optimal timing for outcome assessment and to determine the necessary follow-up length.
Since the course of BP-related outcomes after adrenalectomy is unknown, the optimal timing of outcome assessment and follow-up duration are not clear.
In this retrospective single center cohort study, we used a prospectively collected database with all patients referred for difficult-to-control-hypertension-analysis. All patients diagnosed with PA who underwent adrenalectomy were included. AHT drug use in defined daily dose (DDD) and home blood pressure measurements (HBPMs) during the first postoperative year were collected. A mixed-effects model was developed to assess the stability of DDD and HBPM over time and adjust for potential confounders.
In total 1784 patients were assessed for difficult-to-control-hypertension of whom 41 were included. Both the DDD and HBPM showed the strongest decrease in the first postoperative month (mean 1.6DDD; mean 140/85 mm Hg) compared with preoperative values (4.5DDD; 153/92 mm Hg). Thereafter, both outcomes showed a stable course from 4 to 6 months (1.6DDD; 136/86 mm Hg) up to 12 months postoperatively (2.0DDD; 136/83 mm Hg).
This study showed that AHT drug use and HBPM decreased substantially within the first month after adrenalectomy for PA and afterwards generally remained stable during the year following adrenalectomy. We propose that BP-related outcomes can be assessed reliably early after adrenalectomy and question the need for routine long-term follow-up in referral centers.
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.
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.
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