Background In multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (pNETs) are the leading MEN1-related cause of death. Objective To evaluate EUS and11 C-5-hydroxytryptophan ...positron emission tomography (11 C-5-HTP PET), compared with the recommended screening techniques in MEN1 patients for early detection of pNETs. Design Cross-sectional study. Setting Tertiary-care university medical center. Patients This study involved 41 patients with a proven MEN1 mutation or with one MEN1 manifestation and a mutation carrier as a first-degree family member, with recent screening by abdominal CT or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS). Interventions EUS by using a linear Pentax echoendoscope and Hitachi EUB-525 and11 C-5-HTP PET. Main Outcome Measurements Patient-based and lesion-based positivity for pNET was calculated for all imaging techniques. The McNemar test was used to compare the yield of the 4 imaging techniques. Results In 35 of 41 patients, 107 pancreatic lesions were detected in total. EUS detected 101 pancreatic lesions in 34 patients,11 C-5-HTP PET detected 35 lesions in 19 patients, and CT/MRI + SRS detected 32 lesions in 18 patients ( P < .001).11 C-5-HTP PET performed similarly to CT/MRI + SRS and better compared with SRS only (13 lesions in 12 patients), both at a patient-based and lesion-based level ( P < .05). Limitations Single-center study. Conclusion EUS is superior to CT/MRI + SRS for pancreatic lesion detection in patients with MEN1. In this setting,11 C-5-HTP PET is not useful. We recommend EUS as the first-choice pancreas imaging technique in patients with MEN1. (Clinical trial registration number: NTR1668 .)
OBJECTIVE:To assess if surgery for Multiple Endocrine Neoplasia type 1 (MEN1) related nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) is effective for improving overall survival and ...preventing liver metastasis.
BACKGROUND:MEN1 leads to multiple early-onset NF-pNETs. The evidence base for guiding the difficult decision who and when to operate is meager.
METHODS:MEN1 patients diagnosed with NF-pNETs between 1990 and 2014 were selected from the DutchMEN1 Study Group database, including > 90% of the Dutch MEN1 population. The effect of surgery was estimated using time-dependent Cox analysis with propensity score restriction and adjustment.
RESULTS:Of the 152 patients, 53 underwent surgery and 99 were managed by watchful waiting. In the surgery group, tumors were larger and faster-growing, patients were younger, more often male, and were more often treated in centers that operated more frequently. Surgery for NF-pNETs was not associated with a significantly lower risk of liver metastases or death, adjusted hazard ratio (HR) = 0.73 (0.25–2.11). Adjusted HRʼs after stratification by tumor size wereNF-pNETs <2 cm = 2.04 (0.31–13.59) and NF-pNETs 2–3 cm = 1.38 (0.09–20.31). Five out of the 6 patients with NF-pNETs >3 cm managed by watchful waiting developed liver metastases or died compared with 6 out of the 16 patients who underwent surgery.
CONCLUSIONS:MEN1 patients with NF-pNETs <2 cm can be managed by watchful waiting, hereby avoiding major surgery without loss of oncological safety. The beneficial effect of a surgery in NF-pNETs 2 to 3 cm requires further research. In patients with NF-pNETs >3 cm, watchful waiting seems not advisable.
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
Until now, well-differentiated bronchopulmonary neuroendocrine tumors (bpNET) occurring either sporadically (sp-bpNET) or in the context of multiple endocrine neoplasia type 1 (MEN1) and diffuse ...idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) are regarded as similar entities. However, in contrast to sp-bpNET: MEN1-related and DIPNECH-related bpNET rarely metastasize or lead to bpNET-related death. We aimed to describe and compare the course of the disease of sp-bpNET, DIPNECH- and MEN1-related bpNET.
All patients with histologically confirmed MEN1-related bpNET from the DutchMEN Study Group database (1990-2017), patients with resected sp-bpNET and DIPNECH patients referred to a Dutch European Neuroendocrine Tumor Society center between 2000 and 2018 were included. Fisher’s exact test was used for comparison between groups. The primary end point was disease-specific mortality (DSM). Kaplan-Meier and logrank test were used to compare survival. Cox regression was used to identify risk factors for DSM in the sp-bpNET subgroup.
We included 112 sp-bpNET, 29 MEN1, and 27 DIPNECH patients. Tumor classification was similar across subgroups. A total of 20 patients (18%) with sp-bpNET died because of bpNET, compared with none in the MEN1 group and DIPNECH group. Median disease-specific survival was 12.3 (confidence interval: 6.3–18.3) years for patients with sp-bpNET, and not estimable for the other subgroups (p < 0.001). Differences in baseline characteristics did not explain worse survival in sp-bpNET. Tumor classification and age at diagnosis were independent risk factors for DSM in sp-bpNET.
Patients with sp-bpNET have a significantly higher DSM compared with MEN1 or DIPNECH-related bpNET, unexplained by differences in baseline characteristics. This implies that not all bpNET are similar entities.
In viral pandemics, most specifically Covid-19, many patients with neuroendocrine neoplasms (NENs), including phaeochromocytomas, paragangliomas and medullary thyroid carcinoma, may develop Covid-19 ...in a mild or severe form, or be concerned about the influence of viral infection relative to their anti-tumoral therapy. In general, newly presenting patients should be assessed, and patients recently receiving chemotherapy, targeted therapy or radionuclide therapy, or showing tumour growth, should be closely followed. For previously diagnosed patients, who have indolent disease, some delay in routine follow-up or treatment may not be problematic. However, patients developing acute secretory syndromes due to functional neuroendocrine neoplasms (such as of the pancreas, intestine or lung), phaeochromocytomas and paragangliomas, will require prompt treatment. Patients with life-threatening Covid-19-related symptoms should be urgently treated and long-term anti-tumoral treatments may be temporarily delayed. In patients with especially aggressive NENs, a careful judgement should be made regarding the severity of any Covid-19 illness, tumour grade, and the immunosuppressant effects of any planned chemotherapy, immunotherapy (e.g. interferon-alpha), targeted therapy or related treatment. In other cases, especially patients with completely resected NENs, or who are under surveillance for a genetic disorder, a telephone or delayed consultation may be in order, balancing the risk of a delay against that of the possible development of Covid-19.
Introduction
Small intestinal neuroendocrine tumors (SI-NETs) often present with metastatic disease. An ongoing debate exists on whether to perform primary tumor resection (PTR) in patients with ...stage IV SI-NETs, without symptoms of the primary tumor and inoperable metastatic disease.
Objective
The aim of this study was to compare a treatment strategy of upfront surgical resection versus a surveillance strategy of watch and wait.
Methods
This was a retrospective cohort study of patients with stage IV SI-NETs at diagnosis, between 2000 and 2018, from two tertiary referral centers (Netherlands Cancer Institute NKI and Aintree University Hospital AUH) who had adopted contrasting treatment approaches: upfront surgical resection and watch and wait, respectively. Patients without symptoms related to the primary tumor were included. Multivariable intention-to-treat (ITT), per-protocol (PP), and instrumental variable (IV) analyses using ‘institute’ as an IV were performed to assess the influence of PTR on disease-specific mortality (DSM).
Results
A total of 557 patients were identified, with 145 patients remaining after exclusion of stage I–III disease or symptoms of the primary tumor (93 from the NKI and 52 from AUH). The cohorts differed in performance status (PS;
p
= 0.006) and tumor grade (
p
< 0.001). PTR was independently associated with reduced DSM irrespective of statistical methods employed: ITT hazard ratio HR 0.60,
p
= 0.005; PP HR 0.58,
p
< 0.001; and IV HR 0.07,
p
= 0.019. Other factors associated with DSM were age, PS, high chromogranin A, and somatostatin analog treatment.
Conclusion
Taking advantage of contrasting institutional treatment strategies, this study identified PTR as an independent predictor of DSM. Future prospective studies should aim to validate these results.
Background
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin.
Aim
To describe clinical outcome and prognostic factors of MCC patients in two expert‐centers.
...Method
Patients with histologically confirmed MCC in 1990‐2014 were included. Data on patient, tumor characteristics and treatment were retrospectively collected.
Results
A total of 351 Patients were evaluated, 153 (44%) males, median age 74 years (range 28‐94). Median follow‐up time was 28 months (IQR 13‐58). Median primary tumor size was 17 mm (range 2‐135). At time of diagnosis 112 (32%) patients had lymph node metastases. The cohorts′ 5‐year overall survival (OS) was 58%. Using a competing risk analysis the 5‐year relapse and MCC related death was 42% and 22%. Adjuvant radiation therapy (XRT) was associated with reduced recurrence (SDH 0.54; CI 0.3‐0.9). Nodal involvement (SDH 2.7; CI 1.1‐6.6) and the male gender were associated with higher MCC related death (SDH 3.1; CI 1.2‐7.9)
Conclusion
In a large cohort a low MCC related death, in the presence of a low OS was seen. This indicates that a significant number of MCC patients die due to other causes than MCC. Adjuvant XRT was associated with relapse. Male gender and nodal metastasis were associated with MCC related death.
Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas ...have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and
CDKN2A
status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (
p
value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of
CDKN2A
as opposed to absence of ARX expression, ALT, or
CDKN2A
deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.
In multiple endocrine neoplasia type 1 (MEN1), endoscopic ultrasound (EUS) is used for identification and follow-up of pancreatic neuroendocrine tumors (PNETs). The role of EUS in surveillance of ...small ( < 20 mm) PNETs is unclear, mostly because the natural course of these lesions is largely unknown. We aimed to determine annual growth and incidence rate of small PNETs in patients with MEN1 using EUS-based surveillance.
Linear array EUS procedures in patients with MEN1 between 2002 and 2015 were identified. Number, size, and location of PNETs were recorded. Annual growth of PNETs < 20 mm identified at the initial EUS ("prevalent" PNETs) and during follow-up ("incident" PNETs) was calculated using mixed model linear regression analysis.
A total of 54 patients were identified and 38 patients were included. In all, 226 PNETs were identified (median size 5.0 mm, interquartile range 3.7 - 7.5) of which 124 (55 %) were prevalent and 102 (45 %) were incident PNETs. Annual incidence rate was 0.79 PNETs/year (95 % confidence interval CI 0.73 to 0.87). Overall growth rate was 0.10 mm/year (95 %CI 0.02 to 0.19;
= 0.01); PNETs < 10 mm (n = 198) did not grow (
= 0.23), whereas PNETs ≥ 10 mm (n = 28) grew 0.44 mm/year (95 %CI 0.10 to 0.78;
= 0.01). Prevalent PNETs grew 0.21 mm/year (95 %CI 0.10 - 0.32;
< 0.001), whereas incident PNETs did not grow (
= 0.26).
The annual growth rate of small, solid PNETs in patients with MEN1 is lower than previously thought. Surveillance intervals could probably be prolonged without compromising safety.
Carcinoid heart disease (CHD) is a rare fibrotic cardiac complication of neuroendocrine tumors. Besides known biomarkers N-Terminal pro-B-type natriuretic peptide (NT-proBNP) and serotonin, activin ...A, connective tissue growth factor (CTGF), and soluble suppression of tumorigenicity 2 (sST2) have been suggested as potential biomarkers for CHD. Here, we validated the predictive/diagnostic value of these biomarkers in a case-control study of 114 patients between 1990 and 2021. Two time-points were analyzed: T0: liver metastasis without CHD for all patients. T1: confirmed CHD in cases (CHD+, n = 57); confirmed absence of CHD five or more years after liver metastasis in controls (CHD−, n = 57). Thirty-one (54%) and 25 (44%) females were included in CHD+ and CHD− patients, respectively. Median age was 57.9 years for CHD+ and 59.7 for CHD- patients (p = 0.290). At T0: activin A was similar across both groups (p = 0.724); NT-proBNP was higher in CHD+ patients (17 vs. 6 pmol/L, p = 0.016), area under the curve (AUC) 0.84, and the most optimal cut-off at 6.5 pmol/L. At T1: activin A was higher in CHD+ patients (0.65 vs. 0.38 ng/mL, p = 0.045), AUC 0.62, without an optimal cut-off value. NT-pro-BNP was higher in CHD+ patients (63 vs. 11 pmol/L, p < 0.001), AUC 0.89, with an optimal cut-off of 27 pmol/L. Serotonin (p = 0.345), sST2 (p = 0.867) and CTGF (p = 0.232) levels were similar across groups. This large validation study identified NT-proBNP as the superior biomarker for CHD. Patients with elevated serotonin levels and NT-proBNP levels between 6.5 and 27 pmol/L, and specifically >27 pmol/L, should be monitored closely for the development of CHD.
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