ABSTRACT
BACKGROUND: High-grade neuroendocrine neoplasms (NENs) comprise both well-differentiated grade 3 neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) nearly always include poorly differentiated NEC as the neuroendocrine component. The efficacy and safety of frontline mFOLFIRINOX chemotherapy has never been investigated in patients with high-grade NENs. PATIENTS AND METHODS: We conducted a multi-institutional retrospective analysis of patients with advanced high-grade NEN of the gastroenteropancreatic tract or of unknown origin seen between February 2016 and April 2023 who received treatment with frontline mFOLFIRINOX. RESULTS: A total of 35 patients were included (G3 NETs: n=2; NECs: n=25; MiNENs: n=8; stage III: n=5; stage IV: n=30). The objective response rate was 77% (complete response: 3%; partial response: 74%). Median progression-free survival was 12 months (95% CI, 9.2-16.2 months) and median overall survival was 20.6 months (95% CI, 17.2-30.6 months). No significant differences in efficacy were seen according to primary site, histopathology, and Ki-67 proliferative index. All 5 patients with stage III disease who received mFOLFIRINOX obtained an objective response and underwent radical surgery or definitive radiotherapy with curative intent, with a recurrence rate of 40%. Grade 3 or 4 adverse events were observed in 43% of patients (mainly neutropenia and diarrhea). Females were at significantly increased risk of developing severe toxicities. CONCLUSIONS: mFOLFIRINOX shows antitumor activity against high-grade NENs. Well-designed, prospective clinical trials are needed to assess the efficacy of mFOLFIRINOX in both the neoadjuvant and metastatic settings.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Irinotecan , Neoplasm Grading , Neuroendocrine Tumors , Pancreatic Neoplasms , Humans , Female , Male , Middle Aged , Neuroendocrine Tumors/drug therapy , Neuroendocrine Tumors/pathology , Aged , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/mortality , Retrospective Studies , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Irinotecan/therapeutic use , Irinotecan/pharmacology , Intestinal Neoplasms/drug therapy , Intestinal Neoplasms/pathology , Intestinal Neoplasms/mortality , Oxaliplatin/therapeutic use , Oxaliplatin/pharmacology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Fluorouracil/therapeutic use , Leucovorin/therapeutic use , Treatment OutcomeABSTRACT
Signet-ring cell (SRC)/poorly cohesive cell carcinoma is an aggressive variant of pancreatic ductal adenocarcinoma (PDAC). This study aimed to clarify its clinicopathologic and molecular profiles based on a multi-institutional cohort of 20 cases. The molecular profiles were investigated using DNA and RNA sequencing. The clinicopathologic parameters and molecular alterations were analyzed based on survival indices and using a validation/comparative cohort of 480 conventional PDAC patients. The primary findings were as follows: (1) clinicopathologic features: SRC carcinomas are highly aggressive neoplasms with poor prognosis, and the lungs are elective metastatic sites; (2) survival analysis: a higher SRC component was indicative of poorer prognosis. In particular, the most clinically significant threshold of SRC was 80%, showing statistically significant differences in both disease-specific and disease-free survival; (3) genomic profiles: SRC carcinomas are similar to conventional PDAC with the most common alterations affecting the classic PDAC drivers KRAS (70% of cases), TP53 (55%), SMAD4 (25%), and CDKN2A (20%). EGFR alterations, RET::CCDC6 fusion gene, and microsatellite instability (3 different cases, 1 alteration per case) represent novel targets for precision oncology. The occurrence of SMAD4 mutations was associated with poorer prognosis; (4) pancreatic SRC carcinomas are genetically different from gastric SRC carcinomas: CDH1, the classic driver gene of gastric SRC carcinoma, is not altered in pancreatic SRC carcinoma; (5) transcriptome analysis: the cases clustered into 2 groups, one classical/exocrine-like, and the other squamous-like; and (6) SRC carcinoma-derived organoids can be successfully generated, and their cultures preserve the histologic and molecular features of parental SRC carcinoma. Although pancreatic SRC carcinoma shares similarities with conventional PDAC regarding the most important genetic drivers, it also exhibits important differences. A personalized approach for patients with this tumor type should consider the clinical relevance of histologic determination of the SRC component and the presence of potentially actionable molecular targets.
Subject(s)
Carcinoma, Pancreatic Ductal , Carcinoma, Signet Ring Cell , Pancreatic Neoplasms , Humans , Precision Medicine , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/pathology , Carcinoma, Signet Ring Cell/genetics , Carcinoma, Signet Ring Cell/pathology , Genomics , Prognosis , Pancreatic NeoplasmsABSTRACT
The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
Subject(s)
Carcinoma, Neuroendocrine/genetics , Genome, Human/genetics , Genomics , Pancreatic Neoplasms/genetics , Base Sequence , Calmodulin-Binding Proteins/genetics , Chromatin Assembly and Disassembly/genetics , Chromosome Aberrations , DNA Copy Number Variations/genetics , DNA Glycosylases/genetics , DNA Mutational Analysis , DNA Repair/genetics , Female , Germ-Line Mutation/genetics , Humans , Male , RNA-Binding Protein EWS , RNA-Binding Proteins/genetics , TOR Serine-Threonine Kinases/metabolism , Telomere/genetics , Telomere/metabolismABSTRACT
This corrects the article DOI: 10.1038/nature21063.
ABSTRACT
OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.
Subject(s)
Intellectual Disability , Neuroendocrine Tumors , Pancreatic Neoplasms , alpha-Thalassemia , Co-Repressor Proteins/genetics , Genes, Homeobox , Homeodomain Proteins , Humans , Intellectual Disability/genetics , Molecular Chaperones/genetics , Neoplasm Recurrence, Local/genetics , Neuroendocrine Tumors/genetics , Nuclear Proteins/genetics , Pancreatic Neoplasms/pathology , Telomere/genetics , Telomere/pathology , Transcription Factors/genetics , X-linked Nuclear Protein/genetics , alpha-Thalassemia/geneticsABSTRACT
Ki-67 assessment is a key step in the diagnosis of neuroendocrine neoplasms (NENs) from all anatomic locations. Several challenges exist related to quantifying the Ki-67 proliferation index due to lack of method standardization and inter-reader variability. The application of digital pathology coupled with machine learning has been shown to be highly accurate and reproducible for the evaluation of Ki-67 in NENs. We systematically reviewed all published studies on the subject of Ki-67 assessment in pancreatic NENs (PanNENs) employing digital image analysis (DIA). The most common advantages of DIA were improvement in the standardization and reliability of Ki-67 evaluation, as well as its speed and practicality, compared to the current gold standard approach of manual counts from captured images, which is cumbersome and time consuming. The main limitations were attributed to higher costs, lack of widespread availability (as of yet), operator qualification and training issues (if it is not done by pathologists), and most importantly, the drawback of image algorithms counting contaminating non-neoplastic cells and other signals like hemosiderin. However, solutions are rapidly developing for all of these challenging issues. A comparative meta-analysis for DIA versus manual counting shows very high concordance (global coefficient of concordance: 0.94, 95% CI: 0.83-0.98) between these two modalities. These findings support the widespread adoption of validated DIA methods for Ki-67 assessment in PanNENs, provided that measures are in place to ensure counting of only tumor cells either by software modifications or education of non-pathologist operators, as well as selection of standard regions of interest for analysis. NENs, being cellular and monotonous neoplasms, are naturally more amenable to Ki-67 assessment. However, lessons of this review may be applicable to other neoplasms where proliferation activity has become an integral part of theranostic evaluation including breast, brain, and hematolymphoid neoplasms.
Subject(s)
Breast Neoplasms , Neuroendocrine Tumors , Pancreatic Neoplasms , Biomarkers, Tumor/analysis , Cell Proliferation , Female , Humans , Image Processing, Computer-Assisted/methods , Ki-67 Antigen/analysis , Neuroendocrine Tumors/diagnosis , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/pathology , Reproducibility of ResultsABSTRACT
INTRODUCTION: The combined use of 68gallium (68Ga)-DOTA-peptides and 18fluorine-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scans in the workup of pancreatic neuroendocrine tumors (PanNETs) is controversial. This study aimed at assessing both tracers' capability to identify tumors and to assess its association with pathological predictors of recurrence. METHODS: Prospectively collected, preoperative, dual-tracer PET/CT scan data of G1-G2, nonmetastatic, PanNETs that underwent surgery between January 2013 and October 2019 were retrospectively analyzed. RESULTS: The final cohort consisted of 124 cases. There was an approximately equal distribution of males and females (50.8%/49.2%) and G1 and G2 tumors (49.2%/50.8%). The disease was detected in 122 (98.4%) and 64 (51.6%) cases by 68Ga-DOTATOC and by 18F-FDG PET/CT scans, respectively, with a combined sensitivity of 99.2%. 18F-FDG-positive examinations found G2 tumors more often than G1 (59.4 vs. 40.6%; p = 0.036), and 18F-FDG-positive PanNETs were larger than negative ones (median tumor size 32 mm, interquartile range [IQR] 21 vs. 26 mm, IQR 20; p = 0.019). The median Ki67 for 18F-FDG-positive and -negative examinations was 3 (IQR 4) and 2 (IQR 4), respectively (p = 0.029). At least 1 pathological predictor of recurrence was present in 74.6% of 18F-FDG-positive cases (vs. 56.7%; p = 0.039), whereas this was not found when dichotomizing the PanNETs by their dimensions (≤/>20 mm). None of the 2 tracers predicted nodal metastasis. The receiver operating characteristic curve analysis showed that 18F-FDG uptake higher than 4.2 had a sensitivity of 49.2% and specificity of 73.3% for differentiating G1 from G2 (AUC = 0.624, p = 0.009). CONCLUSION: The complementary adoption of 68Ga-DOTATOC and 18F-FDG tracers may be valuable in the diagnostic workup of PanNETs despite not being a game-changer for the management of PanNETs ≤20 mm.
Subject(s)
Fluorodeoxyglucose F18 , Octreotide/analogs & derivatives , Organometallic Compounds , Pancreatic Neoplasms/diagnostic imaging , Positron Emission Tomography Computed Tomography , Radiopharmaceuticals , Adult , Aged , Female , Humans , Male , Middle Aged , Outcome and Process Assessment, Health Care , Pancreatic Neoplasms/surgery , Positron Emission Tomography Computed Tomography/standards , Retrospective StudiesABSTRACT
OBJECTIVE: A comprehensive analysis of the immune landscape of pancreatic neuroendocrine tumours (PanNETs) was performed according to clinicopathological parameters and previously defined molecular subtypes to identify potential therapeutic vulnerabilities in this disease. DESIGN: Differential expression analysis of 600 immune-related genes was performed on 207 PanNET samples, comprising a training cohort (n=72) and two validation cohorts (n=135) from multiple transcriptome profiling platforms. Different immune-related and subtype-related phenotypes, cell types and pathways were investigated using different in silico methods and were further validated using spatial multiplex immunofluorescence. RESULTS: The study identified an immune signature of 132 genes segregating PanNETs (n=207) according to four previously defined molecular subtypes: metastasis-like primary (MLP)-1 and MLP-2, insulinoma-like and intermediate. The MLP-1 subtype (26%-31% samples across three cohorts) was strongly associated with elevated levels of immune-related genes, poor prognosis and a cascade of tumour evolutionary events: larger hypoxic and necroptotic tumours leading to increased damage-associated molecular patterns (viral mimicry), stimulator of interferon gene pathway, T cell-inflamed genes, immune checkpoint targets, and T cell-mediated and M1 macrophage-mediated immune escape mechanisms. Multiplex spatial profiling validated significantly increased macrophages in the MLP-1 subtype. CONCLUSION: This study provides novel data on the immune microenvironment of PanNETs and identifies MLP-1 subtype as an immune-high phenotype featuring a broad and robust activation of immune-related genes. This study, with further refinement, paves the way for future precision immunotherapy studies in PanNETs to potentially select a subset of MLP-1 patients who may be more likely to respond.
Subject(s)
Genes, Neoplasm/immunology , Molecular Mimicry/immunology , Neuroendocrine Tumors/immunology , Pancreatic Neoplasms/immunology , Tumor Microenvironment/immunology , Disease Progression , Female , Gene Expression Profiling , Humans , Male , Neoplasm Grading , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/pathology , Phenotype , Prognosis , Tumor BurdenABSTRACT
OBJECTIVE: To develop a nomogram estimating the probability of recurrence free at 5âyears after resection for localized grade 1 (G1)/ grade 2 (G2) pancreatic neuroendocrine tumors (PanNETs). BACKGROUND: Among patients undergoing resection of PanNETs, approximately 17% experience recurrence. It is not established which patients are at risk, with no consensus on optimal follow-up. METHOD: A multi-institutional database of patients with G1/G2 PanNETs treated at 2 institutions was used to develop a nomogram estimating the rate of freedom from recurrence at 5âyears after curative resection. A second cohort of patients from 3 additional institutions was used to validate the nomogram. Prognostic factors were assessed by univariate analysis using Cox regression model. The nomogram was internally validated using bootstrap resampling method and on the external cohort. Performance was assessed by concordance index (c-index) and a calibration curve. RESULTS: The nomogram was constructed using a cohort of 632 patients. Overall, 68% of PanNETs were G1, the median follow-up was 51âmonths, and we observed 74 recurrences. Variables included in the nomogram were the number of positive nodes, tumor diameter, Ki-67, and vascular/perineural invasion. The model bias-corrected c-index from the internal validation was 0.85, which was higher than European Neuroendocrine Tumors Society/ American Joint Committee on Cancer 8th staging scheme (c-index 0.76, P = <0.001). On the external cohort of 328 patients, the nomogram c-index was 0.84 (95% confidence interval 0.79-0.88). CONCLUSION: Our externally validated nomogram predicts the probability of recurrence-free survival at 5âyears after PanNETs curative resection, with improved accuracy over current staging systems. Estimating individual recurrence risk will guide the development of personalized surveillance programs after surgery.
Subject(s)
Neuroendocrine Tumors/surgery , Pancreatic Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Databases, Factual , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Neoplasm Staging , Neuroendocrine Tumors/mortality , Neuroendocrine Tumors/pathology , Nomograms , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Predictive Value of Tests , Survival RateABSTRACT
PURPOSE OF REVIEW: Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by some types of malignancies, including pancreatic neuroendocrine tumors, to overcome the issue of telomere shortening, thus supporting tumor growth and cell proliferation. This review is focused on the most important achievements and opportunities deriving from ALT assessment in PanNET onco-pathology, highlighting the most promising fields in which such biomarker could be implemented in clinical practice. RECENT FINDINGS: In pancreatic neuroendocrine tumors (PanNET), ALT is strongly correlated with the mutational status of two chromatin remodeling genes, DAXX and ATRX. Recent advances in tumor biology permitted to uncover important roles of ALT in the landscape of PanNET, potentially relevant for introducing this biomarker into clinical practice. Indeed, ALT emerged as a reliable indicator of worse prognosis for PanNET, helping in clinical stratification and identification of "high-risk" patients. Furthermore, it is a very specific marker supporting the pancreatic origin of neuroendocrine neoplasms and can be used for improving the diagnostic workflow of patients presenting with neuroendocrine metastasis from unknown primary. The activation of this process can be determined by specific FISH analysis. ALT should be introduced in clinical practice for identifying "high-risk" PanNET patients and improving their clinical management, and as a marker of pancreatic origin among neuroendocrine tumors.
Subject(s)
Genetic Predisposition to Disease/genetics , Mutation , Neuroendocrine Tumors/genetics , Pancreatic Neoplasms/genetics , Telomere Homeostasis , Telomere/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Co-Repressor Proteins/genetics , Humans , In Situ Hybridization, Fluorescence/methods , Molecular Chaperones/genetics , Neuroendocrine Tumors/metabolism , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , X-linked Nuclear Protein/genetics , X-linked Nuclear Protein/metabolismABSTRACT
BACKGROUND: Synovial sarcoma (SS) is a rare soft tissue tumor. Among different anatomical locations where it can be found, gastric localization is a very uncommon one. Based on soft tissue sarcoma guidelines, complete tumor excision is considered the main treatment approach. Depending on size and localization of the tumor, both wedge and major gastric resections have been performed in the past for the treatment of this condition. CASE PRESENTATION: We present the case of a 43-year-old woman who underwent a laparoscopic intragastric excision of a gastric 10-mm SS located nearby the esophagogastric junction. Pathology examination confirmed the presence of a SS. The resected specimen confirmed margin-free excision of a monophasic spindle cell neoplasm invading the submucosa and presenting the rearrangement of SS18 gene at fluorescence in situ hybridization (FISH). No adjuvant treatment was offered, and 18 months after surgery, the patient was alive and disease free. CONCLUSIONS: This represents the first case reported in literature of a laparoscopic intragastric resection for a gastric SS. This approach allowed to obtain a full thickness radical tumor resection with the advantages of minimally invasive and organ preserving surgery.
Subject(s)
Laparoscopy , Sarcoma, Synovial , Stomach Neoplasms , Adult , Female , Humans , In Situ Hybridization, Fluorescence , Prognosis , Sarcoma, Synovial/diagnostic imaging , Sarcoma, Synovial/surgery , Stomach Neoplasms/surgeryABSTRACT
BACKGROUND: Data on the reliability of the Ki-67 index and grading calculations from endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic neuroendocrine tumors (PanNETs) are controversial. We aimed to assess the accuracy of these data compared with histology. METHODS: Cytological analysis from EUS-FNA in patients with suspected PanNETs (nâ=â110) were compared with resection samples at a single institution. A minimum of 2000 cells were considered to be adequate for grading. Correlation and agreement between cytology and histology in grading and Ki-67 values, respectively, were investigated. Secondary outcomes included the diagnostic performance of EUS-FNA. RESULTS: EUS-FNA samples were adequate for PanNET diagnosis and PanNET grading in 98/110 (89.1â%) and 77/110 (70.0â%) patients, respectively; thus, 77 samples were adequate for comparing cytology vs. histology. There were 67 (62.0â%), 40 (36.4â%), and 1 (0.9â%) patients with a final diagnosis of G1, G2, and G3 tumors, respectively. EUS-FNA grading was concordant with surgical pathology in 81.8â% of patients; under- and overgrading occurred in 15.6â% and 2.6â%, respectively. The overall level of agreement for grading was moderate (Cohen's κâ=â0.59, 95â% confidence interval [CI] 0.34â-â0.78). Spearman's rho for Ki-67 in tumors ≤â20âmm and >â20âmm was strong and moderate, respectively (rhoâ=â0.68, 95â%CI 0.47â-â0.83; rhoâ=â0.59, 95â%CI 0.35â-â0.75). The Blandâ-âAltman plot showed that the Ki-67 values were comparable and reproducible between the two measurements. CONCLUSIONS: Although they were not available for a significant number of patients, grading and Ki-67 values from cytology correlated with histology moderately to strongly.
Subject(s)
Neuroendocrine Tumors , Pancreatic Neoplasms , Endoscopic Ultrasound-Guided Fine Needle Aspiration , Humans , Ki-67 Antigen , Neoplasm Grading , Neuroendocrine Tumors/diagnostic imaging , Pancreatic Neoplasms/diagnostic imaging , Reproducibility of Results , Retrospective StudiesABSTRACT
OBJECTIVE: The objective of the present analysis is 2-fold: first, to define the evolution of time trends on the surgical approach to pancreatic neuroendocrine neoplasms (Pan-NENs); second, to perform a complete analysis of the predictors of oncologic outcome. BACKGROUND: Reflecting their rarity and heterogeneity, Pan-NENs represent a clinical dilemma. In particular, there is a scarcity of data regarding their long-term follow-up after surgical resection. METHODS: From the Institutional Pan-NEN database, 587 resected cases from 1990 to 2015 were extracted. The time span was arbitrarily divided into 3 discrete clusters enabling a balanced comparison between patient groups. Analyses for predictors of recurrence and survival were performed, together with conditional survival analyses. RESULTS: Among the 587 resected Pan-NENs, 75% were nonfunctioning tumors, and 5% were syndrome-associated tumors. The mean age was 54 years (±14 years), and 51% of the patients were female. The median tumor size was 20âmm (range 4 to 140), 62% were G1, 32% were G2, and 4% were G3 tumors. Time trends analysis revealed that the number of resected Pan-NENs constantly increased, while the size (from 25 to 20âmm) and G1 proportion (from 65% to 49%) decreased during the study period. After a mean follow-up of 75 months, recurrence analysis revealed that nonfunctioning tumors, tumor grade, N1 status, and vascular invasion were all independent predictors of recurrence. Regardless of size, G1 nonfunctioning tumors with no nodal involvement and vascular invasion had a negligible risk of recurrence at 5 years. CONCLUSIONS: Pan-NENs have been increasingly diagnosed and resected during the last 3 decades, revealing reliable predictors of outcome. Functioning and nodal status, tumor grade, and vascular invasion accurately predict survival and recurrence with resulting implications for patient follow-up.
Subject(s)
Neuroendocrine Tumors/surgery , Pancreatectomy/methods , Pancreatectomy/trends , Pancreatic Neoplasms/surgery , Female , Hospitals, High-Volume , Humans , Male , Middle Aged , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.
Subject(s)
Antineoplastic Agents/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Everolimus/therapeutic use , Metformin/therapeutic use , Neuroendocrine Tumors/drug therapy , Pancreatic Neoplasms/drug therapy , Somatostatin/analogs & derivatives , Adolescent , Adult , Aged , Aged, 80 and over , Child , Diabetes Mellitus, Type 2/mortality , Disease-Free Survival , Female , Humans , Hypoglycemic Agents/therapeutic use , Italy/epidemiology , Kaplan-Meier Estimate , Male , Middle Aged , Neuroendocrine Tumors/mortality , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Retrospective Studies , Time Factors , Treatment Outcome , Young AdultABSTRACT
BACKGROUND/AIMS: Pancreatic neuroendocrine tumors (pan-NENs) represent an increasingly common indication for pancreatic resection, but there are few data regarding possible recurrence after surgery. The aim of the study was to describe the frequency, timing, and patterns of recurrence after resection for pan-NENs with consequent implications for postoperative follow-up. METHODS: We performed a retrospective analysis of pan-NENs resected between 1990 and 2015 at The Pancreas Institute, University of Verona Hospital Trust. Predictors of recurrence were assessed. Survival analysis was conducted using the Kaplan-Meier and conditional survival (CS) methods. RESULTS: The cohort consisted of 487 patients with a median follow-up of 71 months. Recurrence developed in 12.3%: 54 (11.1%) liver metastases, 11 (2.3%) local recurrence, 10 (2.1%) nodal recurrence, and 8 (1.6%) metastases in other organs. Thirty-one (6.4%) died due to disease recurrence. Size > 21 mm, G3 grade, nodal metastasis, and vascular infiltration were independent predictors of overall recurrence. Recurrence occurred either during the first year of follow-up (n = 9), or after 10 years (n = 4). CS analysis revealed that nonfunctioning G1 pan-NEN ≤20 mm without nodal metastasis or vascular invasion had a negligible risk of developing recurrence. In the present series, after 5 years of follow-up without developing recurrence, tumor recurrence occurred only in the form of liver metastases. CONCLUSIONS: Recurrence of pan-NENs is rare and is predicted by tumor size, nodal metastasis, grading, and vascular invasion. Patients with G1 pan-NEN without nodal metastasis and vascular invasion may be considered cured by surgery. After 5 years without recurrence, follow-up should focus on excluding the development of liver metastases.
Subject(s)
Neoplasm Recurrence, Local/epidemiology , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Adult , Aged , Female , Humans , Italy/epidemiology , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Retrospective Studies , Risk Factors , Survival Analysis , Time FactorsABSTRACT
INTRODUCTION: Cystic pancreatic neuroendocrine tumors (CPanNETs) represent an uncommon variant of pancreatic neuroendocrine tumors (PanNETs). Due to their rarity, there is a lack of knowledge with regard to clinical features and postoperative outcome. METHODS: The prospectively maintained surgical database of a high-volume institution was queried, and 46 resected CPanNETs were detected from 1988 to 2015. Clinical, demographic, and pathological features and survival outcomes of CPanNETs were described and matched with a population of 92 solid PanNETs (SPanNETs) for comparison. RESULTS: CPanNETs accounted for 7.8% of the overall number of resected PanNETs (46/587). CPanNETs were mostly sporadic (n = 42, 91%) and nonfunctioning (39%). Two functioning CPanNETs were detected (4.3%), and they were 2 gastrinomas. The median tumor diameter was 30 mm (range 10-120). All tumors were well differentiated, with 38 (82.6%) G1 and 8 (17.4%) G2 tumors. Overall, no CPanNET showed a Ki-67 >5%. A correct preoperative diagnosis of a CPanNET was made in half of the cases. After a median follow-up of >70 months, the 5- and 10-year overall survival of resected CPanNETs was 93.8 and 62.5%, respectively, compared to 92.7 and 84.6% for SPanNETs (p > 0.05). The 5- and 10-year disease-free survival rates were 94.5 and 88.2% for CPanNETs and 81.8 and 78.9% for SPanNETs, respectively (p > 0.05). CONCLUSION: In the setting of a surgical cohort, CPanNETs are rare, nonfunctional, and well-differentiated neoplasms. After surgical resection, they share the excellent outcome of their well-differentiated solid counterparts for both survival and recurrence.
Subject(s)
Neuroendocrine Tumors/diagnosis , Neuroendocrine Tumors/surgery , Pancreatic Cyst/diagnosis , Pancreatic Cyst/surgery , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Diagnostic Errors , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Neuroendocrine Tumors/mortality , Neuroendocrine Tumors/pathology , Pancreatic Cyst/mortality , Pancreatic Cyst/pathology , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Tumor Burden , Young AdultABSTRACT
OBJECTIVES: To evaluate MRI derived whole-tumour histogram analysis parameters in predicting pancreatic neuroendocrine neoplasm (panNEN) grade and aggressiveness. METHODS: Pre-operative MR of 42 consecutive patients with panNEN >1 cm were retrospectively analysed. T1-/T2-weighted images and ADC maps were analysed. Histogram-derived parameters were compared to histopathological features using the Mann-Whitney U test. Diagnostic accuracy was assessed by ROC-AUC analysis; sensitivity and specificity were assessed for each histogram parameter. RESULTS: ADCentropy was significantly higher in G2-3 tumours with ROC-AUC 0.757; sensitivity and specificity were 83.3 % (95 % CI: 61.2-94.5) and 61.1 % (95 % CI: 36.1-81.7). ADCkurtosis was higher in panNENs with vascular involvement, nodal and hepatic metastases (p= .008, .021 and .008; ROC-AUC= 0.820, 0.709 and 0.820); sensitivity and specificity were: 85.7/74.3 % (95 % CI: 42-99.2 /56.4-86.9), 36.8/96.5 % (95 % CI: 17.2-61.4 /76-99.8) and 100/62.8 % (95 % CI: 56.1-100/44.9-78.1). No significant differences between groups were found for other histogram-derived parameters (p >.05). CONCLUSIONS: Whole-tumour histogram analysis of ADC maps may be helpful in predicting tumour grade, vascular involvement, nodal and liver metastases in panNENs. ADCentropy and ADCkurtosis are the most accurate parameters for identification of panNENs with malignant behaviour. KEY POINTS: ⢠Whole-tumour ADC histogram analysis can predict aggressiveness in pancreatic neuroendocrine neoplasms. ⢠ADC entropy and kurtosis are higher in aggressive tumours. ⢠ADC histogram analysis can quantify tumour diffusion heterogeneity. ⢠Non-invasive quantification of tumour heterogeneity can provide adjunctive information for prognostication.
Subject(s)
Liver Neoplasms/secondary , Neuroendocrine Tumors/pathology , Pancreatic Neoplasms/pathology , Adult , Aged , Female , Humans , Lymphatic Metastasis , Magnetic Resonance Imaging/methods , Magnetic Resonance Imaging/standards , Male , Middle Aged , ROC Curve , Retrospective Studies , Sensitivity and Specificity , Statistics, NonparametricABSTRACT
PURPOSE: Lu-DOTATATE (Lu-PRRT) is a valid therapeutic option in differentiated pancreatic neuroendocrine tumors (P-NETs). FDG PET seems to be an important prognostic factor in P-NETs. We evaluated the efficacy of Lu-PRRT and the role of FDG PET in 60 patients with advanced P-NETs. METHODS: From March 2008 to June 2011, 60 consecutive patients with P-NETs were enrolled in the study. Follow-up lasted until March 2016. Eligible patients were treated with two different total cumulative activities (18.5 or 27.8 GBq in 5 cycles every 6-8 weeks), according to kidney and bone marrow parameters. RESULTS: Twenty-eight patients received a mean full activity (FA) of 25.9 GBq and 32 a mean reduced activity (RA) of 18.5 GBq. The disease control rate (DCR), defined as the sum of CR+PR+SD was 85.7 % in the FA group and 78.1 % in the RA group. Median progression-free survival (mPFS) was 53.4 months in the FA group and 21.7 months in the RA group (P = 0.353). Median overall survival (mOS) was not reached (nr) in FA patients and was 63.8 months in the RA group (P = 0.007). Fifty-five patients underwent an FDG PET scan before Lu-PRRT, 32 (58 %) showing an increased FDG uptake in tumor sites. mPFS was 21.1 months in FDG PET-positive patients and 68.7 months in the FDG PET-negative group (P < 0.0002), regardless of the total activity administered. CONCLUSION: Both FA and RA are active in patients undergoing Lu-PRRT. However, an FA of 27.8 GBq of Lu-PRRT prolongs PFS and OS compared to an RA of 18.5 GBq. Our results indicate that FDG PET is an independent prognostic factor in this patient setting.
Subject(s)
Fluorodeoxyglucose F18 , Neuroendocrine Tumors/diagnostic imaging , Pancreatic Neoplasms/diagnostic imaging , Positron Emission Tomography Computed Tomography , Radiopharmaceuticals , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Neuroendocrine Tumors/radiotherapy , Octreotide/analogs & derivatives , Octreotide/therapeutic use , Organometallic Compounds/therapeutic use , Pancreatic Neoplasms/radiotherapy , Predictive Value of TestsABSTRACT
OBJECTIVE: The aim of this study was to evaluate the usefulness of digital image subtraction of contrast-enhanced magnetic resonance (MR) images for detection and characterization of pancreatic neuroendocrine neoplasms (PanNENs). METHODS: Magnetic resonance examinations of 50 histologically verified PanNENs were retrospectively evaluated by 2 radiologists; 50 ductal adenocarcinomas were included as a control group. Late arterial phase images and correspondent subtracted images were analyzed. Tumor detectability on a subjective 3-point scale and contrast-to-noise ratios were compared across sequences using paired Student t tests. Tumor signal intensity was compared between sequences using χ or Fisher exact tests. RESULTS: Subjective conspicuity and contrast-to-noise ratios of PanNENs were significantly higher on subtracted images compared with correspondent late arterial phase images (P < 0.001 and P = 0.002). The rate of clearly hyperenhancing PanNENs was higher on subtracted images compared with arterial phase images (76% vs 36%). CONCLUSIONS: Digital image subtraction improves tumor conspicuity and allows better characterization of PanNENs compared with late arterial phase images.
Subject(s)
Angiography, Digital Subtraction/methods , Carcinoma, Neuroendocrine/diagnostic imaging , Magnetic Resonance Imaging/methods , Pancreatic Neoplasms/diagnostic imaging , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Pancreas/diagnostic imaging , Retrospective Studies , Sensitivity and Specificity , Young AdultABSTRACT
BACKGROUND: Since prognosis and treatment of pancreatic endocrine tumors (pNET) are based on tumor grade, contrast-enhanced multidetector computed tomography (MDCT) features of solid non-functioning pNETs were studied and correlated with pathology tumor grading. METHODS: MDCTs of diagnosed pNETs were reviewed retrospectively. Each tumor was analyzed for location, size, homogeneity, margins, arterial and venous phase enhancement, main pancreatic duct diameter, calcifications, vascular invasion, lymph-nodes enlargement, and liver metastases. RESULTS: Of 154 pNETs presenting between January 2000 and May 2016 with available histology from resected specimen or biopsy, there were 65 G1, 72 G2 and 17 G3 pNETs. Tumor diameter varied significantly between the three groups. Tumors >20 mm were more frequently malignant and non-homogeneous than smaller tumors. G1 tumors were more commonly hypervascular and G3 tumors more often non-hypervascular in the arterial phase. Arterial phase non-hyperdensity and tumor non-homogeneity had a higher rate of metastatic lesions. Vascular invasion correlated with presence of metastases and histological grade. G3 tumors were all >20 mm (p = 0.007), more often non-hypervascular in the arterial phase (p = 0.0025), and non-hyperdense in the venous phase (p = 0.009), and showed more often vascular invasion (p = 0.0198). CONCLUSION: CT correlated with tumor grade; differentiating low-grade and high-grade pNETs through routine CT imaging might improve patient management.