Digestive Neuroendocrine Tumors Research Articles

Sa1389 Clinical Usefulness of Functional Imaging Tests in the Follow-Up of Digestive Neuroendocrine Neoplasms

Sa1389 Clinical Usefulness of Functional Imaging Tests in the Follow-Up of Digestive Neuroendocrine Neoplasms

Tumeurs neuroendocrines digestives

Digestive neuroendocrine tumors (NETs) are a group of rare tumors with increasing incidence. Pathological analysis is critical to establish the diagnosis and evaluate tumor grade that relies on differentiation and proliferation index. NETs are mostly diagnosed at an advanced stage because of late occurrence of nonspecific symptoms, and can be associated with hormone hypersecretion. Chromogranin A is the main biochemical marker of NETs. Extension workup relies on conventional imaging (CT-scan, MRI) and isotopic imaging including somatostatin-receptor scintigraphy, which should be soon replaced by positron-emitting scintigraphy. The main prognostic factors include tumor stage, metastatic volume, histological differentiation and grade. Hormonal syndromes and poorly differentiated tumors are the two therapeutic emergencies. The treatment of localized well-differentiated tumors relies on endoscopic or surgical resection depending on the location and aggressiveness. Surgical removal is the only potentially curative treatment of metastatic NETs but is rarely feasible and is associated with almost constant relapse. Other antitumor therapies include somatostatin analogs, systemic chemotherapy, liver trans-arterial chemo-embolization, targeted therapies and peptide-receptor radionuclide therapy. Management strategy relies on primary tumor location, tumor aggressiveness, metastatic volume and the presence of extra-hepatic metastases. It must take into account the risk of cumulated toxicity in patients whose survival is often prolonged.

Functional imaging tests and CT scan: Detection of new metastases and clinical usefulness in digestive neuroendocrine neoplasms follow-up.

219 Background: Digestive Neuroendocrine Neoplasms (DNENs) express in up to 80% of cases somatostatin receptors (SSTRs), which can be detected by Functional Imaging Tests (FITs). FITs are needed at DNENs first diagnosis to define therapy but their role in follow-up (FU) is unclear. Moreover, with the introduction of targeted therapies, RECIST criteria are showing difficulties to assess tumor response to these drugs. The aim of this study was to evaluate, in metastatic DNENs FU, the diagnostic yield of FITs associated to Computed Tomography scan (CT) in terms of detecting new distant metastases (primary outcome) and of clinical usefulness (secondary outcome). Methods: Retrospective analysis of stage IV DNENs expressing SSTRs and with at least 24 month-FU. From 1995 to 2008 FIT performed was Octreoscan (OCT), subsequently it was 68Ga-DOTA- PET/CT (GaPET). CT was repeated every 6-12 months, FIT yearly. FU time was divided into 12 month-“units”, in which each patient had faced at least 1 CT and 1 FIT. Units were analyzed separately and then compared to each other. The gold standard adopted was the result of the imaging tests, the surgical and pathological findings collected for each patient during FU. Clinical usefulness was defined as “appropriate changes” in management (indication to further imaging tests, surgery, biopsy, change in therapy) due to CT and/or FITs. Results: Interim analysis of 381 units (median 3 per patient, range 2-7) obtained from 121 patients included so far (67.8% metastatic since diagnosis). New lesions were detected by CT alone in 82.3% of cases; adding OCT, the diagnostic yield was 9.6%, while adding GaPET 21.7% (P<0.05). CT was responsible in 83.5% of cases of useful changes in patients management; adding OCT, the diagnostic yield was 9.7% (P<0.05), while with GaPET 27.9% (P<0.05). Conclusions: In metastatic DNENs FU, the addition of FITs to CT significantly improves the detection rate of new lesions; this advantage influences clinical practice increasing the clinical usefulness, especially when GaPET is adopted.

ENETS 2016 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update

The participants at the conference were asked to focus on the relevant literature published between 2011 and 2015. They met over two and a half days, in which data and new evidence were presented. The participants then retreated to break-out sessions according to their disciplines and were required to answer questions listed in a workbook created by the session chairs and the organizing committee. The workbook questions were tailored on the text of the initial guidelines framework [2, 4] , focusing on the new available evidence. All relevant areas were updated via a thorough literature review and the questions that the chairpersons considered appropriate to discuss the new evidence. All participants were encouraged to challenge the document. Recent data on new evidence and insights were intensely discussed in working-group sessions as well as during the plenary session. Notes were taken continuously, so that the final agreement on each question was noted and returned to each session chair for preparation of the consensus statements. The magnitude of the consensus for each answer was estimated to achieve unanimity. In addition to providing textual guidelines, delegates were requested to elaborate accurate but simple Several guidelines and standards of care on the management of neuroendocrine tumors (NETs) have been published by expert national and international groups in recent years [1–9] ; additional changes in how these patients are managed are evolving rapidly, and since the last European Neuroendocrine Tumor Society (ENETS) Guidelines in 2011/12 [8] , new important data have become available pertaining to novel diagnostic tools and therapies. On October 30th and 31st, 2014, the ENETS held an Advisory Board meeting in Vienna aiming at critically discussing and updating the ENETS Guidelines on the Diagnosis and Treatment of Neuroendocrine Tumors generated initially in 2005–2006 [2, 4] and revised in 2011 [8] . The consensus sessions covered the following neuroendocrine neoplasm-related topics by sites of origin or stage: gastroduodenal, midgut (including appendix), hindgut, functional pancreatic, non-functional pancreatic, and two final sessions that covered liver and other distant metastases from neuroendocrine neoplasms of any origin and a separate session devoted to neuroendocrine high-grade tumors and carcinomas. Published online: January 6, 2016

Morphological classification of digestive neuroendocrine neoplasms: the current concepts and controversies

Neuroendocrine tumors comprise the heterogeneous group of malignant epithelial neoplasms, the diagnosis of which is based on their histopathologic features and immunohistochemical profile. For neuroendocrine tumors of the digestive system in the World Health Organization (2010) classification were introduced main categories, the nomenclature, criterions for grading and staging. However, accumulating evidence demonstrates actual controversies in the histopathology of neuroendocrine neoplasms and unreserved problems in their classification. In this review we focus on some of the common features of neuroendocrine neoplasms, their classification, and differences in pathology, biology of the main categories, and the most important immunohistochemical markers.

Gly388Arg FGFR4 Polymorphism Is Not Predictive of Everolimus Efficacy in Well-Differentiated Digestive Neuroendocrine Tumors

Introduction: Preclinical data suggest that the single nucleotide polymorphism substituting a glycine for an arginine in codon 388 of the FGFR4 transmembrane domain may increase the proliferation of xenografted neuroendocrine cell lines and decrease their sensitivity to everolimus by modulating STAT3 signaling and the mTOR pathway. Aim: To evaluate the prognostic and predictive values of this polymorphism on everolimus efficacy in patients treated for digestive neuroendocrine tumor (NET). Patients and Methods: This monocentric retrospective cohort included patients with small bowel NET (SBNET) and pancreatic NET (PNET) treated with everolimus (2006-2013). The patients were genotyped by classical sequencing, and mTOR pathway activity was assessed by immunochemistry on formalin-fixed paraffin-embedded samples (PTEN/pPTEN/pAKT/pmTOR/pS6/p4EBP1). Results: Forty-one patients (21 males, median age 57 years) with PNET (n = 28), SBNET (n = 12) or NET of unknown origin (n = 1), grade 1 (n = 8), 2 (n = 27), 3 (n = 3) or unknown grade (n = 3), were studied. At least one 388Arg allele was found in 14/23 PNET and 10/11 SBNET. Progression-free survival in the whole population and the PNET subgroup was not influenced by the presence of one or two 388Arg alleles [HR = 1.31 (0.58-2.99), p = 0.52 and HR = 1.11 (0.45-2.73), p = 0.82, respectively]. Similarly, overall survival was not influenced. Finally, mTOR pathway molecule expression was not modified by the presence of at least one 388Arg allele. Conclusion: The Gly388Arg FGFR4 polymorphism does not seem to have a prognostic value in digestive NET. In addition, it neither predicts the response to everolimus nor modifies the activation of the mTOR pathway.

Abstract 3455: Functional imaging tests vs. computed tomography scan: detection of new metastases and clinical usefulness in digestive neuroendocrine neoplasms follow-up

Abstract Background: Digestive Neuroendocrine Neoplasms (DNENs) express in up to 80% of cases somatostatin receptors (SSTRs), that are detected by Functional Imaging Tests (FITs). FITs are needed at DNENs first diagnosis to define therapy but their role in follow-up (FU) is unclear. Moreover, with the introduction of targeted therapies, RECIST criteria are showing difficulties to assess tumor response to these drugs. The aim of this study was to compare the accuracy in detecting new distant metastases (primary outcome) and the clinical usefulness (secondary outcome) of FITs and Computed Tomography scan (CT) in metastatic DNENs FU. Methods Retrospective analysis of stage IV DNENs expressing SSTRs with at least 24 month-FU. From 1995 to 2008 FIT performed was Octreoscan (OCT), from 2008 to 2013 it was 68Ga-DOTANOC PET/CT (GaPET). CT was repeated every 6-12 months, FIT yearly. FU time was divided into 12 month-”units”, in which each patient had at least 1 CT and 1 FIT. Units were analyzed separately and then compared to each other. The gold standard adopted was the result of the imaging tests, the surgical and pathology findings collected for each patient during FU. Clinical usefulness was defined as appropriate changes in management (indication to new imaging test, therapy, surgery or biopsy) due to CT and/or FITs during FU. Results 323 units (median 3 per patient, range 2-7) derived from 99 patients included (66% metastatic since the first diagnosis). New lesions were detected by CT alone in 86.4% of cases, with a positive predictive value (PPV) of 93.3% and a negative predictive value (NPV) of 91.9%; adding OCT, the diagnostic yield was 10.34% (P<0.05; PPV 100%, NPV 98.8%;), while adding GaPET it was 21.7% (P<0.05; PPV 100%, NPV 100%). Appropriate changes were due to CT alone in 84.9% of cases; adding OCT, the diagnostic yield was 11.6% (P<0.05), while with GaPET it was 33.3% (P<0.05). Conclusions The addition of FIT to CT during FU significantly improves the detection rate of new lesions and the clinical management of patients affected by metastatic DNENs. Citation Format: Elettra Merola, Francesco Panzuto, Gabriele Capurso, Patrizia Kump, Rainer Lipp, Noemi Cicchese, Elsa Iannicelli, Daniela Prosperi, Patrizia Pizzichini, Maria Rinzivillo, Stefano Partelli, Anja Rinke, Massimo Falconi, Gianfranco Delle Fave. Functional imaging tests vs. computed tomography scan: detection of new metastases and clinical usefulness in digestive neuroendocrine neoplasms follow-up. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3455. doi:10.1158/1538-7445.AM2015-3455

Gly388Arg FGFR4 polymorphism is not predictive of everolimus efficacy in well-differentiated digestive neuroendocrine tumors

Introduction: Preclinical data suggest that the single nucleotide polymorphism substituting a glycine for an arginine in codon 388 of the FGFR4 transmembrane doma

Tu1918 Correlation Between the 18F-FDG Uptake Assessed by PET/CT and Pathological Data in Well-Differentiated Digestive Neuroendocrine Tumors

The 18F-FDG uptake assessed by PET/CT is correlated to prognosis in most tumors. The aim of our study was to compare the 18F-FDG uptake with tumor proliferation (Ki67) and expression of molecules related to cell metabolism [hypoxia (VHL), glucose transport (GLUT1), regulation of cellular pH (CA9)] in well differentiated digestive neuroendocrine tumors (NET). Patients and Methods: This retrospective study included 22 patients. 18F-FDG uptake was assessed by the SUVmax value (Standardized Uptake Values). An immunohistochemical study was performed with Ki67, VHL, GLUT-1 and CA9 antibodies. A score (0-300) was calculated for each antibody. Results: NET were of pancreatic (15), midgut (3), esophageal (1), rectal (1), undetermined origin (2). 7, 9 and 6 tumors were of grade 1, 2 and 3 respectively; the average/median Ki67 was 15.86%/12% [1-60%]. The mean/median SUVmax was 6.26/5.09 [1.47 to 18.70]. Two tumor with SUVmax <2 were considered as negative at PET scan. Grade 1, 2 and 3 tumors exhibited a median SUVmax 4.45 [1.62 to 6.6]; 5.79 [1.46 to 18.7] and 6.7 [3.05 to 9.61] respectively. The SUVmax correlated with high tumor size (p=0.009), high Ki-67 (p=0.03) and low VHL expression (p=0.08). Conclusion: Our study highlights that well-differentiated digestive neuroendocrine tumors, even of grade 1, are frequently positive at PET scan. The accumulation of 18 F-FDG increases with tumor size and cell proliferation in these tumors and seems to be correlated with the expression of effectors of cellular metabolism.

Tu1919 A Case of Duodenal Gastrinoma Associated With Multiple Endocrine Neoplasia Type 1 (MEN1) Detected by Esopagogastrodudenoscopy (EGD), Which Is Considered Having Been Buried Under Peptic Ulcer

The 18F-FDG uptake assessed by PET/CT is correlated to prognosis in most tumors. The aim of our study was to compare the 18F-FDG uptake with tumor proliferation (Ki67) and expression of molecules related to cell metabolism [hypoxia (VHL), glucose transport (GLUT1), regulation of cellular pH (CA9)] in well differentiated digestive neuroendocrine tumors (NET). Patients and Methods: This retrospective study included 22 patients. 18F-FDG uptake was assessed by the SUVmax value (Standardized Uptake Values). An immunohistochemical study was performed with Ki67, VHL, GLUT-1 and CA9 antibodies. A score (0-300) was calculated for each antibody. Results: NET were of pancreatic (15), midgut (3), esophageal (1), rectal (1), undetermined origin (2). 7, 9 and 6 tumors were of grade 1, 2 and 3 respectively; the average/median Ki67 was 15.86%/12% [1-60%]. The mean/median SUVmax was 6.26/5.09 [1.47 to 18.70]. Two tumor with SUVmax <2 were considered as negative at PET scan. Grade 1, 2 and 3 tumors exhibited a median SUVmax 4.45 [1.62 to 6.6]; 5.79 [1.46 to 18.7] and 6.7 [3.05 to 9.61] respectively. The SUVmax correlated with high tumor size (p=0.009), high Ki-67 (p=0.03) and low VHL expression (p=0.08). Conclusion: Our study highlights that well-differentiated digestive neuroendocrine tumors, even of grade 1, are frequently positive at PET scan. The accumulation of 18 F-FDG increases with tumor size and cell proliferation in these tumors and seems to be correlated with the expression of effectors of cellular metabolism.

Republished: Gastric neuroendocrine neoplasms and related precursor lesions

Gastric neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours showing different clinicopathological features and behaviour, implying a wide spectrum of therapeutic options. They are currently classified using the 2010...

The 2010 WHO Classification of Digestive Neuroendocrine Neoplasms: a Critical Appraisal four years after Its Introduction

This paper briefly illustrates the basis, rules of application, and present outcome of the current World Health Organization (WHO) classification for neuroendocrine neoplasms. Established in 2010 upon the proposal from the European Neuroendocrine Tumor Society (ENETS), the WHO 2010 fostered some definitional changes (most notably the use of neuroendocrine tumor (NET) instead of carcinoid) and indicated the tools of grading and staging. Specific rules for its application were also defined. The data generated from the use of WHO 2010 classification substantially endorsed its rules and prognostic efficacy. In addition, the application demonstrated some issues, among which are the possible re-definition of the cutoff for grading G1 vs G2, as well as the possible identification of cases with somewhat different clinical behavior within the G3 neuroendocrine cancer class. Overall, since the recent introduction of WHO 2010 grading and staging, it appears wise to keep the current descriptors to avoid unnecessary confusion and to generate comparable data. Homogenous data on large series are ultimately needed to solve such issues.

Advanced Digestive Neuroendocrine Tumors

The objective of this study was to determine the impact of different metastatic spread patterns on outcome in advanced digestive neuroendocrine tumors (NETs). This was a retrospective analysis of patients with stage IV NETs, classified as group 1 (unilobar liver metastases), group 2 (bilobar liver metastases), group 3 (extra-abdominal metastases). End points were overall survival (OS) and progression-free survival (PFS). Risk factor analysis was performed using Cox proportional hazard model. Of the 229 patients, 135 (58.9%) had pancreatic, and 94 (41.1%) small bowel NETs: 32 (13.9%) were included in group 1, 179 (78.2%) in group 2, and 18 (7.9%) in group 3. Median Ki67 was 4.5%. Overall, 5-year OS was 55%. Different OS was observed among the 3 groups: median survival not reached, 81 and 8 months, respectively (P < 0.001). Median PFS was 18 months. Both OS and PFS were significantly affected by Ki67 and metastatic spread pattern. The stratification of stage IV NET patients based on metastatic patterns, alongside Ki67, predicts the clinical outcome. The extent of metastatic disease is a previously unrecognized variable, which should be considered when evaluating the results of treatments in NET patients with advanced disease.

Prise en charge des troubles métaboliques observés avec évérolimus chez les patients atteints de tumeurs neuroendocrines bien différenciées non résécables : propositions d’experts

Medical management of pancreatic neuroendocrine tumors has recently been improved by new molecules of which the mTOR inhibitor everolimus. If digestive neuroendocrine tumors are rare, the incidence is in constant increase and the prevalence in digestive cancers put them right behind colorectal cancers. Everolimus has demonstrated efficacy in unresectable and progressive pancreatic neuroendocrine tumors, by doubling the median progression free survival (11 versus 4.6 months), with a median time of exposure to everolimus of nine months. Everolimus is generally maintained until progression or intolerance and some patients are treated during several years. Potential metabolic disorders induced by everolimus (dyslipidemia, hyperglycemia) in patients with life expectancy of several years, justify monitoring of these parameters and accurate treatment management algorithm. These will avoid worsening patient's prognostic, but also prematurely discontinue potentially effective treatment or contraindicate other therapeutic weapons, in a pathology in which there are multiple therapeutic options in metastatic phase. We propose a standard practice in terms of initial assessment, monitoring, care threshold, and therapeutic objectives to manage metabolic disorders, fitted to our patients with advanced pancreatic neuroendocrine tumors.

Evaluating digestive neuroendocrine tumor progression and therapeutic responses in the era of targeted therapies: state of the art

Well-differentiated neuroendocrine tumors (NETs) are a group of heterogeneous rare tumors. They are often slow-growing and patients can have very long survival, even at the metastatic stage. The evaluation of tumor progression and therapeutic responses is currently based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST) criteria. As for other malignancies, RECIST criteria are being reexamined for NETs in the era of targeted therapies because tumor response to targeted therapies is rarely associated with shrinkage, as opposed to prolonged progression-free survival. Therefore, size-based criteria no longer seem to be suitable to the assessment of NET progression and therapeutic responses, especially considering targeted therapies. New imaging criteria, combining morphological and functional techniques, have proven relevant for other malignancies treated with targeted therapies. To date, such studies have rarely been conducted on NETs. Moreover, optimizing the management of NET patients also requires considering clinical, biological, and pathological aspects of tumor evolution. Our objectives herein were to comprehensively review current knowledge on the assessment of tumor progression and early prediction of therapeutic responses and to broaden the outlook on well-differentiated NETs, in the era of targeted therapies.

Grading the neuroendocrine tumors of the lung: an evidence-based proposal

Lung neuroendocrine tumors are catalogued in four categories by the World Health Organization (WHO 2004) classification. Its reproducibility and prognostic efficacy was disputed. The WHO 2010 classification of digestive neuroendocrine neoplasms is based on Ki67 proliferation assessment and proved prognostically effective. This study aims at comparing these two classifications and at defining a prognostic grading system for lung neuroendocrine tumors. The study included 399 patients who underwent surgery and with at least 1 year follow-up between 1989 and 2011. Data on 21 variables were collected, and performance of grading systems and their components was compared by Cox regression and multivariable analyses. All statistical tests were two-sided. At Cox analysis, WHO 2004 stratified patients into three major groups with statistically significant survival difference (typical carcinoid vs atypical carcinoid (AC), P=0.021; AC vs large-cell/small-cell lung neuroendocrine carcinomas, P<0.001). Optimal discrimination in three groups was observed by Ki67% (Ki67% cutoffs: G1 <4, G2 4-<25, G3 ≥25; G1 vs G2, P=0.021; and G2 vs G3, P≤0.001), mitotic count (G1 ≤2, G2 >2-47, G3 >47; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001), and presence of necrosis (G1 absent, G2 <10% of sample, G3 >10% of sample; G1 vs G2, P≤0.001; and G2 vs G3, P≤0.001) at uni and multivariable analyses. The combination of these three variables resulted in a simple and effective grading system. A three-tiers grading system based on Ki67 index, mitotic count, and necrosis with cutoffs specifically generated for lung neuroendocrine tumors is prognostically effective and accurate.

Treatment strategy of digestive neuroendocrine tumours

La prise en charge des tumeurs neuroendocrines digestives est un challenge parfois complexe compte tenu de la diversité des présentations cliniques et des nombreuses options thérapeutiques disponibles. Le contrôle d’un syndrome fonctionnel est la priorité. Le traitement antitumoral devra être décidé dans le cadre d’une concertation multidisciplinaire spécialisée.

Carcinome neuro-endocrine du tractus digestif : revue de la littérature

Neuroendocrine carcinoma is a rare and agressive malignant tumor, mainly developing at the expense of the respiratory and of the digestive tract. Among the digestive tract, appendix, small bowel, and pancreas are the preferential sites of involvement, other locations have been more rarely reported. Neuroendocrine digestive tumors may present with various symptoms in relationship with their localization and a complex pathophysiology. Diagnosis is often made at an advanced stage, explaining partly the bad prognosis of these tumors. The optimal management of digestive neuroendocrine tumors is rendered difficult by their rarity and by a low number of randomized trials. We review the literature regarding epidemiologic and prognostic features of these rare tumors, their diagnostic and therapeutic care. Potential complications are also discussed.

897 Prognostic Heterogeneity Among Patients With Bone Metastases From Well-Differentiated Digestive Neuroendocrine Tumors

Background: There are a paucity of data pertaining to the natural history and outcomes of patients with a well-differentiated rectal carcinoid tumor. There is general consensus that a ≤10 mm, well-differentiated rectal carcinoid that does not infiltrate the muscularis propria or demonstrate nodal spread can be managed by local excision. Conversely, most favor radical resection for lesions ≥ 20mm and/or nodal metastasis. A clearer understanding of the natural history, in particular for intermediate size lesions (11-19mm), is necessary to optimize patient care. Aims: For patients with a well-differentiated rectal carcinoid who underwent endoscopic evaluation to determine the: 1.) lesion size correlating with metastasis, 2.) factors associated with disease progression, 3.) disease stage of 11-19mm lesions, and 4.) 10 year survival rates based on disease extent. Method: A histopathology database was reviewed to identify patients with a well-differentiated rectal carcinoid or neuroendocrine tumor who underwent endoscopy from 1/1/00-1/9/12. Clinical demographics, radiologic, and clinical follow-up data were analyzed. Results: Among the 87 patients diagnosed with a well-differentiated rectal carcinoid, metastatic disease (local or distant) was identified at the time of endoscopy in 2/66 (3%), 4/6 (66%) and 11/15 (73%) of patients for lesions ≤10mm, 11-19mm and ≥20mm, respectively. Metastasis was predicted with 100% sensitivity and 87% specificity using a lesion cut off size of ≥9mm, (AUC 0.948). Metastasis was subsequently discovered in 1/64 (1.6%), 1/2 (50%) and 4/4 (100%) patients with lesions measuring ≤10 mm, 11-19mm and ≥20mm, respectively. These sites included the liver (n= 4), pancreas (n=1) and liver & lung (n=1), at 34.6 (IQR 4.7-33) months from endoscopic evaluation. For patients with locally confined disease at presentation, subsequent disease progression correlated with advanced age (p=0.03), presence of initial symptoms (p=0.02), lesion size (p=0.0001) and immune-stain pattern (p=0.03). Multivariate analysis revealed one independent factor: size .20mm at the time of initial diagnosis (p,0.0001: OR 1.25, 95% CI 1.04-1.5). A lesion cut off size of .10mm, (AUC 0.957) had 83% sensitivity and 98% specificity for predicting disease progression. The ten year survival rates were 87%, 67% and 32% for patients presenting with locally confined, locally advanced and distant disease, respectively. Conclusions: Our data support the contention that small ( ≤10 mm) well differentiated lesions have a generally benign disease course. However, our findings indicate that the clinical behavior of intermediate sized tumors (11-19 mm) mimics that of large (≥20 mm) tumors and, thus, need for a more aggressive management strategy. Examination of other staging and clinical parameters may be key, particularly for patients with intermediate size lesions.

Digestive neuroendocrine tumors (DNET): The era of targeted therapies

Neuroendocrine tumors (NETs) are a heterogeneous group of malignancies. Therapeutic options depend on location of the primitive tumor, its expandability, its hormonal symptoms and its differentiation. Though relatively rare, with an increasing incidence and a high prevalence digestive neuroendocrine tumors (DNETs) are ranked just behind colorectal cancer as the most common digestive cancers in developed countries. Three main therapeutic axes have been individualized in the field of well-differentiated DNETs (corresponding to grades 1 and 2 of new WHO classification 2010), firstly, antitumor activity of somatostatin analogs, particularly in slowly progressive metastatic DNETs with limited hepatic invasion, secondly, targeting angiogenesis in these hypervascular tumors and thirdly targeting the mTOR pathway involved in DNETs carcinogenesis. As a consequence of two major randomized phase III trials in 2011, sunitinib and everolimus have been considered as new therapeutic options for well-differentiated, advanced and progressive pancreatic NETs. For everolimus, another phase III study, although non-significant with the chosen criteria, showed effectiveness notably against small intestine NETs. These targeted therapies are new therapeutic weapons in management of well-differentiated DNETs, but its exact role in care strategy, in comparison with other treatments (somatostatin analogs, chemo-embolization, chemotherapy...) deserves to be precise in the future.