In 2010, the World Health Organization (WHO) classification of neuroendocrine neoplasms was reviewed and validated the crucial role of the proliferative rate. According to the WHO classification ...2010, gastroenteropancreatic neuroendocrine neoplasms are classified as well‐differentiated neuroendocrine tumors (NETs) of grade 1 or 2 in up to 84%, or poorly differentiated neuroendocrine carcinomas in 6%–8%. Neuroendocrine carcinomas are of grade G. Recently, a proportion of neuroendocrine tumors presenting a number of mitoses or a Ki‐67 index higher than 20% and a well‐differentiated morphology have been identified, calling for a new category, well‐differentiated grade 3 NET (NET G‐3). Studies that have reported the characteristics of neuroendocrine neoplasms have identified more well‐differentiated NET G‐3 than neuroendocrine carcinomas. The main localizations of NET G‐3 are the pancreas, stomach, and colon. Treatment for NET G‐3 is not standardized and is balanced between G‐1/2 neuroendocrine tumor and neuroendocrine carcinoma treatments. In nonmetastatic neuroendocrine tumors, the European and American guidelines recommended a surgical resection for localized neuroendocrine neoplasm, irrespective of the tumor grading. In NET G‐3, chemotherapy is the benchmark if the main treatment goal is reduction of the tumor mass, particularly if it would allow a secondary surgery. In the present work, we review the epidemiology and make recommendations for the management of NET G‐3.
Implications for Practice:
Neuroendocrine tumors presenting a number of mitoses or a Ki‐67 index higher than 20% and a well‐differentiated morphology have been identified and named well‐differentiated grade 3 neuroendocrine tumors (NET G‐3). The main localizations of NET G‐3 are the pancreas, stomach, and colon. The prognosis is worse than that for NET G‐2. In nonmetastatic NET G‐3, surgery appeared to be the first option. The chemotherapy regimen in pancreatic NET G‐3 should be in line with that implemented in NET G‐1/2 when the Ki‐67 index is below 55% and should be in line with that implemented for neuroendocrine carcinoma when Ki‐67 is above 55%.
摘要
世界卫生组织(WHO)在2010年对神经内分泌肿瘤的分级进行了审查, 并确认了增殖率具有至关重要的作用。根据WHO分级2010版, 胃肠胰神经内分泌肿瘤可分为: 1级或2级高分化神经内分泌瘤(NET, 多达84%的患者为这一类型), 或者低分化神经内分泌癌(见于6%∼8%的患者)。神经内分泌癌为3级。近期研究确认了一部分出现大量有丝分裂或Ki‐67指数高于20%, 且具有高分化形态学的神经内分泌瘤, 称为3级NET(NET G3)。有研究报告了神经内分泌肿瘤的特征, 发现NET G3分化要好于神经内分泌癌。NET G3主要见于胰腺、胃和结肠。NET G3目前尚无标准治疗, 其治疗方案与NET G1/2或神经内分泌癌均有所区别。对于非转移性NET, 欧洲和美国的指南都建议无论肿瘤分级如何, 均手术切除局部NET病灶。对于NET G3, 如果治疗的主要目的是减小肿瘤体积, 尤其是意图后续手术的, 则应进行化疗。本文回顾了NET G3的流行病学, 并就其治疗管理给出了建议。The Oncologist 2016;21:1191–1199
对临床实践的提示:目前已鉴别出一种有大量有丝分裂或Ki‐67指数>20%, 且形态学分化良好的神经内分泌瘤, 命名为高分化3级神经内分泌瘤(NET G3)。NET G3主要位于胰腺、胃和结肠。NET G3预后差于NET G2。对于非转移性NET G3, 手术看来是治疗的首选措施。对于胰腺NET G3, Ki‐67<55%时化疗方案应该与NET G1/2一致, Ki‐67>55%时应与神经内分泌癌的化疗方案一致。
Neuroendocrine tumors presenting a number of mitoses or a Ki‐67 index higher than 20% and a well‐differentiated morphology have been identified and named well‐differentiated grade 3 neuroendocrine tumors (NET G‐3). The chemotherapy regimen in pancreatic NET G‐3 should be in line with that implemented in NET G‐1/2 when the Ki‐67 index is below 55% and as for the neuroendocrine carcinoma chemotherapy regimen when Ki‐67 is above 55%.
Background Pancreatic fistula (PF) after pancreatoduodenectomy (PD) remains a challenging problem. The only commonly accepted risk factor is the soft consistency of the pancreatic remnant. Methods In ...all, 100 consecutive patients underwent PD. All data, including commonly accepted risk factors for PF and PF defined according to the International Study Group of Pancreatic Fistula, were collected prospectively. On the pancreatic margin, a score of fibrosis and a score of fatty infiltration were assessed by a pathologist blinded to the postoperative course. Results PF occurred in 31% of patients. In univariate analysis, male sex, age greater than 58 years, body mass index (BMI) ≥25 kg/m2 , pre-operative high blood pressure, operation for nonintraductal papillary and mucinous neoplasm (IPMN) disease and for ampullary carcinoma, operative time, blood loss, soft consistency of the pancreatic remnant, absence of pancreatic fibrosis, and presence of fatty infiltration of the pancreas were associated with a greater risk of PF. In a multivariate analysis, only BMI ≥25kg/m2 , absence of pancreatic fibrosis, and presence of fatty pancreas were significant predictors of PF. A score based on the number of risk factors present divided the patient population into 4 subgroups carrying a risk of PF that ranged from 7% (no risk factor) to 78% (3 risk factors) and from 0% to 81%, taking into account only symptomatic PF (grade B and C). Conclusion The presence of an increased BMI, the presence of fatty pancreas, and the absence of pancreatic fibrosis as risk factors of PF allows a more precise and objective prediction of PF than the consistency of pancreatic remnant alone. A predictive score based on these 3 factors could help to tailor preventive measures.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background & Aims Bariatric procedures, such as Roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG), are the most effective approaches to resolve type 2 diabetes in obese ...individuals. Alimentary glucose absorption and intestinal disposal of blood glucose have not been directly compared between individuals or animals that underwent RYGB vs VSG. We evaluated in rats and humans how the gut epithelium adapts after surgery and the consequences on alimentary glucose absorption and intestinal disposal of blood glucose. Methods Obese male rats underwent RYGB, VSG, or sham (control) operations. We collected intestine segments from all rats; we performed histologic analyses and measured levels of messenger RNAs encoding the sugar transporters SGLT1, GLUT1, GLUT2, GLUT3, GLUT4, and GLUT5. Glucose transport and consumption were assayed using ex vivo jejunal loops. Histologic analyses were also performed on Roux limb sections from patients who underwent RYGB 1−5 years after surgery. Roux limb glucose consumption was assayed after surgery by positron emission and computed tomography imaging. Results In rats and humans that underwent RYGB, the Roux limb became hyperplasic, with an increased number of incretin-producing cells compared with the corresponding jejunal segment of controls. Furthermore, expression of sugar transporters and hypoxia-related genes increased and the nonintestinal glucose transporter GLUT1 appeared at the basolateral membrane of enterocytes. Ingested and circulating glucose was trapped within the intestinal epithelial cells of rats and humans that underwent RYGB. By contrast, there was no hyperplasia of the intestine after VSG, but the intestinal absorption of alimentary glucose was reduced and density of endocrine cells secreting glucagon-like peptide-1 increased. Conclusions The intestine adapts differently to RYGB vs VSG. RYGB increases intestinal glucose disposal and VSG delays glucose absorption; both contribute to observed improvements in glycemia.
The roles of intravisceral and subcutaneous fat are unknown, and the prevalence of precancerous lesions in obese patients was never evaluated. This study aims to assess the frequency and severity of ...pancreatic intraepithelial neoplasia (PanIN) and to correlate pathologic findings with metabolic abnormalities, type of fat, and fatty pancreatic infiltration.
Normal pancreatic tissue from surgical specimens was analyzed. Fatty infiltration and fibrosis in intra- and extralobular locations and PanIN lesions were assessed. General characteristics were collected: body mass index (BMI), diabetes, and tobacco intake. Liver steatosis and subcutaneous and intravisceral fat were assessed by CT scan (ImageJ software).
Of note, 110 patients were included median age, 53.8 (17-85) years. Arterial hypertension, diabetes, and tobacco intake were found in 19%, 9%, and 23%, respectively. Median BMI was 24 (16-37; BMI < 25: 45%, 25 ≤ 30: 24%, ≥30: 11%). Overall, PanIN lesions were found in 65% (type I, II, and III PanIN in 62%, 38%, and 1%, respectively). Fibrosis and fatty pancreas (intra- and extralobular locations) were found in 1% and 24% and in 30% and 51%, respectively. A correlation was observed between PanIN lesions and fatty pancreas extralobular (0.01) and intralobular (<0.0001), intralobular fibrosis (0.003), high BMI (P = 0.02), and subcutaneous (P = 0.02) and intravisceral fat (P = 0.02). The number of PanIN lesions was correlated with intravisceral fat (r = 0.22, P = 0.04), but not with subcutaneous fat (r = 0.14, P = 0.22). In multivariate analysis, PanIN lesions were associated with intralobular fibrosis OR, 5.61; 95% confidence interval (CI), 1.18-42.99 and intralobular fat (OR, 17.86; 95% CI, 4.935-88.12).
Obesity (especially android obesity) and pancreatic fatty infiltration are risk factors for pancreatic precancerous lesions.
This ENETS guidance paper, developed by a multidisciplinary working group, provides up‐to‐date and practical advice on the diagnosis and management of digestive neuroendocrine carcinoma, based on ...recent developments and study results. These recommendations aim to pave the road for more standardized care for our patients resulting in improved outcomes. Prognosis is generally poor for digestive NEC, most are advanced at diagnosis and median survival in metastatic disease is 11–12 months. Surgery can be of benefit for localized disease after extensive preoperative imaging. Carboplatin in combination with etoposide is recommended as first‐line treatment for metastatic disease. Irinotecan with fluoropyrimidines has the best evidence as second‐line treatment. Immunotherapy plays a minor role in biomarker‐unselected patients. Molecular profiling if available is encouraged to identify new targets. More prospective clinical trials are highly needed to fulfil the unmet needs in this field, especially on new predictive and prognostic biomarkers and to improve survival of patients with advanced disease.
Full text
Available for:
DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG ...GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments.
IMPORTANCE Nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs) are often indolent neoplasms without lymph node (LN) metastasis at diagnosis. Therefore, in patients with low risk of LN ...metastasis, the extent of surgery and lymphadenectomy could be limited and follow-up adjusted to the very low risk of relapse. OBJECTIVE To construct a predicting model to assess the risk of pN+ prior to surgical resection for NF-PanNETs using preoperative retrievable variables. DESIGN Retrospective review using multiple logistic regression analysis to construct predictive model of pN+ based on preoperatively available data. SETTING The combined prospective databases of the Surgical Departments of the University of Verona, Verona, Italy, and Beaujon Hospital, Clichy, France, were queried for clinical and pathological data. PARTICIPANTS All patients with resected (R0 or R1), pathologically confirmed NF-PanNETs between January 1, 1993 and December 31, 2009. MAIN OUTCOME AND MEASURE Risk of lymph node metastases in patients with pancreatic neuroendocrine tumors. RESULTS Among 181 patients, nodal metastases were reported in 55 patients (30%) and were associated with decreased 5-year disease-free survival (70% vs 97%, P < .001). Multivariable analysis showed that independent factors associated with nodal metastasis were radiological nodal status (rN) (odds ratio OR, 5.58; P < .001) and tumor grade (NET-G2 vs NET-G1: OR, 4.87; P < .001) (first model). When the tumor grade was excluded, rN (OR, 4.73; P = .001) and radiological tumor size larger than 4 cm (OR, 2.67; P = .03) were independent predictors of nodal metastasis (second model). The area under the receiver operating characteristic curve for the first and second models were 80% and 74%, respectively. CONCLUSIONS AND RELEVANCE Patients with NF-PanNET-G1 have a very low risk of pN+ in the absence of radiological signs of node involvement. When preoperative grading assessment is not achieved, the radiological size of the lesion is a powerful alternative predictor of pN+. The risk of pathological nodal involvement in patients with NF-PanNETs can be accurately estimated by a clinical predictive model.
This document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org).
All French medical ...societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019.
The management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET.
These guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
