NET G1 Research Articles

Surgical outcomes of gastro-entero-pancreatic neuroendocrine tumors G3 versus neuroendocrine carcinoma.

To define surgical outcomes of patients with high-grade gastro-entero-pancreatic neuroendocrine neoplasm grade G3 (GEP-NEN G3). Patients who underwent surgical resection between 2000 and 2016 were identified. The overallsurvival(OS) and recurrence-free survival (RFS) of patients withgastro-entero-pancreatic neuroendocrine tumors grade G3(GEP-NET G3)versus neuroendocrine carcinoma (NEC) were evaluated. Fifty-one out of 2182 (2.3%) patients who underwent surgical resection were diagnosed as GEP-NEN G3. The pancreas was the most common primary site (n = 3772.5%). A majority of patients had lymph node metastasis (n = 3262.7%); one in three (n = 1631.4%) had distant metastasis. The median OS and RFS of the entire cohort were 56.4and 34.5 months, respectively. Perineural invasionwas a strong prognostic factor associate with OS after surgical resection. Patients with NEC had a worse survival outcome versus patients with NET G3 (median OS: 33.1 months vs. not attained, p = 0.088). In contrast, among patients who underwent curative-intent resection, patients with NEC had comparable RFS versus patients with NET G3 (median RFS: 35.6 vs. 33.9 months, p = 0.774). Surgical resection provided acceptable short- and long-outcomes for well-selected patients with resectable GEP-NEN G3. NEC was associated with a worse OS versus NET G3.

Ampullary Neuroendocrine Neoplasm: Clinicopathological Characteristics and Novel Endoscopic Entity

Background: Neuroendocrine neoplasms of the ampulla of Vater (ampullary NEN) have features of both gastrointestinal and pancreato-biliary (PB) NEN. However, the limited number of studies examining ampullary NEN makes it difficult to clarify their unique characteristics. This study aimed to elucidate the clinical characteristics of ampullary NEN. Methods: We enrolled 162 patients with PB-NEN diagnosed at Kyushu University Hospital between 2011 and 2020. Clinical features, pathological diagnoses, treatments, and prognoses were retrospectively analyzed. We also compared ampullary NEN with pancreatic NEN (PanNEN). Results: We analyzed 10 ampullary NEN cases and 149 PanNEN cases. The ampullary NEN cases consisted of 4 cases of neuroendocrine tumor Grade 1 (NET G1), 1 NET G2 (Grade 2), and 5 neuroendocrine carcinomas (NECs). The incidences of NEC and cholangitis were significantly higher in ampullary NEN than in PanNEN. All ampullary NETs had a submucosal tumor-like appearance, as identified by endoscopic ultrasound-guided fine needle aspiration. We treated small NET G1 (<10 mm) with endoscopic papillectomy and large NET G1 with pancreaticoduodenectomy. There were no cases of recurrence after resection. All ampullary NECs presented with the characteristic endoscopic finding of a “crater sign” similar to deep-mining ulcers seen in gastric malignant lymphoma. Four cases underwent surgical resection, and 1 case was unresectable. Two patients who underwent multidisciplinary treatment were maintained without recurrence for over 2 years. Conclusions: Endoscopic findings showed identifiable distinctions between ampullary NETs and NECs.

Difficulties and challenges in pathological diagnosis of gastrointestinal pancreatic neuroendocrine tumors

In the 5th edition of WHO Classification of Digestive System Tumours, the classification and designation of gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) were updated, and G3 was redefined. Therefore, the differential diagnosis between well-differentiated neuroendocrine tumour G3(NETG3) and poorly differentiated neuroendocrine carcinomas (NEC) is both important and difficult, which has important clinical treatment and prognostic significance. Based on the latest WHO and 2020 Chinese consensus on pathological diagnosis of GEP-NEN, this paper proposed a comprehensive analysis on the differential diagnosis of gastrointestinal pancreatic neuroendocrine tumor from four aspects, including tumor morphological differentiation、tumor proliferative activity, gene change and disease progression. However, even with the above four diagnostic tools, there are still some difficulties and challenges in the work of pathological diagnosis. This paper briefly expounds and discusses them together, in order to improve the clinical application value.

The diagnosis and treatment of G3 neuroendocrine tumors according to the new NCCN guideline

Gastrointestinal pancreas (GEP) is the most common site of neuroendocrine neoplasms (NENs). In 2019, the World Health Organization (WHO) classification for GEP NET was updated to include a new category of well-differentiated high-grade (Ki 67>20%) GEP-NET G3, distinct from high-grade poorly differentiated neuroendocrine carcinoma (NEC). As a new category, NET G3 are considered a molecularly, radiologically, and prognostically distinct entity compared to NEC and NET G1/G2. The management of NET G3 remains a challenge awaiting future trials taking into consideration the unique characteristics of this new category. The latest NCCN clinical guidelines of neuroendocrine and adrenal tumors firstly gave the recommendation of diagnosis and treatment of G3 NET separately from NEC and G1/G2 NET. Hereon,we aim to summarize the management of G3 NET in combination with the new NCCN guidelines and the current evidences.

Gastric Metastatic Grade 3 Well-Differentiated Neuroendocrine Tumor: A Case Report

Background: Neuroendocrine neoplasms (NENs) are rare tumors .They are defined by the expression of specific biomarkers. Progress in pathological diagnosis has allowed a better identification and classification of these tumors. The 2019-revised World Health Organization (WHO) classification of tumors of endocrine organs classifies grade 3 gastroenteropancreatic neuroendocrine neoplasm (GEP-NENs) into well-differentiated neuroendocrine tumors (NET G3) and poorly differentiated neuroendocrine carcinomas (NEC G3). There are few reported cases of NET G3 occurring in the stomach. Case presentation: A 63-year- man who suffers from dysphagia and Melaena. Fibroscopy revealed a ulcero-budding process of the cardia. Pathologic examination concluded on NET well-differentiated grade 3. Surgical exploration showed peritoneal carcinomatosis and histologically confirmed liver metastases. He underwent chemotherapy with modified folfox 4 protocol for 3 months with satisfactory clinico-morphological response. Conclusion: A definite diagnosis of NET G3 or NEC G3 must be made to determine the appropriate treatment strategy for patients with GEP-NEN G3. the efficacy of treatments for G3 NETs appear modest, as evidenced by the short PFS observed, therefore, more effective therapies are needed with Further case reports and case series. Keywords: Neuroendocrine tumor G3, stomach, modified FOLFOX 4.

Treatment tactics of new NET G3 subgroup in first line of therapy

Considering the fact that the group of neuroendocrine carcinomas (NECs) grade 3 is heterogenous, in the year of 2017 a new subgroup of welldifferentiated neuroendocrine tumors grade 3 (NETs G3) was described. NETs G3 are tumors with more favorable prognosis and less sensitive to platinum-based chemotherapy regimens than NECs, they also have peculiar morphogenetical qualities: lower ki‑67 index (mean 35.0 %), higher somatostatin receptors expression, absence of DAXX/ATRX/MEN 1 genes mutation, p53 expression in the absence of TP53 mutation. Nowadays treatment standard for NETs G3 subgroup is still remain unclear due to lack of prospective clinical trials. At the same time taking in note historical retrospective data, NETs G3 should be treated in line with NETs G1/G2 and only patients with higher ki‑67 index can be treated as NECs with platinum-based chemotherapy. In our non-randomised phase II prospective trial, we accessed the efficacy of different chemotherapy regimens in combination with somatostatin analogues in new NETs G3 subgroup. 153 patients with IHC-confirmed neuroendocrine neoplasm diagnose were included: NETs G3 n = 53 mean ki‑67 36.4 % [21.0–60.0 %], NETs G2 n = 50 mean ki‑67 15.7 % [2.1–20.0 %], NECs n = 50 mean ki‑67 69.0 % [38.0–96.0 %]). Patients from NETs G3 subgroup received 4 chemotherapy regimens: Aranose (n = 19), Aranose (arabinopiranosilmethyl nitrosocarbamide, ALK, – cytostatic drug with a chemical structure similar to Streptozotocin and Nitrosomethylurea, approved in Russian Federation for melanoma and welldifferentiated neuroendocrine tumors treatment), XELOX (n = 8), TemCAP (n = 11), EP/EC (n = 10). mPFS in Aranose-subgroup was 19.3 ± 5.9 months (95 % CI: 7.7–30.8), in XELOX – 10.8 ± 3.6 months (3.7–17.8), in TemCAP – 14.8 ± 4.2 months (6.6–23.1) and in platinum-based regimens – 4.4 ± 1.9 months (0.6–8.2) (p = 0.01). DCR in Aranose subgroup was 73.6 % and ORR – 36.8 %, PDR – 21.1 %, in XELOX subgroup ORR was 62.5 %, SDR was 50.0 % and PDR – 25.0 %, in TemCAP subgroup DCR was 63.6 %, ORR – 9.1 %, PDR – 18.2 % and in platinum-based regimens SDR was 40.0 %, PDR – 50.0 % (p = 0.05).

177Lu]Lu-DOTA-TATE versus standard of care in adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs): a cost-consequence analysis from an Italian hospital perspective

PurposeTo assess and compare clinical outcomes and costs, to the Italian healthcare system, of three therapeutic options approved in the management of adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs).MethodsWe compared the efficacy, safety, and costs of [177Lu]Lu-DOTA-TATE, everolimus (both originator and generic products), and sunitinib in patients with advanced GEP-NETs (NET G1 and G2) that had progressed following treatment with somatostatin analogs (SSAs). A cost-consequence model was developed and validated by a panel of clinical experts from three NET reference centres in Italy. The clinical outcomes included in the model were median progression-free survival and the incidence of grade 3 or 4 adverse events (AEs), as reported in pivotal clinical trials. The costs for acquisition and administration of each treatment, and of managing AEs, were calculated from the perspective of the Italian national health service. Treatment costs per progression-free month were calculated separately for patients with NETs of pancreatic (PanNETs; all three treatments) and gastrointestinal (GI-NETs; [177Lu]Lu-DOTA-TATE and everolimus only) origin.ResultsIn patients with PanNETs, total costs per progression-free month were €2989 for [177Lu]Lu-DOTA-TATE, €4975 for originator everolimus, €3472 for generic everolimus, and €5337 for sunitinib. In patients with GI-NETs, total costs per progression-free month were €3189 for [177Lu]Lu-DOTA-TATE, €4990 for originator everolimus, and €3483 for generic everolimus.Conclusions[177Lu]Lu-DOTA-TATE was associated with lower costs per progression-free month versus relevant treatment options in patients with GI-NETs or PanNETs (NET G1–G2; progressed following SSA treatment), although acquisition and administration costs are higher. These findings provide further economic arguments in the overall context of treatment decision-making.

Combined Quantification of 18F-FDG and 68Ga-DOTATATE PET/CT for Prognosis in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms

High-grade gastroenteropancreatic neuroendocrine neoplasms (G3 GEP-NENs) are pathologically classified into well differentiated neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (G3 NECs). Using a novel parameter, we examined the prognostic value of 18F-FDG and 68Ga-DOTATATE PET/CT quantification in comparison to pathologic assessment in G3 GEP-NENs. A total of 31 patients with G3 GEP-NENs were reviewed. For each patient, the SUVmax on 18F-FDG and 68Ga-DOTATATE PET/CT were used to calculate the FDG-DOTATATE-Z (FDZ) score: a continuous parameter that increases with 68Ga-DOTATATE uptake and decreases with 18F-FDG uptake. The variation in the FDZ score with respect to pathologic variables was examined. Kaplan-Meier and Cox regression analyses were performed to evaluate the effect of FDZ score on overall survival. An external cohort of 21 patients was used for validation. The FDZ score was significantly higher in G3 NETs compared to G3 NECs (p<0.001), and was inversely correlated with Ki67 index (R2=0.33, p<0.001). Patients in the FDZ>0.05 group showed significantly longer survival compared to those in the FDZ≤0.05 group, with median of 34.9 vs. 12.0 months (p<0.001). On univariate regression, FDZ>0.05 (p=0.005), well differentiated disease (p=0.044), and lower Ki67 index (p=0.042) were predictors of survival. On multivariate regression, only FDZ>0.05 could independently predict longer survival with HR=0.16 (p=0.018), which was reproduced in the external validation cohort. Combined quantification of 18F-FDG and 68Ga-DOTATATE PET/CT into a novel parameter, the FDZ score, reflects the pathologic characteristics of G3 GEP-NENs and is a prognostic indicator of overall survival independent of differentiation.

The molecular characteristics of high-grade gastroenteropancreatic neuroendocrine neoplasms.

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.

304 First Reported Case of Metachronous Tumours With Delayed Recurrence from The Neuroendocrine Tumour Arising in A Tailgut Cyst

Abstract Background Malignant transformation of tailgut cysts (benign retrorectal cysts) into Neurodendocrine tumours (NETS) is extremely rare with less than 30 reported cases in the literature. A tiny proportion of these cases report early recurrence (within 2 years) and to our knowledge none have reported delayed recurrence 6 years after primary resection. Case history We report a 55-year-old male who underwent laparoscopic excision of a 5 cm presacral tumour found incidentally and confirmed histologically to be a G1 NET (WHO Classification) arising from a pre-existing tail gut cyst, with no evidence of metastasis.16 months later the patient presented with bowel obstruction secondary to adenocarcinoma of the colon at the splenic flexure. The patient underwent laparoscopic left hemicolectomy; histology confirming a moderately differentiated adenocarcinoma (TNM stage pT3pN0). The patient underwent adjuvant chemotherapy post-operatively based upon immunohistochemistry. The patient was followed up for both tumours with CEA, serum chromogranin A, colonoscopies, and CT scans. At 5th year post hemicolectomy, CT scan revealed a new asymptomatic 18 mm left internal iliac lymph node which was avid on octreotide scan consistent with metastasis secondary to NET resected previously. He, therefore, underwent 30Gy sabre radiotherapy. Conclusions There is no consensus regarding follow up duration post early NET resection. The recurrent NET was picked up incidentally as part of the 5-year colorectal adenocarcinoma follow up at our unit. The recurrent NET would not have been identified had this not been a metachronous case. Thus, consideration must be given to both radiological and biochemical follow up post NET resections.

An analysis of 130 neuroendocrine tumors G3 regarding prevalence, origin, metastasis, and diagnostic features

Limited data exist on high-grade neuroendocrine tumors (NETs G3) which represent a new category among neuroendocrine neoplasms (NEN). We analyzed NETs G3 in a consultation series regarding prevalence, origin, metastasis, and diagnostic problems. Based on the WHO classification of digestive system tumors, 130 NETs G3 (9%) were identified in 1513 NENs. NET G3 samples were more often obtained from metastatic sites (69%) than NET G1/G2 samples (24%). NET G3 metastases presented most frequently in the liver (74%) and originated from the pancreas (38/90, 42%), followed by the lung (9%), ileum (7%), stomach (3%), rectum (1%), and rare sites (2%) such as the prostate and breast. The primaries remained unknown in 15%. NETs G3 had a median Ki67 of 30% that distinguished them from NECs (60%), though with great overlap. The expression of site-specific markers, p53, Rb1, and SST2 was similar in NETs G3 and NETs G1/G2, except for p53 and Rb1 which were abnormally expressed in 8% and 7% of liver metastases from NET G3 but not from NET G1/G2. NETs G3 were frequently referred as NECs (39%) but could be well distinguished from NECs by normal p53 (92% versus 21%) and Rb1 expression (93% versus 41%) expression. In conclusion, NETs G3 are frequently discovered as liver metastases from pancreatic or pulmonary primaries and are often misinterpreted as NEC. p53 and Rb1 are powerful markers in the distinction of NET G3 from NEC. Rarely, carcinomas from non-digestive, non-pulmonary organs with neuroendocrine features may present as NET G3.

Well-differentiated gastroenteropancreatic G3 NET: findings from a large single centre cohort

Neuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.

Well differentiated grade 3 gastroenteropancreatic neuroendocrine tumors:new insights into diagnosis and therapeutic strategy

Gastroenteropancreatic neuroendocrine tumor G3(GEP-NET G3) is a novel subtype of neuroendocrine neoplasms proposed in 2019,which has unique biological behavior characteristics. However,there are still many challenges and controversies in its diagnosis and treatment. There are obvious differences between GEP-NET G3 and neuroendocrine carcinoma (NEC) in genetic alterations and molecular profiles. The most frequently mutated genes in NET G3 are MEN1,DAXX/ATRX,while in NEC,TP53 and Rb are the most frequently mutated genes. Currently,the mainstream view is that NET G3 and NEC are two distinct diseases with different genetic backgrounds,and NET G3 will not develop into NEC. Several clinical and pathological factors should be considered to distinguish GEP-NET G3 and NEC,which including patients' medical history,histopathological morphology of neoplasms,Ki-67 index,immunohistochemical results of TP53,Rb,DAXX/ATRX and other markers. Multidisciplinary treatment,including radical resection,chemotherapy,targeted therapy,peptide receptor radionuclide therapy,immunotherapy should be applied in patients with GEP-NET G3. Overall,given its relatively indolent biological behavior,the therapeutic strategy should be more actively. Although the cure strategy of NET G3 has many similarities with NET G1/2,it is completely different from NEC.

Gastroenteropancreatic grade 3 neuroendocrine tumors: a single entity or a heterogeneous group? A retrospective analysis.

Grade 3 neuroendocrine tumor (NET G3) is a novel pathologic category within gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NENs) but its clinical behavior and therapeutic management still remain challenging. Prognostic and predictive factors aiding NET G3 management are needed. We performed a retrospective analysis from 2015 to 2020 of all patients with > 20% Ki-67, well-differentiated NETs evaluated within our NEN-dedicated multidisciplinary team. We divided the sample according the timing of NET G3 diagnosis, the radiotracers distribution and Ki-67. We analyzed the correlation between these NET G3 features and clinical outcomes. Among 3238 multidisciplinary discussion reports, we selected 55 patients, 48 from GEP and 7 from an occult GEP origin. In 45 patients, NET G3 diagnosis occurred at the beginning of clinical history (upfront-NET G3), whereas in 10, during the NET G1-G2 clinical history (late-NET G3). Patients with ≤ 30% (34/55) vs. > 30% Ki-67 (21/55) had a better overall survival (OS) (p = 0.042); patients with a homogeneous vs. inhomogeneous/negative 68Gallium(68Ga)-DOTA-Peptide Positron Emission Tomography (PET)/computed tomography (CT) showed a trend to a better OS, and a significant better progression-free survival (PFS) (p = 0.033). A better OS was observed for negative/inhomogeneous vs. homogeneous 18-fluorodeoxyglucose (18FDG)-PET/CT (p = 0.027). A trend to a better OS was reported in late- vs. upfront-NET G3, while the latter showed a significantly better response rate (RR) (p = 0.048). Our findings suggested that Ki-67 cutoff, functional imaging and the timing to NET G3 diagnosis may help clinicians in more accurate selection of NET G3 management. Prospective studies are needed.

Clinicopathologic characteristics of extrahepatic biliary neuroendocrine neoplasm: A single center experience of gallbladder, extrahepatic biliary tract and ampulla of Vater

Neuroendocrine neoplasm of extrahepatic bile ducts are very rare. The aim of this study to elucidate the clinicopathological characteristics, therapeutic approach and prognosis of these patients. The subjects were 16 patients who were diagnosed with neuroendocrine neoplasm or mixed adenoneuroendocrine carcinoma (MANEC) after curative resection. There were 8 ampulla of Vater and 8 non ampulla of Vater (6 gallbladder and 2 distal bile duct). The female to male ratio was 1.3/1 with mean age of 57.9 years (ranging from 36 to 74 years). There were 8 cases of incidental diagnosis in health screenings and 2 cases during evaluation for other disease. The most common symptoms were abdominal discomfort (3 pain and 1 dyspepsia) and jaundice (2 cases). According to the 2010 WHO classification, 1 patient had NET G1, 5 NET G2, 6 NET G3 and 5 MANEC. G3 and MANEC were small cell type. Pancreatoduodenectomy was performed in 9 patients (1 combined minor hepatectomy), extended cholecystectomy in 6 cases (1 combined pancreaticoduodenectomy and right hemicolectomy) and radical bile duct resection in 1 case. There were no association between OS and DFS with various clinicopathological factors including TNM stage. Ki-67 (cut-off 20%) was only prognostic factor in OS (5-year survival: 100% vs. 42.3%; p = 0.044) and DFS (5-year survival: 100% vs. 47.6%; p = 0.059). In NET of extrahepatic bile duct, the titer of Ki-67 is more important than TNM according to AJCC, and attention of Ki-67 titer may be needed in treatment of recurrence.

Aberrant Expression of Long Non Coding RNA HOTAIR and De-Regulation of the Paralogous 13 HOX Genes Are Strongly Associated with Aggressive Behavior of Gastro-Entero-Pancreatic Neuroendocrine Tumors

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are rare diseases occurring in the gastrointestinal tract and pancreas. They are characterized by the loss of epithelial tubular gland elements, and by the increased expression of neuroendocrine markers. GEP-NENs are subdivided into two histo-pathological types, gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs). According to WHO 2017 and 2019 classification criteria are graded and staged in four categories, NET-G1, NET-G2, NET-G3, and NEC-G3. The molecular characterization of these tumors can be fundamental for the identification of new diagnostic, prognostic and predictive biomarkers. The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes, normally involved in embryogenic development and frequently deregulated in human cancers, and of the HOX regulating lncRNA HOTAIR in GEP-NENs. The expression of HOX genes is gradually lost in the transition from GEP NET G1 to NET/NEC G3 tumors, while HOTAIR expression, inversely correlated with HOX genes expression and weakly expressed in low-grade GEP NENs, becomes aberrant in NET G3 and NEC G3 categories. Our data highlights their potential role in the molecular stratification of GEP-NENs by suggesting new prognostic markers and potential therapeutic targets.

Treatment outcomes of advanced digestive well-differentiated grade 3 NETs.

There is no standardized treatment for grade 3 neuroendocrine tumors (G3 NETs). We aimed to describe the treatments received in patients with advanced G3 NETs and compare their efficacy. Patients with advanced digestive G3 NETs treated between 2010 and 2018 in seven expert centers were retrospectively studied. Pathological samples were centrally reviewed, and radiological data were locally reviewed. We analyzed RECIST-defined objective response (OR), tumor growth rate (TGR) and progression-free survival (PFS) obtained with first- (L1) or second-line (L2) treatments. We included 74 patients with advanced G3 NETs, mostly from the duodenal or pancreatic origin (71.6%), with median Ki-67 of 30%. The 126 treatments (L1 = 74; L2 = 52) included alkylating-based (n = 32), etoposide-platinum (n = 22) or adenocarcinoma-like (n = 20) chemotherapy, somatostatin analogs (n = 21), targeted therapies (n = 22) and liver-directed therapies (n = 7). Alkylating-based chemotherapy achieved the highest OR rate (37.9%) compared to other treatments (multivariable OR 4.22, 95% CI (1.5-12.2); P = 0.008). Adenocarcinoma-like and alkylating-based chemotherapies showed the highest reductions in 3-month TGR (P < 0.001 and P = 0.008, respectively). The longest median PFS was obtained with adenocarcinoma-like chemotherapy (16.5 months (9.0-24.0)) and targeted therapies (12.0 months (8.2-15.8)), while the shortest PFS was observed with somatostatin analogs (6.2 months (3.8-8.5)) and etoposide-platinum chemotherapy (7.2 months (5.2-9.1)). Etoposide-platinum CT achieved shorter PFS than adenocarcinoma-like (multivariable HR 3.69 (1.61-8.44), P = 0.002) and alkylating-based chemotherapies (multivariable HR 1.95 (1.01-3.78), P = 0.049). Overall, adenocarcinoma-like and alkylating-based chemotherapies may be the most effective treatments for patients with advanced G3 NETs regarding OR and PFS. Etoposide-platinum chemotherapy has poor efficacy in this setting.

State of the art and future directions in the systemic treatment of neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) are rare and heterogeneous malignancies whose natural evolution may be defined according to various prognostic factors, including localization of the primitive tumour, hormone secretory status, histological grade, tumour burden, tumour growth rate, expression of somatostatin receptors and fluorodeoxyglucose-avidity. The treatment of these tumours in an advanced setting is based on relatively little robust data. A recent pathological classification introduced a new category of high-grade but well differentiated neuroendocrine tumours (NET G3), with markedly different behaviour from neuroendocrine carcinomas (NECs). Yet, the optimal treatment of those tumours is still uncertain. Advances are needed in molecular subtyping of NENs to understand better their heterogeneity and inform personalized therapies. The current review summarizes the current knowledge, indicates some exciting future directions and outlines the most interesting ongoing clinical trials likely to impact current practice.

Well-Differentiated Malignant Neuroendocrine Cell Tumor Originating From the Jejunum With Excessive Insulin Secretion

Background: Insulinomas are rare, well-differentiated insulin-secreting neuroendocrine tumors of the pancreas. Insulin-secreting, extra-pancreatic tumors have rarely been reported in the literature. We present a case of a well-differentiated neuroendocrine tumor with clinical, laboratory, and immunohistochemical tumor findings supportive of ectopic insulin production in a non-pancreatic neuroendocrine tumor of the small bowel. Clinical Case: A 70 year-old female with past medical history of end stage renal disease, Type II diabetes mellitus, and hypertension presented to our facility with multiple episodes of dizziness and syncope due to hypoglycemia. She had initially managed her diabetes with metformin but stopped taking the medication due to increasingly frequent episodes of hypoglycemia. Significant labs during the hospitalization include blood glucose <20 mg/dL, insulin 75.9 IU/mL (2.6-21.9 IU/mL) and C-peptide 57.7 ng/mL (1.1-4.4 ng/mL). Her symptoms persisted despite dextrose supplementation. Abdominal and Pelvic CT showed proximal small bowel obstruction and sclerosing mesenteritis with a calcified lymph node but no pancreatic mass. A diagnostic laparoscopy was performed, showing 18 inches of small bowel with malignant appearing masses that were adherent to the mesentery. A 21.0 cm segment of jejunum was resected. There were at least 30, variably sized masses throughout the bowel, involving the mucosa, submucosa, muscularis propria and subserosal fat; along with lymphatic, venous, and perineural space tumor permeation, and metastases involving multiple regional lymph nodes. The tumors ranged in size from 0.5 up to 1.5 cm. They showed well-differentiated nuclear morphology, a mitotic count of 0 per 80 high power fields, and a Ki-67 proliferation index of 1%, indicative of a G1 NET. Immunohistochemical stains confirmed neuroendocrine differentiation with positive staining for chromogranin, synaptophysin, and INSM1 (insulinoma-associated protein 1) transcription factor, while insulin staining was negative. The patient was diagnosed with a pT3N1, G1, ectopic insulin-secreting neuroendocrine tumor of small bowel origin. She was started on diazoxide with significant improvement in her hypoglycemia. Conclusion: Insulin production by non-pancreatic tumors is extremely rare. Clinical, laboratory, and immunohistochemical tumor findings in this case support ectopic insulin production by a well-differentiated neuroendocrine tumor of small bowel origin.

Myeloid and T-Cell Microenvironment Immune Features Identify Two Prognostic Sub-Groups in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms.

High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) >20 mitoses/10 HPF and Ki-67 >20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman’s correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (>55 vs. <55, HR 8.60, CI 95% 2.61–28.33, p < 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20–0.93, p = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies.