NET G1 Research Articles

Treatment outcomes of well-differentiated high-grade (G3) neuroendocrine tumors.

e16691 Background: Recent WHO classification of NET has defined high-grade well-differentiated NET (NET G3) as a distinct entity that is clinically different from neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aims to evaluate NET G3 response to different treatment regimens. Methods: This is a retrospective study of NET G3 patients within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics along with treatment responses and survival were assessed. Primary end points were progression-free survival (PFS) and objective response rate (ORR) by RECIST 1.1 criteria. Results: 71 patients with NET G3 were identified. Systemic treatment data was available in 30 patients who had a median age of 59.5 years at time of diagnosis. The primary tumor was most commonly pancreatic (73.3%). Ki 67 index was ≥55% in 26.7% of cases. 56.7% of cases had > 1 metastatic site. Treatment regimens included: capecitabine+temozolomide (CAPTEM) (n = 20), somatostatin analog (SSA) (n = 14), carboplatin/cisplatin+etoposide (EP) (n = 7), everolimus (n = 2), FOLFOX (n = 7), and lutetium Lu 177 DOTATATE (PRRT) (n = 10). CAPTEM was the most commonly used regimen (10 first-line, and 10 second-line) with ORR of 35%, disease control rate (DCR) of 65%, and median PFS of 9.4 months. The table summarizes the treatment data and responses rates for the various therapies used. Conclusions: Among NET G3 patients treated at Mayo Clinic, CAPTEM was found to be the most commonly used treatment with reasonable efficacy and disease control. Other treatment options include SSA, PRRT, FOLFOX, and EP. Prospective studies evaluating different treatments effects in NET G3 patients are needed to determine an optimal treatment strategy. [Table: see text]

Natural history and clinical outcomes of pancreatic neuroendocrine neoplasms based on the WHO 2017 classification; a single-center experience of 30 years

Background/ObjectivesThis single-center study aimed to evaluate treatment outcomes and long-term prognosis of patients with pancreatic neuroendocrine neoplasms (PanNENs) based on the World Health Organization (WHO) 2017 classification. MethodsWe enrolled 245 patients with PanNENs treated at Kyushu University Hospital between January 1987 and March 2018. PanNENs were categorized according to the WHO 2017 classification or further subdivisions of Ki-67 index. Clinicopathological features, median survival time (MST), and prognostic factors were retrospectively analyzed. ResultsThe number of PanNENs, especially non-functioning PanNENs, has increased over the last decade. The mean MST of all patients was 202 months; which was longest in patients with NET G1 (n = 145, MST = 261 months) relative to NET G2 (n = 72, 132 months), NET G3 (n = 3, 34 months) and NEC G3 (n = 17, 9 months). Prognosis in patients with surgery as the first-line treatment was significantly better than in those with drug therapy. However, 26% of patients who underwent curative resection developed recurrence after a median time of 28.7 months. In unresectable PanNENs (n = 97), the MST and 5-year survival rate were 78 months and 55.8%, respectively. Poor differentiation, Ki-67 index of >10% and presence of liver metastasis were significant unfavorable predictors. Response to first-line therapy (stable disease/partial response) and three or more treatment regimens were significant favorable predictors for unresectable PanNENs according to multivariate analyses (p < 0.01). ConclusionsWe demonstrated the utility of the WHO 2017 classification for PanNENs in the real clinical setting. For better prognosis in PanNENs, the use of three or more regimens should be considered.

Radical intended surgery for highly selected stage IV neuroendocrine neoplasms G3

BackgroundStage IV gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) G3 are the NENs with the worst prognosis. According to ENETS guidelines, platinum-based chemotherapy is the standard treatment for this population. Surgery is only considered in highly selected “resectable” NENs with usually lower Ki67. However, the role of surgery with curative intent has been poorly investigated. ObjectiveTo describe, in a retrospective series of stage IV GEP-NENs G3, overall survival (OS) and recurrence-free survival (RFS) rates after curatively intended surgery. MethodsMulticenter analysis of stage IV GEP-NENs G3 receiving radical resection (R0/R1) from 2007 to 2017, with minimum post-surgical follow-up time of 3 months. ResultsFifteen patients from 6 NEN referral centers, with median follow-up of 29 months (8-86), were included. Eight cases had a neuroendocrine carcinoma (NEC) and 7 a neuroendocrine tumor G3 (NET G3). Median OS after radical surgery was 59 months. All patients recurred, with a median RFS of 8 months. ConclusionsRadical surgery might be considered for highly selected stage IV GEP-NENs G3. Larger series are needed to confirm these results.

Prognostic value of the 2017 World Health Organization Classification System for gastric neuroendocrine tumors: A single-center experience

Gastric neuroendocrine tumors (G-NETs) are rare tumors, but their incidence is gradually increasing. Despite the existence of many classification systems, determining prognosis and planning treatment in patients with G-NETs remains a clinical challenge. In this study, the prognostic value of the World Health Organization (WHO) 2017 grading system and the effect of surgery on survival in low grade neuroendocrine tumors were investigated. G-NETs who were diagnosed between January 2000 and May 2017 were included in the study. Patients' demographic characteristics, treatment details, and survival data were obtained from medical charts. Pathological samples were re-classified according to the WHO 2017 grading system. Of the total 94 evaluated patients, 50 (53.2%) were classified with G1 NETs, 37(39.4%) with G2 NETs, 4(4.2%) with well-differentiated G3 NETs, and the remaining 3 patients with poorly differentiated G3 neuroendocrine carcinoma (NEC). The median follow-up time was 83.2 months. There was a statistically significant difference in 5-year progression free survival (PFS) between G1 tumors (100%) and G2 tumors (76%) (p<0.001). However, there was no statistically significant deference in 5-year overall survival rate (OS) for G1 (97%) and G2 (82%) tumors (p=0.141). When G2 and G1 NETs were compared according to their surgical approach, radical surgery was more frequently performed in patients with G2 tumors (p<0.001). However, radical surgery did not improve PFS in G1 and G2 NETs. The WHO 2017 NET classification system may have low prognostic value for determining the prognosis of patients with G1 and G2 tumors. Radical surgery for G1 and G2 NETs did not improve PFS in our study.

PRRT in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3).

Peptide receptor radionuclide therapy (PRRT) is an established treatment for grade 1 and 2 gastroenteropancreatic neuroendocrine tumors with an increased uptake on somatostatin receptor imaging (SRI). Patients with metastatic high-grade (WHO G3) gastroenteropancreatic neuroendocrine neoplasms (NET G3 and NEC) represent a heterogeneous subgroup with poor prognosis and standard platinum-etoposide chemotherapy have limited therapeutic benefit. However, there is promising emerging evidence supporting the effectiveness of PRRT in SRI-positive G3 disease. A review search for studies reporting on PRRT in gastroenteropancreatic neuroendocrine neoplasms G3 was performed: four studies with more than ten cases were found. PRRT was mainly given as second- or third-line treatment in patients with progressive disease. Most patients had a pancreatic primary, 50% had well-differentiated tumors, and most had a Ki-67 <55%. Three studies showed similar results with promising response rates (31-41%) and disease control rates (69-78%). Progression-free survival (11-16 months) and survival (22-46 months) were best concerning patients with a Ki-67 <55%. Progression-free survival was 19 months in NET G3, 11 months for lowNEC (Ki-67 ≤55%) and 4 months for highNEC (Ki-67 >55%). PRRT should be considered for patients with increased uptake on SRI, both in gastroenteropancreatic NET G3 cases and as well as in NEC cases with a Ki-67 21-55%. PRRT for NEC with a Ki-67 >55% is less defined, but could be considered in highly selected cases after response to initial chemotherapy where all residual disease have high uptake on SRI. Dual tracer using 18F-FDG PET/CT and SRI provides important information for patient selection for PRRT in this heterogeneous complex high-grade disease.

Systemic Therapy of Neuroendocrine Neoplasia: Single Center Experience from a Cohort of 110 Consecutive Cases.

Objective Neuroendocrine neoplasias (NENs) represent a rare and biologically heterogeneous group of malignancies. Treatment of NEN patients remains challenging due to lack of prospective evidence on the choice of ideal therapeutic sequence and therapeutic efficacy in specific individual scenarios. Methods Clinical data on 110 consecutive patients suffering from NEN treated at a single German university center were analyzed, therapeutic regimens applied were assessed, and the outcome was evaluated. Results Histological grading, Ki67 proliferation index, functional activity, and presence of metastases were identified as prognostic markers. 10-year overall survival rates were 92%, 44%, and 0% for G1, G2, and G3 tumors, and 60%, 39%, 69%, 53%, and 0% for Ki67 <2%, 3–5%, 6–20%, 21–49%, and >50%, respectively. Peptide receptor radionuclide therapy (PRRT) and cytostatic chemotherapy were the second most common options, with PRRT being used more frequently in NET G1 and G2 and chemotherapy in NEC G3. Combination chemotherapy with etoposide plus cisplatin or carboplatin showed disease control rates (DCRs) of overall 74%, with a short median progression-free survival (PFS) of 7 or 5 months, respectively. DCR and PFS for PRRT were 89% and 22 months when administered as monotherapy, versus 100% and 27 months upon combination with somatostatin analog (SSA) therapy. Of note, PRRT also achieved disease control as best response in 5/5 (100%) selected cases of NEC G3. Conclusion Further prospective studies are warranted to help stratify available options for therapeutic intervention in NEN patients.

P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms

BackgroundHigh grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) with a Ki67 proliferation index > 20%, include well-differentiated tumours grade 3 (NET G3) and poorly differentiated (PD) neuroendocrine carcinomas (NEC). Abnormal p53-expression is a feature of PD tumours, while expression of chromogranin A (CgA) and somatostatin-receptor 2a (SSTR-2a) may be a feature of well-differentiated tumours. The aim of this study was to elucidate the expression and prognostic value of these three markers in 163 GEP-NEN patients with a Ki67-index > 20%.MethodClinical data, histopathology and overall survival were analysed according to Kaplan-Meier’s method and Cox regression. The expression of SSTR-2a, CgA and synaptophysin was analysed in tumour specimens by immunohistochemistry, and semi-quantitatively scored as negative (< 5%), heterogeneously positive (5–30%) or strongly positive (> 30%). P53 was defined as normal when scored as heterogeneously positive (1–30%), and abnormal when negative (0%) or strongly positive (> 30%).ResultsIn multivariate analysis, better survival was observed among patients with heterogeneously positive p53 compared to strongly positive (p < 0.001). When dichotomised, tumours with a heterogeneously positive p53 vs. negative and strongly positive p53 also showed a significantly better survival (p = 0.002).Survival was significantly worse for negative CgA compared to heterogeneously positive CgA (p = 0.02). Strongly positive SSTR-2a expression was found in 26% of the 163 included patients. Well-differentiated morphology correlated with strong expression of SSTR-2a and CgA, and heterogeneously positive p53-staining, and was more frequent in pancreatic primaries. In pancreatic primaries, strongly positive SSTR-2a was associated with longer survival (univariate analysis, p = 0.02). A significantly lower Ki67 proliferation index was found in patients with a heterogeneously positive p53, a positive SSTR-2a and CgA expression.ConclusionOur results suggest that abnormal p53-expression is an independent negative prognostic marker in GEP-NEN with a Ki67-index > 20%. Patients with heterogeneously positive p53 had the best prognosis. SSTR-2a was a positive prognostic marker in pancreatic NEN. Negative CgA was associated with a significantly worse OS compared to heterogeneously positive CgA-expression in a multivariate sub-analysis. Lower Ki67 index correlated significantly with heterogeneously positive p53, positive SSTR-2a and CgA expression.

Neuroendocrine tumor of Pancreas: Which modality is better, 320-MDCT or 3T-MRI?

Background: Significant improvement in the spatial and temporal resolution of CT have been made over the past decade, with advent of multidetector row CT (MDCT). Also, the increased spatial resolution of the 3T-MRI allows for high-quality abdominal imaging. Therefore, neuroendocrine tumors of pancreas (PNET) and their metastasis are increasingly diagnosed on imaging studied performed for unrelated purposes. Our purpose of this study is to find out the good modality to detect PNETs. Material and Methods: We selected 11 PNETs. Four of the 11 PNETs were diagnosed as NET G2, and seven of the 11 PNETs were diagnosed as NET G1. We took both 320-MDCT and 3T-MRI for all patients before surgery. We used pancreatic protocol CT with and without intravenous contrast. We made 5 kind of CT image such as non-contrast image, early-arterial phase (25sec), late-arterial phase (40sec), portal phase (70sec) and venous phase(180sec). All CT slices were made of 1mm. About 3T-MRI, we selected 2 kind of images, diffusion-weighted image (DWI) and T2 weighted image (T2WI). Slice thickness of both DWI and T2 weighted image was 3mm. We compared CT image with DWI and T2WI. Results: Seven of the 11 PNETS were diagnosed on both CT, DWI and T2WI. All 7 PNETs showed well-enhanced on late-arterial phase on CT and high signal intensity on both DWI and T2WI. Three of the 11 PNETs were able to detect on CT and DWI. All 3 PNET showed iso-signal intensity as compared to the normal pancreas. One of the 11 PNET was able to detect on DWI and T2WI. The PNET showed the same enhancement as the normal pancreatic parenchyma on all phase CT. Conclusion: DWI was the most sensitive image to detect PNET. High cell density PNETs with moderate vascularity may show atypical PNETs on CT and MRI.

Short- and long-term outcomes of endoscopic submucosal dissection for non-ampullary duodenal neuroendocrine tumors.

BackgroundEndoscopic resection is recommended for non-ampullary duodenal neuroendocrine tumors (NAD-NETs) ≤10 mm in diameter and confined to the submucosal layer, without lymph node or distant metastasis. However, the efficacy and safety of endoscopic submucosal dissection (ESD) for NAD-NET remains unclear. The aim of this study was to assess the short-term efficacy and safety and the long-term outcomes of ESD for NAD-NET.MethodsEight patients with 8 NAD-NETs who underwent ESD between 2015 and 2018 were included. The indications for ESD were: i) tumor ≤10 mm in diameter; ii) NET G1; iii) confined to the submucosal layer; and iv) without lymph node or distant metastasis. We retrospectively assessed the short- and long-term outcomes and safety.ResultsThe median patient age was 69 (48-76) years. All tumors were located in the duodenal bulb and showed 0-Is morphology. The median size was 6.4 (3-9.3) mm. The rates of en bloc resection, histologically free horizontal and vertical margins, and curative resection were 100%, 88%, and 88%, respectively. Intraoperative and postoperative perforation each occurred in 13% of patients, all of whom were treated conservatively and avoided emergent surgery. Delayed bleeding was not observed. No local, lymph node or distant recurrence was observed during a median follow-up period of 34 (18.5-62.5) months.ConclusionsThe rates of en bloc and curative resection, and histologically free margins were sufficiently high. Although intraoperative and postoperative perforations occurred, emergency surgery was not needed. The results show that ESD is an efficacious and safe treatment for NAD-NET.

Polypoid gallbladder neuroendocrine tumor diagnosed as benign polyp before surgery: A case report.

Gallbladder neuroendocrine tumors (GB-NETs) comprise only 0.5% of all NET cases, and their biology has been incompletely characterized. In the present study we report the case of a 50-year-old male patient with GB-NET who was admitted to Naito Hospital with diarrhea as the main complaint. At initial diagnosis, serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were within the normal range. Abdominal ultrasonography and contrast-enhanced computed tomography (CT) revealed gallbladder adenomyomatosis and cholecystitis, and an 8-mm pedunculated polypoid lesion was found in the neck of the gallbladder using drip infusion cholecystocholangiography-CT. As it was considered a benign polyp, laparoscopic cholecystectomy was performed. Pathological examination revealed a polypoid lesion that comprised NET cells with a cord-like or ribbon-like arrangement, and the cells exhibited positive immunostaining for chromogranin A and synaptophysin. In addition, immunohistochemical staining showed a Ki-67 index (i.e., proliferation index) of <1%, and no necrosis or mitotic figures were observed in the background. Based on these observations, we diagnosed the following: GB-NET, G1, 10x12 mm in size and located in the gallbladder neck. According to the World Health Organization 2010 classification, NET G1 is a well-differentiated tumor, with the tumor cells having a low proliferative potential [Ki-67 index ≤2%; mitotic figure number <2 (/10 HPF)]. It is regarded as a low- to mild-grade malignancy. Low-grade GB-NET occurs relatively rarely, and no clear guidelines have been formulated regarding its surgical treatment, such as minimal surgical excision margins or lymph node dissection. Detailed treatment recommendations should be developed after systematic studies of additional cases of GB-NET.

P124 LOCALIZED ESOPHAGEAL NEUROENDOCRINE TUMORS. REPORT ON CLINICAL AND TREATMENT PARAMETERS FROM A TERTIARY HOSPITAL

Abstract Aim We retrospectively analyzed the medical files of patients treated with neuroendocrine neoplasms (NENs) of the esophagus in our unit. Background &amp; Methods Esophageal NENs are rare and lacking functional symptoms. This results in a delay of diagnosis that may compromise patient survival. Numerous single cases are reported in literature, without a consensus on their management. The true incidence of esophageal NETs is unknown but evidence indicated geographic variability while smoking and alcohol abuse are the major risk factors. Men (60-70 years) are most commonly afflicted and usual symptoms include dysphagia and loss of appetite with consequent weight loss. The histologic subtypes reported in the literature include high or low-grade NETs and mixed neuroendocrine neoplasms (MINENs). Central pathology assessment significantly contributes to the accurate diagnosis and management. Personalised treatment depends on the grade, involved anatomic region and stage of disease and most commonly comprises combination chemotherapy and radiotherapy and rarely surgery. Results We report on three cases with localized esophageal NET diagnosed with endoscopic biopsies and staged with FDG or Gallium-PET CT scan. The mean age was 56, two were men and histologies included 1 MINEN (lower thoracic esophagus), 1 NET G3 (upper thoracic esophagus) and 1 NET G2 (middle thoracic esophagus). The patient with MINEN was stage 1b and was treated with complete esophagectomy and lymph nodal dissection without any further adjuvant therapy. Two patients with upper and middle thoracic esophagus were treated with combination chemotherapy and definitive IMRT radiotherapy. All patients remain disease free at 12 months follow up. Conclusion Localized esophageal NET are often diagnosed following endoscopic investigation. Long-term survival may be achieved with excellent quality of life after careful evaluation of the clinicopathologic characteristics by a dedicated multidisciplinary group.

172P - Preoperative neutrophil‐to‐lymphocyte ratio (NLR) predicts recurrence after surgery in patient with pancreatic neuroendocrine neoplasm (PanNEN)

BackgroundSeveral inflammation-based markers were found to have a prognostic value in malignancies. Recent studies have reported that the preoperative neutrophil-to-lymphocyte ratio (NLR) is useful for prognostication in a variety of oncologic patients. We analyzed the NLR in determining Pancreatic neuroendocrine neoplasm (PanNEN) clinical outcomes after surgery. MethodsWe evaluated 132 consecutive cases of PanNEN who underwent surgery in Tohoku University Hospital between May 2001 and December 2018. Eight patients with synchronous hepatic metastasis, two patients with NEC, one patient with an active infection at blood sampling, and one patient with R2 noncurative resection were excluded from the study. 120 patients divided into two groups according to the values of NLR based on the receiver operator characteristic (ROC) curve. Differences of the characteristics between the two NLR groups (<3.84 vs. ≥3.84) were investigated with the chi-squared test and the Wilcoxon rank-sum test. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated by univariate or multivariate analyses using Cox’s proportional hazards model. ResultsThe median age was 60 years old (range 12-88). In the WHO2017 histological grade, NET G1, G2, and G3 included 74, 44, and 2 cases, respectively. The median follow-up period was 52.9 months (range, 1-182). The NLR values distributed between 0.44 and 5.32 (average 1.92 ± 0.88). Five- and ten‐year RFS was 90.4% and 80.1%, respectively. Ten (8.3%) cases of relapse were observed. The site of recurrence was liver in nine patients and lymph node metastasis in one. NLR showed a significant correlation with RFS (median RFS time, 44.6 months (NLR ≥ 3.84) and not reached (NLR <3.84), p < 0.001). The multivariate analysis identified ki67 (≥3.4 HR 8.9; 95% CI 2.14 to 60.3; P = 0.002), and preoperative NLR (≥3.84 HR 7.7; 95% CI 1.63 to 30.1; P = 0.013) were an independent predictor of recurrence. ConclusionsNLR could be a useful prognostic marker of the recurrence estimation after surgery and a handy objective screening tool for the host immune response in patients with PanNEN. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Two cases of lung neuroendocrine carcinoma with carcinoid morphology

BackgroundThe category of grade 3 neuroendocrine tumor (NET G3) was newly introduced in the 2017 World Health Organization (WHO 2017) classification of neuroendocrine neoplasms of the pancreas. Pancreatic NET G3 shows a carcinoid-like morphology with high proliferative activity and the prognosis is intermediate between NET G2 and neuroendocrine carcinoma. There is no category corresponding to NET G3 in the current WHO 2015 classification of lung tumors. Herein, we report two cases of lung neuroendocrine carcinoma with carcinoid morphology that correspond to NET G3.Case presentationCase 1: An abnormal chest shadow was detected in a 78-year-old female never-smoker during a routine medical examination. She was asymptomatic. The radiological assessment revealed a mass in the peripheral S4 segment of the right lung. She underwent right middle lobectomy for the mass preoperatively diagnosed as non-small cell lung carcinoma. Postoperative histological examination revealed a neuroendocrine tumor with carcinoid morphology and a mitotic count of 15/2 mm2. Case 2: An abnormal chest shadow was detected in a 74-year-old female never-smoker undergoing follow-up for another disease. She was asymptomatic. The radiological assessment revealed a mass in the peripheral S3 segment of the right lung. She underwent right upper lobectomy for the mass suspected to be lung carcinoma. Postoperative histological examination revealed a neuroendocrine tumor with carcinoid morphology with mitotic count of 13/2 mm2. Both of these tumors showed carcinoid morphology but with a mitotic count exceeding 10/2 mm2; thus, we diagnosed them as small cell lung carcinomas according to the current WHO 2015 classification.ConclusionsOur tumors occurred in female never-smokers and their histology showed carcinoid morphology without extensive necrosis. Moreover, proliferative abilities of them were extremely low compared to small cell lung carcinoma. The clinical and pathological features of our tumors appeared to be different from those of small cell lung carcinoma. Although there is no category corresponding to NET G3 in the current classification of lung tumors, we consider that our tumors may correspond to NET G3 and identification of this subset is relevant for therapeutic management.

APOBEC3B High Expression in Gastroenteropancreatic Neuroendocrine Neoplasms and Association With Lymph Metastasis.

Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3B (APOBEC3B) is known as a source of mutations in multiple cancers. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of heterogeneous tumors. However, the expression and significance of APOBEC3B in GEP-NENs remains unclear. A total of 158 cases of GEP-NENs, including 78 cases of biopsy or endoscopic submucosal dissection resection specimens and 83 cases of surgical resection specimens were collected in this study. The cases were grouped according to tumor classification grade, including 42 cases of neuroendocrine tumors G1 (NET G1), 36 cases of NET G2, 36 cases of NET G3, 44 cases of neuroendocrine carcinoma (NEC). All of the 158 tumors were immunohistochemically studied using a polyclonal antibody against APOBEC3B. We evaluated APOBEC3B expression in GEP-NENs and investigated the relationships among the immunoreactivity of APOBEC3B, clinical and pathologic features, such as age, sex, tumor site, Ki67 cell proliferation index, and lymph metastasis. A total of 33 cases (78.6%) of NET G1 showed high expression of APOBEC3B. A total of 28 cases (77.8%) of NET G2 demonstrated high expression of APOBEC3B. In NET G3 and NEC cases, the positive rates were 52.8% and 2.3%, respectively. The expression of APOBEC3B in NETs was significantly higher than that in NECs, NET G1 and NET G2 were higher than NET G3, and the difference was statistically significant. APOBEC3B high expression cases have lower lymph node metastasis rate, lower Ki67 cell proliferation index. In this study, APOBEC3B is highly expressed in GEP-NETs and is a predictor of lymph node metastasis in NET G3 and NEC cases. These findings might provide new insights into the biological mechanisms of GEP-NENs tumorigenesis and progression.

Management of Well-Differentiated High-Grade (G3) Neuroendocrine Tumors.

In 2017, the World Health Organization (WHO) classification for pancreatic NET was updated to include a new category of well-differentiated high-grade (Ki 67 > 20%) pancreatic tumors (NET G3), distinct from high-grade poorly differentiated neuroendocrine carcinoma (NEC). NET G3 are considered a molecularly, radiologically, and prognostically distinct entity compared to NEC and NET G1/G2. The optimal first-line management in NET G3 and sequencing therapies remains a challenge awaiting future trials taking into consideration the unique characteristics of this category. In this review, we aim to summarize the current evidence in the management of NET G3.

Gastroenteropancreatic Neuroendocrine Neoplasia Characterization in Portugal: Results from the NETs Study Group of the Portuguese Society of Endocrinology, Diabetes and Metabolism.

Background The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has been increasing in the last five decades, but there is no large-scale data regarding these tumours in Portugal. We conducted a cross-sectional, multicentric study in main Portuguese centers to evaluate the clinical, pathological, and therapeutic profile of GEP-NENs. Methods From November, 2012, to July, 2014, data from 293 patients diagnosed with GEP-NENs from 15 centers in Portugal was collected and registered in an online electronic platform. Results Median age at diagnosis was 56.5 (range: 15-87) years with a preponderance of females (54.6%). The most frequent primary sites were the pancreas (31.1%), jejunum-ileum (24.2%), stomach (13.7%), and rectum (8.5%). Data regarding hormonal status was not available in most patients (82.3%). Stratified by the tumour grade (WHO 2010 classification), we observed 64.0% of NET G1, 24.7% of NET G2, and 11.3% of NEC. Poorly differentiated tumours occurred mainly in older patients (p = 0.017), were larger (p < 0.001), and presented more vascular (p = 0.004) and lymphatic (p = 0.001) invasion. At the time of diagnosis, 44.4% of GEP-NENs presented metastatic disease. Surgery (79.6%) and somatostatin analogues (30.7%) were the most frequently used therapies of GEP-NENs with reported grading. Conclusion In general, Portuguese patients with GEP-NENs presented similar characteristics to other populations described in the literature. This cross-sectional study represents the first step to establish a national database of GEP-NENs that may aid in understanding the clinical and epidemiological features of these tumours in Portugal.

Abstract 919: Clinical relevance of comprehensive genomic analysis in patients with advanced-stage neuroendocrine neoplasms: Results from the MASTER trial of the German Cancer Consortium

Abstract Therapeutic options for neuroendocrine neoplasms (NEN) are limited. Within the MASTER program, a multi-institutional registry trial for prospective stratification of younger adults with advanced-stage cancer across all histologies and patients with rare tumors conducted under the auspices of NCT Heidelberg/Dresden and the German Cancer Consortium, we apply prospective whole-exome/genome sequencing (WES/WGS) and RNA sequencing (RNA-seq) to determine therapeutic choices for individual patients who have exhausted standard therapy options. We here report the clinical and molecular characteristics of the NEN cohort within this study. Between 2013 and 2018, 108 patients (male, n=65; female, n=43) were enrolled. Histologies according to the 2017 WHO Classification were neuroendocrine tumor grade 1 (NET G1), n=8; NET G2, n=31; NET G3, n=9; neuroendocrine carcinoma, n=49; and mixed neuroendocrine/non-neuroendocrine neoplasm, n=11. Primary tumor sites were gastrointestinal tract, n=30; pancreas, n=31; thorax, n=21; genitourinary system, n=11; head and neck, n=5; and other regions, n=10. All patients had advanced-stage disease and had received a median of 2 prior lines of systemic therapy. WES, WGS, and RNA-seq were performed in 69, 40, and 87 patients, respectively. Clinical evaluation of germline and somatic molecular data (single-nucleotide variants, small insertions and deletions, copy number variations, mutational burden, mutational signatures, homologous recombination deficiency scores, gene expression patterns, etc.) from 105 patients by a dedicated molecular tumor board yielded evidence-based recommendations for clinical management in 91 cases (87%). Treatment recommendations were grouped as follows: PARP inhibition, n=35; immunotherapy, n=27; mTOR inhibition, n=22; CDK4/6 inhibition, n=15; tyrosine or serine/threonine kinase inhibition, n=57 (ALK, n=1; ERBB, n=6; FGFR, n=10; MET, n=5; RET, n=12; VEGFR, n=4, MEK, n=9; other, n=10), DNA-crosslinking chemotherapy, n=16; anti-claudin18.2 antibody, n=5; BET inhibition, n=5; and DLL3 antibody, n=5. As of November 2018, at least 18 patients had received molecularly guided treatment (PARP inhibition, immunotherapy, mTOR inhibition, tyrosine or serine/threonine kinase inhibition) of which 11 were evaluable for response (partial response, n=4; stable disease, n=2; progressive diseases, n=5). Twenty-seven patients died before therapy could be started, 16 are currently receiving other regimens, and for the remaining patients no follow-up data are available yet. In conclusion, comprehensive molecular profiling offers valuable insight into to the genomic and transcriptomic landscape of NEN and creates additional therapeutic opportunities in a subset of patients. Citation Format: Simon Kreutzfeldt, Leonidas Apostolidis, Malgorzata Oles, Peter Horak, Christoph E. Heilig, Christoph Heining, Barbara Hutter, Laura Gieldon, Barbara Klink, Mario Lamping, Damian T. Rieke, Sebastian Uhrig, Henning Jann, Ulrich F. Pape, Albrecht Stenzinger, Eva C. Winkler, Bertram Wiedenmann, Dirk Jäger, Benedikt Brors, Evelin Schröck, Ulrich Keilholz, Marianne Pavel, Hanno Glimm, Stefan Fröhling. Clinical relevance of comprehensive genomic analysis in patients with advanced-stage neuroendocrine neoplasms: Results from the MASTER trial of the German Cancer Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 919.

Abstract 739: Whole-exome sequencing of neuroendocrine neoplasm of the liver reveals recurrent mutations in components of RTK-RAS pathways

Abstract Aims: Primary hepatic neuroendocrine neoplasms (phNENs) is a rare and poorly understood type of primary liver cancer. We aimed to perform a comprehensive molecular characterization of this malignancy. Methods: Twenty-one cases of phNENs were graded into stepwise increasing malignant potential groups: neuroendocrine tumor grade 1 (NET G1, 3 cases), grade 2 (NET G2, 9 cases), neuroendocrine carcinoma (NEC, 9 cases) based on mitotic activity and proliferative index, according to WHO Classification of Tumors of the Digestive System (2010). The expression of PD-L1(clone 28-8), p53(DO7), NCAM, RB, and synaptophysin were detected. Gene expression profiling, DNA copy number detection, and exome sequencing using formalin-fixed samples from 16 patients with phNENs (9 NETs, 7 NECs) were performed. Comparative genomic analysis was carried out, using independent datasets of pancreas NET (n = 64) and intrahepatic cholangiocarcinoma (ICC) (n = 49). Results: Integrative genomic analysis of phNENs revealed that NEC represents a distinct biliary- derived entity compared with the NET types. NET were, chromosomally stable (mean chromosomal aberrations 4.7 vs. 14.1, p = 0.008), showed significant upregulation of MAPK and PI3K signaling and enrichment of inflammation-related and immune response signatures (p &amp;lt;0.001). NEC tumors were characterized by the mutation signature associated with failure double-strand DNA break repair homologous recombination on its high mutation burdern in samples harbouring BRCA1 or BRCA2 mutation (6/7 vs. 0/9, p &amp;lt;0.001), neural cell adhesion molecule (NCAM) positive (6/7 vs. 1/9, p &amp;lt;0.001), enrichment of progenitor-like signatures, activation of specific oncogenic pathways (i.e., P53-Rb and Wnt), and signatures related to poor clinical outcome. In the NET type, there was a significant correlation in the copy number variation of the ICC, suggesting a clonal origin. Exome sequencing revealed an average of 104 non-synonymous mutations per tumor (2 mean driver mutations per tumor). Among those, TP53 was the most frequently mutated gene (4/7, 57.1%) in phNECs. Intratumor expression of PD-L1 was significantly associated with poorly-differentiated NEC, p53-positive patients. Overall survival rate was significantly correlated to tumor differentiation, growth pattern, necrosis, TP53 mutation (P&amp;lt;0.05), but not correlated to PD-L1expression and vascular invasion(P&amp;gt;0.05). Conclusions: phNEN represents a heterogeneous group of tumors, with the NEC type characterized by features of poor prognosis, and the NET type with common lineage for iCCA. PhNET stands alone as a distinct biliary-derived entity associated with chromosomal stability and active RTK-RAS signaling. The elevated expression of immune related genes and pathways in NENs suggests a therapeutic opportunity for immunotherapy. Note: This abstract was not presented at the meeting. Citation Format: Lingli Chen, Yuan Ji, Jing Zhao, Lingtong Hao, Yixue Li, Xi Zhang, Huichuan Sun, Rongkui Luo, Jing Han, Jie Huang, Yingyong Hou, Jia Liu. Whole-exome sequencing of neuroendocrine neoplasm of the liver reveals recurrent mutations in components of RTK-RAS pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 739.

Clinicopathological characteristics and risk factors for recurrence of well-differentiated pancreatic neuroendocrine tumors after radical surgery: a case-control study

BackgroundWell-differentiated pancreatic neuroendocrine tumors (PanNETs) usually have a good prognosis; however, there are patients that experience recurrence after curative resection.AimTo explore recurrence-related risk factors by analyzing clinicopathological data of PanNETs after radical surgery.MethodsClinical and pathological data from 47 patients with well-differentiated PanNETs at China-Japan Friendship Hospital from January 2012 to March 2016 were analyzed retrospectively. Univariate and multivariate analyses of the risk factors of PanNETs for postoperative recurrence were conducted.ResultsAmong the 47 patients with well-differentiated PanNETs, there were 38 cases with non-functioning tumors, 9 cases with functional tumors (6 insulinomas, 1 gastrinoma, 1 glucagonoma, and 1 VIPomas). There are 17 cases (36.2%) in the pancreatic head, 17 (36.2%) in the body and tail, 9 (19.1%) in the tail, and 4 (8.5%) in the body. The median tumor size was 3.65 (IQR 2–5.5) cm. Fourteen cases (29.8%) were NET G1, and 33 cases (70.2%) were NET G2. In regard to the clinical stage, 9 (19.1%) cases were IA, 14 (29.8%) cases were IB, 7 (14.9%) cases were IIA, 14 (29.8%) cases were IIB, and 3 cases unknown. There were 17 patients who presented with postoperative recurrence. Univariate analysis showed that AJCC TNM staging, Ki67 index, vascular invasion, margin status, and the regional stage of the tumors are related to the recurrence of patients with PanNETs (p < 0.05). The results of multivariate analysis showed that Ki67 index ≥ 10% is an independent risk factor for the postoperative recurrence of PanNETs (p < 0.05).ConclusionThe Ki67 index ≥ 10% is an independent risk factor for recurrence in well-differentiated PanNETs after radical surgery, and close surveillance for these patients may be needed.

Value of 111In-Pentetreotide scintigraphy and 18F-FDG PET for clinical prognosis of patients with neuroendocrine neoplasms

Despite the existence of biological markers of aggressiveness, the clinical course of gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NEN) remains difficult to predict. Discrepancies between imaging data generated with 111In-pentetreotide scintigraphy and 18F-FDG-PET could reflect the degree of cellular de-differentiation. NEN patients with both types of studies were identified retrospectively from the SwissNET database, which is collecting information on Swiss NEN patients since 2008. Progression free survival (PFS) and overall survival (OS) were assessed depending on functional imaging results. Correlation between histological grading (according to the WHO 2010 classification) and functional imaging status was also assessed. We identified 31 patients with both imaging studies, either on the primary tumor site (21/31) or for metastases (21/31), with 12/31 on both sites. Mean follow-up was 36 months (95% CI 27–45). 21 patients had a metastatic disease at diagnosis and 11 died at follow-up. 7/31 (22%) were NET G1, 16/31 (52%) were NET G2 and 8/31 (26%) were NEC G3. Only 18F-FDG PET status almost reached statistical significance (P=0.054) with histological grading. Progression free-survival was significantly poorer in the 18F-FDG positive group (n=21), with a median time for progression of 8 months, compared to 51 months in the negative group (n=10) with a HR of 3.2 (97.5% CI 1.1–9.5, P=0.04). Overall survival tended to be worse with a positive PET and a negative 111In-pentetreotide scintigraphy status with a HR 1.63 (97.5%CI 0.11–21, P=0.08). 111In-pentetreotide scintigraphy status was not found to be predictive of survival nor progression. ConclusionThese data demonstrate the poorer prognostic value of a positive 18F-FDG-PET imaging in this cohort of patients.