Neuroendocrine Tumor G1 Research Articles

Evaluating the Role of Theranostics in Grade 3 Neuroendocrine Neoplasms.

The diagnosis and subsequent therapy of neuroendocrine neoplasms (NENs) have long relied on somatostatin receptor (SSTR) expression. The field of theranostics now uses newer SSTR-based PET imaging with 68Ga-DOTATATE or 68Ga-DOTATOC as a prerequisite for the administration of peptide receptor radionuclide therapy (PRRT). In the United States, Food and Drug Administration approval of 177Lu-DOTATATE, a form of PRRT, in 2018 for use in gastroenteropancreatic NENs was obtained on the basis of prolonged progression-free survival versus high-dose octreotide long-acting release in a phase III clinical trial of well-differentiated midgut NENs. Well-differentiated grade 1 and grade 2 NENs have a low proliferation index (Ki-67 < 20%) and longer overall survival (>10 y), whereas higher-grade (grade 3 [G3]) NENs have a high Ki-67 (>20%) and shorter overall survival (<1 y). Here, we present a review on the role of SSTR-based imaging and PRRT in G3 NENs, including a discussion of well-differentiated G3 NENs, the newest histologic classification. Some studies suggest that G3 NENs are less likely to be positive on SSTR-based imaging (but more likely on 18F-FDG PET) than are well-differentiated NENs, but these data are limited. We found only 13 studies mentioning the use of PRRT in G3 NENs and a total of only 151 patients across these studies in whom radiologic response was measured. Of these 151 patients, 99 (66%) demonstrated at least stable disease or a partial response, indicating that some G3 NENs can be responsive to PRRT. We suggest that patients with G3 NENs should receive both 18F-FDG PET and SSTR-based imaging to aid in both diagnosis and treatment selection, as positivity on SSTR-based imaging helps with patient identification for PRRT and discordance may suggest important clues to tumor biology and prognosis. However, prospective studies are needed to fully understand the role of PRRT in G3 NENs, especially in well- versus poorly differentiated G3 disease.

中耳カルチノイド腫瘍症例 ─これまでの報告、術式に対する検討とともに─

中耳カルチノイド腫瘍症例 ─これまでの報告、術式に対する検討とともに─

Comparison of Temozolomide-Capecitabine to 5-Fluorouracile-Dacarbazine in 247 Patients with Advanced Digestive Neuroendocrine Tumors Using Propensity Score Analyses

Introduction: Although chemotherapy combining 5-fluorouracil (5FU)-dacarbazine (DTIC) or temozolomide (TEM)-capecitabine (CAP) is extensively used in patients with neuroendocrine tumors (NET), they were never compared. We compared their tolerance and efficacy in advanced NET. Methods: We evaluated the records of consecutive patients with pancreatic or small-intestine advanced NET who received 5FU-DTIC or TEM-CAP between July 2004 and December 2017 in 5 French centers. Tolerance, tumor response and progression-free survival (PFS) were compared. Factors associated with PFS were analyzed using Cox multivariate regression model. To reduce the confounding bias of the nonrandomized design, PFS was compared using propensity score analyses. Results: Ninety-four (5FU-DTIC) patients and 153 (TEM-CAP) patients were included. Pancreatic NET represented 82.3% of cases and 17.1, 61.8 and 10.9% of patients had G1, G2 or G3 NET respectively. Progression at baseline was reported in 92.7% of patients with available data. Grades 3–4 adverse events occurred in 24.7 and 8.5% of TEM-CAP and 5FU-DTIC patients respectively (p = 0.002). The overall response rate was 38.3 and 39.2% respectively (p = 0.596). Median PFS on raw analysis was similar to 5FU-DTIC and TEM-CAP (13.9 vs. 18.3 months, respectively p = 0.86). TEM-CAP was associated with an increased risk of progression on the raw multivariate analysis (hazard ratio [HR] 1.90, 95% CI [1.32–2.73], p = 0.001) and when adjusted on propensity score (HR 1.65, 95% CI [1.18–2.31], p = 0.004). Conclusion: PFS may be longer with 5FU-DTIC than TEM-CAP in patients with advanced NET. Although patients often prefer oral chemotherapy, 5FU-DTIC is a relevant alternative. A randomized comparison is needed to confirm these results.

Updates of pancreatic neuroendocrine neoplasm in the 2017 World Health Organization classification

The new 2017 World Health Organization (WHO) classification of pancreatic neuroendocrine neoplasms (PanNEN) modifies the previous 2010 version with new grading and staging systems to provide a better prognostic stratification and therapeutic guidance. The discovery of heterogeneity in WHO 2010 G3 category leads to the introduction of the new ‘well‐differentiated neuroendocrine tumor G3’ entity, which is distinct from the poorly‐differentiated pancreatic neuroendocrine carcinoma (PanNEC). The latest findings from molecular studies of PanNEN allow us to have a better understanding of respective biology of PanNET and PanNEC. This review aims at highlighting refinements in the 2017 classification and discusses some of the molecular updates in PanNEN.

Endoscopic submucosal resection using a ligation device without injection for duodenal neuroendocrine tumors.

Duodenal neuroendocrine tumors (NETs) measuring ≤ 10mm in diameter that are confined to the submucosal layer without metastasis are suitable for endoscopic treatment. We previously reported the efficacy and safety of endoscopic submucosal resection with a ligation device (ESMR-L) for duodenal NETs. In order to make the procedure simpler, we attempted ESMR-L without submucosal injection. The aim of this study was to evaluate the efficacy of ESMR-L without injection for duodenal NETs. A total of 12 patients with small (≤ 10mm) sporadic duodenal NETs were treated via endoscopic resection at the National Cancer Center Hospital East between December 2010 and May 2018. All patients were evaluated via endoscopy and endoscopic ultrasound, and abdominal computed tomography was performed to rule out metastatic lesions. The patients' characteristics, clinical courses, and complications, such as perforation and bleeding, were retrospectively assessed. We examined the correlation between ESMR-L with or without submucosal saline injection and clinicopathological parameters. The median procedural time for ESMR-L was 13min. All lesions invaded the submucosal layer, and the histological diagnoses were classified as NET G1 in 11 lesions and NET G2 in one lesion. En bloc resection and complete resection were achieved in 12 and 11 lesions, respectively. The postoperative duration of hospital stay was 4 days. At the median follow-up of 17 months, there was no incidence of local recurrence or distant metastasis. Perforation and intraoperative bleeding were not observed. However, delayed bleeding was found in one patient. ESMR-L without submucosal injection required a significantly shorter procedural time than ESMR-L with submucosal saline injection (10min vs. 15min, respectively; p = 0.007). ESMR-L is safe and effective. Particularly, ESMR-L without submucosal injection could be used to treat these NETs safely within a short period of time.

A case of primary hepatic neuroendocrine tumor

Introduction: A 48-year-old woman visited our hospital because a liver tumor was detected by medical checkup. Method: Ultrasonography revealed a well-defined hypoechoic mass with a partial anechoic area in segment 5 of the liver. Contrast-enhanced multidetector-row computed tomography revealed a 55mm low-density mass in segment 5 of the liver, which was contrasted strongly in the arterial phase and the contrast effect disappeared in the portal phase. Contrast-enhanced magnetic resonance imaging revealed a high intensity mass on T2-weighted images, which was contrasted strongly in the arterial phase, and the contrast effect was completely lost in the hepatobiliary phase. We diagnosed her with primary or metastatic neuroendocrine tumor (NET) of the liver. Hepatic hemangioma or hepatocellular carcinoma were considered as differential diagnosis. Result: We performed partial hepatectomy for tumor resection. She had a good postoperative course and was discharged on day 9 after the surgery. Macroscopic analysis of the resected specimen revealed a white solid tumor. Histological examination revealed that the tumor cells with circular nuclei containing fine granular chromatin and pale eosinophils were proliferating. Immunohistochemical examination revealed that the tumor cells were positive for Chromogranin A, synaptophysin, ER, CD56 and CK7, and that the Ki-67 labeling index was 5%. The histological diagnosis was hepatic NET G2. After we diagnosed her histologically, we performed 111In-Pentetreotide Somatostatin Receptor Scintigraphy (Octreoscan®) and 18-Fluorodeoxyglucose positron emission tomography to make the liver lesion clear whether primary or metastatic tumor, but there were no lesions. Finally, we diagnosed her with primary hepatic NET. She has been alive without recurrence for 15 months after the surgery. Conclusion: Primary hepatic NET is rare and we report this case with short discussion.

Fatores Prognósticos Associados à Eficácia da Embolização Transarterial Hepática em Pacientes com Tumores Neuroendócrinos

INTRODUCTION: To evaluate the safety and e?cacy of hepatic transarterial embolization (TAE) or transarterial chemoembolization (TACE) in patients with irresectable liver metastases from neuroendocrine tumors (NETs) treated at two Brazilian cancer centers. METHODS: Retrospective multicenter analysis of patients (pts) with histological diagnosis of neuroendocrine tumor of any origin with unresectable and measurable hepatic metastases who underwent at least one procedure of TAE or TACE. ENDPOINTS: Hepatic progression free survival (HPFS), overall survival (OS), tumor response and toxicity assessment. RESULTS: Thirty-six pts were evaluated. Primary tumors were as follow: midgut 20 pts, pancreas 7 pts, others 9 pts. Most of patients had grade (G) 1-2 tumors (93.3%). In patients with functioning NETs, clinically signi?cant symptomatic control was 41.7%. Concerning type of embolization (TAE vs TACE), there were no signi?cant di?erences in the proportion of patients achieving reduction of at least 50% of 5HIAA (45.5% vs 50%) and radiological disease control rate (91.3% vs 92.3%), respectively. In a median follow up of 40.8 months (m), median HPFS was 38.9m, and mean OS was 98m (median not reached). No signi?cant di?erences were found in HPFS or OS by type of embolization procedure. Pancreatic primary tumor and G3 tumor by WHO classi?cation were associated with signi?cantly shorter HPFS. Tumor G3 was also associated with shorter OS. Adverse events of any grade were: abdominal pain (13.8%), fever (5.5%), and 2 pts developed biloma. CONCLUSION: Our study is the ?rst in our region reporting results of TAE/TACE in patients with irresectable liver metastases from NETs. We observed that pts with pancreatic or G3 NET derive less bene?t from these procedures. In pts with G1-2 NETs, both techniques oer similar results.

Mixed Adenoma Well-differentiated Neuroendocrine Tumor (MANET) of the Digestive System: An Indolent Subtype of Mixed Neuroendocrine-NonNeuroendocrine Neoplasm (MiNEN).

Mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN) consisting of adenoma and well-differentiated neuroendocrine tumor (NET) has been recently defined as "MANET." However, the clinico-pathologic and pathogenetic features of this entity are not thoroughly studied. We examined the clinico-pathologic features of 12 MANETs by expanding their p53 and β-catenin expression profiles as well as the presence of microsatellite instability and KRAS, BRAF, and PIK3CA mutations in the 2 tumor components. In all cases, the adenomatous component represented the larger part of the lesions and the NET was localized in the deep central portion of polyps. In 9 cases the latter was represented by NET G1, in 2 by NET G2, and in 1 by NET G3. In all cases, the glandular and NET components were intimately admixed, with zone of transition between the tumor components. The NET component was p53 negative in all cases and 3 of 8 cases showed variable nuclear positivity for β-catenin. All patients with follow-up data were alive and free of disease after a mean follow-up time of 9 years. No mutations in KRAS, BRAF, and PIK3CA genes and no microsatellite instability were found in both tumor components. Review of the literature also identified 59 previously reported MANETs and no tumor-related death has been found. Like mixed adenoneuroendocrine carcinomas, a high-grade malignant form of MiNENs with a poorly differentiated neuroendocrine carcinoma component, a common origin for both tumor constituents may be hypothesized. Moreover, the current series provides evidence that MANET is an indolent disease that needs to be distinguished from aggressive high-grade MiNENs.

A well differentiated neuroendocrine tumor of the jejunum with peritoneal carcinomatosis: A case report.

Neuroendocrine tumors (NETs), belong to a group of neoplasms that arise from neuroendocrine cells and express markers such as synaptophysin and chromogranin A. The digestive system (DS) is the most common site of NET development. The World Health Organization classification divides NETs into low grade (G1-G2) tumors (NETs) and high grade carcinomas [neuroendocrine carcinomas (NECs)], based on mitotic index and histological criteria. NET prognosis depends on tumor stage and grade. Low grade G1 NETs are characterized by a low proliferative rate and an indolent clinical course with a 5-year survival rate ranging between 38% (pancreas) and 88% (rectum). The present study reports a case of a low grade (G1) multifocal jejunal tumor with histologically confirmed features of aggressiveness, namely peritoneal carcinomatosis, lymph node metastasis and vascular carcinomatous emboli. Prediction of clinical behavior and survival in such a case is challenging. Although multiplicity and nodal metastases is not unusual for low grade NETs in this part of the gastrointestinal tract, peritoneal carcinomatosis is an extremely rare finding. Surgeons and histopathologists should be familiar with such eventualities and tumor boards are required in order to conclude whether aggressive therapeutic interventions may have any impact on patients' long term survival.

Ten-Year Survival After Peptide Receptor Radionuclide Therapy of a Metastatic Well-differentiated G3 Pancreatic Neuroendocrine Neoplasm

Substantial molecular and clinical heterogeneity of high-grade neuroendocrine neoplasms (NENs) G3, all of which were previously referred to as neuroendocrine carcinomas, has been observed. Although data are still limited, somatostatin receptor expression in well-differentiated G3 NENs of the pancreas (according to the new WHO 2017 classification) may enable peptide receptor radionuclide therapy for these patients. We report our treatment experience of a G3 NEN patient with discordant Ki-67 proliferation indices (between primary tumor and the metastases), who had a long survival over a span of 10 years with excellent quality of life and no adverse effects after repeated cycles of PRRT.

Preoperative tumour size predicts the risk of recurrence following pancreatectomy for G1–G2 neuroendocrine tumours: a multiinstitutional spanish study

Preoperative tumour size predicts the risk of recurrence following pancreatectomy for G1–G2 neuroendocrine tumours: a multiinstitutional spanish study

Diagnosis, Pathological Findings, and Clinical Management of Gangliocytic Paraganglioma: A Systematic Review.

Background: Although gangliocytic paraganglioma (GP) is considered a rare benign neuroendocrine tumor, cases of mortality have been reported. Occasionally, GP is misdiagnosed as neuroendocrine tumor G1, which is associated with a poorer prognosis than GP. To avoid such misdiagnoses, it is important to understand the clinicopathological characteristics of GP. Thus, herein, we discuss the current literature on the clinicopathological characteristics of GP.Methods: We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed and Japana Centra Revuo Medicina searches were used to identify papers describing GP. Inclusion criteria included confirmation of epithelioid, spindle-shaped, and ganglion-like cells in the main article and/or figures and whether the paper was cited in other studies of GP. Data were collected on age, sex, site of the primary lesion, tumor size, treatment, prognosis, lymph node metastasis (LNM), depth of tumor invasion, rate of preoperative diagnosis, and clinical symptoms.Results: In total, 162 papers containing 263 cases of GP met the criteria. The mean age at diagnosis was 53.5 years. The male-to-female ratio was 157:104. The mean tumor size was 25.7 mm. The predominant site of the primary tumor was the duodenum (89.7%). The most common clinical sign of GP was gastrointestinal bleeding (47.9%). Other signs and symptoms of GP included abdominal pain (44.7%), anemia (20.3%), incidental findings (12.9%), nausea (6.9%), weight loss (5.5%), general fatigue (5.1%), jaundice (4.6%), and incidental autopsy findings (5.1%). LNM was observed in 11.4% of patients. Liver metastasis was observed in 1.1% of patients. Depth of tumor invasion (penetrating beyond the submucosal layer or sphincter of Oddi) was by far the most significant risk factor for LNM in patients with GP. This suggests, along with histological heterogeneity, that GP may have hamartomatous characteristics. Furthermore, immunohistochemical expression of progesterone receptor and pancreatic polypeptide were useful in distinguishing between GP and neuroendocrine tumor G1, even in small biopsy specimens.Conclusions: We reveal the clinicopathological characteristics of GP, including risk factors for LNM, differential diagnostic approaches, and improvements in the clinical management of this tumor.In addition, GP may have hamartomatous characteristics.

Leucine-rich repeat-containing G-protein-coupled receptor 5 expression and clinicopathological features of colorectal neuroendocrine neoplasms.

LGR5 is expressed in various tumors and has been identified as a putative intestinal stem cell marker. Here we investigated LGR5 expression in colorectal neuroendocrine neoplasms and analyzed the correlation with pathological characteristics. We evaluated the clinicopathological features of 8 neuroendocrine tumor (NET) grade 1 (NET G1), 4 NET Grade 2 (NET G2), and 8 NET Grade 3 (NET G3; also termed neuroendocrine carcinoma, or NEC) cases. We examined LGR5 expression using an RNAscope, a newly developed RNA in situ hybridization technique, with a tissue microarray of the neuroendocrine neoplasm samples. LGR5 staining in individual tumor cells was semi-quantitatively scored using an H-score scale. We also performed a combination of LGR5 RNA in situ hybridization and synaptophysin immunohistochemistry. All cases contained tumor cells with some LGR5-positive dots. For all cases, H-scores showed a positive correlation with nuclear beta-catenin expression. In the NEC group, there was a strong positive correlation between H-score and beta-catenin expression. Our findings suggest that LGR5 may serve as a stem cell marker in NEC, as is the case in colon adenocarcinoma. The positive correlation between H-score and beta-catenin expression suggests that LGR5 expression might be affected by beta-catenin expression in neuroendocrine neoplasms and especially in NEC.

A 0.8-cm clear cell neuroendocrine tumor G1 of the gallbladder with lymph node metastasis: a case report

BackgroundNeuroendocrine tumors (NETs) of the gallbladder are rare and generally considered low-grade malignancies. We herein describe a case of a patient with a 0.8-cm clear cell NET G1 of the gallbladder with nodal involvement.Case presentationA 65-year-old man with no medical history indicative of von Hippel-Lindau (VHL) disease underwent laparoscopic cholecystectomy for cholecystolithiasis. There was a 0.8-cm tumor in the neck of the gallbladder. Histologic examination revealed nests or trabecular growth of clear cells with small round-to-oval nuclei. Immunohistochemically, tumor cells showed positivity for chromogranin A and synaptophysin; Ki-67 index was < 1.0%. Based on the World Health Organization 2010 classification, we made a diagnosis of clear cell variant of NET G1 without VHL disease. The tumor invaded the muscular layer and had no extension to the perimuscular connective tissue but had metastasized to a cystic duct node. A radical second resection with regional lymphadenectomy of the gallbladder was performed, and there was no metastasis on histology. After the definitive surgery, he was followed up for 10 months without adjuvant therapy and is alive and well with no evidence of recurrence.ConclusionsOur experience suggests that, even when smaller than 1 cm, NET G1 of the gallbladder can metastasize. When NET G1 is incidentally identified in the gallbladder of a surgical specimen, detailed pathologic examination of the cystic duct node, when found, should be performed to guide whether a radical second resection with regional lymphadenectomy is appropriate.

Neuroendocrine Tumor Diagnosis and Management: 68Ga-DOTATATE PET/CT.

The purpose of this article is to provide a review of the use of 68Ga tetraazacyclododecanetetraacetic acid-DPhe1-Tyr3-octreotate (DOTATATE) PET/CT, a functional imaging modality for assessment of well-differentiated neuroendocrine tumors (NETs). It has become the preferred imaging modality for initial diagnosis, selection of patients for peptide receptor radionuclide therapy, and localization of unknown primary tumors. The National Comprehensive Cancer Network guideline has added 68Ga-DOTATATE PET/CT as an appropriate test in the management of NETs. In combination with FDG PET/CT, 68Ga-DOTATATE PET/CT can noninvasively assess tumor heterogeneity, especially in G2 and G3 NETs, for personalized management of patients.

Prognostic factors of patients with gastroenteropancreatic neuroendocrine neoplasms

There is an increasing trend in the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) worldwide. The aim of the present study was to identify the prognostic factors of patients with GEP-NENs. A cross-sectional, retrospective chart review study was conducted among patients with pathologically proven GEP-NENs between January 2003 and December 2016 at Kaohsiung Chung-Gung Memorial Hospital. A total of 97 patients who met the inclusion criteria were included (male/female = 56/41, age: 57.7 ± 15.4 years). The presentation, clinical characteristics, and disease outcomes were reviewed and analyzed. The most common primary site of the GEP-NENs was the rectum (49.5%), followed by the pancreas (17.5%), duodenum (11.3%), stomach (10.3%), colon (6.2%), and appendix (5.2%), and most GEP-NENs were hormonally nonfunctional (94.8%). There were 56 tumors classified as G1 neuroendocrine tumors (NETs), 9 as G2 NETs, and 14 as G3 neuroendocrine carcinoma (NEC). Metastasis was found in 15 patients (15%). Curative treatments, such as surgery or endoscopic resection, were performed in 83.5% of patients (n = 81). The mean overall survival duration was 107.2 ± 7.8 months. The estimated 3- and 5-year overall survival rates for all patients were 84% and 82%, respectively. Logistic regression analysis showed that large tumor size, non-rectal NENs, high histopathological grading, lymphatic metastases and distant metastases were associated with poor survival. This study suggested that the presence of lymphatic or distant metastases at diagnosis is an independent risk factor for poor prognosis in patients with GEP-NENs.

Clinicopathological features and outcome of type 3 gastric neuroendocrine tumours

With the widespread use of endoscopy, small and low-grade type 3 gastric neuroendocrine tumours (NETs) are increasingly being detected. The clinicopathological features, biological behaviour and appropriate treatment strategy for these NETs remain unclear. Patients with biopsy-proven gastric NET and a normal fasting serum gastrin level were identified from a prospectively maintained database. Clinicopathological features and long-term outcome of local resection for type 3 NETs were reviewed retrospectively and compared according to tumour grade. Some 32 patients with type 3 gastric NETs were included (25 patients with NET grade G1, 5 with G2 and 2 with G3). Pathological tumour size was 2·0 cm or less in 30 patients. All tumours were well differentiated, even G3 lesions, and all tumours but one were confined to the submucosal layer. G1 NETs were significantly smaller and had a significantly lower lymphovascular invasion rate than G2 and G3 NETs. Twenty-two patients with a G1 NET without lymphovascular invasion were treated with wedge or endoscopic resection. After a median follow-up of 59 (range 6-102) months, no patient with a G1 NET of 1·5 cm or smaller developed recurrence and one patient with a G1 NET larger than 1·5 cm had recurrence in a perigastric lymph node. Among seven patients with a G2 or G3 NET, two had lymph node metastasis and one had liver metastases. Low-grade type 3 gastric NET has non-aggressive features and a favourable prognosis. Wedge or endoscopic resection may be a valid option for patients with type 3 gastric G1 NET no larger than 1·5 cm without lymphovascular invasion.

Grading of pancreatic neuroendocrine neoplasms using pharmacokinetic parameters derived from dynamic contrast-enhanced MRI.

The present study aimed to evaluate the diagnostic efficacy of pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in prospective evaluation of pancreatic neuroendocrine neoplasms (pNENs) grading. A total of 25 histologically proven patients with pNENs (30 lesions in total) who underwent DCE-MRI were enrolled. Lesions were divided into G1, G2 neuroendocrine tumor (NET) and G3 NET/neuroendocrine carcinoma (NEC) groups based on their histological findings according to 2017 World Health Organization Neuroendocrine Tumor Classification Guideline. In addition, the same numbers of tumor-free regions were selected using as normal control group. For each group, pharmacokinetic DCE parameters: volume transfer constant (Ktrans); contrast transfer rate constant (kep); extravascular extracellular space volume fraction (ve); and plasma volume fraction (vp) were calculated with Extended Tofts Linear model. Receiver operator characteristics analysis was conducted to assess the diagnostic efficacy of these parameters in pNENs grading. There were significant differences of Ktrans, kep, ve and vp between tumor-free areas and G1, G2 NET (P<0.001). The Ktrans and kep of G1 NET were significantly lower compared with those of G2 ones (P<0.005). The area under the curve of Ktrans and kep in differentiating G2 from G1 NET were 0.767 and 0.846, respectively. When Ktrans was >0.667 and kep >1.644, the sensitivity of diagnosing G2 NET was the lowest (53.85%), but the specificity was the highest (93.75%). When Ktrans was >0.667 or kep >1.644, the sensitivity of diagnosing G2 NET was 92.31%, but the specificity was 75.00%. Pharmacokinetic parameters of DCE-MRI, particularly the quantitative values of Ktrans and kep, are helpful for differentiating G2 NET from G1 ones.

Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3

Pancreatic neuroendocrine carcinoma is a rare aggressive tumor commonly harboring TP53 and RB1 alterations and lacking neuroendocrine-related genetic changes such as mutations in MEN1 and ATRX/DAXX. Little is known about its genetic profile with regard to that of pancreatic ductal adenocarcinoma. We therefore conducted a detailed genetic study in 12 pancreatic neuroendocrine carcinomas of large cell (n = 9) and small cell type (n = 3) using massive parallel sequencing applying a 409-gene panel on an Ion Torrent system. The genetic data were compared with known data of pancreatic ductal adenocarcinoma and correlated with exocrine lineage marker expression. A similar analysis was performed in 11 pancreatic neuroendocrine tumors G3. Neuroendocrine carcinomas harbored 63 somatic mutations in 45 different genes, affecting most commonly TP53 (8/12 cases), KRAS (5/12 cases), and RB1 (loss of expression with or without deletion in 4/12 cases). Five carcinomas had both TP53 and KRAS mutations. Neuroendocrine tumors G3 only shared singular mutations in 5 different genes with neuroendocrine carcinomas, including TP53, CDKN2A, ARID1A, LRP1B, and APC, affecting 5 different cases. Most KRAS-positive neuroendocrine carcinomas also expressed MUC1 (4/5) and carcinoembryonic antigen (3/5) as markers of ductal differentiation. Our data indicate that almost half of the pancreatic neuroendocrine carcinomas are genetically and phenotypically related to pancreatic ductal adenocarcinoma, and might therefore respond to chemotherapies targeting the latter carcinomas.

Hepatic intra-arterial therapies in metastatic neuroendocrine tumors: lessons from clinical practice.

Liver metastases are common in patients with neuroendocrine tumors (NETs), having a negative impact on disease prognosis. The options for selective therapy in patients with unresectable multiple liver metastases are limited to TACE (transarterial chemoembolization), TAE (transarterial embolization), or SIRT (selective internal radiation therapy). To explore the clinical outcome, survival and safety of these therapies in NETs patients. Retrospective case series of consecutive patients (mean age 56.6 years, 59% male) treated at two tertiary university medical centers from 2005 to 2015. Fifty-seven patients with G1, G2, and low G3 NETs with liver metastases were investigated (pancreatic NET (pNET), 24; small bowel, 16; unknown origin (UKO), 9; rectal, 3; lung, 3; and gastric, 2). Fifty-three patients underwent TACE, three patients underwent TAE, and one patient underwent SIRT. Clinical improvement and tumor response were observed in 54/57 patients (95%), together with marked decreased in tumor markers. The median time to tumor progression following the first treatment was 14 ± 16 months. The median overall survival was 22 ± 18 months, more pronounced in the pNET, followed by small bowel and UKO subgroups. There was a trend for a better survival in patients with disease limited to the liver and in whom the primary tumor was resected. Hepatic intra-arterial therapies are well tolerated in the majority of patients with NETs and liver metastases and associated with both clinical improvement and tumor stabilization for prolonged periods. These therapies should be always considered, irrespective of the presence of extrahepatic metastasis.