Gastrointestinal Neuroendocrine Tumors Research Articles

Progression-free survival (PFS) and subgroups analyses of lenvatinib in patients (pts) with G1/G2 advanced pancreatic (panNETs) and gastrointestinal (giNETs) neuroendocrine tumors (NETs): Updated results from the phase II TALENT trial (GETNE 1509).

332 Background: Pts with advanced G1/G2 NETs have limited treatment options with overall response rates (ORR) with targeted agents (TA) < 10%. Benefit on PFS after TA therapy has not been demonstrated. The mechanism of action of lenvatinib (VEGFR1-3 & FGFR1-4 inhibitor) may increase efficacy and revert primary and acquired resistance to TA. We report the updated results on PFS, safety and subgroups. Methods: This prospective phase II study had two cohorts: G1/G2 panNETs and giNETs. All pts had baseline documented disease progression (PD) by RECIST. For panNETs, PD to TA was mandatory, regardless prior therapy with somatostatin analogs (SSAs) or chemotherapy (CHT), and for giNETs, PD on SSAs. Pts were treated with lenvatinib at 24 mg qd until PD or intolerable toxicity. The primary endpoint was ORR by central radiology review. PFS was calculated by investigator assessment. Biochemical responses were defined as reduction from baseline > 50%. With 55 pts per arm our study was powered to identify an ORR ≥ 25% (90% power, 5% α-error). Results: We recruited 111 pts (55 panNETs/56 giNETs). Prior therapies were CHT 32%, SSAs 87%, everolimus (E) 70% and sunitinib (S) 30% for panNETs. ORR was 29%, 40% for panNETs and 18.5% for giNETs. With a median follow-up of 17 months (m), PFS for panNETs was 15.8 m (95% CI 11.4-NR) and 15.4 m (95% CI 11.5-19.5) for giNETs. Dose reductions/interruptions were needed in 91.8% with a median dose of 20 mg qd. In the subgroups analyses, all pts obtained the same benefit in PFS and ORR, including grade and prior therapy with S (PFS: 16.4 m, ORR: 43.7%) or E (PFS: 15 m, ORR: 37.1%) (p = ns). A significant correlation of chromogranin A decrease and prolonged PFS in giNETs (17.6 m vs NR, p = 0.032) was observed. The most frequent G3-4 adverse events were hypertension (20.7%), asthenia (13.5%), diarrhea (7.2%) and abdominal pain (5.4%). Conclusions: Lenvatinib showed the highest reported ORR with a TA by central radiology assessment in panNETs and giNETs with promising PFS in a pretreated population. The benefit was observed across subgroups analyses, including pretreated pts with TA. Clinical trial information: NCT02678780.

An Unusual Cause of Acute Pancreatitis in a Young Woman

Question: A 27-year-old woman presented to the emergency department with intermittent epigastric pain radiating to the back of one week’s duration. The pain was dull and associated with nausea. Her medical and family history was unremarkable. She denied any alcohol or drug intake. There was no history of fever, yellowish discoloration of the sclera or urine, or weight loss. Upon arrival, she had mild tachycardia (heart rate: 103 beats per minute). Physical examination revealed tenderness in the epigastric and right upper quadrant of the abdomen. The Murphy’s sign was negative, and there were no peritoneal signs. The remainder of the physical examination was unremarkable. Laboratory studies showed an elevated serum aspartate aminotransferase level of 176 IU/l, alanine aminotransferase of 240 IU/l, gamma-glutamyl transpeptidase of 757 IU/L, alkaline phosphatase of 308 IU/l, total bilirubin of 0.6 mg/dL, lipase of 6,641 U/L, amylase of 667 U/L, and high sensitivity C-reactive protein of 3.416 mg/L; white blood cell count, serum bilirubin, triglyceride, and calcium levels were all within normal limits. Contrast-enhanced computed tomography (CT) of the abdomen showed marked peripancreatic fat stranding, no dilatation of the biliary tract or pancreatic duct, and no evidence of regional lymphadenopathy (Figure A). An endoscopic retrograde cholangiopancreatography (ERCP) was carried out to rule out biliary pancreatitis. Duodenoscopy showed a 3-cm pedunculated tumor with a smooth surface and soft texture at the Vater’s papilla (Figure B and C). Endoscopic ultrasonography (EUS) revealed the tumor as smooth-margined, homogenous, hypoechoic lesion arising from the submucosal layer (Figure D). What is your diagnosis of the lesion of the Vater’s papilla?A.CholedochocoeleB.Neuroendocrine tumor (NET)C.Gastrointestinal stromal tumor (GIST)D.Gangliocytic paraganglioma Look on page 621 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image(s) to Practical Teaching Cases. The correct answer is D. Gangliocytic paraganglioma (GP) of the Vater’s papilla. The patient underwent surgical wedge resection of the tumor (Figure E). The histopathological examination showed the tumor located in the submucosa (Figure F, H&E, 40×). GP is typically composed of spindle cells, ganglion cells, and epithelioid cells with the appearance of neuroendocrine cells (Figure G, H&E, 200×; Figure H, H&E, 400×). There was no mitosis or necrosis in the tumor. Immunohistochemistry examination revealed that the neuroendocrine cells stained positive for CD56 and chromogranin A, and the spindle cells were immunoreactive for S100 protein. These findings confirmed the diagnosis of GP. Answer A is incorrect because choledochocele is an anechoic lesion on EUS. Gastrointestinal NETs are homogenously hypoechoic lesions arising from the second or third layer, sometimes with muscularis propria expansion (Answer B). The EUS imaging feature of a GIST is a hypoechoic mass arising from the muscularis propria, and larger GIST are sometimes composed of heterogeneous echo patterns and anechoic spaces (Answer C). However, the definitive diagnosis of the lesion requires histology. GP is a rare, generally benign neuroendocrine tumor. However, GP with regional lymph node involvement and distant metastasis have been reported.1Li B. Li Y. Tian X.Y. et al.Malignant gangliocytic paraganglioma of the duodenum with distant metastases and a lethal course.World J Gastroenterol. 2014; 20: 15454-15461Crossref PubMed Scopus (28) Google Scholar The most common site of the tumor is the second portion of the duodenum.2Okubo Y. Nemoto T. Wakayama M. et al.Gangliocytic paraganglioma: a multi-institutional retrospective study in Japan.BMC Cancer. 2015; 15: 269Crossref PubMed Scopus (28) Google Scholar, 3Okubo Y. Wakayama M. Nemoto T. et al.Literature survey on epidemiology and pathology of gangliocytic paraganglioma.BMC Cancer. 2011; 11: 187Crossref PubMed Scopus (74) Google Scholar Gastrointestinal bleeding—followed by abdominal pain and anemia—are the most common symptoms of the disease.3Okubo Y. Wakayama M. Nemoto T. et al.Literature survey on epidemiology and pathology of gangliocytic paraganglioma.BMC Cancer. 2011; 11: 187Crossref PubMed Scopus (74) Google Scholar GPs without distant metastasis are usually treated via endoscopic resection or pylorus-preserving pancreaticoduodenectomy.2Okubo Y. Nemoto T. Wakayama M. et al.Gangliocytic paraganglioma: a multi-institutional retrospective study in Japan.BMC Cancer. 2015; 15: 269Crossref PubMed Scopus (28) Google Scholar The patient recovered uneventfully and had no evidence of tumor recurrence after a surgical wedge resection of the duodenal GP at the one-year follow-up. In conclusion, GP may be an uncommon cause of acute pancreatitis. This rare and benign disease can be treated via endoscopic or surgical resection of the tumor. CME Exam 1: An Unusual Cause of Acute Pancreatitis in a Young WomanGastroenterologyVol. 157Issue 3Preview Full-Text PDF

Real-World Treatment Patterns and Clinical Outcomes in Advanced Gastrointestinal Neuroendocrine Tumors (GI NET): A Multicenter Retrospective Chart Review Study.

We assessed treatment patterns and outcomes of patients with advanced gastrointestinal (GI) neuroendocrine tumors (NET) at four large tertiary referral centers in the U.S. We performed a retrospective chart review of patients aged ≥18 years at advanced GI NET diagnosis, treated between July 2011 and December 2014. Index date was the histologically confirmed diagnosis date of locally advanced/metastatic GI NET. Data included baseline characteristics, treatment patterns, progression, death, and GI NET-related health care resource utilization from index date through last contact or death. Time-to-event analyses, including treatment discontinuation, progression, and overall survival (OS), were performed using Kaplan-Meier analysis. We identified 273 patients; 156 (57%) had primary ileum NET, and 174 (64%) had functional NET. First-line treatments included somatostatin analog (SSA) alone (89%) or in combination (2%), liver-directed therapy (LDT; 8%), and cytotoxic chemotherapy or interferon (2%). One hundred fifty-five patients continued with second-line therapy, including SSA alone (17%) or in combination (75%, with 3% combined with peptide receptor radionuclide therapy), LDT (4%), and other treatments (3%). Median time (months) to first-line discontinuation was 154.0 for SSAs and 3.8 for cytotoxic chemotherapy. Overall median time to investigator-assessed progression following treatment initiation was 30.3 months. Median OS (months) following first-line initiation was 151.8 for all patients and 178.9 for first-line SSA. Our study illustrates the common use of SSAs in both first-line and subsequent treatment of patients with GI NETs, as well as the relatively long survival durations and multiple additional treatments received by patients with this condition. Treatment pattern assessment at later times, following approval of newer treatments, is warranted. This study, assessing treatment patterns over a period of up to 30 years, showed that SSAs, LDT, cytotoxic chemotherapy, and interferon are common treatments for advanced GI NETs. SSAs alone or in combination with other treatments were the most frequent therapy in first and subsequent lines. Patients in this study remained on SSAs long-term, with median treatment duration of 12.8 years in first line. Treatment patterns should be assessed beyond this study's time period, given recent U.S. Food and Drug Administration approvals for additional treatments for GI NET, which will likely be incorporated in the continuum of care of patients.

Gastric neuroendocrine tumors

Gastrointestinal neuroendocrine tumors are rare neoplasms. Currently, incidence of gastric neuroendocrine tumors (gNETs) is being significantly increased. There are 3 groups of gNETs: types I, II and III. Each type has important features regarding clinical picture, prognosis and treatment strategy. Type I is the most common (70-80%) and associated with chronic atrophic gastritis including autoimmune gastritis and Helicobacter associated atrophic gastritis. Type II (5-6%) is associated with multiple endocrine neoplasia type I and Zollinger-Ellison syndrome (MEN I - ZES). Both types are characterized by hypergastrinemia and small tumor dimension. These neoplasms are multiple and mostly benign. On the contrary, NETs type III (10-15%) is not associated with hypergastrinemia and represented by single large neoplasms. Tumors are malignant as a rule. Therefore, surgical resection and chemotherapy are preferred for these tumors. Endoscopic surgery followed by observation is acceptable for almost all NETS type I and II. At the same time, this approach is advisable only for small and highly differentiated neoplasms type III.

Genomic dissection of gastrointestinal and lung neuroendocrine neoplasm.

ObjectiveNeuroendocrine neoplasms (NENs) are relatively rare and heterogeneous malignancies with two major subtypes: low-grade neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). Comprehensive molecular characterization of NENs is needed to refine our understanding of the biological underpinnings of different NEN subtypes and to predict disease progression more accurately.MethodsWe performed whole-exome sequencing (WES) of NEN samples from 49 patients (25 NETs and 24 NECs) arising from the stomach, intestines or lung. Clinicopathologic features were assessed and associated with molecular events.ResultsNENs generally harbor a low mutation burden, with TP53 being the top mutated gene found in 31% of patients. Consistent with other studies, p53 signaling pathway dysfunction is significantly enriched in NECs compared to NETs (P<0.01). Other thanTP53, tissue type-specific mutation profiles of NENs were observed in our cohort compared to those reported in pancreatic NETs. Importantly, we observed significant genomic instability, with increased copy number alterations observed across the NEN genome, which was more profound in NECs and independently correlated with poor overall survival (OS) (P<0.001). NECs could be further stratified into two molecular subtypes based on OS (P<0.001) and the chromosomal instability score (CIS). Interestingly, we discovered that the gain of whole chromosome 5 occurred at the early stage of NEN development, followed by the loss of 5q exclusively in NECs (P<0.001). ConclusionsThese findings provide novel insights into the molecular characteristics of NENs and highlight the association of genomic stability with clinical outcomes.

When laparoscopic liver resection is preferred to liver biopsy - a case of a neuroendocrine metastase

Background: Liver tumors can sometimes be a difficult diagnostic. Without specific imagistic findings and with negative tumor markers,. Methods: We present the case of a 63years old man who presented with a liver tumor in segment 2 with no specific findings on MRI and negative tumor markers. Colonoscopy and upper GI endoscopy were negative for any lesions. A laparoscopic liver resection was performed - segment 2-3 resection with a smooth postoperative course. The pathology result was a neuroendocrine tumor metastases. Results: Two month after the operation the gastroscopy was repeated and a small tumor was endoscopically excised from the gastric antrum. The pathology result was a gastrointestinal non-secretant neuroendocrine tumor. Conclusion: Due to an increase in the expertise in laparoscopic liver resections, a minimally invasive hepatectomy was the first step in this case.

Benign and non-neoplastic tumours of the duodenum.

This review study describes the problem of duodenal tumours, which are rare but important in gastrological practice. The most common location of small intestinal tumours is the duodenum, and this observation is probably partly due to the greater diagnostic availability for most proximal segments of the small intestine. Among tumours the following should be mentioned – benign: adenomas, lipomas, haemangiomas, and leiomyomas; and malignant: malignant tumours of epithelial origin, primary gastrointestinal stromal tumours, neuroendocrine tumours and carcinoids, lymphomas, sarcomas, teratomas, and secondary metastases. Early duodenal tumour recognition, especially with histological assessment, plays a crucial diagnostic role with future therapeutic implications. In recent years the prevalence of benign duodenal tumours has been rising due to a higher level of clinicians’ doubts and the convenience of gastrointestinal endoscopy; hence, knowledge of this problem is important in routine clinical practice. The method of duodenal tumour treatment should be selected on an individual basis.

Clinical characteristics, treatment outcomes and potential novel therapeutic options for patients with neuroendocrine carcinoma of the prostate.

BackgroundNeuroendocrine carcinomas of the prostate (NEPCs) are rare tumors with poor prognosis. While platinum and etoposide-based chemotherapy regimens (PE) are commonly applied in first-line for advanced disease, evidence for second-line therapy and beyond is very limited.MethodsRetrospective analysis of all patients with NEPCs including mixed differentiation with adenocarcinoma component and well differentiated neuroendocrine tumors (NETs, carcinoids) at two high-volume oncological centers between 12/2000 and 11/2017.ResultsOf 46 identified patients 39.1 % had a prior diagnosis of prostatic adenocarcinoma only, 43.5 % had a mixed differentiation at NEPC diagnosis, 67.4 % developed visceral metastases, 10.9 % showed paraneoplastic syndromes. Overall survival (OS) from NEPC diagnosis was 15.5 months, and significantly shorter in patients with a prior prostatic adenocarcinoma (5.4 vs. 32.7 months, p=0.005). 34 patients received palliative first-line systemic therapy with a median progression-free survival (PFS) of 6.6 months, mostly PE. Overall response rate (ORR) for PE was 48.1 %. 19 patients received second-line therapy, mostly with poor responses. Active regimens were topotecan (1 PR, 3 PD), enzalutamide (1 SD), abiraterone (1 SD), FOLFIRI (1 SD), and ipilimumab+nivolumab (1 PR). One patient with prostatic carcinoid was sequentially treated with octreotide, peptide receptor radionuclide therapy and everolimus, and survived for over 9 years.ConclusionsEP in first-line shows notable ORR, however limited PFS. For second-line therapy, topotecan, FOLFIRI, enzalutamide, abiraterone and immune checkpoint blockade are treatment options. Prostatic carcinoids can be treated in analogy to well differentiated gastrointestinal NETs.

Duodenal Malignancies

Although malignancies involving the small bowel are rare, one-third of these are located in the duodenum. The majority of duodenal tumors are adenocarcinoma but also may include gastrointestinal stromal tumors (GIST), carcinoid or neuroendocrine tumors, sarcomas, and lymphoma. These commonly present with nonspecific symptoms, but obstructive patterns predominate when symptoms are present. Preoperative diagnosis is made via endoscopy and/or cross-sectional imaging. This section focuses on treatment and surgical management for adenocarcinoma, carcinoid tumors, and GISTs of the duodenum. Surgical resection is the primary treatment of for all three of these, but all have significant nuances in surgical planning and decision-making as well as variability in the role of adjunctive treatment in their management. Functional carcinoid tumors can have hormone-driven symptoms and are associated with an increase in risk of carcinoid crisis, which may be prophylactically treated with intravenous octreotide. Resection of these tumors relies heavily on tumor relationship to the ampulla. Key anatomic distinctions and clinical tips to identify the ampulla to ensure an appropriate duodenal resection are discussed in this review. This review contains 12 figures, 5 tables, and 54 references. Key Words: carcinoid, duodenal carcinoma, duodenal adenocarcinoma, duodenal resection, duodenal tumors, neuroendocrine tumor, gastrointestinal stromal tumor, small bowel tumors

Duodenal Malignancies

Although malignancies involving the small bowel are rare, one-third of these are located in the duodenum. The majority of duodenal tumors are adenocarcinoma but also may include gastrointestinal stromal tumors (GIST), carcinoid or neuroendocrine tumors, sarcomas, and lymphoma. These commonly present with nonspecific symptoms, but obstructive patterns predominate when symptoms are present. Preoperative diagnosis is made via endoscopy and/or cross-sectional imaging. This section focuses on treatment and surgical management for adenocarcinoma, carcinoid tumors, and GISTs of the duodenum. Surgical resection is the primary treatment of for all three of these, but all have significant nuances in surgical planning and decision-making as well as variability in the role of adjunctive treatment in their management. Functional carcinoid tumors can have hormone-driven symptoms and are associated with an increase in risk of carcinoid crisis, which may be prophylactically treated with intravenous octreotide. Resection of these tumors relies heavily on tumor relationship to the ampulla. Key anatomic distinctions and clinical tips to identify the ampulla to ensure an appropriate duodenal resection are discussed in this review. This review contains 12 figures, 5 tables, and 54 references. Key Words: carcinoid, duodenal carcinoma, duodenal adenocarcinoma, duodenal resection, duodenal tumors, neuroendocrine tumor, gastrointestinal stromal tumor, small bowel tumors

SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2018)

NENs are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise across all sites, stages and grades. Although improved diagnostic techniques have led to earlier detection and stage migration, the improved prognosis documented over time for advanced gastrointestinal and pancreatic neuroendocrine tumors also reflect improvements in therapy. The aim of this guideline is to update practical recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification and therapeutic options are briefly discussed, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, and treatment algorithms are provided.

Where to "cut-off"?

Where to "cut-off"?

Ghrelin-O-Acyltransferase (GOAT) Enzyme as a Novel Potential Biomarker in Gastroenteropancreatic Neuroendocrine Tumors.

ObjectivesThe association between the presence and alterations of the components of the ghrelin system and the development and progression of neuroendocrine tumors (NETs) is still controversial and remains unclear.MethodsHere, we systematically evaluated the expression levels (by quantitative-PCR) of key ghrelin system components of in gastroenteropancreatic (GEP)-NETs, as compared to non-tumor adjacent (NTA; n = 42) and normal tissues (NT; n = 14). Then, we analyzed their putative associations with clinical-histological characteristics.ResultsThe results indicate that ghrelin and its receptor GHSR1a are present in a high proportion of normal tissues, while the enzyme ghrelin-O-acyltransferase (GOAT) and the splicing variants In1-ghrelin and GHSR1b were present in a lower proportion of normal tissues. In contrast, all ghrelin system components were present in a high proportion of tumor and NTA tissues. GOAT was significantly overexpressed (by quantitative-PCR (qPCR)) in tumor samples compared to NTA, while a trend was found for ghrelin, In1-ghrelin and GHSR1a. In addition, expression of these components displayed significant correlations with key clinical parameters. The marked overexpression of GOAT in tumor samples compared to NTA regions was confirmed by IHC, revealing that this enzyme is particularly overexpressed in gastrointestinal NETs, where it is directly correlated with tumor diameter.ConclusionsThese results provide novel information on the presence and potential pathophysiological implications of the ghrelin system components in GEP-NETs, wherein GOAT might represent a novel diagnostic biomarker.

A Rare Case of Gastric Neuroendocrine Tumor in a Patient with History of Familial Adenomatous Polyposis - Is There an Association?

Familial adenomatous polyposis (FAP), is one of the genetic colorectal cancer syndromes. It is an autosomal dominant inherited disease caused by a somatic mutation in the APC tumor suppressor gene on the chromosome 5q21 with an estimated prevalence of this syndrome between 1 per 5,000-7,000. Adenomatous polyps of the upper intestinal tract (gastric, duodenal, periampullary, and ileal adenomas) are also commonly found in familial adenomatous polyposis (FAP). Gastric neuroendocrine tumors (GNETs) are a rare disease with a reported incidence of 1 to 2 cases/1,000,000 persons per year, comprising 8.7% of gastrointestinal neuroendocrine tumors. Rarely have GNETs been associated with FAP. We present a rare case of gastric neuroendocrine tumor in a patient with FAP. A 56-year-old woman with a past medical history of hypertension, hyperlipidemia, type 2 diabetes, hypothyroidism and FAP with a history of colectomy performed in 1989. As part of her surveillance for extracolonic manifestations of FAP, an Upper endoscopy was performed. Upper endoscopy revealed few 2-3mm gastric body and antral polyps, and multiple 2-3 mm polyps in the duodenal bulb.(Figure 1) Duodenal biopsy showed tubular adenomas. Biopsy of the gastric polyps revealed tubular adenomas with low-grade dysplasia and a low-grade neuroendocrine neoplasm. The tumor cells were positive for pancytokeratin (AE1/AE3), synaptophysin and chromogranin staining and were negative for CD3, CD20, and CD138, consistent with a diagnosis of neuroendocrine tumor. (Figure 2).The patient is undergoing further workup including a magnetic resonance imaging of abdomen and pelvis, and an octreotide scan to stage her disease.2663_A Figure 1. Endoscopic view of gastric and duodenal polyps2663_B Figure 2. Synaptophysin Positive, 400x, confirming presence of carcinoid tumor cells.Gastrointestinal neuroendocrine tumors may be found in association with neurofibromatosis (periampullary carcinoids), Zollinger-Ellison, and multiple endocrine neoplasia syndromes and have rarely been reported in association with FAP. Patients with FAP have dysregulation of the Wnt/b-catenin signaling pathway. Recent findings of b-catenin mutations in neuroendocrine tumors suggest that Wnt/b-catenin alterations may be the common pathway for both tumors. The presence of these two rare entities in the same patient might suggest an association and further research is indicated to determine this association.

Diagnostic imaging of gastrointestinal neuroendocrine tumours (GI-NETs): relationship between MDCT features and 2010 WHO classification.

We aimed to present our series of gastrointestinal neuroendocrine tumours (GI-NETs) in order to illustrate and highlight the associated contrast-enhanced multi-detector computed tomography (MDCT) features. We also attempted to identify a relationship between MDCT imaging and the 2010 World Health Organization (WHO) classification system. We selected all patients with pathologically proven GI-NETs diagnosed between January 2010 and August 2017. Only patients undergone contrast-enhanced MDCT imaging in the immediate preoperative period were included in our study. Later, two expert radiologists retrospectively assessed MDCT intestinal and extra-intestinal signs. We also analysed the relationship between MDCT imaging and the 2010 WHO classification. A total of 20 patients (13 males, 7 females, age range 37-89years, mean age 69.9years) were included in our study. The majority of GI-NETs (85%) occurred in the small bowel and mainly in the terminal ileum. Forty-five percentage of our GI-NETs were diagnosed after an access to emergency medical service for obstruction symptoms or gastrointestinal bleeding. Regarding intestinal signs, 15/20 patients showed an intraluminal nodular mass and 5/20 a wall thickening. Extra-intestinal signs were present in 75% of cases. Desmoplastic reaction and lymph nodes metastases were significantly correlated with higher grade of GI-NETs. The majority of GI-NETs appears as intraluminal mass often associated with extra-intestinal signs. We found a significantly correlation between higher grade of GI-NETs and extra-intestinal signs. MDCT imaging may be useful in predicting the pathological classification of GI-NETs.

Everolimus, lutetium-177 DOTATATE and sunitinib for advanced, unresectable or metastatic neuroendocrine tumours with disease progression: a systematic review and cost-effectiveness analysis.

Neuroendocrine tumours (NETs) are a group of heterogeneous cancers that develop in cells in the diffuse neuroendocrine system. To estimate the clinical effectiveness of three interventions [everolimus (Afinitor®; Novartis International AG, Basel, Switzerland), lutetium-177 DOTATATE (177Lu-DOTATATE) (Lutathera®; Imaging Equipment Ltd, Radstock, UK) and sunitinib (Sutent®; Pfizer Inc., New York, NY, USA)] for treating unresectable or metastatic NETs with disease progression and establish the cost-effectiveness of these interventions. The following databases were searched from inception to May 2016: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE Daily, Epub Ahead of Print, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science. We systematically reviewed the clinical effectiveness and cost-effectiveness literature on everolimus, 177Lu-DOTATATE and sunitinib for treating advanced, unresectable or metastatic progressive NETs. The following NET locations were considered separately: pancreas, gastrointestinal (GI) tract and lung, and GI tract (midgut only). We wrote a survival partition cohort-based economic evaluation in Microsoft Excel® 2013 (Microsoft Corporation, Redmond, WA, USA) from the UK NHS and Personal Social Services perspective. This comprised three health states: (1) progression-free survival (PFS), (2) progressed disease and (3) death. Three randomised controlled trials (RCTs), RADIANT-3 [RAD001 in Advanced Neuroendocrine Tumors, Third Trial; pancreatic NETs (pNETs): everolimus vs. best supportive care (BSC)], A6181111 (pNETs: sunitinib vs. BSC) and RADIANT-4 (RAD001 in Advanced Neuroendocrine Tumors, Fourth Trial; GI and lung NETs: everolimus vs. BSC), met the inclusion criteria for the clinical effectiveness systematic review. The risk of bias was low. Although the NETTER-1 (Neuroendocrine Tumors Therapy) RCT, of 177Lu-DOTATATE plus 30 mg of octreotide (Sandostatin®, Novartis) compared with 60 mg of octreotide, was excluded from the review, we nonetheless present the results of this trial, as it informs our estimate of the cost-effectiveness of 177Lu-DOTATATE. The pNETs trials consistently found that the interventions improved PFS and overall survival (OS) compared with BSC. Our indirect comparison found no significant difference in PFS between everolimus and sunitinib. Estimates of OS gain were confounded because of high rates of treatment switching. After adjustment, our indirect comparison suggested a lower, but non-significant, hazard of death for sunitinib compared with everolimus. In GI and lung NETs, everolimus significantly improved PFS compared with BSC and showed a non-significant trend towards improved OS compared with BSC. Adverse events were more commonly reported following treatment with targeted interventions than after treatment with BSC. In the base case for pNETs, assuming list prices, we estimated incremental cost-effectiveness ratios (ICERs) for everolimus compared with BSC of £45,493 per quality-adjusted life-year (QALY) and for sunitinib compared with BSC of £20,717 per QALY. These ICERs increased substantially without the adjustment for treatment switching. For GI and lung NETs, we estimated an ICER for everolimus compared with BSC of £44,557 per QALY. For GI (midgut) NETs, the ICERs were £199,233 per QALY for everolimus compared with BSC and £62,158 per QALY for a scenario analysis comparing 177Lu-DOTATATE with BSC. We judge that no treatment meets the National Institute for Health and Care Excellence's (NICE) end-of-life criteria, although we cannot rule out that sunitinib in the A6181111 trial does. A RCT with included comparators was not identified for 177Lu-DOTATATE. The indirect treatment comparison that our economic analysis was based on was of a simple Bucher type, unadjusted for any differences in the baseline characteristics across the two trials. Given NICE's current stated range of £20,000-30,000 per QALY for the cost-effectiveness threshold, based on list prices, only sunitinib might be considered good value for money in England and Wales. Further analysis of individual patient data from RADIANT-3 would allow assessment of the robustness of our findings. The data were not made available to us by the company sponsoring the trial. This study is registered as PROSPERO CRD42016041303. The National Institute for Health Research Health Technology Assessment programme.

Synchronous Triple Neoplasms in a Patient with von Recklinghausen’s Disease: Gastrointestinal Stromal Tumor and Neuroendocrine Tumor in the Periampullary Region, and Schwannoma in the Neck of the Gallbladder

von Recklinghausen病（以下，VR病と略記）に十二指腸gastrointestinal stromal tumor（以下，GISTと略記），十二指腸乳頭神経内分泌腫瘍，神経鞘腫を合併した1例を経験した．症例は45歳の男性で，黒色便を認め受診した．上部消化管内視鏡検査で十二指腸水平脚に粘膜下腫瘍を認めた．造影CTで十二指腸水平脚28 mm大，十二指腸乳頭8 mm大，胆囊頸部35 mm大の腫瘤を認めた．以上の所見から，VR病に伴う十二指腸多発GIST，胆囊神経鞘腫と診断し幽門輪温存膵頭十二指腸切除術を行った．病理診断は十二指腸水平脚腫瘍はGIST，十二指腸乳頭腫瘍は神経内分泌腫瘍，胆囊頸部腫瘍は神経鞘腫であった．術後補助療法は行わず19か月無再発生存中である．VR病で併存疾患を検討する際は，組織学的に異なる起源の腫瘍が同時期に発生する可能性を考慮し全消化管の検索が重要である．

ACTH-Secreting Neuroendocrine Carcinoma of the Cecum: Case Report and Review of the Literature

BackgroundApproximately 30% of neuroendocrine tumors (NETs) present with secretory syndromes or develop one during the course of the disease. Cushing syndrome caused by a gastrointestinal tract NET is rare, with limited published information. We describe a patient with florid Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) from a NET of colonic origin. A literature review was conducted to describe the spectrum of this clinical and pathologic entity as reported in the scientific literature. Patient and MethodsNext-generation sequencing and microsatellite instability testing was carried out on the tumor from our case. A preliminary PubMed search was conducted using the following terms under the publication type “Case Reports”: “Cushing” AND “colon,” “neuroendocrine” AND “colon” and “neuroendocrine AND Cushing AND “colon.” A manual search was performed to review all references for inclusion and relevant clinical, biochemical and pathologic data was abstracted. ResultsMutations in BRAF V600E and TP53 were detected in our case. We retrieved 18 previously reported cases of Cushing syndrome associated with a NET of colonic origin, none of which had next-generation sequencing performed. Median age at diagnosis was 54.5 years (range, 24-74 years), with equal gender distribution. ACTH was detected by immunohistochemistry in the primary tumor and/or metastatic lesion in 61.5%. Review of the reports suggested that ectopic ACTH secretion from a colonic tumor might be more common in mixed glandular and NETs, including mixed adenocarcinoma–neuroendocrine carcinoma. Among studies reporting outcomes, the unadjusted mortality rate was 77.7%, with median overall survival from presentation of 63 days (range, 17-380 days). ConclusionCushing syndrome associated with ectopic ACTH from tumors of colonic origin is a rare phenomenon with poor outcomes and can be associated with pure NETs, adenocarcinomas, and mixed-phenotype tumors, including mixed adenocarcinoma–neuroendocrine carcinoma.

Ampullary neuroendocrine neoplasms: surgical experience of a rare and challenging entity

Ampullary neuroendocrine neoplasms (NENs) account for < 0.3% of gastrointestinal NENs. Surgical options include transduodenal ampullectomy/tumour excision or pancreaticoduodenectomy (PD). We report the experience of two high-volume pancreatic surgical centres of ampullary NENs. Clinical records of patients who underwent surgery for ampullary NENs (January 2007-November 2017) in the study centres were retrieved retrospectively. We evaluated clinical-pathological features, post-operative outcome and follow-up (FU). Eighteen patients (9 M/9 F, averaging 62years) were enrolled. All but one were non-functioning NENs; four (22%) patients presented with jaundice. Seven (39%) of the patients underwent ampullectomy/excision (median tumour size 1.5cm), and 11 (61%) patients underwent PD (median tumour size 2.4cm). The median operation time of ampullectomy/excision was 221min with operative blood loss of 75ml (vs. 506min and 425ml in PD). The median hospital stay was 10days in both groups. Overall surgical morbidity was 33%, due to four biochemical leaks, one pancreatic fistula and one abdominal haemorrhage. No reoperations were needed. The median tumour size was 1.8 (range 0.5-6.7)cm. All G2-G3 NENs were N1 (vs. 1/7 in G1 NENs). Three (17%) cases were mixed exocrine/G3 NECs. After a median FU of 45 (up to 124)months, recurrence occurred in four G3 NEC (31%) patients (median disease-free survival 14months) after an R0 PD. Disease-related survival was 93, 77 and 66% at 1, 3 and 5years, respectively. Ampullary NENs are mostly G1-G2 neoplasms. Lymph node metastases rarely occur in G1 NENs < 2cm in size, which may be treated with ampullectomy/excision. Survival is 66% 5years after surgery.

Histopathology of Neuroendocrine Neoplasms of the Gastrointestinal System

Tumors arising from neuroendocrine cells are defined as epithelial neoplasms with predominantly neuroendocrine differentiation. They comprise a distinct group of tumors with a characteristic histological structure and functional properties that develop at various sites, particularly the gastrointestinal system (67%) and lungs (25%). Although such tumors are usually slow-growing and indolent, almost all have malignant potential and most can produce active hormones. Clinical signs vary, and many are dependent on the site at which the tumor develops. Although these tumors were identified more than 130 years, their classification remains unclear. This review provides a comprehensive overview of the human neuroendocrine system and its neoplasms, from their discovery to current terminology and classifications. In addition, the clinical symptomatology and macroscopic/microscopic features of tumors arising from endocrine cells of the gastrointestinal tract are described, with an emphasis on their classification, diagnostic criteria for their grading and TNM (tumor, node, metastasis) staging, and how these tumors differ according to their localization in the gastrointestinal tract. Tumors arising from neuroendocrine cells are rare and can cause typical symptoms of carcinoid syndrome. However, most of these tumors are asymptomatic, which, together with their typical small size and localization in the gut, makes them difficult to access endoscopically and often leads to diagnosis at an advanced stage. To successfully diagnose and treat tumors arising from neuroendocrine cells, they should be assessed using a differential diagnostic procedure and be histopathologically classified, graded, and staged according to specified criteria and the latest classifications and guidelines. Although the terms "carcinoid", "neuroendocrine tumor", and "neuroendocrine carcinoma" are often used synonymously in the literature and by professionals, more precise terminology is required for nomenclature and classification. Key words: gastrointestinal neuroendocrine neoplasms - neuroendocrine tumors - neuroendocrine carcinomas - classification - NET - NEC The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 21. 3. 2018 Accepted: 16. 4. 2018.