Michelle K. Kim

Consensus guidelines for the management and treatment of neuroendocrine tumors.

Neuroendocrine tumors are a heterogeneous group of tumors originating in various anatomic locations. The management of this disease poses a significant challenge because of the heterogeneous clinical presentations and varying degrees of aggressiveness. The recent completion of several phase 3 trials, including those evaluating octreotide, sunitinib, and everolimus, demonstrate that rigorous evaluation of novel agents in this disease is possible and can lead to practice-changing outcomes. Nevertheless, there are many aspects to the treatment of neuroendocrine tumors that remain unclear and controversial. The North American Neuroendocrine Tumor Society published a set of consensus guidelines in 2010, which provided an overview for the treatment of patients with these malignancies. Here, we present a set of consensus tables intended to complement these guidelines and serve as a quick, accessible reference for the practicing physician.

Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature

Based on the current medical literature, the worldwide incidence of neuroendocrine tumours (NETs) seems to have increased; however, a systematic literature overview is lacking. This study aimed to collect all available data on the incidence of gastroenteropancreatic (GEP)-NETs and characteristics of population to establish their epidemiology. A sensitive MEDLINE search was carried out. The papers were selected via a cascade process that restricted the initial pool of 7991 articles to 33, using predefined inclusion and exclusion criteria. Original articles evaluating the incidence of sporadic GEP-NETs in regional, institutional and national registries were considered. The majority of data originated from the US National Cancer Institute Surveillance, Epidemiology and End Results database and from national cancer registries in Western Europe. Generally, because of the retrospective nature of existing databases the outcomes of studies might be biased, which hinders the drawing of firm conclusions. The age-adjusted incidence of GEP-NETs has increased steadily over the past four decades (1973-2007), increasing 3.65-fold in the USA and 3.8- to 4.8-fold in the UK. Incidence has changed variably from one anatomical site to another. The greatest increase in incidence occurred for gastric and rectal NETs, while the smallest increase occurred for small intestine NETs. There were gender and racial differences, which differed site by site and, in some cases, changed over time. The incidence rates (IRs) of GEP-NETs have increased significantly in the last 40 years. Data are only available from North America, Western Europe and Japan. A site-by-site analysis revealed that the IRs of some NETs increased more than those of others.

Gastroduodenal Ulceration Associated with Radioembolization for the Treatment of Hepatic Tumors: An Institutional Experience and Review of the Literature

BackgroundMicrosphere radioembolization is a method of delivering radiation therapy directly to tumors, thereby minimizing toxicity to adjacent structures. Despite the relatively high precision of this modality, numerous adverse effects have been recognized. One particularly untoward complication is the development of severe gastroduodenal ulceration.MethodsIn order to further characterize gastroduodenal ulceration associated with radioembolization, our institutional experience as well as the reported literature were reviewed.ResultsThe current evidence suggests that radioembolization-associated gastroduodenal ulceration results from inadvertent delivery of microspheres to the microvasculature of the gastrointestinal tract, leading to direct radiation toxicity. The reported incidence of this entity ranges between 2.9% and 4.8%. Most patients with this complication present with abdominal pain, often associated with nausea, vomiting, and anorexia. Symptoms can arise from hours to months after radioembolization treatment; diagnosis is made by endoscopic biopsy and histopathologic evaluation of the ulcer specimen. Radiation-induced ulcers have proven to be extremely difficult to treat. Current therapy based on acid suppression has had limited success, and the evidence for the addition of antioxidants and anti-inflammatory agents is still sparse.ConclusionsThe increasing utilization of radioembolization will lead to adverse events including gastroduodenal ulceration. This entity must be considered in any patient treated with radioactive microspheres presenting with symptoms of dyspepsia. Accurate diagnosis and aggressive treatment are necessary to improve patient outcomes.

Neuroendocrine tumors of the pancreas: endoscopic diagnosis.

Purpose of review Endoscopic ultrasound (EUS) is a valuable tool in the diagnosis and management of pancreatic neuroendocrine tumors. This review highlights advances over the last year in EUS in the evaluation of pancreatic neuroendocrine tumors. Recent findings We will focus on recent findings regarding the accuracy of EUS, EUS-guided fine needle aspiration (EUS-fine needle aspiration), emerging cytologic markers obtained from fine needle aspiration samples, and the role of EUS screening for patients with multiple endocrine neoplasia type 1 syndrome. Additionally, we will introduce potential therapeutic EUS interventions in the treatment of pancreatic neuroendocrine tumors. Summary The present review highlights recent advances in the utility of EUS in the clinical management of pancreatic neuroendocrine tumors. Key studies from the last year demonstrate the important role of EUS in the diagnosis, prognosis, and treatment of pancreatic neuroendocrine tumors.

Endoscopic Ultrasound in Gastroenteropancreatic Neuroendocrine Tumors

Endoscopic ultrasound (EUS) is an advanced endoscopic technique currently used in the staging and diagnosis of many gastrointestinal neoplasms. The proximity of the echoendoscope to the gastrointestinal tract lends itself to a detailed view of the luminal pathology and the pancreas. This unique ability enables endoscopists to use EUS in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Diagnostic EUS allows previously unidentified NETs to be localized. EUS also determines tumor management by staging the GEP-NETS, enabling the clinicians to choose the appropriate endoscopic or surgical management. The ability to obtain a tissue diagnosis with EUS guidance enables disease confirmation. Finally, recent developments suggest that EUS may be used to deliver therapeutic agents for the treatment of NETs. This review will highlight the advances in our knowledge of EUS in the clinical management of these tumors.

Diagnostic yield and safety of jumbo biopsy forceps in patients with subepithelial lesions of the upper and lower GI tract

BACKGROUND EUS-FNA often fails to make a definitive diagnosis in the evaluation of subepithelial lesions. The addition of jumbo biopsy forceps has the potential to improve diagnostic yield, but published series are limited. OBJECTIVE To assess the likelihood of definitive diagnosis for subepithelial lesions by using jumbo biopsy forceps during EUS examination. DESIGN Pooled retrospective analysis. SETTING 6 tertiary referral centers. PATIENTS All patients having undergone EUS examination for a subepithelial lesion in which jumbo biopsy forceps were used for tissue acquisition. MAIN OUTCOME MEASUREMENTS Diagnostic yield of jumbo biopsy forceps use, complication rates, and comparison of diagnostic yield with that of EUS-FNA. RESULTS A total of 129 patients underwent EUS with jumbo biopsy forceps; 31 patients (24%) had simultaneous EUS-FNA. The lesion locations were stomach (n = 98), esophagus (n = 14), duodenum (n = 11), colon (n = 5), and jejunum (n = 1). The average lesion size was 14.9 mm ± 9.3 mm. Overall, definitive diagnosis was obtained in 87 of 129 patients (67.4%) by using either method. A definitive diagnosis was provided by jumbo biopsy forceps use in 76 of 129 patients (58.9%) and by FNA in 14 of 31 patients (45.1%) (P = .175). The results in third-layer lesions were definitive with jumbo biopsy forceps in 56 of 86 lesions (65.1%) and with FNA in 6 of 16 lesions (37.5%) (P = .047). For fourth-layer lesions, the results with jumbo biopsy forceps were definitive in 10 of 25 (40.0%) and with FNA in 8 of 14 (57.1%) (P = .330). Forty-five of 129 patients (34.9%) experienced significant bleeding after biopsy with jumbo forceps and required some form of endoscopic hemostasis. LIMITATIONS Retrospective study. CONCLUSIONS Jumbo forceps are a useful tool for the definitive diagnosis of subepithelial lesions. The greatest benefit appears to be with third-layer (submucosal) lesions. The risk of bleeding is significant.

Clinical and Prognostic Features of Rectal Neuroendocrine Tumors

Background: Rectal neuroendocrine tumors (NETs) are among the most common NETs. The aim was to validate European Neuroendocrine Tumor Society (ENETS)/North American Neuroendocrine Tumor Society (NANETS) staging and grading systems with regard to clinical outcomes. Methods: A comprehensive database was constructed from existing databases of the Mount Sinai Division of Gastrointestinal Pathology and the Carcinoid Cancer Foundation. Analysis was performed on 141 patients identified with rectal NETs seen at Mount Sinai Hospital between 1972 and 2011. Results: The median age was 52.7 years; 43% were males. Average tumor size was 0.88 cm. NETs <1 cm accounted for 75.6% of the tumors. Stage I, II, III and IV accounted for 79.4, 2.8, 5.0 and 12.8% of the tumors, respectively. G1 tumors accounted for 88.1%, G2 8.3% and G3 3.6%. Of G1 tumors, 94.6% were stage I and 5.4% were stage IV. The median survival time for all 141 patients was 6.8 years (range, 0.8-34.7 years). The overall 5-year survival rate was 84.4%. The 5-year survival rates for patients in stages I-IV were 92.7, 75.0, 42.9 and 33.2%, respectively. The 5-year survival rates for patients with G1-G3 tumors were 87.7, 47.6 and 33.3%, respectively. Univariate analysis of increased survival showed significance for lower stage, lower grade, smaller size, absence of symptoms and endoscopically treated tumors. Multivariate analysis showed that stage alone was statistically significant as the strongest predictor of survival. Conclusion: The results of our study validated ENETS/NANETS guidelines for staging and grading of rectal NETs in the US setting of a tertiary referral center. Staging according to ENETS/NANETS guidelines should be used in the treatment algorithm rather than size alone.

Feasibility and preliminary accuracy of high-resolution imaging of the liver and pancreas using FNA compatible microendoscopy (with video).

BACKGROUND EUS-guided FNA is one of the few techniques that can obtain cells and tissue from the liver and pancreas. However, the technique remains vulnerable to poor specimen quality and sampling error. OBJECTIVE To evaluate the ability of a high-resolution microendoscope (HRME) to visualize the cellular and architectural features of normal and malignant liver and pancreatic tissue ex vivo, to assess the ability of endosonographers to identify normal and neoplastic tissue by using HRME images, and to demonstrate preliminary technical feasibility of in vivo HRME imaging via EUS fine-needle puncture (FNP). DESIGN Ex vivo pilot feasibility study in human tissue; in vivo swine model. SETTING Two academic medical centers. PATIENTS Co-registered HRME images and biopsies were obtained from surgically resected hepatic and pancreatic tissues from 44 patients. INTERVENTION Images were divided into training (12 images) and test (80 images) sets containing a range of normal and pathologic conditions for each organ. After viewing the training sets, 9 endosonographers attempted to distinguish malignant tissue from normal or benign lesions in the test sets, each of which contained 40 unique images with individual diagnoses from pathology. MAIN OUTCOME MEASUREMENTS Image acquisition feasibility, ex vivo and in vivo. Ability of endosonographers to recognize features of normal/benign or malignant tissue from the liver and pancreas. RESULTS Overall, the 9 endosonographers achieved median accuracy figures of 85% in the liver and 90% in the pancreas. The endosonographers with prior experience in reading HRME images achieved accuracy rates between 90% and 95%. Technical feasibility of HRME imaging through a 19-gauge EUS-FNP needle was demonstrated in an in vivo swine model. LIMITATIONS Ex vivo study. CONCLUSION High-resolution microendoscopy allows real-time imaging of cellular-level morphology and tissue architecture in the liver and pancreas. The technique appears to have a short learning curve, after which endosonographers achieved high accuracy rates in distinguishing malignant tissue from normal and benign pathology in both organs. Translating this imaging platform to the in vivo setting appears technically feasible.

The Surgical Management of Small Bowel Neuroendocrine Tumors: Consensus Guidelines of the North American Neuroendocrine Tumor Society

Abstract Small bowel neuroendocrine tumors (SBNETs) have been increasing in frequency over the past decades, and are now the most common type of small bowel tumor. Consequently, general surgeons and surgical oncologists are seeing more patients with SBNETs in their practices than ever before. The management of these patients is often complex, owing to their secretion of hormones, frequent presentation with advanced disease, and difficulties with making the diagnosis of SBNETs. Despite these issues, even patients with advanced disease can have long-term survival. There are a number of scenarios which commonly arise in SBNET patients where it is difficult to determine the optimal management from the published data. To address these challenges for clinicians, a consensus conference was held assembling experts in the field to review and discuss the available literature and patterns of practice pertaining to specific management issues. This paper summarizes the important elements from these studies and the recommendations of the group for these questions regarding the management of SBNET patients.

Revised Staging Classification Improves Outcome Prediction for Small Intestinal Neuroendocrine Tumors

PURPOSE Small intestinal (SI) neuroendocrine tumors (NETs) have heterogeneous outcomes. The NET societies have recently proposed a TNM staging classification. In this study, we used population-based data to assess the validity of the staging system. PATIENTS AND METHODS We identified patients with SI-NETS diagnosed between 1988 and 2009 from the Surveillance, Epidemiology, and End Results registry. We used Kaplan-Meier analysis to assess disease-specific survival according to TNM status. Cox models were constructed to evaluate differences in prognosis after controlling for potential confounders. RESULTS We identified 6,792 patients with SI-NET. Although the current staging system was predictive of prognosis, there was overlap among some groups (stage I/IIA, P = .36; stage IIB/IIIB, P = .70). Additionally, stage IIIB patients had better survival than stage IIIA patients (P < .001). Adjusted analyses showed similar outcomes for T1 versus T2 disease (hazard ratio [HR], 1.02; 95% CI, 0.63 to 1.66). Patients with T3 (HR, 3.60; 95% CI, 2.28 to 5.69) and T4 (HR, 5.50; 95% CI, 3.42 to 8.86) tumors had significantly worse survival than patients with T1 disease. N1 involvement conferred worse survival in T1 (HR, 3.08; 95% CI, 1.75 to 5.44) and T2 disease (HR, 2.73; 95% CI, 1.84 to 4.07) but not in T3 (HR, 0.99; 95% CI, 0.76 to 1.30) or T4 (HR, 0.98; 95% CI, 0.71 to 1.35) disease. A revised classification showed no overlap in survival across groups. CONCLUSION Progressively more advanced T status is associated with worse SI-NET prognosis. Regional lymph node involvement is a marker of worse survival only among patients with T1 or T2 status. These results suggest that revisions to the current staging classification may be helpful.