Gastrointestinal neuroendocrine tumors in 2020

Gastrointestinal neuroendocrine tumors are rare slow-growing tumors with distinct histological,biological,and clinical characteristics that have increased in incidence and prevalence within the last few decades.They contain chromogranin A,synaptophysin and neuron-specific enolase which are necessary for making a diagnosis of neuroendocrine tumor.Ki-67 index and mitotic index correlate with cellular proliferation.Serum chromogranin A is the most commonly used biomarker to assess the bulk of disease and monitor treatment and is raised in both functioning and non-functioning neuroendocrine tumors.Most of the gastrointestinal neuroendocrine tumors are non-functional.World Health Organization updated the classification of neuroendocrine tumors in 2017 and renamed mixed adenoneuroendocrine carcinoma into mixed neuroendocrine neoplasm.Gastric neuroendocrine tumors arise from enterochromaffin like cells.They are classified into 4 types.Only type I and type II are gastrin dependent.Small intestinal neuroendocrine tumor is the most common small bowel malignancy.More than two-third of them occur in the terminal ileum within 60 cm of ileocecal valve.Patients with small intestinal neuroendrocrine tumors frequently show clinical symptoms and develop distant metastases more often than those with neuroendocrine tumors of other organs.Duodenal and jejunoileal neuroendocrine tumors are distinct biologically and clinically.Carcinoid syndrome generally occurs when jejuno-ileal neuroendocrine tumors metastasize to the liver.Appendiceal neuroendocrine tumors are generally detected after appendectomy.Colonic neuroendocrine tumors generally present as a large tumor with local or distant metastasis at the time of diagnosis.Rectal neuroendocrine tumors are increasingly being diagnosed since the implementation of screening colonoscopy in 2000.Gastrointestinal neuroendocrine tumors are diagnosed and staged by endoscopy with biopsy,endoscopic ultrasound,serology of biomarkers,imaging studies and functional somatostatin scans.Various treatment options are available for curative and palliative treatment of gastrointestinal neuroendocrine tumors.

Real-world treatment patterns of gastrointestinal neuroendocrine tumors: A claims database analysis

AIM To describe real-world treatment patterns of gastrointestinal neuroendocrine tumors(GI NET).METHODS In this retrospective cohort study,we used 2009-2014 data from 2 United States commercial claims databases to examine newly pharmacologically treated patients using tabular and graphical techniques. Treatments included somatostatin analogues(SSA),cytotoxic chemotherapy(CC),targeted therapy(TT),interferon(IF) and combinations. We identified patients at least 18 years of age,with ≥ 1 inpatient or ≥ 2 outpatient claims for GI NET who initiated pharmacologic treatment from 7/1/09-6/30/14. A 6 mo clean period prior to first treatment ensured patients were newly treated. Patients were followed until end of enrollment or the study end date,whichever was first.RESULTS We identified 2258 newly treated GI NET patients: mean(SD) age was 55.6 years(SD = 9.7),47.2% of the patients were between 55 and 64 years,and 48.8% were female. All regions of the United States were represented. 59.6% started first-line therapy with SSA monotherapy(964 with octreotide LAR,380 with octreotide SA,and 1 with lanreotide),33.3% CC,3.6% TT,and 0.5% IF. The remainder received combinations. Mean follow up was 576 d. Overall mean first-line therapy duration was 361 d(449 d for SSA,215 for CC,267 for TT). 58.9% of patients had no pharmacological treatment beyond first line. The most common secondline was combination therapy with SSA. In graphical pattern analysis,there was no clear pattern visible after first line therapy.CONCLUSION In this study,60% of patients initiated treatment with SSA alone or in combination. The relatively long time to discontinuation suggests possible sustained effectiveness and tolerability.

Predictive factors associated with carcinoid syndrome in patients with gastrointestinal neuroendocrine tumors

AIM To discover unknown factors associated with carcinoid syndrome(CS) with the goal of earlier diagnosis of CS.METHODS In this retrospective case-control study using United States administrative claims, patients(≥ 18 years) newly-diagnosed with gastrointestinal neuroendocrine tumors(GI NETs) without CS(controls) were exactly matched to patients with CS(cases) based on NET diagnosis date at a 3-to-1 ratio. Study index date was first CS diagnosis(controls: same distance from NET diagnosis as cases). The most observed conditions, excluding CS-associated symptoms/diagnoses, during the year before index date were assessed. Forwardstepwise logistic regression models were used to derive predictors, and were validation within another claims database. RESULTS In the development database, 1004 patients with GI NETs were identified; 251(25%) had CS and 753(75%) were controls. In the validation database, 724 patients with GI NETs were identified; 181(25%) had CS and 543(75%) were controls. A total of 33 common diagnoses(excluding conditions already known to be associated with CS) in the development database were entered in forward step-wise logistic regression models. In the final, validated logistic regression model, three factors prior to CS diagnosis were found consistently associated with higher risks for CS, including liver disorder [odds ratio(95%CI): 3.38(2.07-5.51)], enlargement of lymph nodes [2.13(1.10-4.11)], and abdominal mass [3.79(1.87-7.69)].CONCLUSION GI NET patients with CS were 2-4 times as likely to have preexisting diagnoses(i.e., liver disorder, enlarged lymph nodes, abdominal mass) than non-CS patients.

Molecular factors,diagnosis and management of gastrointestinal tract neuroendocrine tumors:An update

The prevalence of gastrointestinal neuroendocrine tumors(GI-NETs) is increasing,and despite recent advances in their therapy,it remains inadequate in patients with advanced well-differentiated neuroendocrine tumors.These tumors present many challenges concerning the molecular basis and genomic profile,pathophysiology,clinicopathological features,histopathologic classification,diagnosis and treatment.There has been an ongoing debate on diagnostic criteria and clinical behavior,and various changes have been made over the last few years.Neuroendocrine carcinoma of the gastrointestinal system is a rare but highly malignant neoplasm that is genetically distinct from gastrointestinal system neuroendocrine tumors(NETs).The diagnosis and management have changed over the past decade.Emerging novel biomarkers and metabolic players in cancer cells are useful and promising new diagnostic tools.Progress in positron emission tomography-computerized tomography and scintigraphy with new radioactive agents(^(64)Cu-DOTATATE or ^(68)Ga-DOTATATE) replacing enough octreoscan,has improved further the current diagnostic imaging.Promising results provide targeted therapies with biological agents,new drugs,chemotherapy and immunotherapy.However,the role of surgery is important,since it is the cornerstone of management.Simultaneous resection of small bowel NETs with synchronous liver metastases is a surgical challenge.Endoscopy offers novel options not only for diagnosis but also for interventional management.The therapeutic option should be individualized based on current multidisciplinary information.

Medical therapy for advanced gastro-entero-pancreatic and bronchopulmonary neuroendocrine tumors

Neuroendocrine tumors(NETs)represent a spectrum of rare neoplasms arising in different organism sites.Depending on the site of onset,they also can be distinguished using lab exams(secreting vs.nonsecreting),clinical symptoms(functioning vs.nonfunctioning),behavioral,morphological characteristics(tumor cells’architectural growth patterns,mitotic and Ki-67 index,presence of necrosis),and grade of cellular differentiation.The aim of this review is to focus on the main signaling pathways targeted by medical treatments of advanced sporadic gastro-entero-pancreatic(GEP)and bronchopulmonary(BP)neuroendocrine neoplasms.The scientific literature regarding treatment of advanced GEP and BP-NETs has been extensively reviewed using MEDLINE and PubMed databases,selecting principal and more recent research articles,clinical trials,and updated guidelines.Somatostatin analogues represent a valid approach to control symptoms in functioning tumors and to inhibit tumor progression in certain categories on the basis of the typical somatostatin receptor expression observed in NETs.The pathogenesis of NETs has been the subject of increased interest in recent years.Many driver mutations pathway genes have been identified as important factors in the carcinogenesis process and,therefore,as potential targets for new anticancer therapies.Activating mutations have been shown in epidermal growth factor receptor,stem cell factor receptor,platelet-derived growth factor receptor,vascular endothelial growth factor,basic-fibroblastic growth factor,transforming growth factor,insulin-like growth factor-1,and their receptors.Effective M-Tor inhibition pathway modulation has led to the approval of drugs in this field such as everolimus.New drugs and several combination regimens with targeted and newer biological agents are being developed and tested in recently conducted and ongoing trials.