Gastroenteropancreatic neuroendocrine neoplam (GEP-NEN) is a rare group of tumors with its incidence rising significantly in recent decades. Because of the late presentation of the disease and limitations in conventional biomarkers, about 50% of GEP-NEN patients manifests advanced disease when diagnosed. Therefore, it is vital to identify circulating biomarkers which can not only be used for early diagnosis but also accurately evaluating the biological behavior of GEP-NEN. This review summarizes the advances of circulating biomarkers in diagnosing and evaluating efficacy of treatment in GEP-NEN. Well-known circulating biomarkers include chromogranin A (CgA), pancreastatin (PST), chromogranin B (CgB), neuron-specific enolase (NSE) and pancreatic peptide(PP). Novel biomarkers including circulating tumor cell(CTC), microRNA and NETest are promising biomarkers with potential clinical benefit, but further researches are needed before their clinical applications.
Biomarkers, Tumor ; blood ; Chromogranin A ; blood ; Chromogranin B ; blood ; chemistry ; Gastrointestinal Neoplasms ; blood ; chemistry ; diagnosis ; genetics ; Humans ; MicroRNAs ; blood ; Neoplastic Cells, Circulating ; Neuroendocrine Tumors ; blood ; chemistry ; diagnosis ; genetics ; Pancreatic Neoplasms ; blood ; chemistry ; diagnosis ; genetics ; Pancreatic Polypeptide ; blood ; Phosphopyruvate Hydratase ; blood

OBJECTIVETo study the rate of elevated common biomarkers of digestive tumors, including carcinoembryonic antigen (CEA), alpha fetoprotein (AFP), carbohydrate antigen 125 (CA125) and carbohydrate antigen 19-9 (CA19-9), in gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) and their prognostic values in GEP-NEN.

METHODSClinicopathological data of patients with GEP-NEN treated in The First Affiliated Hospital, Sun Yat-sen University from January 2011 to December 2016 were retrospectively studied. The inclusion criteria were as follows: patients with complete clinicopathological data including AFP, CEA, CA125 and CA19-9 level before treatment; patients without previous or other concomitant cancer; patients diagnosed as sporadic but not familial NEN. Serum AFP level >30 μg/L, CEA level >7.5 μg/L, CA125 level >52.5 μg/L and CA19-9 level >52.5 kU/L were defined as elevation respectively. Kaplan-Meier analysis and Log-rank test were applied to investigate the prognostic role of these biomarkers.

RESULTSA total of 170 patients with GEP-NEN were enrolled, and 105 (61.8%) patients were male with median age of 52.5 years. Thirty-six (21.2%), 77 (45.3%) and 57 (33.5%) cases were gastric, intestinal and pancreatic NEN respectively. Elevated AFP, CEA, CA125 and CA19-9 were found in 3(1.8%), 19(11.2%), 22(12.9%) and 21(12.4%) patients. Elevated CEA was related with G3 disease (OR=4.78, 95%CI:1.28-17.85, P=0.020) and elevated CA125 was related with distant metastasis (OR=51.60, 95%CI:5.76-462.44, P=0.000) while elevated CA19-9 was related with both G3 disease (OR=3.81; 95%CI:1.21-11.99, P=0.022) and distant metastasis(OR=4.87; 95%CI:1.41-16.75, P=0.012). The median follow-up was 22.5 months. Forty-six patients (27.1%) died during the follow-up. Patients with elevated CEA, CA125 or CA19-9 had worse overall survival compared with their counterparts with the median survivals of 14 months (95%CI:5.4 to 22.6 months, χ=15.582, P=0.000), 6 months (95%CI:3.2 to 8.8 months, χ=37.627, P=0.001) and 10 months (95%CI:0 to 20.6 months, χ=50.187, P=0.000) respectively. Furthermore, patients with more than two elevated biomarkers (median survival 6 months, 95%CI:4.37-7.63 months) had worse survival than patients with only one elevated biomarker (median survival 26 months, 95%CI:15.68-36.32 months, χ=9.295, P=0.002).

CONCLUSIONSElevation of AFP, CEA, CA125 or CA19-9 is not common in GEP-NEN. Patients with elevation of these biomarkers have poor survival.

Objective To explore the clinical characteristics and related background diseases of type 1 gastric neuroendocrine tumor (g-NET) and to provide reference information for clinical diagnosis and treatment.Methods From Januayy 2011 to February 2019,at the First Affiliated Hospital of Sun Yat-sen University and China-Japan Friendship Hospital,the clinical features and related background diseases of type 1 g-NET patients (41 cases and 93 cases respectively)were retrospectively analyzed.The clinical symptoms,serological indicators,gastroscopic and pathological features,tumor location,metastasis and treatment,and concomitant diseases were statistically described.Results Among 134 patients with type 1 g-NET,there were 53 males (39.6％) and 81 females (60.4 ％);and the mean diagnosed age was (51 ± 11) years (21 to 76 years).Main clinical manifestations were non-specific gastrointestinal symptoms.The mean level of serum chromogranin A was (237.7 ± 176.8) μg/L.The endoscopic findings of 97.8％ (131/134) of the patients were polypoid or protuberant lesions at gastric fundus or gastric body.And 75.0％ (96/128) of the patients had multiple tumors.65.7％ (88/134) of the patients had the tumors with the maximum diameter less than 1 cm (77.2％,88/114) and the lesions mainly located in mucosa (59.8％,52/87) and submucosa (40.2％,35/87).The pathological classification of 79.3％ (96/121) of the tumors was G1 grade and 20.7％ (25/121) were G2 grade.The rate of local lymph node metastasis was 1.4％ (1/73) and no distant metastasis was found.About 70.9％ (95/134) of the patients received endoscopic treatment.Among the patients,93.6％ (103/110) of the patients had chronic atrophic gastritis confirmed by endoscopy or pathology,45.6％ (47/103) were confirmed by both endoscopy and pathology.Among the patients with chronic atrophy gastritis,serum gastrin levels of 93.2％ (96/103) patients were twice higher than the upper limit of the normal value.The positive rates of antiparietal cells antibody (PCA) and intrinsic factor (IFA) were 78.5％ (73/93) and 51.9％ (14/27),respectively.The incidence of Helicobacter pylori (H.pylori) infection was 28.1％ (16/57).The incidence of autoimmune atrophy gastritis was 80.6％ (75/93).The percentage of patients with deficiency of serum vitamin B12 and ferritin was 70.8％ (63/89) and 30.7％ (27/88),respectively.Patients with anemia accounted for 27.8％ (25/90).The patients with microcytic anemia,normocyticanemia and macrocytic anemia were 28.0％ (7/25),56.0％ (14/25) and 16.0％ (4/25),respectively.46.9％ (45/96) of the patients had increased thyroid autoantibodies and 17.9％ (17/95) patients had changes of thyroid hormone level.Conclusions Type 1 g-NET is more common in women and mainly caused by autoimmune atrophic gastritis.The level of serum PCA and IFA increase in more than half of the patients.And it is often accompanied by vitamin B12 deficiency and autoimmune thyroid disease.

Objective To investigate the clinical features and prognostic factors of small (maximum diameter≤ 2.0 cm) non-functional pancreatic neuroendocrine tumors (NF-PNET).Methods From January 2002 to April 2017,the clinical data of 18 patients with small NF-PNET were retrospectively analyzed.The prognosis and clinical pathological features were investigated.According to the prognosis,the patients were divided into death group (four cases) and disease-free survival group (14 cases).Fisher's exact test and Mann-Whitney rank inspection were performed for statistical analysis.Results All 18 patients (nine males,nine females) aged 23 to 80 years old,median age 52.5 years old received radical resection.The median follow-up time was 54 months.Four patients died during the follow-up.There was no statistically significant difference in median age (61.0 years,32.0 to 80.0 years vs 49.0 years,23.0 to 72.0 years) and median tumor maximum diameters (1.9 cm,0.8 to 2.0 cm vs 1.5 cm,0.8 to 2.0 cm) between the death group and disease-free survival group (Z=-1.223 and-0.752,P=0.233 and 0.505).Compared with that of disease-free survival group,tumor differentiation degree of the death group was lower (poor/high differentiation,2/2 vs 0/14),and the difference was statistically significant (Fisher's exact test,P=0.039).However,there was no significant difference in histological grades (G1/G2/G3,1/1/2 vs 9/5/0;Fisher's exact test,P=0.057).The distribution of tumor in death group and disease-free survival group was similar.The proportion of patients with tumor at pancreatic head was 2/4 and 6/14 of the death group and disease free survival group,respectively.The surgical methods of the death group included pancreaticoduodenectomy (two cases),distal pancreatectomy (one case),and total pancreatectomy (one case),and there was no statistically significant difference in rates of surgical methods between the two groups (Fisher's exact test,P=0.260).Conclusion Age,tumor maximum diameter,degree of differentiation,histological grade and surgical methods may be correlated with poor prognosis of small NF PNET.

Neuroendocrine neoplasms(NEN) is a rare group of tumors with gastrointestinal tract as one of the most common primary locations. The most commonly used guidelines are proposed by European Neuroendocrine Tumor Society (ENETS) and National Comprehensive Cancer Network(NCCN) respectively, while the management of gastrointestinal NEN is generally identical in these two guidelines. Surgery is still the sole curative method which should be considered as the first choice of locoregional NEN. Otherwise, 40% to 50% of patients manifests metastatic disease when diagnosed. Hence, somatostatin analogs, targeted drugs, chemotherapy, and peptide receptor radionuclide therapy should be used comprehensively, especially for unresectable lesions. Therapeutic decision making should be based on the tumor location, functional status, tumor grade, tumor stage, somatostatin receptor status and adverse effect of drugs, etc.
Gastrointestinal Neoplasms ; chemistry ; therapy ; Humans ; Neuroendocrine Tumors ; therapy ; Pancreatic Neoplasms ; Receptors, Somatostatin

American Joint Committeeon Cancer (AJCC) released the eighth edition staging system manual in October 2016. Based on the shortcomings in the seventh edition of AJCC staging system, staging classifications for gastroenteropancreatic neuroendocrine tumor (GEP-NET) were updated. The changes are as follow: small intestinal NET was divided into two groups, duodenal and jejunoileal NET and lymphatic metastasis was redefined into N1 and N2 in jejunoileal NET; stages were condensed except colorectal NET; the staging classification for pancreatic NET proposed by European Neuroendocrine Tumor Society(ENETS) was adopted. However, problems still exist in the eighth edition AJCC staging classifications for GEP-NET. For instance, whether the definitions of N1 and N2 in jejunoileal NET are accurate in clinical management is still less understood. Thus, further clinical validations of the AJCC eighth edition staging system for GEP-NET are needed. Meanwhile, the eighth edition AJCC staging classifications for GEP-NET still did not step towards precision medicine and risks assessment models with high quality are still absent.