Neuroendocrine neoplasms (NENs) are a rare group of tumors with high heterogeneity. Gastroenteropancreatic NENs (GEP- NENs) consist of thelargest proportion of NENs. Chinese doctors did not pay much attention to this group of tumors until the nomenclature and classification ofneuroendocrine tumors of digestive system were updated by the World Health Organization (WHO) in 2010. Since then, more and more studies ofGEP- NENs have been carried out, and the clinical characteristics, biomarkers and treatment outcome of GEP- NENs in Chinese patients havegradually been explored.

Clinical characteristics of GEP- NENs in China

There are still no epidemiological data of NENs based on the population in mainland China. Our previous study showed that the most commonprimary sites for GEP- NENs were pancreas (34.8%) and rectum (20.2%), followed by stomach (14.0%). Neuroendocrine tumor (NET) accounts for thelargest proportion (69.8%). Neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC) account for 27.2% and 3.0%,respectively.1 A multicenter retrospective study of GEP- NENs in China also showed that pancreas and rectum were the most common primarylocations.2

In recent years, several multicenter studies were conducted to investigate the clinicopathological features of NENs in different tumor locations. Forexample, we recently summarized the clinicopathological characteristics of colorectal NENs including 41 patients with colonic NENs and 288patients with rectal NENs.3 Colonic NENs had a more aggressive nature than that of rectal NENs. In these 41 colonic NENs patients, 61.0% and 17.1%patients were NEC and MANEC, respectively. 48.8% of the patients manifested distant metastases when diagnosed. The most common endoscopicappearance of colonic NENs was ulcerative or cauliflower- like tumors. The prognosis of colonic NENs was not favorable with a 3- year survival rateof only 46.1%. In contrast, most of the rectal NENs (92.7%) were well differentiated NET. Only 7.0% and 0.3% of patients were NEC and MANEC,respectively. In addition, rectal NENs tended to be a local- regional disease with only 8.3% having advanced diseases when diagnosed. Submucosaltumor was the most common appearance under endoscopy. The 3- year survival rate of rectal NENs was 94.0%, which was much better than that ofcolonic NENs.

Another multicenter study with a large sample (977 patients included) compared the clinicopathological features of pancreatic NENs betweenChinese patients and American patients.4 This study showed that Chinese patients with pancreatic NENs were inclined to be younger, have less non-functional tumors larger in size than American patients. In Chinese patients, insulinoma was the most common pancreatic NENs subtype (52.2%),followed by non- functional tumor (39.7%). Most of the tumors (49.6%) were located in the head/neck region of pancreas. 57.7%, 38.3% and 3.8% ofpatients had grade 1, grade 2 and grade 3 diseases, respectively. Metastatic rate of lymph node and distant location were 5.4% and 22.7%,respectively. Recently, a multicenter study supported by ten medical centers, including eight Chinese centers and two American centers, proposed amodified staging classification for pancreatic NENs.5 This multicenter study found the deficiencies of current staging classifications and proposed amodified one which had a higher prognostic validity for pancreatic NENs in both Chinese patients and American patients.

Stomach is also a common location of NENs in Chinese patients. In the recent consensus guideline proposed by the European NeuroendocrineTumor Society (ENETS),6 gastric NENs is divided into three types according to the serum gastrin levels and gastric pH. Type 1 and type 2 are

Authors Luohai Chen, Minhu Chen, Jie Chen

E- mail chen0jie@hotmail.com

Institute Department of Gastroenterology, the First Affiliated Hospital, Sun Yat- sen University

City/Nationality Guangdong, China

Title of Article

Clinical characteristics, biomarkers and treatment outcome ofGEP- NENs in China

respectively caused by atrophic gastritis- associated and Zollinger- Ellison syndrome- associated hypergastrinemia. Type 3 gastric NENs are notassociated with hypergastrinemia, which is mostly thought as a high grade (often grade 3 NEC) tumor. However, in China, some experts suggest tofurther divide type 3 gastric NENs into two more types (new type 3 and type 4). New type 3 is considered as well or moderately differentiated tumor,which is not associated with hypergastrinemia, while type 4 G- NENs are grade 3 NEC. A study including 241 gastric NENs based on this novelclassification was published recently.7 25.3% and 36.1% of patients were new type 3 and type 4, respectively. Survival analysis showed patients withnew type 3 and type 4 had significantly different overall survival. Whether dividing gastric NENs into 4 types helps improving the management ofpatients or not needs further study.

Biomarkers study of GEP- NENs in China

Currently circulating biomarker studies in China focus on investigating the value of serum chromogranin A (CgA) in GEP- NENs. However, in China,only several large medical centers provide serum CgA measurement. Our previous study showed a serum CgA cutoff value of 95 ng/mL could helpdiscriminate between healthy subjects or disease- free patients, and patients with active disease with sensitivity of 51.2% and specificity of 87.5%.8

Furthermore, serum CgA could be used to evaluate tumor burden and therapeutic response, and predict the survival outcomes in GEP- NENs patients.Other studies from China also showed similar results.9,10 Additionally, a multicenter study revealed that serum CgA was not significantly elevated inpatients with insulinoma.11 Therefore, serum CgA had limited value in patients with insulinoma.

There are also a number of studies from China investigating tissue biomarkers for evaluating the biologic behavior of GEP- NENs. Here, we reviewedseveral representative studies. In gastrinoma and insulinoma of pancreas, loss of heterozygosity (LOH) of chromosome 1q was successively found,which was associated with tumor aggressive growth.12,13 The presence of LOH of chromosome 1q was found to be correlated with aggressivegrowth, presence of liver metastases and postoperative development of hepatic metastases.12 Han X, et al. found the role of expression of CK19 andKIT in resectable pancreatic NENs.14 Their study showed that KIT- positive tumor was associated with higher Ki- 67 index and advanced tumor nodemetastasis (TNM) stage compared with KIT- negative tumor. Meanwhile positive CK19 expression was correlated with non- functioning tumors,regional lymph nodes metastases, and advanced stage. Also in pancreatic NENs, another biomarker, alpha- internexin was tested.15 This studyshowed that reduced expression of alpha- internexin was correlated with advanced stage, metastases, and recurrence. Furthermore, reducedexpression of alpha- internexin indicated shorter overall survival in patients with pancreatic NENs.

Our previous study investigated the expression of O(6)- methylguanine- DNA methyltransferase (MGMT) and its clinical significance in GEP- NENs.16

MGMT expression deficiency was thought to be associated with better response to temozolomide- based chemotherapy. In this study, we found thatthe MGMT deficiency rate was similar in pancreatic NENs and in gastrointestinal NENs. This result indicated that temozolomide- basedchemotherapy might have comparable efficacy on pancreatic NENs and gastrointestinal NENs in Chinese patients. Recently, we also investigated theprognostic significance of somatostatin receptors (SSTR) in advanced GEP- NET patients. We found expression of SSTR2/SSTR5 were prognosticfactors indicating favorable survival.17

Treatment outcome of GEP- NENs in China

In China, GEP- NENs patients were treated by operation (by endoscopy or surgery), interventional therapy, chemotherapy, biotherapy and moleculartarget therapy. Peptide receptor radionuclide therapy (PRRT) is not available yet. Still, there are few publications related with the treatment outcomesof GEP- NENs in China.

Recently, two multicenter retrospective studies of octreotide long- acting repeatable (LAR) and sunitinib in the treatment of advanced GEP- NET wereconducted. In the first study, 54 patients with advanced GEP- NET who received octreotide LAR treatment in four centers across China were includedto investigate the efficacy and safety of octreotide LAR in Chinese GEP- NET patients. The median time to progression was 20.2 months with theobjective response rate being 5.6% and the stable disease rate being 79.6%. 25.9% of the patients experienced adverse drug reactions. No oneexperienced a serious adverse event.17

In the second study, a total of 50 patients with unresectable or metastatic GEP- NET who were treated with sunitinib were evaluated retrospectively.The median time to progression (TTP) was 15.1 months. This study demonstrated that sunitinib had similar treatment efficacy in Chinese patientscompared to western patients. A 25 mg/day dosage was better tolerated than 37.5 mg/day in Chinese patients. Sunitinib- related hypertension mightbe a predictor of a better treatment effect.18

More recently, a phase II study evaluated the activity and safety of irinotecan plus cisplatin (IP) followed by maintenance treatment of octreotidelong- acting release (LAR) in advanced GEP- NEC.19 To date, this is the sole prospective study assessing treatment response of GEP- NEC in China. Inthis study, patients were further classified into two groups: high proliferation neuroendocrine tumor (NET) group with well differentiation and Ki- 67index between 20- 60% and poorly differentiated NEC (PDNEC) group. This study revealed that the patients in high proliferation NET group had alower response rate compared to the PDNEC group. Hence, IP might not be an effective treatment strategy in patients with high proliferation NET.

DISCUSSION

The clinicopathological features of GEP- NENs in Chinese patients and the value of different biomarkers are gradually gaining understanding in therecent years. There are several differences of clinical characteristics between Chinese patients and western patients with GEP- NENs. On the onehand, the tumor locations of GEP- NENs are different. The most common tumor locations of GEP- NENs in Chinese patients are rectum and pancreas,followed by stomach. Small intestine is not a common site of GEP- NENs.20 While in western patients, small intestine and rectum are twopredominant tumor sites of GEP- NENs.21,22 On the other hand, at the same tumor site, Chinese patients share different clinicopathological featuresfrom western patients. For instance, Chinese patients with pancreatic NENEs tended to be younger, have less non- functional tumors and largertumor size than those of American patients.4 These heterogeneities may have derived from ethnic differences.

Biomarkers including circulating biomarkers and tissue biomarkers are crucial in the management of patients with GEP- NENs. In China, the mostwidely used circulating biomarker is serum CgA. However, this biomarker is limited by its relatively low specificity. As for the tissue biomarker, agroup of biomarkers were studied and have shown certain significance in evaluating the biologic nature of GEP- NENs. However, most of thesestudies focused on pancreatic NENs. The role of these biomarkers in gastrointestinal NENs is less understood.

Data of the treatment outcome of GEP- NENs in China is still limited. Our present two studies are limited by their retrospective nature. In the future,more well- designed prospective studies are required to help Chinese doctors to better understand the treatment outcome of GEP- NENs in Chinesepatients.

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