胃肠胰神经内分泌肿瘤诊疗进展

神经内分泌肿瘤（neuroendocrine neoplasm,NEN）的发病率和患病率近年来迅速增长，其中以原发于胃肠道和胰腺的NEN最常见。2022年，美国国家综合癌症网络（National Comprehensive Cancer Network,NCCN）NEN指南及中国胃肠胰NEN专家共识进行了更新。本文主要参照比对2022年NCCN指南及2022版中国胃肠胰NEN专家共识对NEN的诊疗新进展进行评述。     

胃肠胰高级别神经内分泌肿瘤病理诊断现状及研究进展

Abstract： Gastroenteropancreatic neuroendocrine neoplasm(GEP-NEN) are classified into low-grade and high-grade tumors according to the WHO classification criteria for digestive system tumors. The high-grade NEN include well differentiated neuroendocrine tumor G3 and poorly differentiated neuroendocrine cancer. The clinical pathological characteristics and treatment options of the two are significantly different, however, it is difficult in differential diagnosis pathologically. This paper summarizes the current pathological diagnostic criteria and research progress on immunohistochemical and molecular marker of these two types of tumors, to provide reference for the development of appropriate treatment plans.     

胃肠胰神经内分泌肿瘤的免疫治疗研究进展

晚期胃肠胰神经内分泌肿瘤(Gastroenteropancreatic neuroendocrine neoplasms,GEP-NENs)的治疗药物有限,且疗效不佳。免疫治疗作为一种有前景的治疗方式,近年来在GEP-NENs中进行了初步应用探索。目前已有研究结果显示免疫检查点抑制剂在GEP-NENs中有良好的抗肿瘤活性和安全性。程序性死亡配体(PD-L1)在不同GEP-NENs的原发部位中表达有所差异,且与肿瘤分化程度呈负相关。PD-L1表达程度及免疫细胞浸润对GEP-NENs患者预后的影响仍有争议。能够预测免疫治疗获益的生物标志物尚未确定。本文就GEP-NENs的免疫治疗研究进展做一综述。     

胃肠胰-神经内分泌肿瘤的研究进展

胃肠胰-神经内分泌肿瘤(GEP-NENs)起源于胃肠胰的神经内分泌细胞系统,发病率低,临床表现多样,缺乏特异性.CgA、Syn是“通用”的肿瘤标记物,影像学检查是重要的定位诊断手段,但最终诊断依靠病理.按照“2013年国内共识”,将神经内分泌癌中肿瘤组织形态学分化良好,但Ki-67指数达到G3级(＞20％,＜60％),命名为“高增殖活性NET”.GEP-NENs的治疗需要以患者的基础健康状况、临床症状和肿瘤分期、分级等信息为根据,以循证医学为基础,应用多学科及多种手段,成立GEP-NENs的多学科专家团队,对患者进行个体化、多学科综合治疗.使患者达到控制功能性神经内分泌肿瘤激素过量分泌导致的相关症状或者综合征,并且控制肿瘤生长.生物治疗和分子靶向治疗在晚期GEP-NENs治疗中显示了较好的前景.     

中国胃肠胰神经内分泌肿瘤专家共识

1907年德国病理学家Obemdorfer首次提出了“类癌（carcinoid）”或“类癌瘤（carcinoidtumor）”这一术语,指的是一组发生于胃肠道和其他器官嗜银细胞的新生物,临床、组织化学和生化特征可因其发生部位不同而异。由于类癌是起源于神经内分泌细胞的肿瘤,能够合成、贮存和分泌生物活性胺、小分子多肽类或肽类激素,故又称为小分子多肽或肽类结构瘤（amineprecursoruptakeanddecarboxyla—tiontumor,APUDtumor,APUDOMA）。     

肽受体放射性核素治疗在胃肠胰神经内分泌肿瘤治疗中的研究进展

晚期胃肠胰神经内分泌肿瘤(gastroenteropancreatic neuroendocrine neoplasm,GEP-NEN)的肽受体放射性核素治疗(peptide receptor radionuclide therapy,PRRT)研究逐渐在国内外开展。其基本原理是放射性核素标记的生长抑素类似物与神经内分泌肿瘤细胞表面过表达的生长抑素受体结合。对不可手术切除或转移性的晚期GEP-NEN来讲,肽受体放射性核素治疗在一些临床研究中表现出比传统的生长抑素类似物治疗、靶向治疗、系统化疗等方法更好的疗效,如药物Lutetium Lu ¹⁷⁷Dotatate(¹⁷⁷Lu-dotatate)已被欧美相关机构批准。安全性方面以放射性药物为主的肽受体放射性核素治疗存在骨髓毒性和肾毒性等不良反应,但相关研究表明,其安全性在一定范围内可控。本文结合国内外相关临床研究,对PRRT的原理、临床应用、未来展望进行综述。     

胃肠胰神经内分泌肿瘤患者预后的多因素分析

目的:分析胃肠胰神经内分泌肿瘤患者预后的危险因素,并探讨对应的干预对策,以期为临床提供借鉴。方法:回顾自2002年6月至2013年12月入院治疗的胃肠胰神经内分泌肿瘤患者的资料,对患者的一般情况如性别、年龄、肿瘤大小、肿瘤部位、肿瘤侵犯程度、淋巴结转移、血管侵犯、手术切缘、远处转移、总生存期等数据进行分析,总结胃肠胰神经内分泌肿瘤患者预后的危险因素。结果:123患者平均发病年龄56.9岁,男性平均发病年龄59.5岁,女性平均发病年龄52岁。＜60岁患者68例,≥60岁55例,从发病到明确诊断时平均时间为9.8月,中位生存时间为46.1个月,1年生存率为69%,3年生存率为37.4%, 5年生存率为29.6%。通过单因素分析,年龄、肿瘤大小、肿瘤侵犯程度、淋巴结转移、血管侵犯、手术切缘、远处转移与胃肠胰神经内分泌肿瘤患者预后显著相关,P＜0.05;性别、肿瘤部位与胃肠胰神经内分泌肿瘤患者预后无明显相关,P分别为0.784、0.988。通过多因素COX回归分析,年龄(HR=1.93,95%CI:1.06~3.50)及远处转移(HR=1.83,95%CI:1.24~2.72)为胃肠胰神经内分泌肿瘤患者预后的独立危险因素。结论:年龄、肿瘤大小、肿瘤侵犯程度、淋巴结转移、血管侵犯、手术切缘、远处转移等是胃肠胰神经内分泌肿瘤患者生存预后的危险因素,年龄大、远处转移患者生存预后最差。     

胃肠胰神经内分泌肿瘤分子生物学研究进展

神经内分泌肿瘤（NEN）是一组起源于肽能神经元和神经内分泌细胞的异质性肿瘤，可发生于多个系统，以胃肠胰神经内分泌肿瘤（GEP-NEN）最常见。目前关于NEN的研究主要包括肿瘤相关的基因、肿瘤相关的通路、肿瘤相关RNA等，本文通过查阅文献对NEN分子生物学研究进展作一综述，并在此基础上提出以不同系统的NEN在分子生物学上的区别及其对肿瘤发生、发展的影响作为下一步的研究方向。     

胃肠胰神经内分泌肿瘤药物治疗进展

随着胃肠胰神经内分泌肿瘤（gastroenteropancreatic neuroendocrine tumors,GEP-NETs）发病率的增高,对GEP-NETs的治疗越来越受到关注。根据2010年第4版世界卫生组织（WHO）消化系统肿瘤病理的最新分类方法,将神经内分泌肿瘤（neuroendocrine neoplasms,NENs）分为3级:G1、G2、G3级,其中G1、G2级为神经内分泌瘤（neuroendocrime tumor,NETs）,G3级为神经内分泌癌（neuroendocrine carcinoma,NECs）。对于G1、G2级NETs现有的药物治疗方案主要包括生长抑素类似物（somatostatin analogs,SSAs）、靶向治疗、干扰素、化疗,而对于G3级NECs一般以铂类为基础的化疗为主。免疫因素可能是NENs的发病因素之一,现关于NENs免疫治疗的临床试验正在开展。本文将对GEP-NETs的药物治疗进行综述。      

液体活检在胃肠胰神经内分泌肿瘤中的应用现状

胃肠胰神经内分泌肿瘤(gastroenteropancreatic neuroendocrine neoplasms,GEP-NENs)是一类起源于神经内分泌细胞且具有神经内分泌功能的肿瘤。由于GEP-NENs的临床症状和生物学行为缺乏特异性,因此早期误诊率和漏诊率极高。同时,原发部位和分级不同的GEP-NENs分子生物学特性差异较大,因此该类肿瘤具有高度的异质性。目前对于该类疾病的诊断主要依靠于影像学和组织活检等传统方法。这导致只能获得取样位置的基因信息,而不能反映肿瘤的整体情况。近年来,随着基因组测序技术的高度发展,循环生物标志物和液体活检技术弥补了组织活检所带来的局限性,为提高GEP-NENs的诊断率和实现精准治疗带来了新机遇。本文将总结并比较液体活检在GEP-NENs中的应用现状。     

胃肠胰腺神经内分泌肿瘤国际诊断共识的解读

近年来胃肠胰腺神经内分泌肿瘤的发病率不断上升,随着对疾病认识的不断深入,现在从疾病术语、诊断到治疗规范都发生了巨大的变化。本文结合世界卫生组织(WHO)2010版消化系统肿瘤病理分类、欧洲神经内分泌肿瘤协会(ENETs)共识、北美神经内分泌肿瘤协会(NANETs)共识和美国国立癌症网络(NCCN)指南,对胃肠胰腺神经内分泌肿瘤诊断进行解读。     

胃肠胰腺神经内分泌肿瘤治疗共识（NCCN、ENETs、NANETs）解读

胃肠胰腺神经内分泌肿瘤(GEP-NEN)是一类罕见肿瘤,对其研究相对较少,目前暂无公认的治疗共识,欧洲采用欧洲神经内分泌肿瘤协会(ENETs)共识,美国采用北美神经内分泌肿瘤协会(NANETs)共识以及美国国立综合癌症网络(NCCN)指南的神经内分泌肿瘤版。本文结合ENETs共识(2009版)、NANETs共识(2010版)、NCCN指南(2010第二版),以及分子靶向治疗的新进展,对GEP-NEN的治疗进行全方位的回顾。     

Clinical characteristics and prognostic analysis of gastroenteropancreatic neuroendocrine neoplasm （GEP-NEN）

Objective： The aim of the study was to analyze the clinicopathologic characteristics of gastroenteropancreatic neuroendocrine neoplasm （GEP-NEN） and to explore the prognostic factors for patients and differences of immunohisto- chemical markers between neuroendocrine tumor （NET） and neuroendocrine carcinoma （NEC）. Methods： Retrospective reviews were conducted for the charts of 119 patients with GEP-NEN at the Affiliated Hospital of Qingdao University （China） from August 2003 to December 2013. Kaplan-Meier method was used to do the overall survivals analysis for the patients at different levels of predictive factors. Meanwhile, Cox proportional hazard model was used to select independent risk factors of surJival. Analysis of variance was used to compare the expression of immunohistochemical markers among different patho- logical grades. Results：Among 119 patients, pancreas （45/119, 37.82%） and rectum （33/119, 27.73%） were mostly involved. The onset age of GEP-NEN in female group was younger than that of the male group. There were 13 deaths （10.92%） during 18.9 （0.1-133.4） months follow-up period. Multivariate analysis indicated that neural invasion, gender and pathological grades of NET and NEC were independent risk factors. In neuroendocrine neoplasm （NEN）, Syn expression in G2 was higher than G1 and G3, while CgA showed no significant difference. All markers showed no significant differences between NET and NEC. Conclusion： GEP-NEN may occur at multiple sites of digestive system and lack specific clinical manifestations. Syn expression detected for the prognosis of G1, G2 and G3 tumors have clinical significance. Neural invasion, sex and patho- logical grades were independent prognostic factors for GEP-NEN patients. No significant difference was found in different pathological grades of NET and NEC.     

Good performance of platinum-based chemotherapy for high-grade gastroenteropancreatic and unknown primary neuroendocrine neoplasms

To evaluate efficacy and safety of platinum and etoposide combination in the treatment of advanced gastroenteropancreatic (GEP) and unknown primary (CUP) neuroendocrine carcinomas (NEC), we analysed the records of 21 consecutive patients treated with this regimen from 1999 to 2012. Objective responses were obtained in 11 patients (52%) and disease stability (DS) in 5 (24%). Median progression-free survival (PFS) was 7 months (95% CI, 5.33–8.66). Median overall survival (OS) was 16 months (95% CI, 14.97–17.03). Patients with limited liver disease had a significantly (p = 0.002) better PFS than patients with extrahepatic disease at diagnosis with 9 months (95% CI, 7.14–10.85) vs. 4 months (95% CI, 1.60–6.40). Two patients experienced durable complete response (30 and 90 months). The most common grade 3–4 toxicities were neutropenia (61%), anaemia (50%), nausea and vomiting (27%) and fatigue (22%). The platinum plus etoposide regimen has an acceptable toxicity profile and is effective in patients with GEP and CUP-NECs.     

Mouse models of medulloblastoma

Medulloblastoma is the most common malignant pediatric brain tumor. Despite its prevalence and importance in pediatric neuro-oncology, the genes and pathways responsible for its initiation, maintenance, and progression remain poorly understood. Genetically engineered mouse models are an essential tool for uncovering the molecular and cellular basis of human diseases, including cancer, and serve a valuable role as preclinical models for testing targeted therapies. In this review, we summarize how such models...     

Clinicopathologic characteristics and prognosis of gastroenteropancreatic neuroendocrine neoplasms:a multicenter study in South China

Background: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of rare tumors. Many issues in terms of epidemiologic features, pathogenesis, and treatment of GEP-NENs are still under discussion. Our study aimed to analyze the clinicopathologic characteristics and prognosis of Chinese patients with GEP-NENs. Methods: Complete clinicopathologic data and survival information of 1183 patients with GEP-NENs treated between 2005 and 2015 were collected from five medical centers in Guangdong Province, China. Patient survival was estimated using the Kaplan–Meier method and analyzed using the log-rank test; prognostic factors were analyzed using the Cox proportional hazards model. Results: The most common tumor location was the rectum (37.4%), followed by the pancreas (28.1%), stomach (20.7%), small intestine (7.2%), appendix (3.4%), and colon (3.3%). After initial definitive diagnosis, 1016 (85.9%) patients underwent surgery. The 1-, 3-, and 5-year overall survival (OS) rates for the entire cohort were 87.9%, 78.5%, and 72.8%, respectively. The 3-year OS rates of patients with G1, G2, and G3 tumors were 93.1%, 82.7%, and 43.1%, respectively (P < 0.001). The 3-year OS rates of patients with stage Ⅰ, Ⅱ, Ⅲ, and Ⅳ tumors were 96.0%, 87.3%, 64.0%, and 46.8%, respectively (P < 0.001). Patients with distant metastasis who underwent palliative surgery had a longer survival than those who did not (P = 0.003). Similar survival benefits of palliative surgery were observed in patients with neuroendocrine tumor (P = 0.031) or neuroendocrine carcinoma (P = 0.046). In multivariate analysis, age, grade, N category, M category, and surgery were found to be independent prognostic factors. Conclusions: Patients with GEP-NENs who are women, younger than 50 years old, have smaller tumor size, have lower tumor grade, have lower T/N/M category, and who undergo surgery can have potentially longer survival time. Our data showed that surgery can improve the prognosis of GEP-NEN patients with distant metastasis. However, randomized controlled trials need to be conducted to establish the optimal criteria for selecting patients to undergo surgery.     

Clinicopathological features and survival analysis of gastroenteropancreatic neuroendocrine neoplasms: a retrospective study in a single center of China

Objective

To investigate the clinicopathological features, survival and prognostic factors for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) in a Chinese population.

Methods

We investigated 154 consecutive patients (88 males, 66 females; median age 56 years, age range 9-86 years) diagnosed with GEP-NENs between 2001 and 2013 at The Affiliated Hospital of Qingdao University. Demographic, clinical and pathological variables and survival data were retrieved.

Results

The pancreas was the most common site of involvement (63/154, 40.9%). Tumor size varied from 0.3 to 16.0 cm (median, 1.2 cm). The patients were followed up for a median period of 22 months (range, 1-157 months). The estimated 3- and 5-year overall survival (OS) rates for all patients were 84.0% and 81.9%, respectively. Multivariate analysis showed that larger tumor size, lymphatic metastases and distant metastases were significant predictors for poor survival outcome.

Conclusions

Our data provide further information on the clinicopathological features of GEP-NENs in China. Additionally, we identified tumor size, lymphatic metastases and distant metastases as independent prognostic factors for long-term survival.     

HSP90 expression and early recurrence in gastroenteropancreatic neuroendocrine tumors: Potential for a novel therapeutic target

BackgroundHeat shock protein (HSP)-90 promotes tumor growth and is overexpressed in many malignancies. HSP90 expression profile and its potential as a therapeutic target in primary and metastatic neuroendocrine tumors (NETs) are not known.MethodsHSP90 cytoplasmic expression and Ki-67 index were re-reviewed and scored by a pathologist blinded to all other clinicopathologic variables for patients who underwent resection of primary and metastatic gastroenteropancreatic (GEP) neuroendocrine tumors at a single institution (2000–2013). Primary outcome was recurrence-free survival (RFS).ResultsOf 263 tumors reviewed, 73% (n = 191) were primary GEP NETs, and 12% (n = 31) were NET liver metastases. Of the primary GEP-NETs, mean age was 56 years, 42% were male; 53% (n = 103) were pancreatic and 23% (n = 44) were small bowel. HSP90 expression was high in 34% (n = 64) and low in 66% (n = 127). Compared to low expression, high HSP90 was associated with advanced T-stage (T3/T4) (47 vs 27%; p = 0.02). Among patients who underwent curative-intent resections for primary, non-metastatic NETs (n = 145), high HSP90 was independently associated with worse RFS (HR 5.09, 95% CI 1.65–15.74; p = 0.005), after accounting for positive margin, LN involvement, increased tumor size, site of primary tumor, and Ki-67. When assessing NET liver metastases, 13% (n = 4) had high HSP90 expression and 87% (n = 26) had low expression. Patients with liver metastases with high HSP90 tended to have worse 1- and 3-year progression-free survival (25%, 25%) compared to those with low HSP90 (69%, 49%; p = 0.059).ConclusionHSP90 exhibits differential expression in resected GEP-NETs and liver metastases. High cytoplasmic expression is associated with early disease recurrence, even after accounting for other adverse pathologic factors. HSP90 inhibition may be a potential therapeutic target for neuroendocrine tumors.