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。     

不同年龄胃肠胰神经内分泌肿瘤患者预后分析

  目的  本研究旨在描述中国不同诊断年龄胃肠胰神经内分泌肿瘤（gastroenteropancreatic neuroendocrine neoplasms,GEP-NENs）患者的临床病理特征和治疗信息,探讨诊断年龄与术后5年生存率之间的关系。  方法  作为一项以医院为基础的全国多中心临床流行病学研究,本研究回顾性收集了2001年1月至2010年12月在研究医院就诊的GEP-NENs患者的病历信息和术后生存情况。采用Cox风险比例回归模型估计研究对象的术后死亡风险比和95%可信区间（95%CI）。  结果  共2 002例患者被纳入最终分析。患者按照诊断年龄分为≤50岁组和>50岁组。术后5年生存数据分析显示,与年龄≤50岁的患者相比,年龄>50岁的患者术后死亡风险显著增加（HR=2.83,95%CI:1.87～4.28）。在调整了原发部位、功能状态、TNM分期、分级、肿瘤浸润和转移情况、放化疗、靶向治疗和生物治疗情况后,不同年龄组之间的死亡风险差异无统计学意义（HR=1.63,95%CI:0.98～2.72）。对性别亚组进行多因素分析结果显示,在男性患者中,年龄>50岁组患者术后死亡风险显著增加（HR=2.65,95%CI:1.28～5.47）。  结论  不同年龄组GEP-NENs患者的临床病理特征和治疗方式选择存在差异,但年龄不是GEP-NENs患者预后的独立影响因素,提示对于诊断年龄不同的患者,临床医生应根据现有临床实践指南及患者个体情况,选择精准治疗方案。      

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）。     

98例胃肠胰神经内分泌肿瘤的临床病理特征及生存分析

目的:探讨98例胃肠胰神经内分泌肿瘤的临床、病理特点及预后因素,以提高对该疾病的认识及诊治水平。方法:选取 2008年1月至2016年6月新疆医科大学附属肿瘤医院收治98例资料完整的胃肠胰神经内分泌肿瘤患者的临床资料,对其临床表现、病理特征、生存等进行回顾性分析。结果:本组患者共98例（男67例,女31例）,平均年龄（54.5±12.8）岁,发病部位最常见于胃(33/98,33.7%),其次直肠(31/98、31.6%)。肿瘤大小0.2至9.2厘米（平均:1.2厘米）。平均随访时间为18个月（范围1~101个月）。患者1年、3 年和5年总生存率分别为80.6％、64.1％、56.2％。单因素分析显示肿瘤部位、大小、分级、淋巴结转移、远处转移及手术方式是预后不良的预测因子,多因素分析未发现任何独立的危险因素。结论:胃肠胰神经内分泌肿瘤是一种少见的疾病,临床表现不典型,最常见的发生部位是胃,多为高度恶性肿瘤;其次多见于直肠,多为低度恶性肿瘤。胃肠胰神经内分泌肿瘤以手术治疗为主。     

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.     

胃肠道混合性神经内分泌-非神经内分泌肿瘤临床病理观察

目的 探讨胃肠道混合性神经内分泌-非神经内分泌肿瘤(MiNEN)的临床病理特征.方法 回顾性分析2017年1月至2020年6月郑州大学第一附属医院47例胃肠道MiNEN患者的临床病理资料,分析其病理学形态特征及免疫表型.结果 47例胃肠道MiNEN患者中,男34例,女13例,年龄42～81岁,中位年龄59岁.病灶位于胃...     

109例直肠神经内分泌肿瘤患者的临床病理特征与预后分析

[目的]探讨直肠神经内分泌肿瘤的临床病理特征及预后.[方法]回顾性分析109例直肠神经内分泌肿瘤患者的临床病理及随访资料.观察患者肿瘤的分类情况,并通过Kaplan-Meier法估计受试者的预后生存情况,利用Cox等比例风险模型来探讨影响直肠神经内分泌肿瘤预后的危险因素.[结果] 109例直肠神经内分泌肿瘤患者,其中神经内分泌肿瘤患者91例(83.48％)、神经内分泌癌患者和未知分级患者各9例(8.26％).患者的平均年龄(50.58±11.90)岁,男、女性别比为1.51:1,且多数患者(90.83％)居住在城镇.经过8.12年(中位随访时间,95％CI:7.32～8.85年)的随访,全组患者的3年、5年和10年生存率分别为91.23％05％CI:83.83％～95.34％)、88.20％(95％CI:80.14％～93.12％)和84.20％(95％CI:74.85％～90.29％).Cox等比例风险模型的结果显示,年龄(HR=5.80,95％CI:1.36～24.77)、淋巴结转移(HR=7.15,95％CI:2.27～24.83)和远处转移(HR=7.42,95％CI:1.98～27.76)是影响直肠神经内分泌肿瘤预后的独立危险因素.[结论]直肠神经内分泌肿瘤多发生于城镇地区的中年男性人群,预后较好.年龄、淋巴结转移和远处转移是直肠神经内分泌肿瘤预后的独立危险因素.     

Imaging of gastroenteropancreatic neuroendocrine tumors

Imaging of gastroenteropancreatic neuroendocrine tumors can be broadly divided into anatomic and functional techniques. Anatomic imaging determines the local extent of the primary lesion, providing crucial information required for surgical planning. Functional imaging, not only determines the extent of metastatic disease spread, but also provides important information with regard to the biologic behavior of the tumor, allowing clinicians to decide on the most appropriate forms of treatment. We review the current literature on this subject, with emphasis on the strengths of each imaging modality.     

The molecular genetics of gastroenteropancreatic neuroendocrine tumors

The pathobiology of neuroendocrine tumors (NETs) is hampered by the lack of scientific tools that define their mechanisms of secretion, proliferation, and metastasis; and, currently, there are no accurate means to assess tumor behavior and disease prognosis. Molecular biologic techniques and genetic analysis may facilitate the delineation of the molecular pathology of NETs and provide novel insights into their cellular mechanisms. The current status and recent advances in assessment of the molecular basis of tumorigenesis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) were reviewed (1981-2004). The objectives of this retrospective study were to provide a cohesive overview of the current state of knowledge and to develop a molecular understanding of these rare tumor entities to facilitate the establishment of therapeutic targets and rational management strategies. Multiple differences in chromosomal aberration patterns were noted between gastrointestinal (GI) neuroendocrine and pancreatic endocrine tumors (PETs). Divergence in gene expression patterns in the development of GI carcinoids and PETs was identified, whereas examination of the PET and GI carcinoid data demonstrated only few areas of overlap in the accumulation of genetic aberrations. These data suggest that the recent World Health Organization classification of GEP-NETs may require updating. In addition, previous assumptions of tumor similarity (pancreatic vs. GI) may be unfounded when they are examined at a molecular level. On the basis of the evolution of genetic information, enteric neuroendocrine lesions (carcinoids) and PETs may need to be classified as two distinct entities rather than grouped together as the single entity "GEP-NETs."     

New targeted agents in gastroenteropancreatic neuroendocrine tumors

Neuroendocrine carcinomas are rare neoplasms although of increasing incidence and concern. While traditionally considered of indolent nature, once they progress beyond surgical resectability, the outcome is ultimately fatal for the majority of patients. Somatostatin analogs are useful to control symptoms in functioning tumors and may slow tumor progression in certain disease settings, but sensitivity to conventional cytotoxic chemotherapy is rather limited. In this context, results of the recently published randomized trials with sunitinib and everolimus have demonstrated for the first time that there are agents able to positively impact on the natural history of this complex disease. In this review, we will discuss available data on angiogenesis and mammalian target of rapamycin inhibitors for the treatment of advanced well-differentiated gastroenteropancreatic neuroendocrine tumors.     

Emerging therapies for advanced gastroenteropancreatic neuroendocrine tumors

Neuroendocrine tumors comprise a heterogeneous group of neoplasms derived from peptide- and amine-producing cells of the neuroendocrine system. Gastroenteropancreatic NET are differentiated into tumors and carcinomas based on their malignant potential and subdivided into those arising from the pancreas (islet cell tumors or pancreatic NET) and the more classical gut "carcinoids". Moderate to well differentiated NET have historically been considered rare tumors but recent epidemiological statistics suggest that their frequency has increased substantially over the past three decades. While the incidence of NET is increasing, data from both the US and UK demonstrate no improvement in outcomes over a similar time period. Due to the generally indolent biology of NET, most patients present with advanced disease before symptoms become apparent. In patients with localized NET, the 5-year survival rates after resection range from 60 to 90%, while regional lymph node involvement decreases the 5-year survival rates after surgery to 50-75%. Patients with distant metastases have a 5 year survival rate of approximately 25-40%. Conventional cytotoxic chemotherapy is of unclear benefit in patients with these generally slow growing tumors. Multiple agents have been tested in Phase 2 and Phase 3 trials. In general, the lack of major objective responses with significant toxicities has limited routine use of traditional chemotherapy agents and has emphasized the need to develop new agents in these diseases. This review will focus on emerging molecularly-targeted treatments with an emphasis on their underlying biologic and preclinical rationale.     

分化好的胃肠胰神经内分泌瘤G3的诊治新进展

神经内分泌肿瘤属于少见肿瘤,发病率低,异质性强,可发生于全身多个器官.在中国,胃肠胰是神经内分泌肿瘤发病率最高的部位,自2017年世界卫生组织(World Health Organization,WHO)消化系统肿瘤病理学分类关于胃肠胰神经内分泌肿瘤提出分化好的神经内分泌瘤G3(neuroendocrine tumor...     

Priorities for improving the management of gastroenteropancreatic neuroendocrine tumors

A National Cancer Institute summit meeting on gastroenteropancreatic neuroendocrine and carcinoid tumors was held in September 2007 to present the currently accepted standards of care for patients with these tumors and to identify areas requiring investigation and development. These tumors are clinically and pathologically heterogeneous, present commonly with obscure symptoms that lead to delays in diagnosis of years, and have an incidence in the United States of 2.5 to 5 cases per 100,000. The 5-year survival rates range between 15% and 95%, depending on the site and extent of disease. This report delineates the main conclusions of the meeting, including the best practice diagnosis and treatment strategies for gastropancreatic neuroendocrine tumors, and the identification of clinical and scientific areas that are most in need of attention. The most pressing needs were public and physician education, identification of molecular markers for early diagnosis and therapeutic monitoring, improved imaging modalities and molecular prognostication, development of a standardized pathological classification system, and creation of regional centers of expertise with tumor and laboratory data banks. In addition, adequately validated neuroendocrine tumor models and cell lines should be established to investigate the molecular mechanisms involved in the control of their growth and secretion, and to facilitate the development of specific therapies that should be examined in well-designed multicenter studies of defined patient groups.     

Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors

PURPOSE: The predictive role of the quantification of thymidylate synthase (TS) in tumors treated with antifolate drugs, such as 5-fluorouracil (5-FU), has been extensively reported in a variety of human tumors. Neuroendocrine tumors (NET) represent potential targets of antifolate agents, but no data on TS expression level in these tumors are currently available. EXPERIMENTAL DESIGN: A series of 116 NETs were collected, including 58 gastroenteropancreatic (GEP) and 58 lung NETs. In 24 well-differentiated GEP neuroendocrine carcinomas (WD-NEC), a 5-FU-based treatment was given. Total RNA was extracted from microdissected paraffin blocks. TS mRNA quantification was done by real-time PCR, whereas protein expression was evaluated by immunohistochemistry. RESULTS: By means of both quantification by real-time PCR and immunohistochemistry, a higher TS expression in pulmonary small cell lung cancer and large cell NEC compared with typical and atypical carcinoids was observed (P < 0.01). Similarly, in GEP tumors, a higher TS expression in poorly differentiated carcinomas than both WD-NEC and benign tumors (P < 0.01) was found. In patients with WD-NEC treated with 5-FU, high TS mRNA levels were associated with shorter time to progression (P = 0.002) and overall survival (P = 0.04). This negative prognostic role was confirmed in multivariate analysis adjusting for major prognostic variables (P = 0.01). No association between TS mRNA and survival was observed in WD-NEC patients not receiving 5-FU. CONCLUSIONS: This study, for the first time, (a) reports the differential TS expression in the spectrum of NETs and (b) indicates TS as a possible predictive marker of treatment efficacy in WD-NEC patients treated with 5-FU.     

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.     

Molecular targeted therapies in the treatment of gastroenteropancreatic neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEPNETs) are rare neoplasms that require a multidisciplinary approach for an optimal management. The traditional cytotoxic agents are of limited efficacy in the treatment of these tumors. A better understanding of the molecular pathways that characterize tumor growth has provided novel targets in cancer treatment. Several proteins have been implicated as having a crucial role in GEPNETs. Several proangiogenic molecules are overexpressed in GEPNETs including vascular endothelial growth factor (VEGF) and its receptors, and related signaling pathway components such as epidermal growth factor receptor (EGFR), insulin growth factor-I receptor (IGF-IR) and PI3K-AKT-mTOR pathway. In this article we aim to review the recent development of the main molecules that target these proteins and have showed promising activity in the treatment of GEPNETs.