Functioning and nonfunctioning neuroendocrine tumors of the pancreas

PURPOSE OF REVIEW: Neuroendocrine tumors of the pancreas are a small subgroup of tumors characterized by a variety of biological behaviors. Recent changes in their classification should help better define the prognosis of this diverse group of tumors. With recent advances in diagnosis and staging, the treatment options for all neuroendocrine tumors have evolved. Presented here is a review of the current-day knowledge for neuroendocrine tumors of the pancreas. RECENT FINDINGS: A consensus by leading experts in the neuroendocrine tumors field has proposed an algorithm for the diagnosis, treatment and follow-up of these rare tumors. Surgical resection remains the first-line therapy. Alternative forms of cytoreduction such as radiofrequency ablation and embolization, have increased the ability of the surgeon to debulk these tumors, resulting in improved survival and better palliation. Contrary to adenocarcinoma of the pancreas, hormonal and biotherapy offer unique treatment strategies for these rare tumors. Very recent developments utilizing radionuclide therapy hold promise for not only palliation, but may prove to be a beneficial form of adjuvant therapy. SUMMARY: Presented here is a summary of the recent literature on the diagnosis and treatment of neuroendocrine tumors of the pancreas.     

Neuroendocrine Tumors of the Pancreas

This literature review briefly summarizes the epidemiology, pathophysiology, clinical management, and outcomes of patients with pancreatic neuroendocrine tumors (PNETs) and highlights recent advances in PNET research. PNETs are rare neoplasms, compared with carcinomas arising from pancreatic exocrine tissue. They, like other neuroendocrine tumor types, display variable malignant potential, hormone‐related syndromes (functionality), localization, and genetic background. Although tumor origin and molecular pathogenesis remain poorly understood, recently established grading and staging systems facilitate patient risk stratification, and thereby directly impact clinical decision making. Although the optimal clinical management of PNETs involves a multidisciplinary approach, surgery remains the only curative treatment for early‐stage disease. Surgery may also have a role in patients with advanced‐stage disease, including those with hepatic metastases. Alternative therapeutic approaches applied to PNETs, including chemotherapy, radiofrequency ablation, transarterial chemoembolization, biotherapy, polypeptide radionuclide receptor therapy, antiangiogenic therapy, and selective internal radiotherapy, have failed to demonstrate a long‐term survival benefit. Surgery remains the primary therapeutic option for patients with PNETs. Research on PNETs is desperately needed to improve the therapeutic options for patients with this disease.     

Recent progress in the understanding, diagnosis, and treatment of gastroenteropancreatic neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are relatively rare tumors that arise from the diffuse neuroendocrine system. This heterogeneous group of tumors was often considered a single entity. This belied their biological diversity, and the biggest advance in understanding these tumors over the past decades has been in understanding this diversity. Diagnosis of these tumors has been aided by advances in pathological diagnosis and classification and tumor imaging with endoscopic ultrasound and somatostatin receptor fusion imaging. Genetic and molecular advances have identified molecular targets in the treatment of these tumors. Surgery remains the mainstay of treatment, amply supported by interventional radiological techniques, including embolization. Treatment of metastatic disease has improved significantly with the addition of several new agents, including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and yttrium-90-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and lutetium-177-DOTA octreotate. Despite significant advances in the understanding and management of GEP-NETs, the survival of patients remains largely unchanged and there remains a need for the development of national and international research collaborations to spearhead future efforts.     

多层螺旋CT诊断胰腺癌的进展

胰腺癌是恶性程度很高的癌症之一,目前诊断出胰腺癌的患者大多都错过了最佳手术时机。胰腺癌的早期且准确诊断对于患者的治疗和预后十分关键。多层螺旋CT（multidetector-row computed tomography,MDCT）已成为胰腺癌诊断、肿瘤分期、治疗计划制定和治疗后随访的重要检查方式。然而,大约11%的胰腺导管腺癌在多层螺旋CT图像中由于病变和邻近胰腺实质之间密度差异仍出现漏诊情况。本文总结当前的多层螺旋CT在胰腺癌诊断方面的进展、限制及其它影像学检查方式的临床应用。     

改良胰腺神经内分泌肿瘤分期的临床解读

胰腺神经内分泌肿瘤是一种常见的胰腺恶性肿瘤,异质性极强,诊治手段多样,因此,统一、实用的分期系统将有助于临床诊治及研究.目前,胰腺神经内分泌肿瘤包括欧洲神经内分泌肿瘤协会(European Neuroendocrine Tumor Society System,ENETS)和美国癌症联合委员会(American Joint Committee on Cancer,AJCC)两种分期,然而两种分期系统对临床指导价值有限,且两种分期系统的并存造成了分期系统混乱的局面.复旦大学附属肿瘤医院胰腺肝胆外科通过结合ENETS中TNM的定义及AJCC中分期的定义,建立了改良的分期系统,该分期能更好地区分出不同预后的人群,更适合于指导临床应用,有利于建立统一的临床分期标准.研究结果发表在《临床肿瘤学杂志》(Journal of Clinical Oncology,JCO)上.研究得到了国际同行的高度重视与认可,被评为"2017 Best of JCO:Gastrointestinal edition".JCO编辑部进行了专篇述评.该研究就改良分期系统的临床应用进行解读.     

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。     

17例无功能性胰腺神经内分泌肿瘤的诊治分析

目的:报道17例无功能性胰腺神经内分泌肿瘤并分析其诊治方法。方法:回顾性分析自2002年1月至2014年8月我院收治的17例无功能性胰腺神经内分泌肿瘤患者的临床资料并结合文献进行复习讨论。结果:肿瘤位于胰头部8例,胰体尾部8例,弥漫整个胰腺1例。17例患者均行手术治疗,术后病理检查均提示无功能性胰腺神经内分泌肿瘤。瘤体直径3-15cm,均呈浸润性生长,3例发生肝转移。1例术后3小时因肺梗塞死亡,另随访到13例,9例存活至今,2例死于肿瘤复发,各有1例死于肺部感染及术后肝转移。结论:无功能性胰腺神经内分泌肿瘤确诊需依赖病理学检查,以手术为主的综合治疗能够提高患者生存率,改善预后。     

Current treatments of neuroendocrine tumors role of biotherapy and chemotherapy

Neuroendocrine tumors are rare neoplasms originating from cells belonging to a diffuse or confined neuroendocrine system and characterized by a significant histopatologic and biologic heterogeneity. Timely diagnosis is delayed because they are often clinically silent for their low differentiation grade and the absence of any symptom due to abnormal hormone release. For these reasons, many neuroendocrine tumor patients are not treated medically for metastatic or inoperable disease. Medical treatments include biotherapy, with interferon-alpha and somatostatin analogues, and chemotherapy. Somastostatin analogues are widely used in patients with symptoms and with carcinoids of low differentiation grade. Interferon-alpha is used alone or in combination with somatostatin analogues. Chemotherapy is active in patients with poorly differentiated neuroendocrine tumors. The therapeutic regimen commonly used is the combination of cisplatinum and etoposide. In conclusion, no standard treatment for NET has yet been identified, and the response criteria suggested by ITMO remain a reference point. The clinical aspect of the disease and biologic features suggest the identification of neuroendocrine tumors patients suitable for the appropriate therapies. On these bases, it is recommended that diagnosis and treatment of neuroendocrine tumors be carried out at specialized oncological centers involved in clinical trials.     

21例无功能性胰腺神经内分泌肿瘤诊疗的回顾性分析

目的:回顾性分析无功能性胰腺神经内分泌肿瘤（non-functioning pancreatic neuroendocrine neoplasms，NF-pNENs)的发生部位、临床表现、影像学表现、病理特点、诊断、治疗及预后情况，加强对该病的认识、诊断和治疗。方法:收集2011年9月至2017年1月中国医科大学附属盛京医院收治的21例无功能性pNENs手术患者的临床病例资料、影像学检查和病理学结果，进行随访、回顾性分析。结果:21例非功能性胰腺神经内分泌肿瘤患者主要表现为腹痛、腹部不适、腹部肿块等，其中8例无明显症状；21例患者全部接受手术治疗。随访时间3~66个月、中位随访时间25个月，19例存活，其中18例未见肿瘤复发，1例复发，1例死亡，1例失访。结论:胰腺神经内分泌肿瘤缺乏特异性临床症状，高分化的神经内分泌瘤多见，术前联合CT、MRI、超声内镜等影像学检查，有助于提高早期诊断、发现转移灶及术前评估，手术是目前治疗无功能性胰腺神经内分泌肿瘤最主要的方式，多数患者术后恢复良好，术后应行长期随访。     

Endoscopic ultrasound in the diagnosis and staging of pancreatic cancer

Patients with signs and symptoms suggestive of a pancreatic neoplasm typically undergo initial imaging with transabdominal ultrasound or computed tomography. This evaluation often reveals the presence of a pancreatic mass or fullness. At times, the nature of the lesion is poorly characterized, with uncertainty remaining as to whether the lesion is an inflammatory mass or a neoplasm, and if it is cystic or solid. In these circumstances, endoscopic procedures such as endoscopic retrograde cholangiopancreatography and/or endoscopic ultrasound may be required. These procedures offer other means of tissue sampling, disease staging, and an option for palliative therapy. In this article, we review the role of endoscopy for the diagnosis and staging of pancreatic tumors, with a particular focus on endoscopic ultrasound.     

Future perspectives on neuroendocrine tumors

In the last 30 years the incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) has increased substantially. This could be partly due to improvements in diagnostic imaging, which lead to the incidental diagnosis of asymptomatic cases. However, despite these improvements, patients typically experience long delays before they are diagnosed. In this review, we discuss both the limitations and advances in our understanding of the pathogenesis, molecular and cellular biology, diagnosis, classification, staging, and treatment of GEP-NETs in order to identify which factors could be contributing to the delay in diagnosis and timely treatment of these patients. Within this context, the results from the most relevant clinical trials the available targeted therapies for the treatment of GEP-NETs, such as the "RAD001 in Advanced Neuroendocrine Tumors," will be discussed.     

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 jejuno-ileal 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.     

A shining light in the darkness for the treatment of pancreatic neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors are rare neoplasms; past decades have seen limited research channeled into this area. Recently, 2 placebo-controlled phase III trials using 2 drugs--everolimus and sunitinib--with distinct molecular rationales achieved their principal objective of increasing survival in patients with advanced pancreatic neuroendocrine tumors (PNET). Nonetheless, several questions remain unanswered, notably defining the optimal schedule for integrating these targeted agents with conventional cytotoxics and other treatment options, and identifying appropriate biomarkers for patients with the potential to derive greater benefit. In this article, we analyze the results of the 2 largest studies ever completed in patients with PNETs and discuss the challenges for future drug development in this setting. SUMMARY: Sunitinib and everolimus will become new treatment options for patients with PNETs and will be integrated into the complex therapeutic management of this disease. In this review, we summarize the evidence-based data of these drugs as well as the molecular-based science in this setting that will lay the groundwork for future studies.     

Cystic neoplasms of the pancreas: a heterogeneous disorder.

Cystic neoplasms of the pancreas are rare tumors with a relatively better prognosis as compared to other pancreatic cancers. They may be mistaken for pseudocysts. Seventeen patients who underwent surgical resection were analyzed. Seventy percent of the patients were females and 76.7% of the tumors were located in the tail of the pancreas. Preoperative diagnosis was made on the basis of ultrasonography and/or computed tomography findings in 60% of patients. Retrospective review of the imaging modalities revealed one or more findings suggestive of cystic neoplasms in 90% of the patients. These included multiloculated cysts, thickened cyst wall, intracystic mass or calcifications, and presence of liver metastasis. All the tumors were completely or partly excised. The final histopathological diagnosis was microcystic adenoma in 2, mucinous cyst adenoma in 1, papillary cystic neoplasm in 3, cystic neuroendocrine tumor in 5, and cystadenocarcinoma in 6. Of the 17 patients, 10 had malignant tumors. Seven patients with benign tumors and 3 patients with malignant tumors are disease free 12-30 months after resection. Cystic neoplasm must always be considered as a possibility when dealing with cystic lesions of the pancreas and a careful evaluation of ultrasonography and computed tomographic scan may give a clue to the diagnosis.     

Neuroendocrine tumors of the gastrointestinal tract: recent advances in molecular genetics, diagnosis, and treatment

PURPOSE OF REVIEW: Neuroendocrine tumors of the gastrointestinal tract represent a small area within oncology, but many new data have been reported during the past year. This paper updates the recent findings. RECENT FINDINGS: An N-terminally truncated variant of heat shock protein 70 (Hsp70) has been identified in neuroendocrine tumors but not in normal pancreatic islets. CDX-2 is a homeobox gene product essential for intestinal development and differentiation that is expressed at high levels in intestinal neuroendocrine tumors, but not in other types. A new marker has been identified, neuroendocrine secretory protein-55, a member of the chromogranin family, specific for endocrine pancreatic tumors but not for intestinal neuroendocrine tumors. Positron emission tomography has significantly improved imaging of neuroendocrine tumors of the gastroenteropancreatic tract. Tracers such as C-5-hydroxy-L-tryptophan show very high sensitivity for detection of tumors, higher than for somatostatin receptor scintigraphy. A new somatostatin analogue SOM230 binding to four of five somatostatin receptors has recently come into clinical trials. SUMMARY: Increased knowledge of the molecular background for the development of neuroendocrine tumors may improve the management of these tumors in the future. New tumor markers have been developed and the localization techniques have been significantly improved. That will of course lead to earlier diagnosis and improved possibilities for surgical cure of these patients.     

A rare cystic non-functioning neuroendocrine pancreatic tumor with an unusual presentation

This report describes a patient with a cystic non-functioning neuroendocrine glucagon cell pancreatic tumor presenting with demyelination of the optical nerve that had initially provoked marked monolateral reduced vision and had led to a suspected diagnosis of multiple sclerosis. Cystic degeneration is uncommon in endocrine pancreatic tumors due to their abundant vascular supply. Very few cases of cystic neuroendocrine non-functioning pancreatic tumors have been reported in the international literature. The presence of atypical neurological symptoms, such as sudden visual impairment, should be taken into account in the differential diagnosis for such tumors. The prognosis is poor, because most of these tumors are malignant and diagnosed at an advanced stage. The three-year disease-free survival of our patient, however, encourages the use of aggressive surgical treatment.     

Retroperitoneal sarcomas: Combined-modality treatment approaches

Retroperitoneal sarcomas (RPS) are rare tumors, accounting for approximately 15% of soft tissue sarcomas. Surgical resection of localized tumors with gross and microscopically negative margins remains the standard of care. However, because RPS are frequently large and locally advanced, resections are often incomplete, resulting in local recurrence. Investigators are evaluating combined-modality therapies to improve local control and disease-specific survival. This review outlines current concepts and evolving treatment strategies in the diagnosis, staging, and management of RPS.     

Pancreatic neuroendocrine tumors G3 and pancreatic neuroendocrine carcinomas: Differences in basic biology and treatment

In 2017 the World Health Organization revised the criteria for classification of pancreatic neuroendocrine neoplasms (pNENs) after a consensus conference at the International Agency for Research on Cancer. The major change in the new classification was to subclassify the original G3 group into well-differentiated pancreatic neuroendocrine tumors G3 (pNETs G3) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs), which have been gradually proven to be completely different in biological behavior and clinical manifestations in recent years. In 2019 this major change subsequently extended to NENs involving the entire digestive tract. The updated version of the pNENs grading system marks a growing awareness of these heterogeneous tumors. This review discusses the clinicopathological, genetic and therapeutic features of poorly differentiated pNECs and compare them to those of well-differentiated pNETs G3. For pNETs G3 and pNECs (due to their lower incidence), there are still many problems to be investigated. Previous studies under the new grading classification also need to be reinterpreted. This review summarizes the relevant literature from the perspective of the differences between pNETs G3 and pNECs in order to deepen understanding of these diseases and discuss future research directions.     

胰腺癌:新辅助治疗

In spite of the high mortality in pancreatic cancer, significant progress is being made. This review discusses multimodality therapy for patients with pancreatic cancer. Surgical therapy currently offers the only potential monomodal cure for pancreatic adenocarcinoma. However only 10%-20% of patients present with tumors that are amenable to resection,and even after resection of localized cancers, long term survival is rare. The addition of chemoradiation therapy significantly increases median survival. To achieve long-term success in treating this disease it is therefore increasingly important to identify effective neoadjuvant/adjuvant multimodality therapies. Preoperative chemoradiation for potentially resectable pancreatic cancer has the following advantages:(1) neoadjuvant treatment would eliminate the delay of adjuvant treatment due to postoperative complications; (2) neoadjuvant treatment could avoid unnecessary surgery for patients with metastatic disease evident on restaging after neoadjuvant therapy; (3) downstaging after neoadjuvant therapy may increase the likelihood for negative surgical margins; and (4) neoadjuvant treatment could prevent peritoneal tumor cell implantation and dissemination caused during surgery. This review systematically summarizes the current status, controversies, and prospects of neoadjuvant treatment of pancreatic cancer.     

One size does not fit all for pancreatic cancers: A review on rare histologies and therapeutic approaches

Exocrine pancreatic neoplasms represent up to 95% of pancreatic cancers (PCs) and are widely recognized among the most lethal solid cancers, with a very poor 5-year survival rate of 5%-10%. The remaining < 5% of PCs are neuroendocrine tumors that are usually characterized by a better prognosis, with a median overall survival of 3.6 years. The most common type of PC is pancreatic ductal adenocarcinoma (PDAC), which accounts for roughly 85% of all exocrine PCs. However up to 10% of exocrine PCs have rare histotypes, which are still poorly understood. These subtypes can be distinguished from PDAC in terms of pathology, imaging, clinical presentation and prognosis. Additionally, due to their rarity, any knowledge regarding these specific histotypes is mostly based on case reports and a small series of retrospective analyses. Therefore, treatment strategies are generally deduced from those used for PDAC, even if these patients are often excluded or not clearly represented in clinical trials for PDAC. For these reasons, it is essential to collect as much information as possible on the management of PC, as assimilating it with PDAC may lead to the potential mistreatment of these patients. Here, we report the most significant literature regarding the epidemiology, typical presentation, possible treatment strategies, and prognosis of the most relevant histotypes among rare PCs.