21例消化系统神经内分泌癌临床病理回顾性分析

 目的　探讨消化系统神经内分泌癌的临床病理特点及其组织发生和预后。方法　回顾性分析2 1例消化系统神经内分泌癌的临床病理资料 ,对肿瘤进行光镜观察 ,并做免疫组化。结果　消化系统神经内分泌癌可分为三个临床病理类型 ,其病理学特点、生物学行为及预后均有不同。本组资料中典型类癌 6例 ,不典型类癌 7例 ,小细胞癌 8例。免疫组织化学上 ,NSE阳性 14例 ,Syn阳性 14例 ,CgA阳性 4例。随访期内三种类型生存率分别为 6 6 .7%、5 0 %、5 7.1%。结论　消化系统神经内分泌癌病理类型及临床分期与预后密切相关 ,对其治疗有指导作用 ,免疫组化的合理应用可提高神经内分泌癌的诊断率 ,组织发生上支持来自全能干细胞。     

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.     

Expression of platelet-derived growth factor and its receptors in neuroendocrine tumors of the digestive system.

Carcinoid tumors are slowly growing neuroendocrine neoplasms which often present pronounced fibrosis around the tumor cells. We have previously shown by immunohistochemistry that carcinoid tumors express platelet-derived growth factor (PDGF) beta-receptors on surrounding stromal cells. In this report, 22 midgut carcinoids and 5 endocrine pancreatic tumors were examined for the presence of PDGF with a monoclonal antibody raised against a peptide corresponding to a part of the B-chain of PDGF which reacts strongly with the B-chain and weakly with the A-chain. They were also examined for PDGF alpha-receptors with an affinity-purified polyclonal peptide antibody and for PDGF beta-receptor with the monoclonal antibody PDGFR-B2. PDGF was expressed on tumor cells and on adjacent stroma. PDGF alpha-receptor was seen on clusters of tumor cells and occasionally on adjacent stroma, whereas beta-receptors were seen only in the stroma. Tissue sections from some of these midgut carcinoids were also investigated by in situ hybridization for mRNA of PDGF A- and B-chains as well as alpha- and beta-receptors. By in situ hybridization, abundant expression of mRNA for PDGF beta-receptor and PDGF A-chain was observed in stromal cells adjacent to carcinoid tumor cell clusters, but the mRNA expression in the tumor cells themselves was at a low level. A few clustered tumor cells and stromal cells expressed mRNA for the PDGF alpha-receptor, thus consolidating the immunohistochemical findings. mRNA for the PDGF B-chain was detected in both tumor cells and stroma, but only at low levels. Our data suggest that PDGF is involved in the growth stimulation of the carcinoid tumor cells in an autocrine fashion and in the stimulation of stromal cell growth through paracrine and possibly autocrine mechanisms. Moreover, remarkably strong immunostaining of PDGF and the PDGF alpha-receptor was seen on peripheral nerve fibers.     

New developments in the treatment of gastrointestinal neuroendocrine tumors

Patients with metastatic gastrointestinal neuroendocrine tumors have traditionally been faced with few effective treatment options. Somatostatin analogs often successfully control symptoms of hormonal hypersecretion but seldom result in tumor regression. Some patients with hepatic metastases are also candidates for ablative therapies such as surgical debulking or embolization. The role of systemic agents such as interferon alfa or cytotoxic chemotherapy remains ill defined. The more prevalent use of these modalities has been restricted by low tumor response rates and the potential for toxicity. Novel agents, including radiolabeled somatostatin analogs, inhibitors of the vascular endothelial growth factor pathway, and inhibitors of mammalian target of rapamycin, have shown promising activity in recent clinical studies. Continued investigation of these agents should render a better understanding of their efficacy in patients with advanced neuroendocrine tumors.     

Bronchopulmonary neuroendocrine tumors

Bronchopulmonary neuroendocrine tumors (BP-NETs) comprise approximately 20% of all lung cancers and represent a spectrum of tumors arising from neuroendocrine cells of the BP-epithelium. Although they share structural, morphological, immunohistochemical, and ultrastructural features, they are separated into 4 subgroups: typical carcinoid tumor (TC), atypical carcinoid tumor (AC), large-cell neuroendocrine carcinoma (LCNEC), and small-cell lung carcinoma (SCLC), which exhibit considerably different biological characteristics. The clinical presentation includes cough, hemoptysis, and obstructive pneumonia but varies depending on site, size, and growth pattern. Less than 5% of BP-NETs exhibit hormonally related symptoms such as carcinoid syndrome, Cushing, acromegaly, and SIADH. SCLC is the most common BP-NET, while LCNEC is rare, approximately 10% and < or =1%, respectively, of all lung cancers. Both SCLC and LCNEC progress rapidly, are aggressively metastatic, and exhibit a poor prognosis. The incidence of BP-carcinoids (TC and AC) in the US was 1.57 of 100,000 in 2003 (an unexplained and substantial increase over the last 30 years, approximately 6% per year). No curative treatment except for radical surgery (almost never feasible) exists. The slow-growing TC exhibit a fairly good prognosis ( approximately 88%, 5-year survival), whereas AC demonstrate a 5-year survival of approximately 50%, and the highly malignant LCNEC and SCLC5-year survival of 15% to 57% and <5%, respectively. This review provides a broad overview on BP-NETs and focuses on the evolution of the disease, general features, and current diagnostic and therapeutic options.     

Pancreatic neuroendocrine tumors

BACKGROUND:

Although surgical resection is generally recommended for patients with localized pancreatic neuroendocrine tumors (PNETs), the impact of resection on overall survival is unknown. The authors investigated the survival advantage of pancreatic resection using a national database.

METHODS:

This is a retrospective survival analysis of patients with PNETs from the Surveillance, Epidemiology, and End Results database (1988‐2002).

RESULTS:

A total of 728 patients with PNETs were identified with a median survival of 43 months using Kaplan‐Meier survival methods. Resection of tumor was associated with significantly improved survival compared with those patients who were recommended for but did not undergo resection (114 months vs 35 months; P < .0001). This survival benefit was demonstrated for patients with localized, regional, and metastatic disease. A multivariable Cox proportional hazards model was constructed to assess the overall effect of surgical resection on survival, and demonstrated an adjusted odds ratio of 0.48 (95% confidence interval, 0.35‐0.66) compared with those who were recommended for surgery but did not proceed to surgery.

CONCLUSIONS:

The authors have demonstrated in a large national study that resection of primary tumor in patients with PNETs is associated with improved survival across all disease stages. Patients with localized, regional, and metastatic PNETs who are reasonable operative candidates should be considered for resection of their primary tumors. Cancer 2009. © 2009 American Cancer Society.     

Sunitinib in pancreatic neuroendocrine tumors

Sunitinib is an oral multitarget tyrosine kinase inhibitor with potent antiangiogenic properties. Preclinical data have demonstrated that pancreatic neuroendocrine tumors depend on vascular endothelial growth factor receptors and platelet growth factor receptors-signaling pathways for tumor angiogenesis. Sunitinib has recently been approved for the treatment of patients with advanced, progressive pancreatic neuroendocrine tumors. Sunitinib has demonstrated clinically meaningful improvements in progression-free survival in a double-blinded randomized trial against placebo, setting progression-free survival as a valid endpoint for the evaluation of novel agents in patients with pancreatic neuroendocrine tumors. Although patients who progressed in this phase III trial were allowed to cross-over, a trend toward improvement in overall survival was also observed. In this trial, side effects reported with sunitinib were those previously reported in other tumor types, including hand-foot syndrome, diarrhea, and hypertension. This trial also investigated patient-reported outcome and showed that treatment with sunitinib did not affect quality of life of patient. Interestingly, this trial showed that sunitinib could be combined with somatostatin analogues without affecting the safety profile of either sunitinib or somatostatin analogues. Since the overall survival of patients with well-differentiated neuroendocrine tumors remains sufficiently long, it is worth considering using alternate sequences of targeted therapy (such as everolimus) and chemotherapy to optimize the care of patients with advanced diseases. The optimal sequence for using chemotherapy, everolimus, and sunitinib will remain to be established in clinical trials.     

Radio-guided surgery in neuroendocrine tumors

The majority of Neuroendocrine tumors (NET) express somatostatin (SS) receptors, and thus can be successfully targeted with radiolabeled SS analogs in vivo. Somatostatin receptor scintigraphy (SRS) with (111)In-DTPA Octreotide is the main imaging technique for evaluation of NETs. Radio-guided surgery for NETs, therefore, primarily utilizes (111)In-DTPA Octreotide tumor localization mechanism and kinetics. Somatostatin analog radiopharmacy continues to evolve to include the development of more selective and higher affinity analogs and PET tracers. These changes are expected to open new venues for radio-guided surgery technology.     

Expression and function of vinculin in neuroendocrine tumors.

Transfection of chicken vinculin into highly malignant neuroendocrine tumor cells, vasostatin-transformed (vaso-transformed) Bon cells which expressed low levels of vinculin protein, reversed their malignant behavior and restored expression of tumor suppressor genes. Conversely, small interfering RNA (siRNA)-mediated knockout of vinculin resulted in fast cell growth and augmentation of colony formation in wild-type cells. Moreover, expression of a tight junction protein, claudin 4 (CLD4), was found to be associated with vinculin expression. In the vaso-transformed Bon cells, CLD4 expression was reduced, whereas a significantly increased CLD4 expression was observed in the cells with vinculin overexpression. Furthermore, vinculin knockout brought about CLD4 downregulation in wild-type cells. However, vinculin and CLD4 expression was inversely correlated in neuroendocrine tumors, respectively. Based on these findings, we hypothesize that vinculin plays a role in growth regulation of neuroendocrine tumors. Further studies are necessary to analyze the relationship between the course of the disease, and vinculin and CLD4 expression in large tumor samples.     

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 study of biological behavior based on the expression of a proliferating antigen in neuroendocrine tumors of the digestive system.

The expression of a proliferating antigen by Ki-67 immunohistochemistry was evaluated in 32 gastrointestinal carcinoids and in 5 pancreatic islet cell tumors. In the tissue sections the number of labelled nuclei was calculated per tumor area. The tumors were classified as low proliferating (less than 0.3 labelled cells/mm2), medium proliferating (0.3-1 labelled cells/mm2), and high proliferating (greater than 1 labelled cell/mm2). In 26 tumors obtained from patients receiving antitumor therapy (alpha-interferon) the proliferative activity was decreased. In treated midgut carcinoids the proliferative activity in metastatic tissue was significantly reduced (p less than 0.05). Though not statistically significant, primary midgut carcinoids collected from untreated patients displayed a lower proliferative activity than liver metastases. A survival analysis revealed that patients with tumors displaying low proliferative activity had a better survival than those with high proliferative activity (p less than 0.05). Single cell cytofluorometric DNA analyses showed regular diploid stem cell lines in the majority of tumors from untreated patients (9/11 cases). No correlation was found between the calculated proliferative activity and the DNA profile. The obtained results indicate that the expression of a proliferation antigen by Ki-67 immunohistochemistry can be used to evaluate the biological behavior of neuroendocrine tumors of the digestive system and predict survival.     

Imaging of neuroendocrine tumors

Neuroendocrine tumors may arise from a wide range of organs and may occur in various locations in the body. They include carcinoid tumors, paragangliomas (pheochromocytomas), medullary thyroid carcinomas, and islet cell tumors of the pancreas. In this article the authors focus on the more common tumors with origins primarily in the abdomen, namely carcinoid, paraganglioma, and pancreatic islet cell tumors. Imaging assists in delineating the sites and extent of disease, in preoperative planning for resection of the primary tumor and metastatic disease, and in follow-up. Discussion is restricted to the main imaging modalities used in these tumors: cross-sectional imaging, namely CT and MRI, and nuclear medicine studies.     

RET and neuroendocrine tumors

Glial cell line-derived neurotrophic factor (GDNF), a ligand of RET tyrosine kinase, and its family ligands promote the survival and differentiation of a variety of neurons. Gene ablation studies have revealed that the GDNF-RET receptor system is essential for the development of kidney and peripheral neurons, including sympathetic, parasympathetic and enteric neurons. RET can activate various signaling pathways such as RAS/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/AKT, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways. These signaling pathways are activated via binding of adaptor proteins to intracellular tyrosine residues of RET phosphorylated by its own kinase activity. The RET is profoundly involved in the development of several human neuroendocrine diseases. The constitutive activation of the RET by somatic rearrangement with other partner genes or germ-line mutations causes a considerable population of human papillary thyroid carcinomas or multiple endocrine neoplasia (MEN) type 2A and 2B, respectively, whereas the dysfunction of RET by germ-line missense and/or nonsense mutations causes Hirschsprung's disease. Biological properties of mutant RET protein determine the disease phenotype. For example, the MEN 2B mutation alters the substrate specificity of RET tyrosine kinase and RET carrying the MEN 2B mutation hereby induces the different set of genes from that carrying the MEN 2A mutation. In this review, we describe the current knowledge about the molecular mechanism of RET activation in human neuroendocrine tumors as well as the physiological roles and signal transduction of RET tyrosine kinase.     

New strategies for advanced neuroendocrine tumors in the era of targeted therapy

Low- to intermediate-grade neuroendocrine tumor (NET) constitutes a group of indolent malignancies that share the capacity for secreting hormones and neuroamines. Until recently, there were few therapeutic options for oncologic control. The PROMID study showed that octreotide long-acting repeatable formulation can delay tumor growth in midgut NETs. And, recent phase III studies showed both everolimus and sunitinib improved progression-free survival in pancreatic NETs, validating the phosphoinositide 3-kinase/Akt/mTOR pathway and angiogenesis as important targets for further advances. Ongoing and planned pivotal studies targeting these pathways in other NET subtypes may widen their therapeutic application. Development of rational combinations may further improve therapeutic outcome. These successes and our improved understanding of the underlying molecular biology are likely to lead to further important advances on the horizon.     

New drug development in non-hodgkin lymphomas

The non-Hodgkin lymphomas (NHL) are characterized by initial responsiveness to a variety of chemotherapeutic regimens. Nevertheless, most patients progress and die from their disease. A number of new agents with unique mechanisms of action are in clinical development. Agents that are currently considered to be the most promising include those that induce apoptosis; those that interfere with cell cycling, tumor-associated angiogenesis, farnesylation of the Ras gene, and histone deacetylase; and those that inhibit the proteasome, among others. Increasing insights into the differences between tumors and among patients will lead to more individualized therapeutic strategies using agents directed at specific genetic and immunologic targets. More rapid accrual to high-quality clinical studies will facilitate dissemination of new agents to patients and lead to an increased cure rate for NHL.     

视黄酸代谢与常见消化道肿瘤关系的研究进展

视黄酸是维生素A最重要的代谢产物,在调控细胞分化、生长,调节免疫功能,维持上皮细胞完整性等生理过程中起着至关重要的作用。其生理功能的发挥是通过与其特异性受体结合,调节靶细胞目的基因转录,进而激活下游信号通路来完成。而机体视黄酸浓度主要由视黄醇的有效性、相关转运因子、视黄酸合成酶和视黄酸分解酶来决定。在我国,消化道肿瘤是一种高发病率、高死亡率的疾病,常见的如口咽癌、食管癌、胃癌和结直肠癌,这些疾病严重威胁人类身体健康,降低人们生活质量。近年来,有研究显示,消化道肿瘤组织中存在视黄酸代谢酶及因子表达的异常,并且一些消化道肿瘤的危险因素,如槟榔、幽门螺杆菌、高脂饮食等会影响视黄酸合成酶、视黄酸分解酶及其相关因子的表达和功能,进而影响视黄酸调控的下游信号通路,最终影响肿瘤的发生、发展。本文主要就视黄酸的代谢及其与常见消化道肿瘤之间关系的研究进展做一综述,为消化道肿瘤的分子机制研究及营养预防提供理论依据。