血浆嗜铬粒蛋白A对胃肠胰腺内分泌肿瘤的诊断价值

背景：嗜铬粒蛋白A（CgA）广泛存在于神经内分泌细胞中，其血浆水平升高提示存在神经内分泌来源的肿瘤。目的：确定血浆CgA诊断胃肠胰腺内分泌肿瘤的临界点，并探讨其诊断价值。方法：以酶联免疫吸附测定（EUSA）检测39例胃肠胰腺内分泌肿瘤和37例嗜铬细胞瘤患者的血浆C外水平，以30例非内分泌肿瘤消化疾病患者和30例正常人作为对照。绘制接受者操作特征曲线（ROC曲线），确定ROC曲线下面积（AUROC）和血浆C小的诊断临界点。结果：胃肠胰腺内分泌肿瘤、嗜铬细胞瘤和非内分泌肿瘤消化疾病组的血浆CgA水平均显著高于正常对照组（86、135和30U／L对20U／L，P〈0．001）。以正常对照组和胃肠胰腺内分泌肿瘤组数据绘制ROC曲线，AUROC为0．912．CgA的诊断临界点为30U／L，敏感性为80．0％，特异性为96．7％；以正常对照组和嗜铬细胞瘤组数据绘制ROC曲线，AUROC为0．914，CgA的诊断临界点为30．5U／L，敏感性为89．2％，特异性为96．7％。结论：血浆C外水平对神经内分泌肿瘤，尤其是胃肠胰腺内分泌肿瘤具有较高诊断价值，可作为可靠的肿瘤标志物应用于临床。     

Cyclooxygenase-2 expression in gastroenteropancreatic neuroendocrine tumors

BACKGROUND/AIMS: The aim of this multicenter study was to investigate cyclooxygenase-2 protein expression in gastroenteropancreatic neuroendocrine tumors and to examine the relationship to various clinicopathological parameters. METHODOLOGY: Thirty-seven gastroenteropancreatic neuroendocrine tumor specimens were analyzed immunohistochemically. Correlations between expression and some parameters such as age, sex, tumor size, location, presence of multiple neuroendocrine tumor, lymphatic/vascular/muscularis propria invasion and lymph node metastases were evaluated. Results were interpreted as significant if p < 0.05. RESULTS: Mean age of patients (15 men/22 women) was 52 +/- 17. Tumor size varied between 0.1 and 12 cm. (mean; 3.17 +/- 3.29 cm). Expression was detected in 75% of cases and in 92% of gastric neuroendocrine tumors. Expression in mixed endocrine and non-endocrine carcinomas was found to be significantly higher than in well-differentiated neuroendocrine tumors and carcinomas (p = 0.016). A relationship was observed between overexpression and lymphatic and vascular invasion (p = 0.029). However, no significant correlation was found between expression and sex, tumor location, size, muscularis propria invasion and lymph node metastasis. CONCLUSIONS: Cyclooxygenase-2 expression may play a role in the evolution of gastroenteropancreatic neuroendocrine tumors. However, further studies are necessary to determine the importance of this role, prognostic relevance and whether cyclooxygenase isoenzyme can be a target for treatment in these tumors.     

胃肠胰腺神经内分泌肿瘤药物治疗进展

胃肠胰腺神经内分泌肿瘤（GEP-NETs）起源于胃肠胰腺神经内分泌细胞（属APUD细胞），分泌多种活性激素，此类肿瘤的临床表现复杂多样，且恶性程度较高，极易误诊、误治。近年来GEP-NETs的治疗。特别是内科治疗取得了较大的进展，主要包括控制症状治疗、化疗、肽受体介导的放射性核素治疗、生物治疗等。本文参考国内外近期文献，就GEP-NETs的药物治疗进展作一概述。     

Somatostatin and other Peptide receptors as tools for tumor diagnosis and treatment

Somatostatin receptors are expressed in selected human cancers. They are particularly frequently expressed in gastroenteropancreatic neuroendocrine tumors (GEP NET), including both primaries and metastases. The density is often high, the distribution is usually homogeneous. While various somatostatin receptor subtypes can be expressed in these tumors, sst2 is clearly predominant. These receptors represent the molecular basis for a number of clinical applications, including symptomatic therapy with cold octreotide in hormone-secreting GEP NET, in vivo diagnostic with Octreoscan to evaluate the extend of the disease, and 90Y-DOTATOC radiotherapy. GEP NET can, however, express peptide receptors other than somatostatin receptors: insulinomas have more glucagon-like peptide 1 receptors than somatostatin receptors, gut NET (carcinoids) may also express cholecystokinin 2, bombesin or vasoactive intestinal peptide receptors. Often, several of these peptide receptors are expressed simultaneously in GEP NET, providing a molecular basis for in vivo multireceptor targeting of those tumors.     

Endocrine tumors of the pancreas.

Neuroendocrine tumors of the pancreas are rare neoplasms of the heterogeneous group of neuroendocrine gastroenteropancreatic tumors that originate from totipotential stem cells or preexisting endocrine cells within the pancreas. Most neuroendocrine tumors of the pancreas are benign or show an indolent course of disease.A subset of them shows a very aggressive behavior, becomes highly malignant, and metastasizes early with life-limiting consequences. An effective disease-management includes the diagnostic approach with hormonal testing and localization and surgical treatment with histologic classification in combination with biotherapy, chemotherapy, or therapy with radionucleotides, de-pending on the individual behavior of the tumor. The primary goal is the improvement of symptoms leading to an acceptable quality of life in the individual patient.     

New pharmacologic therapies for gastroenteropancreatic neuroendocrine tumors

Successful treatment of unresectable and metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) requires the thoughtful choice of systemic therapy as a component of a multidisciplinary therapeutic approach. The role of somatostatin analogues is established in symptom relief, but the efficacy of interferon and radiopeptide targeted therapy is not clear. The utility of a variety of tyrosine kinase and antiangiogenic agents is variable and under investigation, whereas the role of cytotoxic chemotherapy in poorly differentiated GEP-NETs is accepted. Overall, the ideal treatment of more indolent tumors is less certain. Reassessments of the GEP-NET pathology classification has provided improved logic for the role of a variety of agents, whereas the precise positioning of many new agents that target molecular pathways of angiogenesis and proliferation is under examination. This article describes the current options for systemic therapy for GEP-NETs within the framework of the current World Health Organization classification system.     

Current updates and future directions in diagnosis and management of gastroenteropancreatic neuroendocrine neoplasms

Gastroenteropancreatic neuroendocrine neoplasms are a heterogenous group of rare neoplasms that are increasingly being discovered, often incidentally, throughout the gastrointestinal tract with varying degrees of activity and malignant potential. Confusing nomenclature has added to the complexity of managing these lesions. The term carcinoid tumor and embryonic classification have been replaced with gastroenteropancreatic neuroendocrine neoplasm, which includes gastrointestinal neuroendocrine and pancreatic neuroendocrine neoplasms. A comprehensive multidisciplinary approach is important for clinicians to diagnose, stage and manage these lesions. While histological diagnosis is the gold standard, recent advancements in endoscopy, conventional imaging, functional imaging, and serum biomarkers complement histology for tailoring specific treatment options. In light of developing technology, our review sets out to characterize diagnostic and therapeutic advancements for managing gastroenteropancreatic neuroendocrine tumors, including innovations in radiolabeled peptide imaging, circulating biomarkers, and endoscopic treatment approaches adapted to different locations throughout the gastrointestinal system.     

Lung and digestive neuroendocrine neoplasms. From WHO classification to biomarker screening: Which perspectives?

The recent classifications of lung and digestive neuroendocrine neoplasms (NENs) make a fundamental distinction between well- and poorly-differentiated neoplasms. Well-differentiated NENs are termed carcinoids in the lung and neuroendocrine tumors in the gastroenteropancreatic sphere; their risk of malignancy is highly variable; histological grading is used to stratify patients into prognostically significant groups. Poorly-differentiated NENs are termed neuroendocrine carcinoma in both the lung and the digestive sphere; they constantly are of high grade of malignancy; two types are recognized on the basis of tumor cell morphology, the small cell and the large cell types. Recent studies have largely uncovered the genetic landscape of several subsets of well-differentiated NENs (lung, pancreas, small intestine) and of poorly-differentiated NENs. Some molecular markers may help to the differential diagnosis between highly proliferative neuroendocrine tumors and neuroendocrine carcinomas, especially in the pancreas. In well-differentiated tumors, MGMT status is proposed as a predictive marker of the response to temozolomide, but remains to be validated. In poorly-differentiated neoplasms, large cell neuroendocrine carcinoma has been shown to be a heterogeneous category, with some cases presenting the same molecular signature than small cell carcinoma and others the same signature than adenocarcinomas of the same body site. Rb protein has been recently shown to be a potential marker of response to platinum salts in neuroendocrine carcinoma. Much remains to be done to translate the rapid progress in the molecular understanding of NENS into diagnostic, prognostic or predictive markers.     

Role of 111In-DTPA-pentetreotide scintigraphy in accurate diagnosis of neuroendocrine gastroenteropancreatic tumors

Most gastroenteropancreatic neuroendocrine tumors contain high‐affinity binding sites for somatostatin, and somatostatin‐receptor scintigraphy has been introduced for the in‐vivo evaluation of such tumors. We report two patients with gastroenteropancreatic neuroendocrine tumors, in whom it was quite difficult to localize the tumors by conventional techniques, and in whom we found that ¹¹¹In‐pentetreotide scintigraphy was useful for accurate information on tumor localization. In the first patient, who had gastrinoma, multiple tumors were shown in the gastrinoma triangle, but we could not clarify whether there were any tumors in the pancreatic body. The selective arterial secretin injection (SASI) test diagnosed that the gastroduodenal artery was the feeder of the gastrinomas, and ¹¹¹In‐pentetreotide scintigraphy with single‐photon emission computed tomography indicated the absence of tumors in the pancreatic body. In the second patient, who had insulinoma, multiple liver tumors and a large mass in the hilum of the spleen were shown. ¹¹¹In‐pentetreotide scintigraphy was useful in determining that there was no secretion of insulin from the tumor in the hilum of the spleen. In conclusion, X‐ray computed tomography is superior for detection of neuroendocrine tumors, because not all neuroendocrine tumors have somatostatin receptors; however, somatostatin receptor scanning, as well as the SASI test, may be useful for the surveillance of patients with known primary tumors, for monitoring patients with disseminated disease, and for following the treatment of these patients.     

Study protocol for a multi-institutional randomized phase III study comparing combined everolimus plus lanreotide therapy and everolimus monotherapy in patients with unresectable or recurrent gastroenteropancreatic neuroendocrine tumors; Japan Clinical Oncology Group Study JCOG1901 (STARTER-NET study)

Everolimus is recognized as one of the standard drugs for the treatment of unresectable or recurrent gastroenteropancreatic neuroendocrine tumors (NET). However, recent evidence has suggested that addition of somatostatin analogs to everolimus may yield better survival outcomes as compared to everolimus alone. In April 2020, we have initiated a randomized phase III trial in Japan, to confirm the superiority of combined everolimus plus lanreotide therapy over everolimus monotherapy in patients with unresectable or recurrent gastroenteropancreatic NETs with poor prognostic factors (Ki-67 labeling index: LI 5%–20% or Ki-67 LI < 5% with diffuse liver metastases). We plan to enroll a total of 250 patients from 76 institutions over an accrual period of 5 years. The primary endpoint is progression-free survival. The key secondary endpoint is overall survival, with response rate, disease control rate, and proportion of patients with adverse events as the other secondary endpoints. This trial is registered with the Japan Registry of Clinical Trials as jRCT1031200023 [https://jrct.niph.go.jp/en-latest-detail/jRCT1031200023].     

Nuclear survivin is a powerful novel prognostic marker in gastroenteropancreatic neuroendocrine tumor disease

Gastroenteropancreatic neuroendocrine tumors represent a heterogeneous tumor entity. The growth pattern ranges from very slowly to fast growing, aggressive types of tumors. Survivin, a member of the family of apoptosis inhibitors, is a bifunctional protein that suppresses apoptosis and regulates cell division. In this study we determined the prognostic value of survivin in this tumor entity. Tumor specimens from 104 patients (38 foregut, 53 midgut, 13 hindgut) were studied immunohistochemically for cytoplasmic and nuclear survivin expression as well as for ki-67 antigen expression. 5-year-follow-up was complete in 89 patients. 29 patients with localized, well-differentiated gastroenteropancreatic neuroendocrine tumors (WDET, WHO class 1) had been curatively treated by surgical or endoscopic tumor resection. 50 patients suffered from well-differentiated endocrine carcinomas (WDEC, WHO class 2), 10 patients were diagnosed with poorly differentiated neuroendocrine carcinomas (PDEC, WHO class 3). Survivin expression was correlated with survival for the 50 patients with metastatic WDEC disease. All 29 WDETs were negative for nuclear survivin, whereas all 10 PDECs stained positive for nuclear survivin. In the 50 patients with metastatic WDECs, 5/50 (10%) tumors were nuclear survivin positive. Those 5 patients had a statistically significant worse prognosis (survival of 41 vs. 103 months, p=0.01). ki-67 was not a prognostic factor in this subgroup of patients. Nuclear survivin expression thus appears to be upregulated during progression of gastroenteropancreatic neuroendocrine tumors. The analysis of nuclear survivin expression identifies subgroups in metastatic disease (WHO class 2) with good (survivin-) or with less favorable prognosis (survivin+). We propose that the determination of nuclear survivin expression could be used to individualize therapeutic strategies in this tumor entity in the future.     

The role of targeted therapy for gastrointestinal tumors

Many targeted drugs have been studied to target the molecular pathways involved in the development of gastrointestinal cancers. Anti-VEGF, anti-EGFR agents, and recently also multi-kinase inhibitor regorafenib, have already been available for the treatment of metastatic colorectal cancer patients. To date, Her-2 positive, gastric cancer patients, are also treated with trastuzumab, while the multi-targeted inhibitor, sorafenib, represents the standard treatment for hepatocellular carcinoma patients. Finally, sunitinib and everolimus, have been approved for the treatment of the neuroendocrine gastroenteropancreatic tumors. Actually a great number of further drugs are under preclinical and clinical development. The aim of this review is to provide a comprehensive overview of the state of art, focusing on the new emerging strategies in the personalized treatment of gastrointestinal tumors.     

Effects of tumor origins and therapeutic options on the prognosis of hepatic neuroendocrine tumors: A retrospective study

Hepatic neuroendocrine tumors (HNETs) are uncommon neoplasms that can be subdivided into 2 types: primary and metastatic HNETs. Due to its rarity, heterogeneity and complexity, the diagnosis, treatment modalities and prognosis are still controversial.This retrospective study reviewed the effects of tumor origins and therapeutic options on the prognosis of gastroenteropancreatic neuroendocrine tumors with liver metastasis (GEP-NETLM) and primary hepatic neuroendocrine tumors (PHNETs), providing additional evidence for clinicians evaluating patients.HNETs consisted of PHNETs and GEP-NETLM. GEP-NETLM (76.2%, 112/147) was more common, which was mainly manifested as multiple lesions in both lobes of the liver. PHNETs were relatively rare (23.8%, 35/147) and were mainly single lesion located in the right lobe of the liver. In patients with GEP-NETLM, primary tumor resection could prolong survival (P = .044). As the most widely used treatment method, systematic therapy alone could not achieve a satisfactory survival. However, the combination with hepatectomy or liver-directed therapy improved the prognosis (P = .023). As the main treatment, patients with PHNETs treated with local therapy could achieve a better prognosis (P = .049). Compared with PHNETs patients, GEP-NETLM patients with higher ki-67 index showed higher mortality and poorer prognosis (P = .006).Therefore, patients with PHNETs can be distinguished from GEP-NETLM by comprehensive imaging examinations and long-term follow-ups. The choice of appropriate treatment strategies can improve the prognosis of HNETs patients.     

Identification of gastroenteropancreatic neuroendocrine cells in normal and neoplastic human tissue with antibodies against synaptophysin, chromogranin A, secretogranin I (chromogranin B), and secretogranin II

Gastroenteropancreatic human neuroendocrine (NE) cells (normal and neoplastic) were investigated for the expression of the neuroendocrine-specific polypeptides synaptophysin, chromogranin A, secretogranin I (chromogranin B), and secretogranin II, using immunohistochemistry and immunoblotting. Monoclonal antibody against synaptophysin stained most, and possibly all, of the neuroendocrine cells in both normal and neoplastic tissue. Monoclonal antibody against chromogranin A also stained a high proportion of normal and neoplastic neuroendocrine cells. Immunostaining with polyclonal antisecretogranin I and antisecretogranin II antibodies was detectable in almost all of the normal and neoplastic tissue sections that were analyzed, and it was confined to a smaller population of neuroendocrine cells than that observed for synaptophysin and chromogranin A. Consistent with the immunohistochemical observations, immunoblotting revealed the presence of all four antigens in various tumors. The data show that synaptophysin and chromogranin A, for which monoclonal antibodies are commercially available, may be used as diagnostic markers for human gastroenteropancreatic tumors. Our results also suggest that the development of monoclonal antibodies against human secretogranins I and II will provide additional tools for a refined diagnosis of such tumors.     

Therapeutic strategies for advanced neuroendocrine carcinomas of jejunum/ileum and pancreatic origin

Multimodal treatment options for advanced gastroenteropancreatic neuroendocrine tumours (NET) of jejunum/ileum and of pancreatic origin are reviewed. Current topics being discussed are: European Neuroendocrine Tumour Society 2006/7, American Joint Cancer Committee/Union Internationale Contre le Cancer 2009 and WHO 2010 recommendations for grading and staging of NET; surgery of the primary tumour in distant metastasised disease; surgery of metastatic liver disease and impact on survival; somatostatin analogues for symptom control and for tumour control; selective internal radiation therapy with 90Y-microspheres as novel local ablative therapy in liver metastases; peptide receptor radionuclide therapy; novel chemotherapy regimens (eg, temozolomide) and novel targeted therapies (eg, sunitinib and everolimus).     

Hypokalemic rhabdomyolysis without watery diarrhea: an unexpected presentation of a pancreatic neuro-endocrine tumor

Pancreatic polypeptide (PP) islet cell tumors are usually not associated with a distinct clinical syndrome, although some reports suggest that they can cause a watery diarrhea syndrome similar to vasoactive intestinal polypeptide (VIP) cell tumors. We report the case of a young woman with an unusual presentation of a pancreatic neuroendocrine tumor mainly secreting PP. The patient developed a reversible hypokalemic rhabdomyolysis very likely secondary to the presence of the tumor. The myopathy resolved following the restoration of normokaliemia using potassium supplementation and a partial laparoscopic pancreasectomy. Isolated cases of hypokalemic rhabdomyolysis induced by intestinal diseases have been described in literature but these did not include gastroenteropancreatic neoplasms. We suggest that pancreatic neuroendocrine tumors should be added to the list of intestinal diseases capable of producing hypokalemic myopathy.     

Combination therapy with octreotide and alpha-interferon: effect on tumor growth in metastatic endocrine gastroenteropancreatic tumors

OBJECTIVE: We investigated the antiproliferative efficacy of the addition of alpha-interferon to the somatostatin analogue octreotide in patients with metastasized gastroenteropancreatic tumors unresponsive to octreotide monotherapy. METHODS: In an open prospective trial, 21 patients with metastasized neuroendocrine gastroenteropancreatic tumors (nine patients with carcinoid syndrome, eight with nonfunctioning tumors, four with gastrinoma) were treated with 5 x 10(6) IU alpha-interferon tiw in addition to 200 microg of octreotide tid. All patients, including 16 patients with preceding monotherapy with 200 microg of octreotide tid, had tumor progression documented by computed tomography before entering the study. Growth response (computed tomography documented) and biochemical response were assessed at 3-month intervals. RESULTS: Inhibition of tumor growth was observed in 14 patients (67%), 11 of whom had preceding octreotide monotherapy; complete regression was observed in one patient lasting for 49 months and stable disease (stand-still) in 13 patients lasting for 3 to 52 months (median, 12 months). Seven patients failing this combination therapy exhibited a significantly shorter overall survival (median, 23 months; range, 5 to 42 months) than the 14 patients responding to this regimen (median, 68 months; range, 12 to 112 months; p = 0.007). Two patients are still alive. Biochemical response was achieved in 69% of patients with functioning tumors: in three of four patients with gastrinoma and in six of nine patients with carcinoid syndrome. CONCLUSIONS: These data suggest that the addition of alpha-interferon to octreotide has antiproliferative efficacy in a subgroup of patients with advanced metastatic disease unresponsive to octreotide monotherapy. Prolonged survival was seen in the responder group.     

Tumour biology and histopathology of neuroendocrine tumours

The tumours of the disseminated/diffuse neuroendocrine cell system are a group of neoplasms sharing uniformly appearing cells which differ from each other in their biology, prognosis and genetics. In the lung they are called carcinoid and small/large-cell neuroendocrine carcinomas. In the gastroenteropancreatic compartment they are classified as well-differentiated neuroendocrine tumours or carcinomas and poorly differentiated neuroendocrine carcinomas. Depending on their localization these neoplasms reveal distinct phenotypes with respect to pathology, immunohistochemistry, and hormonal syndromes. Their clinical behaviour--ranging from benign and low-grade to high-grade malignancy--can be predicted on the basis of clinicopathological criteria. Currently extensive work is being performed to unravel the genetic background.