Notch信号通路和神经内分泌肿瘤

Notch信号通路既简单又复杂,表达于多个物种且高度保守.在不同的细胞类型中,Notch信号通路可促进或抑制细胞增殖、分化和凋亡.Notch信号通路与肿瘤的关系比较复杂,既可以作为癌基因,也可以作为抑癌基因,它的作用与细胞类型有关.在神经内分泌肿瘤(NETs)如类癌、小细胞肺癌(SCLC)和甲状腺髓样癌(MTC)中Notch信号通路失活,若激活Notch信号通路可抑制肿瘤细胞生长、减少NETs标志物,证明Notch信号通路在NETs中发挥肿瘤抑制作用.因此,Notch信号通路激活剂可能会成为NETs患者的一个潜在治疗药物.     

Secretagogin is a novel marker for neuroendocrine differentiation

Our previous microarray-based studies identified secretagogin to be highly expressed in normal colon mucosa compared to basal expression in colon adenocarcinomas. The aim of this study was to analyze the differential expression of secretagogin in normal mucosa, adenocarcinomas, and neuroendocrine tumors. Western blotting, immunohistochemistry, immunofluorescence microscopy and ELISA were applied. Western blot analysis detected a 32-kDa secretagogin band in samples from normal mucosa. Immunohistochemical analyses on tissue specimens showed that secretagogin is exclusively expressed in neuroendocrine cells and nerve cells in normal mucosa of the digestive tract. Tissues adjacent to benign hyperplasic polyps and adenomas showed a decreased number of secretagogin-expressing neuroendocrine cells. Secretagogin co-localized with neuroendocrine markers (chromogranin A, neuron-specific enolase, synaptophysin) in neuroendocrine cells in crypts of normal mucosa, and in tumor cells of carcinoids. Secretagogin was strongly expressed in the cytosol and the nucleus of 19 well-differentiated neuroendocrine carcinoids and carcinoid metastases, as well as in neuroendocrine tumors from the lung, pancreas and adrenal gland. Secretagogin was detected in plasma from carcinoid patients with distant metastasis. Combined immunohistochemical analysis of secretagogin and FK506-binding protein 65, a protein de novo synthesized in adenocarcinomas, distinguished well-differentiated carcinoids, adenocarcinoids and undifferentiated carcinomas. We conclude that secretagogin is a novel marker for neuroendocrine differentiation.     

Establishment and characterization of a human carcinoid in nude mice and effect of various agents on tumor growth.

The authors have established a long-term tissue culture cell line (BON) derived from a metastatic human carcinoid tumor of the pancreas. The cells have been in continuous passage for 46 months. Tissue culture cells produce tumors in a dose-dependent fashion after SC inoculation of cell suspensions in athymic nude mice. BON tumors, grown in nude mice, are histologically identical to the original tumor; they possess gastrin and somatostatin receptors, synthesize serotonin and chromogranin A, and have a doubling time of approximately 13 days. The antiproliferative effects of the long-acting somatostatin analogue, SMS 201-995 (300 micrograms/kg, t.i.d.), and 2% alpha-difluoromethylornithine on BON xenografts in nude mice were examined. Tumor size was significantly decreased by day 14 of treatment with either agent and at all points of analysis thereafter until the animals were killed (day 33). In addition, tumor weight, DNA, RNA, and protein contents were significantly decreased in treated mice compared with controls. Establishment of this human carcinoid xenograft line, BON, provides an excellent model to study further the biological behavior of carcinoid tumors and the in vivo effect of chemotherapeutic agents on tumor growth.     

Expression of cyclo-oxygenase-2 in gastrointestinal carcinoid tumors

BACKGROUND: Cyclo-oxygenase (COX)-2 overexpression is observed in various neoplasms and COX-2 inhibition has been attempted as prevention and/or therapy in these neoplasms. Carcinoid tumors are thought to arise from neuroendocrine cells and originate mainly in the gastrointestinal tract. Cyclo-oxygenase-2 is reportedly expressed in neuroendocrine cells of normal colorectal mucosa. The role of COX in carcinoids has not previously been investigated. The aim of the present paper was to clarify the expression of COX-1 and -2, and their role in human gastrointestinal carcinoids. METHODS: Expression of COX-1 and -2 was studied immunohistochemically in 38 gastrointestinal carcinoids. Five bronchopulmonary and seven metastatic carcinoids were also examined, for comparison with gastrointestinal carcinoids. The immunohistochemical score (IHS) was calculated from staining intensity and immunoreactive cell population, and ranked according to four grades (negative to strong). RESULTS: Cyclo-oxygenase-2 was expressed in all gastrointestinal carcinoids (weak, 1; moderate, 13; strong, 24) and bronchopulmonary carcinoids (weak, 1; moderate, 4), as well as their metastases (moderate, 3; strong, 4). The IHS of COX-2 in larger tumors was significantly lower than that in smaller tumors. However, the IHS of COX-2 at the advancing tumor edge was significantly higher than that at the centers of tumors >or=10 mm in size. Faint COX-1 expression was detected in only one duodenal, one rectal and four bronchopulmonary carcinoids. CONCLUSIONS: Enhanced COX-2 expression was observed in gastrointestinal as well as bronchopulmonary carcinoids and their metastases, especially at the advancing edges of the tumors. Cyclo-oxygenase-2 may play a role in carcinoid progression.     

Classification of gastric neuroendocrine tumors and its clinicopathologic significance

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Carcinoid of the ampulla of Vater

Endocrine neoplasms only rarely occur at the ampulla of Vater, comprising mostly carcinoids and malignant carcinoids, as well as few cases of poorly differentiated endocrine carcinomas (small cell carcinomas). Only 105 cases are reported in the literature, most as single case reports. For many years, the neoplasms of the disseminated neuroendocrine cell system of the gastrointestinal tract have been subsumed as 'carcinoids'. Instead, in the latest World Health Organization (WHO) classification published in 2000, it is recommended to distinguish between (i) well-differentiated endocrine tumors (carcinoids); (ii) well-differentiated endocrine carcinomas (malignant carcinoids); and (iii) poorly differentiated endocrine carcinomas (small cell carcinomas). Patients with carcinoid tumors of the ampulla of Vater are very often free of clinical and laboratory findings that belong to the carcinoid syndrome. Approximately 26% of all patients with carcinoid tumor reported in the literature had neurofibromatosis. Besides endoscopic retrograde cholangiopancreatography, endosonography, computed tomography or magnetic resonance imaging may complete the staging approach of this tumor. The Kausch-Whipple procedure or pylorus-preserving pancreaticoduodenectomy is considered the treatment of choice for ampullary, well-differentiated carcinoids >2.0 cm and for ampullary neuroendocrine carcinomas. However, it should be considered that long-term survival of patients with ampullary carcinoids is also reported after local tumor excision (5-year survival rate of 90%). The dilemma is that the differentiation of neuroendocrine tumors cannot be assessed intraoperatively in most cases. Therefore, considering that the 5-year survival rate in patients with neuroendocrine carcinomas of the ampulla of Vater is very low without radical resection, neuroendocrine tumors of the ampulla of Vater without definite histological differentiation should undergo extended surgery.     

Neuroendocrine gastric carcinoma. A case report and review of current management

Neuroendocrine or carcinoid tumors of the gastrointestinal tract considered previously extremely rare, are diagnosed at present with increased frequency due to the better capacity to identify neuroendocrine system cells in normal and pathologic conditions. Occasionally, these tumors secrete a great variety of vasoactive substances, producing the carcinoid syndrome. Gastric carcinoids are classified, according to their degree of differentiation into well differentiated and poorly differentiated tumors, also called neuroendocrine carcinomas. Neuroendocrine gastric carcinomas or poorly differentiated gastric carcinoids are seen in 5-15% of all gastric carcinoids, mainly in older male patients. Generally they are large, very aggressive tumors with extensive local infiltration. Due to poor differentiation, they are not frequently associated with an endocrine syndrome. They can be located in any part of the stomach but are mainly seen in antrum. These tumors have an aggressive behavior and must be treated in a radical manner; recurrences are not uncommon. We report the case of a patient with a neuroendocrine gastric carcinoma treated with an en bloc subtotal gastrectomy and colectomy.     

Expression of tyrosine kinase receptors in malignant midgut carcinoid tumors

BACKGROUND: The expression of certain tyrosine kinase receptors (TKR) has been shown to have a prognostic value in many tumor entities. In recent years, inhibitors and monoclonal antibodies directed towards these receptors have been developed. Several have shown antitumoral effects and have been tested in clinical trials. We wanted to investigate whether midgut carcinoid tumors express TKR and therefore would be suitable for clinical trials with TKR inhibitors (TKRI) or monoclonal antibodies. MATERIAL AND METHODS: Tumor tissue from 36 patients (24 women and 12 men) with a malignant midgut carcinoid tumor was obtained. The tissues were examined with immunohistochemistry, using polyclonal antibodies against platelet-derived growth factor receptor-alpha (PDGFRalpha), platelet-derived growth factor receptor-beta (PDGFRbeta), epidermal growth factor receptor (EGFR) and c-kit. Human BON1 cells were cultivated and stimulated with PDGF-BB. We also present a case report of a patient with a malignant midgut carcinoid tumor who had stabilization of tumor growth during treatment with imatinib. RESULTS: Immunohistochemical staining for PDGFRalpha in tumor cells showed immunoreaction for the receptor in 13/34 (38%) for PDGFRbeta in 29/33 (88%), and 24/33 (73%) were immunoreactive for EGFR. No tumor tissue showed immunoreaction for c-kit. In tumor stroma PDGFRalpha was expressed in 35%, PDGFRbeta in 94% and EGFR in 9%. We show that human neuroendocrine tumor cells respond to PDGF, indicating that these tumors express functional PDGF receptors. CONCLUSION: Malignant midgut carcinoid tumors may express three of the four TKR tested in this investigation. Therefore, these tumors might be susceptible for treatment with TKRI or monoclonal antibodies and this should be further explored in clinical trials.     

Current diagnosis and treatment of gastrointestinal carcinoids in a series of 101 patients: the significance of serum chromogranin-A, somatostatin receptor scintigraphy and somatostatin analogues

BACKGROUND/AIMS: Carcinoids are relatively rare tumors that arise from neuroendocrine cells and have proved to be slow growing malignancies which involve many organs and most frequently the gastrointestinal (GI) tract. Herein we present in this study 101 pts with carcinoid tumors that originated from the GI tract and pancreas. Also, we analyze the clinical and pathological features, pointing out the characteristics of this group of neoplasms and describing our diagnostic and therapeutical approach, in parallel with a brief review of the literature. METHODOLOGY: One hundred and one (66 females and 35 males, aged from 16 to 79 years) pts were included in our study. The primary tumors originated from the GI tract in 97/101 pts (appendix 34%, small intestine 31%, stomach 14%, duodenum 6%, colon 6%, rectum 3%) and from the pancreas in 4/101 (4%). The diagnosis was confirmed histologically in all cases, after surgical excision of the primary tumor or by biopsies taken during endoscopy. All pts were evaluated several times per year with clinical, biochemical and imaging assessments, including neuroendocrine markers [urinary 5-Hydroxyindoleacetic acid (5-HIAA), serum Chromogranin-A (CgA)] and Somatostatin Receptor Scintigraphy (OCTREOSCAN). The follow-up period ranged between 1.5 to 12.5 years (mean time: 5 years and 3 months) and it is still in progress. RESULTS: Patients were referred to us with gastrointestinal symptoms or symptoms of the "carcinoid syndrome" (flushing, and diarrhea), depending mainly on the location of the primary tumors and the existence or not of metastases. CgA and 5-HIAA levels were increased especially in metastatic tumors. Localization of the primary tumors to facilitate surgery was made by many imaging techniques (US, CT, MRI, Enteroclysis, OCTREOSCAN) and endoscopic procedures. OCTREOSCAN was positive in 94% pts with metastatic disease. Furthermore, it revealed the primary and the metastatic lesions in 16% and 33% of pts with carcinoids of the small intestine respectively, while other conventional imaging procedures (including MRI) were negative at the same time. Seventy-four percent of the pts underwent a surgical resection of the primary tumor, while in 21%, an endoscopic polypectomy was performed. All pts with metastatic tumors and positive OCTREOSCAN, were treated with Somatostatin analogues, which resulted in control of symptoms (75%), stabilization of tumor growth (71%) or tumor shrinkage (9%). A combined therapy with the addition of interferon-a was initiated in pts in whom, despite the increase of drug dosage and the shortening of administration intervals, a complete clinical and biochemical response was no more achieved with Somatostatin analogues alone. Pancreatic carcinoids and also those that originated from the proximal colon were found to have worst prognosis. CONCLUSIONS: a) Tumor size (especially in appendiceal and gastric carcinoids) and, also, the dispersion of disease, highly predict the evolution of the patients; b) serum Chromogranin-A seems to be a very useful tumor marker for the diagnosis and follow-up of pts with GI carcinoids; c) the introduction of new imaging techniques and especially OCTREOSCAN contributes to a better localization of the primary tumors and their metastases, as well as, to the right decision of the appropriate medical treatment; d) surgical excision is the treatment of choice in nonmetastatic tumors; and e) in pts with metastatic disease, the administration of Somatostatin analogues improves their quality of life.     

异位ACTH综合征的研究进展

能引起异位促肾上腺皮质激素(ACTH)综合征的肿瘤种类较多,β连环蛋白相关的Wnt信号通路、Nouch信号通路、P21活化的蛋白激酶3在异位分泌ACTH肿瘤的发生、发展中起重要作用,促阿片黑素细胞皮质素原基凶启动子区去甲基化与肿瘤异位分泌激素密切相关.在诊疗方面,血清嗜铬粒蛋白A的测定大大提高了异位ACTH综合征的阳性预测率.除手术治疗外,联合用药较单独使用生长抑素或选择性多巴胺受体激动剂更为有效.     

Immunohistochemical localization of endothelin-converting enzyme-1 in neuroendocrine tumors and normal human tissue

Endothelin-converting enzyme-1 (ECE-1) is the key enzyme of endothelin biosynthesis, catalyzing the final step in the process. In this study, we investigated the cellular distribution of ECE-1 in 19 normal human tissues and 16 neuroendocrine tumors using immunohistochemical staining with antigen retrieval. ECE-1 was expressed in vessel endothelial cells as well as nearly all epithelial cells, glands and duct cells in normal human tissues including the esophagus, stomach, small intestine, appendix, colon, liver, gallbladder, pancreas, endometrium, cervix, breast, skin, prostate, urinary bladder, lung, kidney, sympathetic ganglion, thyroid gland, and adrenal gland. The most interesting finding was that ECE-1 was expressed in normal neuroendocrine cells. ECE-1 was also expressed in all 16 neuroendocrine tumors, including three paragangliomas, five pheochromocytomas, three carcinoid tumors, four medullary carcinomas of the thyroid, and one islet cell tumor of the pancreas. In conclusion, ECE-1 is enriched in neuroendocrine cells and neuroendocrine tumors, suggesting an important biologic role for the enzyme in the neuroendocrine system.     

En-bloc resection of multiple type 1 gastric carcinoid tumors by endoscopic multi-band mucosectomy

Background and Aim:  Gastric carcinoid tumors are rare but increasing in incidence. Current recommendations suggest endoscopic resection for type I carcinoids found in the stomach, however reports of incomplete resection have led to difficulty planning future management. Our purpose was to describe the application of the endoscopic multi-band mucosectomy (MBM) device to achieve en-bloc resection of multiple gastric carcinoid tumors.
Methods:  Over a 30-month period (June 2006–January 2009) eight patients attending for endoscopic assessment of gastric carcinoid tumors were identified at two tertiary referral centers. Patients underwent endoscopic resection of the carcinoids with an MBM device. En-bloc specimens underwent histological evaluation for identification and tumor resection margins. Patients with type I carcinoids were subsequently enrolled in an endoscopic follow-up program.
Results:  A total of 34 gastric carcinoid tumors were removed from eight patients. On histological analyses seven out of eight patients were diagnosed with type I tumors. In the remaining patient a single, sporadic (type III) gastric carcinoid was diagnosed. No complications of severe bleeding or perforation occurred. All specimens were shown to have clear deep and peripheral histological resection margins.
Conclusion:  Complete 'en-bloc' endoscopic resection of multiple 'type I' gastric carcinoid tumors can be safely and easily performed with an MBM technique.     

Gastrointestinal carcinoid tumors

BACKGROUND: Carcinoid or neuroendocrine tumors of the gastrointestinal tract, although characteristically indolent, are also quite heterogeneous both with respect to histologic and endocrine features and with respect to clinical presentation and behavior. PURPOSE: This study was undertaken to review and summarize the current literature on classification controversies, site-specific carcinoid presentation and behavior, and diagnostic and management strategies for primary and advanced carcinoid tumors and the carcinoid syndrome. RESULTS: For carcinoid tumors, oncologic results depend on the location of the primary tumor, extent of locoregional and metastatic disease, functioning status of the tumor, and the feasibility of complete surgical extirpation. Whereas favorable survival rates are typically observed for appendiceal and rectal primaries, less favorable rates are often observed for colonic and ileal tumors. A search for additional tumors is generally advised because multiple carcinoids and second neoplasms are not uncommon. Because of the indolent nature of the tumor and because these therapies have been shown to improve quality and quantity of life, otherwise fit patients with advanced carcinoid disease should be treated with aggressive medical and surgical therapies. Development of a malignant carcinoid syndrome indicates the presence of a functionally active carcinoid tumor and portends a poor prognosis. CONCLUSION: Gastrointestinal carcinoids, although malignant, behave differently from other carcinomas. Results are highly variable and must be individualized according to the site of the primary tumor, extent of spread, and general condition of the patient. A prolongation of quality life can often be accomplished through aggressive medical and surgical therapies.     

Gastrointestinal carcinoid tumor]

Carcinoid tumors originate from the neuroendocrine cells throughout the body and occur most frequently (74%) in the gastrointestinal tract. The clinical course is often indolent but can also be aggressive and resistant to therapy. Clinical manifestations are often vague or absent. Nevertheless, in approximately 10% of patients, the tumors secrete bioactive mediators which may engender various elements of characteristic carcinoid syndrome. In many instances, the neoplasms are detected incidentally at the time of surgery for other gastrointestinal disorders. The tendency for metastatic spread correlates with tumor size, and is substantially higher in lesions larger than 2.0 cm. Management of patients with carcinoid tumors requires an understanding of the disease process and a multimodality approach. Treatment consists of radical surgical excision of the tumor, although gastric (type I and II) and rectal carcinoids may be managed with local excision. However, advanced carcinoid tumor remains incurable.     

The antral mucosa as a new site for endocrine tumors in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndromes

Carcinoid tumors were identified in the antro-pyloric mucosa of four patients with multiple endocrine neoplasia type 1 (MEN-1)/Zollinger-Ellison syndrome, accounting for 8.7% of 46 patients with this condition examined by endoscopy and histology. In contrast, no tumors were found in the antral biopsies from 124 cases of sporadic Zollinger-Ellison syndrome (P < 0.001), indicating a prominent role for the MEN-1 gene defects in tumor development. Immunohistochemically the tumors did not express the hormones produced by antral endocrine cells (gastrin, somatostatin, serotonin). In contrast, two of them were diffusely immunoreactive for the isoform 2 of the vesicular monoamine transporter (VMAT-2), a marker specific for the gastric nonantral enterochromaffin-like (ECL) cells. In one of these patients a second antral VMAT-2-positive carcinoid was seen 21 months after the first diagnosis. The other two antral carcinoids were unreactive for VMAT-2. Multiple ECL cell tumors were found in the gastric body-fundus mucosa of the two patients with VMAT-2-positive, but not in those with VMAT-2-negative, antral carcinoids. In one case, the former tumors were diagnosed 22 months after the detection of the antral tumor. We conclude that the antral mucosa is an additional tissue that may harbor endocrine tumors in MEN-1 syndrome. These tumors did not express the phenotype of normal antral endocrine cells and, in at least two cases, were identified as ectopic ECL cell carcinoids.     

Bronchoscopic long-term palliation of a recurrent atypical carcinoid tumor

Bronchial carcinoid tumors account for 1-2% of all primary lung tumors and are separated into 2 subgroups: typical and atypical carcinoids. Atypical carcinoids as intermediate-grade malignancies can metastasize more frequently, thus exhibiting poorer prognosis than the low-grade typical carcinoid tumors. Surgical resection remains the mainstay of treatment for pulmonary carcinoids. Bronchoscopic treatment using ablation techniques is an effective alternative to surgery in selected patients with typical carcinoid tumors. However, evidence is lacking regarding the effect of bronchoscopic resection of atypical carcinoid tumor and its recurrences. We report the case of a 73-year-old male with frequent endobronchial recurrences of a previously surgically resected atypical carcinoid tumor successfully treated using Nd:YAG laser photoresection. Furthermore, the therapeutic and local staging aspects of the disease are discussed emphasizing the efficacy of bronchoscopic resection strategies and the value of novel bronchoscopic imaging techniques in detailed inspection of the structures of the bronchial wall.     

Resection of multiple rectal carcinoids with transanal endoscopic microsurgery:Case report

Multiple rectal carcinoids are rare.Due to the unreliability of endoscopic polypectomy in treating these submucosal lesions,a laparotomy is usually performed.We present a case report on multiple rectal carcinoids with three carcinoid foci<10 mm in diameter located in the midrectum.Preoperative examination showed the lesions to be confined to the submucosal layer with no perirectal nodal involvement.A transanal endoscopic microsurgerywas successfully performed to remove the three lesions with accurate full-thickness resection followed by secured suture closure.The postoperative pathology revealed neuroendocrine tumors G1(carcinoids)located within the submucosal layer without lymphatic or vessel infiltration.Both the deep and lateral surgical margins were completely free of tumor cells.The patient recovered quickly and uneventfully.No tumor recurrence was observed at the six-month follow-up.For the multiple small rectal carcinoids without muscularis propria or lymphatic invasion,transanal endoscopic microsurgery offers a reliable and efficient alternative approach to traditional laparotomy for select patients,with the added advantages of minimally invasive surgery.     

Clinical review of gastrointestinal carcinoid tumor and analysis of the factors predicting metastasis]

BACKGROUND/AIMS: Carcinoid tumors are submucosal tumors with metastatic potential. We tried to determine the clinical course of gastrointestinal (GI) carcinoid tumors and find the factors predicting metastasis. METHODS: We reviewed the clinical records of 81 cases with GI carcinoid tumors. Involved organ, age, sex, symptoms, treatments, and metastatic patterns were reviewed. We evaluated the macroscopic and microscopic parameters to predict the metastatic potential of GI carcinoid tumors. RESULTS: The common sites of GI carcinoids were rectum (71.7%), stomach (13.6%), and duodenum (8.6%). Mean age of the patients was 49 years old with a peak incidence of sixth decade. Male to female ratio was 1.38:1. Most symptoms were usually nonspecific. Fifty five patients (67.9%) received endoscopic treatments while 23 patients (28.4%) received surgical treatment. Patients were followed up for a mean period of 15.6 months. There were 10 cases (12.3%) of metastasis. There were significantly more metastasis in patients with tumor size>10 mm (p<0.001), central depression or ulcer (p=0.009) in macroscopic parameter, and with invasion below submucosa, lymphatic or venous invasion, number of mitosis>2, or Ki-67 labeling index>2 in microscopic parameter (p<0.05). Independent factors predicting metastasis were tumor size and central depression or ulcer in multivariate analysis (p=0.002 and p=0.035, respectively). CONCLUSIONS: Patients with tumor size>10 mm, central depression or ulcer, invasion below submucosa, lymphatic or venous invasion, mitosis>2, and Ki-67 labeling index>2 have higher metastatic potential. Those with risk factors predicting metastasis should be treated and followed carefully.