Different patterns of chromogranin A and Leu-7 (CD57) expression in gastrointestinal carcinoids: immunohistochemical and confocal laser scanning microscopy study

Thirty-seven carcinoids of the gastrointestinal tract were studied with immunohistochemical staining for chromogranin A (CgA) and Leu-7 (CD57). The aim of this study was to distinguish and describe the differences in patterns of distribution of immunostaining of these two non-specific neuroendocrine markers in neuroendocrine tumors of different degree of differentiation (typical, vs. atypical carcinoids) at different gastrointestinal sites. Selected 5 tumors from this group were studied in detail using confocal laser scanning microscopy (CLSM) and double immunofluorescence staining to disclose the patterns of distribution of CgA and CD57 positive granules within the individual tumor cells. Prominent differences in the patterns of immunohistochemical staining for both studied markers related to the degree of differentiation of the tumors were observed in studied neoplasms. Regular (diffuse) strongly positive immunoreaction for CgA predominated in typical carcinoids, whereas atypical tumors were characterized by irregular patchy staining. Both typical and atypical tumors displayed predominantly irregular patchy staining for CD57. The results of CLSM study indicate that different modes of CgA and CD57 expression and/or co-expression can occur in neuroendocrine tumors. Neoplastic cells that contained either CgA positive neuroendocrine granules (NEG), or Leu-7 positive NEG, were frequently observed in different areas of the tumor samples, especially in atypical carcinoids. Varying number of cells revealed co-localisation of both CgA and Leu-7 within the NEG. Similar co-localisation of CgA and CD57 was found in non-neoplastic Kultschitski cells of the mucosa of small intestine. In conclusion, our results suggest that the differences in CgA and CD57 expression in human neuroendocrine tumors are related to the degree of differentiation of the neoplasms and probably reflect the degree of maturation (functional state) of neuroendocrine granules within the neoplastic cells.     

Ghrelin-producing endocrine tumors of the stomach and intestine

Ghrelin is a novel gastrointestinal hormone produced by about 20% of the rat and human gastric neuroendocrine cell population, which possesses strong GH-releasing activity, but also plays other central and peripheral roles, including influence on food intake, gastric motility, and acid secretion. The aim of the present study was to determine whether gastrointestinal endocrine hyperplastic and neoplastic lesions produce ghrelin, at both protein (immunohistochemistry) and mRNA (in situ hybridization and/or RT-PCR) levels, and express the GH secretagogue receptor mRNA by RT-PCR. Sixteen gastric and 20 intestinal carcinoids as well as normal gastrointestinal mucosa and atrophic gastritis-associated neuroendocrine cell hyperplasia were studied. The majority (12 of 16, 75%) of gastric carcinoids and only 5 of 18 (27%) of intestinal endocrine tumors were immunoreactive for ghrelin. In situ hybridization confirmed the immunohistochemical data, but also showed ghrelin mRNA in 1 gastric and 8 intestinal additional tumors. RT-PCR showed ghrelin mRNA in 14 of 14 cases, indicating a low level of ghrelin gene expression in all gastrointestinal endocrine tumors tested. Gastric neuroendocrine hyperplastic cells were also strongly positive for ghrelin. GH secretagogue receptor mRNA was absent in 3 gastric, but present in 7 of 11 intestinal carcinoids studied by RT-PCR. These findings demonstrate that most gastric carcinoids (and related neuroendocrine cell hyperplasias) and some intestinal carcinoids produce ghrelin. These hyperplastic/neoplastic conditions could represent the clinical model to clarify the existence and impact of ghrelin hypersecretion on endocrine and nonendocrine functions.     

Midgut neuroendocrine tumor presenting with acute intestinal ischemia

Neuroendocrine tumors represent a heterogeneous group of neoplasms that arise from neuroendocrine cells and secrete various peptides and bioamines. While gastrointestinal neuroendocrine tumors,commonly called carcinoids,account for about 2/3 of all neuroendocrine tumors,they are relatively rare. Small intestine neuroendocrine tumors originate from intestinal enterochromaffin cells and represent about 1/4 of small intestine neoplasms. They can be asymptomatic or cause nonspecific symptoms,which usually leads to a delayed diagnosis. Imaging modalities can aid diagnosis and surgery remains the mainstay of treatment. We present a case of a jejunal neuroendocrine tumor that caused nonspecific symptoms for about 1 year before manifesting with acute mesenteric ischemia. Abdominal X-rays revealed pneumatosis intestinalis and an abdominal ultrasound and computed tomography confirmed the diagnosis. The patient was submitted to segmental enterectomy. Histopathological study demonstrated a neuroendocrine tumor with perineural and arterial infiltration and lymph node metastasis. The postoperative course was uneventful and the patient denied any adjuvant treatment.     

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.     

Hypergastrinemia and recurrent type 1 gastric carcinoid in a young Indian male： Necessity for antrectomy？

Carcinoid tumors are the most common neuroendocrine tumors. Gastric carcinoids represent 2% of all carcinoids and 1% of all gastric masses. Due to the wide-spread use of Esophagogastroduodenoscopy for evaluating a variety of upper gastrointestinal symptoms, the detection of early gastric carcinoids has increased. We highlight an alternative management of a young patient with recurrent type 1 gastric carcinoids with greater than 5 lesions, as well as lesions intermittently greater than 1 cm. Gastric carcinoi...     

A Retrospective Analysis of 1570 Appendiceal Carcinoids

Objective : Information about the management and outcome of appendiceal carcinoids is sparse, because few series comprise more than 100 cases. In this study we have analyzed the epidemiology of 1570 appendiceal carcinoids, to compare outcome with other gastrointestinal carcinoid tumors. Methods : We evaluated 1570 appendiceal carcinoids in a series of 8305 carcinoid tumors from the SEER, the End Results Group, and the Third National Cancer Survey programs of the National Cancer Institute over the time period 1950–1991. Results : Appendiceal carcinoids comprised 18.9% of all carcinoid tumors and exhibited a marked female predominance (M/F ratio: 0.47). Age-adjusted incidence rates were 1.7-fold higher in women compared to men. Appendiceal carcinoids present earlier (average age: 42.2 yr) than other gastrointestinal carcinoids (62.9 yr) or noncarcinoid appendiceal tumors (61.9 yr). At the time of diagnosis 35.4% were nonlocalized. The overall 5-yr survival for localized lesions was 94%, for regional invasion 84.6%, and for distant metastases 33.7%. The 5-yr survival of appendiceal carcinoids (85.9%) was the highest among all types of carcinoid tumors. In 14.6% noncarcinoid tumors at other sites were also evident. Conclusion : The high relative incidence of carcinoid tumors in the appendix is still poorly understood. The good overall 5-yr survival rates of appendiceal carcinoids as opposed to other carcinoids represents either a different biological behavior, earlier diagnosis, or expeditious management (appendectomy). However, the increased likelihood of coexisting neoplasms and the not uncommon presentation of metastatic disease should warrant careful evaluation and postoperative follow-up of such lesions.     

Liver transplantation for metastatic neuroendocrine tumor： A case report and review of the literature

Neuroendocrine tumors are divided into gastrointestinal carcinoids and pancreatic neuroendocrine tumors. The WHO has updated the classification of these lesions and has abandoned the term "carcinoid". Both types of tumors are divided into functional and non-functional tumors. They are characterized by slow growth and frequent metastasis to the liver and may be limited to the liver for long periods. The therapeutic approach to hepatic metastases should consider the number and distribution of the liver metastases as well as the severity of symptoms related to hormone production and tumor bulk. Surgery is generally considered as the first line therapy. In patients with unresectable liver metastases, alternative treatments are dependent on the type and the growth rate. Initial treatments consist of long acting somatostatin analogs and/or interferon. Streptozocin-based chemotherapy is usually reserved for symptomatic patients with rapidly advancing disease, but generally the therapy is poorly tolerated and its effects are short-lived. Locoregional therapy directed such as hepatic-artery embolization and chemoembolization, radiofrequency thermal ablation and cryosurgery, is often used instead of systemic therapy, if the disease is limited to the liver. However, liver transplantation should be considered in patients with neuroendocrine metastases to the liver that are not accessible to curative or cytoreductive surgery and if medical or locoregional treatment has failed and if there are life threatening hormonal symptoms. We report a case of liver transplantation for metastatic neuroendocrine tumor of unknown primary source and provide a detailed review of the world literature on this controversial topic.     

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.     

Carcinoid tumors of the gastrointestinal tract. Analysis of 21 cases

Twenty-one patients with carcinoid tumors have been analysed. Out of 18 patients the diagnostic was made at operation and out of 3 by autopsy. The most frequent sites of the primary tumors were the appendix (38.1%), ileum (23.8%) and colon (19.9%). Asymptomatic tumors were found incidentally in 10 patients (55.5%). The symptomatic neoplasms were more common in the ileum. No one patients in this series obtained the diagnostic of carcinoid tumors before operation or autopsy. It was not observed the malignant carcinoid syndrome. Sixteen patients (88.8%) were submitted to resection and the mean survival was 10.7 years. Two patients (11.1%) were submitted to palliative operations and the mean survival was 3.5 months. The incidence of metastases in cases with carcinoid greater than 2.0 cm in diameter was 71.4%; on the other hand, the patients with carcinoids 2.0 cm in diameter or smaller than this size disclosed metastases in 7.6%. No patients with appendix carcinoid showed metastases and all patients with metastases presented ileum or colon carcinoids. In this series, the prognostic was related with the lesion's size, the localization of the tumor in the gastrointestinal tract and with the resection or not of the primary neoplasm.     

Neuroendocrine carcinomas arising in ulcerative colitis： Coincidences or possible correlations？

Patients with inflammatory bowel disease （IBD） are at increased risk of colorectal malignancies. Adenocarcinoma is the commonest type of colorectal neoplasm associated with ulcerative colitis （UC） and Crohn＇s disease, but other types of epithelial and non-epithelial tumors have also been described in inflamed bowel. With regards to non-epithelial malignancies, lymphomas and sarcomas represent the largest group of tumors reported in association with IBD, especially in immunosuppressed patients. Carcinoids and in particular neuroendocrine neoplasms other than carcinoids （NENs） are rare tumors and are infrequently described in the setting of IBD. Thus, this association requires further investigation. We report two cases of neoplasms arising in mild left-sided UC with immuno- histochemical staining for neuroendocrine markers： a large cell and a small cell neuroendocrine carcinoma of the rectum. The two patients were different in age （35 years vs 77 years） and disease duration （11 years vs 27 years）, and both had never received immunosuppressant drugs. Although the patients underwent regular endoscopic and histological follow-up, the two neoplasms were locally advanced at diagnosis. One of the two patients developed multiple liver metastases and died 15 mo after diagnosis. These findings confirm the aggressiveness and the poor prognosis of NENs compared to colorectal adenocarcinoma. While carcinoids seem to be coincidentally associated with IBD, NENs may also arise in this setting. In fact, long-standing inflammation could be directly responsible for the development of pancellular dysplasia involving epithelial, goblet, Paneth and neuroendocrine cells. It has yet to be established which IBD patients have a higher risk of developing NENs.     

Amyloid precursor-like protein 1 is differentially upregulated in neuroendocrine tumours of the gastrointestinal tract

We have examined the global gene expression profile of small intestinal carcinoids by microarray analysis. High expression of a number of genes was found including amyloid precursor-like protein 1 (APLP1). Quantitative real-time PCR and western blot analysis demonstrated higher expression of APLP1 in carcinoid metastases relative to primary tumours indicating a role of APLP1 in tumour dissemination. Tissue microarray analysis of gastroentero-pancreatic tumours demonstrated a high frequency of APLP1 expression and a low frequency of APLP2 expression in neuroendocrine (NE) tumours when compared with non-NE tumours at the same sites. Meta-analysis of gene expression data from a large number of tumours outside the gastrointestinal tract confirmed a correlation between APLP1 expression and NE phenotype where high expression of APLP1 was accompanied by downregulation of APLP2 in NE tumours. Cellular localization of APLP1, APLP2 and amyloid precursor protein (APP) in carcinoid cells (GOT1) by confocal microscopy demonstrated partial co-localization with synaptophysin. This suggests that the APP family of proteins is transported to the cell membrane by synaptic microvesicles and that they may influence tumour cell adhesion and invasiveness. We conclude that APLP1 is differentially upregulated in gastrointestinal NE tumours and that APLP1 may be important for the dissemination of small intestinal carcinoids. Identification of APLP1 in NE tumours offers a novel target for treatment and may also serve as a tumour-specific marker.     

Expression of inducible nitric oxide synthase and cyclooxygenase-2 in pancreatic adenocarcinoma： Correlation with microvessel density

AIM: Cyclooxygenases (COX) are key enzymes for conversion of arachidonic acid to prostaglandins. Nitric oxide synthase (NOS) is the enzyme responsible for formation of nitric oxide. Both have constitutive and inducible isoforms. The inducible isoforms (iNOS and COX-2) are of great interest as regulators of tumor angiogenesis, tumorigenesis and inflammatory processes. This study was to clarify their role in pancreatic adenocarcinomas. METHODS: We investigated the immunohistochemical iNOS and COX-2 expression in 40 pancreatic ductal adenocarcinomas of different grade and stage. The results were compared with microvessel density and clinicopathological data. RESULTS: Twenty-one (52.5%) of the cases showed iNOS expression, 15 (37.5%) of the cases were positive for COX-2. The immunoreaction was heterogeneously distributed within the tumors. Staining intensity was different between the tumors. No correlation between iNOS and COX-2 expression was seen. There was no relationship with microvessel density. However, iNOS positive tumors developed more often distant metastases and the more malignant tumors showed a higher COX-2 expression. There was no correlation with other clinicopathological data. CONCLUSION: Approximately half of the cases expressed iNOS and COX-2. These two enzymes do not seem to be the key step in angiogenesis or carcinogenesis of pancreatic adenocarcinomas. Due to a low prevalence of COX-2 expression, chemoprevention of pancreatic carcinomas by COX-2 inhibitors can only achieve a limited success.     

Ultrastructural diagnosis of neuroendocrine tumors using fine needle biopsy

Ultrasonic-guided fine-needle-biopsies of primary pancreatic tumours or liver metastasis were performed in 13 patients with neuroendocrine tumours of the gastrointestinal tract (5 carcinoids, 3 gastrinoma, 1 PPoma, 1 calcitoninoma, 1 insulinoma, and 2 non-functional tumours). Specimens obtained were examined on the light- and electronmicroscopic level. In all cases ultrastructural examination sufficiently revealed the correct diagnosis, due to the presence of cytoplasmic neuroendocrine granules within the tumour cells. Additionally performed immunocytochemical investigations at the ultrastructural level enabled the discrimination of gastrinomas, insulinomas, and PPomas. In contrast, light-microscopic examination was less sensitive for tumour classification. It is concluded that ultrastructural investigation of fine needle biopsies represents a valuable method to sufficiently discriminate neuroendocrine neoplasms.     

Enhanced cyclooxygenase-2 expression in sporadic and familial adenomatous polyposis of the human colon

BACKGROUND: The cyclooxygenase (COX) enzymes exist in two related but unique isoforms (COX-1 and COX-2) and catalyze the formation of prostaglandins (PGs). COX-1 is constitutively expressed, and is responsible for the synthesis of PGs necessary for gastroprotection and normal renal function. The COX-2 isoform is important in a variety of pathophysiological conditions such as inflammation and tumorigenesis. Numerous studies report that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) can decrease the incidence of some tumor types, including gastrointestinal polyposis. METHODS: In this study, we evaluated COX-1 and COX-2 expression in 30 polyps collected from 10 patients with familial adenomatous polyposis (FAP) and in 18 polyps collected from 18 patients with sporadic adenomatous polyposis (SAP) using COX-1 or COX-2 isoform-specific antibodies. All tissues were formalin-fixed and paraffin-embedded. Immunoreactivity was detected using tyramide signal amplification and evaluated utilizing an immunohistochemical scoring system. RESULTS: COX-2 was minimally detected in the distant non-neoplastic epithelium, which also served as an internal negative control. In comparison, all polyps collected from SAP or FAP patients overexpressed COX-2 in the neoplastic epithelial cells (P < or = 0.002). Additionally, pronounced COX-2 expression was observed in the stromal cells underlying and adjacent to adenomatous lesions. COX-1 immunoreactivity was weak to mild throughout each tissue evaluated and did not change in the neoplastic or stromal cells of the polyps. CONCLUSIONS: COX-2 expression is upregulated in the adenomatous epithelium of SAP and FAP, while the COX-1 isoform appears to be constitutively expressed at low levels in both neoplastic and non-neoplastic regions. The differential expression of COX-1 and COX-2 in these neoplasms suggests that COX-2 rather than COX-1 may play a role in adenoma formation and/or growth in cases of SAP and FAP in humans.     

The significance of CD44 expression in gastrointestinal neuroendocrine tumors

BACKGROUND/AIMS: Expression of CD44 and its isoforms has been demonstrated to be a prognostic marker in many neoplasms. Gastrointestinal neuroendocrine tumor is a slow-growing neoplasm, whose behavior is determined by site of occurrence, size or specific histologic growth pattern. In this study, the feasibility of using CD44 as a prognostic marker in gastrointestinal neuroendocrine tumor is evaluated. METHODOLOGY: Representative paraffin-embedded sections of gastrointestinal neuroendocrine tumor from 22 patients were studied by immunohistochemical staining using monoclonal antibodies against CD44, Ki-67, and p53 retrospectively. The correlation between these markers and clinical behavior of the tumors was analyzed. RESULTS: Positive expression of CD44 was observed in 15 cases (68%) of gastrointestinal neuroendocrine tumor. Expression of CD44 showed significant inverse correlation with lymph node status (P=0.049), distant metastasis (p<0.001) and mortality (p=0.002). Neither p53 nor Ki-67 correlated with lymph node status, distant metastasis and overall survival. Both lymph node status and distant metastasis showed strong correlation to survival after multivariate analysis. Patients with the tumor growing from the hindgut had better survival (p=0.024). The patients with stronger CD44 immunoreactivity (> or = 2+) tumors had significantly favorable survival (p=0.004) compared with those with weaker immunoreactivity (< or = 1+) tumors. CONCLUSIONS: Expression of CD44 in gastrointestinal neuroendocrine tumor inversely correlates with tumor metastasis, associates with a favorable outcome and may serve as one of the prognostic indicators.     

Small bowel cancer: single-centre results over a period of 12 years

BACKGROUND/AIMS: Tumors of the small bowel are rare, accounting for about 3-6% of all gastrointestinal neoplasms. However, diagnosis and treatment are difficult and an ongoing challenge. METHODOLOGY: Follow-up and clinical data of 43 patients with small bowel cancer who underwent surgery at our hospital. RESULTS: Subgroups consisted of adenocarcinoma (n=16; 37.2%), neuroendocrine tumors (n=12; 27.9%), gastrointestinal stroma tumor (GIST) (n=10; 23.3%), lymphoma (n=3; 7%) and desmoid tumor (n=2; 4.6%). Tumor localizations were within duodenum (46.5%), jejunum (16.3%) and ileum (37.2%). Thirty patients were curatively operated, 13 for palliative treatment or diagnostic purpose. Adenocarcinoma patients showed preponderance of advanced tumor stages: stage I/II in 5 pts, III/IV in 11 patients. Stage distribution for patients with neuroendocrine tumors was 3 each for I and II and 6 for III. Localization was predominantly within the ileum (n=7). Overall survival after five/ten years was 48/37%. Patients with neuroendocrine tumors showed best survival results (75/57%), GIST patients 60/35% and adenocarcinoma (27% each). There was a strong trend towards better survival at early tumor stages in patients with adenocarcinoma and neuroendocrine tumors. CONCLUSIONS: Early diagnosis is essential for prognosis of small bowel malignancies. Cure is unlikely if lymph node or distant metastases have already developed.     

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.     

Management of early gastrointestinal neuroendocrine neoplasms

Neuroendocrine neoplasms (NENs) of the stomach, duo- denum, appendix or rectum that are small (≤ 1 cm) and well differentiated can be considered "early" tumors, since they generally have a (very) good prognosis. In the new WHO classification of 2010, these neoplasms are called neuroendocrine tumors/ carcinoids (NETs), grade (G) 1 or 2, and distinguished from poorly differentiated neuroendocrine carcinomas (NECs), G3. NETs are increasing, with a rise in the age-adjusted incidence in the U.S.A. by about 700 % in the last 35 years. Improved early detection seems to be the main reason for these epidemiological changes. Both the better generalavailability of endoscopy, and imaging techniques, have led to a shift in the discovery of smaller-sized (≤ 10-20 mm) intestinal NETs/carcinoids and earlier tumor stages at diagnosis. Endoscopic screening is therefore effective in the early diagnosis, not only of colorectal adenocarcinomas, but also of NETs/carcinoids. Endoscopic removal, followed up with endoscopic surveillance is the treatment of choice in NETs/carcinoids of the stomach, duodenum and rectum that are ≤ 10 mm in size, have a low proliferative activity (G1), do not infiltrate the muscular layer and show no angioinvasion. In all the other intestinal NENs, optimal treatment generally needs surgery and/or medical therapy depending on type, biology and stage of the tumor, as well as the individual situation of the patient.     

Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors

Background We conducted a nationwide survey to estimate the incidence of neuroendocrine gastrointestinal tumors (NETs) newly diagnosed in Japan from 2002 through 2004. Methods Data on 1541 patients, 514 pancreatic endocrine tumors (PETs) and 1027 gastrointestinal carcinoids (GICs), were collected and analyzed. Results Nonfunctioning tumors (NF-PET) constituted 47.7% of PETs. Next in frequency were insulinoma (31.7%) and gastrinoma (8.6%). Malignancy was frequent in NF-PETs (46.1%) and gastrinomas (45.5%), but only 7.4% of insulinomas were malignant. The incidence of multiple endocrine neoplasia type-1 associated with PETs was 7.4%. The incidence of GICs was 28.8%, 5.2%, and 66.0% in foregut, midgut, and hindgut, respectively. Carcinoid syndrome and metastases were observed in only 1.7% and 5.6% of GICs, respectively. Conclusions The incidence of NETs in Japan was clarified by this preliminary study. Comparatively large differences in GICs between Japan and Western nations were present with regard to the location, symptomatic status, and prevalence of malignancy.     

Array comparative genomic hybridization-based characterization of genetic alterations in pulmonary neuroendocrine tumors

The goal of this study was to characterize and classify pulmonary neuroendocrine tumors based on array comparative genomic hybridization (aCGH). Using aCGH, we performed karyotype analysis of 33 small cell lung cancer (SCLC) tumors, 13 SCLC cell lines, 19 bronchial carcinoids, and 9 gastrointestinal carcinoids. In contrast to the relatively conserved karyotypes of carcinoid tumors, the karyotypes of SCLC tumors and cell lines were highly aberrant. High copy number (CN) gains were detected in SCLC tumors and cell lines in cytogenetic bands encoding JAK2, FGFR1, and MYC family members. In some of those samples, the CN of these genes exceeded 100, suggesting that they could represent driver alterations and potential drug targets in subgroups of SCLC patients. In SCLC tumors, as well as bronchial carcinoids and carcinoids of gastrointestinal origin, recurrent CN alterations were observed in 203 genes, including the RB1 gene and 59 microRNAs of which 51 locate in the DLK1-DIO3 domain. These findings suggest the existence of partially shared CN alterations in these tumor types. In contrast, CN alterations of the TP53 gene and the MYC family members were predominantly observed in SCLC. Furthermore, we demonstrated that the aCGH profile of SCLC cell lines highly resembles that of clinical SCLC specimens. Finally, by analyzing potential drug targets, we provide a genomics-based rationale for targeting the AKT-mTOR and apoptosis pathways in SCLC.