Our aim is to provide an overview of small bowel neuroendocrine tumours (NETs), clinical presentation, diagnosis algorithm and management options. We also highlight the latest evidence on management and suggest areas for future research.

Dodecanetetraacetic acid (DOTATATE) scan can detect NETs with an improved sensitivity than when compared with an Octreotide scan. It is complimentary to small bowel endoscopy that provides mucosal views and allows the delineation of small lesions undetectable on imaging. Surgical resection is the best management modality even in metastatic disease. Prognosis can be improved with the administration of somatostatin analogues and Evarolimus as second-line therapies.

NETs are heterogenous tumours affecting most commonly the distal small bowel as single or multiple lesions. Their secretary behaviour can lead to symptoms, most commonly diarrhoea and weight loss. Metastases to the liver are associated with carcinoid syndrome.

Significant augmentation of the incidence of duodenal neuroendocrine tumors duodenum has been observed in recent decades. There are 5 histological types of these tumors: gastrinoma (50-60%), somatostatin-producing tumor (15%), inactive serotonin-containing tumors (20%), poorly differentiated neuroendocrine carcinoma (<3%) and gangliocytic paraganglioma (<2%). The majority of tumors are localized within the bulb and postbulbar part of duodenum, 20% are found in periampular area. Treatment strategy depends on dimensions, localization, histological class, stage and type of tumor. It is believed that endoscopic resection is permissible for small inactive tumors (G1) located above major duodenal papilla. The majority of other neoplasms requires surgical resection. Personal experience of various surgeons is limited by small group of patients. Therefore, it is necessary to summarize results for selection of optimal treatment.

Pancreatic neuroendocrine neoplasms (pNENs) are relatively rare tumors representing 1% to 2% of all pancreatic neoplasms. These tumors can secrete a variety of biologically active substances giving rise to distinct clinical symptoms or can be clinically nonfunctioning. Apart from insulinomas and gastrinomas, which constitute the majority of functioning pNENs, some tumors may secrete serotonin presenting with the features of the carcinoid syndrome. These so-called pancreatic carcinoids are considered relatively rare tumors and are associated with increased urinary levels of 5-hydroxyindoleacetic acid (5-HIAA). It has recently been suggested that the prevalence of such tumors might be underestimated.

We present a series of 5 patients from our database of 138 pNENs (5/138, 3.62%), harboring serotonin-producing pNENs and describe their distinctive clinical, biochemical, histopathological features, and response to treatment along with a review of the relevant available literature.

Such tumors are considered rare, although this may be an underestimate as systematic screening for the presence of serotonin in tissue or elevated urinary 5-HIAA levels in patients with apparently nonfunctioning pNENs is not currently recommended. In order to reach such a consensus, data from large prospective studies are needed in order to evaluate the impact of this type of tumors in survival and clinical outcome, since some studies have suggested a worse prognosis.

Pancreatic endocrine tumors (PET) represent a heterogenous group of neoplasms. Although surgical resection is considered a safe and effective treatment for many PET, therapeutic options for inoperable and progressive PET are limited. The expression of heat-shock protein (HSP) 90 was investigated in 120 clinically and pathomorphologically well-characterized PET from 84 patients using immunohistochemistry. In addition, in 19 snap-frozen PET and in three healthy pancreatic tissues, we performed immunoblot analyses, and in 15 snap-frozen PET and in three healthy pancreatic tissues, we investigated the expression of HSP90 isoforms by means of semiquantitative RT-PCR. Functional tests were conducted using the human pancreas carcinoid cell line BON and the mouse insulinoma cell line β-TC-3. HSP90 was expressed in 95% of the PET patients. The transcript levels of the HSP90 isoforms HSP90α, HSP90β, glucose-related protein 94, and TNF receptor-associated protein 1 were significantly increased in PET compared with non-neoplastic pancreatic tissues. The treatment of the cell lines BON and β-TC-3 with the HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin resulted in significant, dose-dependent reduction of cell viability, cell cycle arrest, and increased apoptosis. Furthermore, HSP90 inhibition induced the degradation and inactivation of several oncogenetic HSP90 client proteins in a time- and dose-dependent manner. HSP90 inhibitors increased the therapeutic effects of doxorubicin and 5-fluorucacil in BON and β-TC-3 cells. HSP90 is expressed in the vast majority of PET and its inhibition reveals significant treatment effects in vitro. Thus, HSP90 qualifies as a promising new target.

Pancreatic endocrine tumors represent morphologically and biologically heterogeneous neoplasms. Well-differentiated endocrine tumors (benign or of uncertain behavior) can be distinguished from well-differentiated and poorly differentiated endocrine carcinomas. Although many well-differentiated endocrine carcinomas show rather low rates of tumor growth, more than two-thirds of pancreatic endocrine carcinomas display distant metastases at the time of diagnosis. As the currently applied therapies beyond surgery only achieve partial or complete response rates of approximately 15%, additional chemotherapeutic targets are needed, especially in the therapy of inoperable and progressive pancreatic endocrine carcinomas.

The expression of epidermal growth factor receptor (EGFR) and cyclooxygenase (COX)-2 were investigated in 110 clinically and pathomorphologically well-characterized pancreatic endocrine tumors, using immunohistochemistry and immunoblot analyses. Functional tests were performed using the human pancreas carcinoid cell line BON and the mouse insulinoma cell line beta-TC-3.

The expression of EGFR correlated significantly with the grade of malignancy, increasing from low rates of expression in benign tumors and tumors of uncertain behavior to high rates of expression in well- and poorly differentiated endocrine carcinomas. The expression of COX-2 was independent of the malignant potential, but was more frequently expressed in primary tumors than in metastases. The treatment of the human pancreas carcinoid cell line BON and the mouse insulinoma cell line beta-TC-3 with EGFR and COX-2 inhibitors (monotherapy and combined therapy) resulted in a significant, dose-dependent reduction of cell viability coupled with increased apoptosis.

Our results suggest that EGFR and COX-2 may represent useful additional chemotherapeutic targets in pancreatic endocrine tumors.

Since the first reports with laparoscopic resection of islet cell tumors in 1996, the experience worldwide is still limited, with only short-term outcomes available. Some have suggested that a malignant tumor is a contraindication to laparoscopic resection. Aim The aim of this study was to evaluate the feasibility, safety, and long-term outcome of the laparoscopic approach in patients with functioning, nonfunctioning, or overt malignant pancreatic neuroendocrine tumor (PNT). To our knowledge this is the largest single-institution series on this subject to date. Patients and methods A total of 49 consecutive patients (43 women, 6 men; mean age 58 years, range 22-83 years) underwent laparoscopic pancreatic surgery (LPS) from April 1998 to June 2007. Preoperative localization was done by computed tomography, magnetic resonance imaging, endoscopic ultrasonography, and Octreoscan imaging. Other than 9 PNTs localized in the head of the pancreas, all tumors were located in the left pancreas. Malignancy was diagnosed based on the presence of lymph nodes or liver metastasis. There were 33 patients with functioning tumors: 4 with gastrinomas (mean size 1.2 cm), 1 with a glucagonoma (4 cm), 3 with vipomas (3.2 cm), 2 with carcinoids (5.2 cm), 20 with sporadic insulinomas (1.4 cm), 2 with insulinoma/multiple endocrine neoplasia type 1 (MEN-1) (4.4 cm), and 1 with a malignant insulinoma (13 cm). Sixteen patients had a nonfunctioning tumor (mean size 5 cm). The following techniques were performed: laparoscopic spleen-preserving distal pancreatectomy (Lap SPDP), laparoscopic distal pancreatectomy with splenectomy (Lap SxDP) and laparoscopic enucleation (Lap En)/laparoscopic excision (Lap E). Lymph node dissection was performed when malignancy was suspected (Strasberg s technique). Evaluation criteria included operative and postoperative factors, pathologic data including R0 or R1 resection (the pancreatic transection margin and all transection margins on the specimen were inked). Long-term outcomes were analyzed by tumor recurrence and patient survival. Results Four cases (8.2%) were converted to open surgery. Overall, Lap SPDP, Lap SxDP, and Lap En/Lap E were performed in 15 (33.3%), 8 (17.8%), and 22 (48.9%) patients, respectively. The operative time and blood loss was significantly lower in the Lap En group compared with the other laparoscopic techniques. The group of patients with malignant tumors undergoing Lap SxDP had a longer operating time and greater blood loss compared with the other distal pancreatectomy (Lap DP) techniques. Overall, the postoperative complications were significantly higher in the Lap En group (42.8%) than in the Lap DP (Lap SPDP+Lap SxDP) group (22%). These complications were mainly pancreatic fistula: 8.7% after Lap DP and 38% after Lap En. The overall morbidity was significantly higher after Lap SPDP (26.7%) than after Lap SxDP (12.5%) owing to the occurrence of splenic complications in the Lap SPDP group without splenic vessel preservation two of seven (28.5%). The means and ranges of hospital stay after Lap SPDP, Lap SxDP, and Lap En/Lap E were 5.9 (5-14), 7.5 (5-12), and 5.5 (5-7) days, respectively (NS). Pathology examination of the specimen showed R0 resection in all patients with malignant PNT. The mean time to resumption of previous activities for patients undergoing Lap DP or Lap En was 3 weeks. There were no postoperative (30 days) or hospital deaths. Conclusions This series demonstrates that LPS is feasible and safe in benign-appearing and malignant neuroendocrine pancreatic tumors (NEPTs). The benefits of minimally invasive surgery were manifest in the short hospital stay and acceptable pancreas-related complications in high-risk patients. LPS can achieve negative tangential margins in a high percentage of patients with malignant tumors. Although surgical cure is rare in malignant NEPTs, significant long-term palliation can be achieved in a large proportion of patients with an aggressive surgical approach.

It is unclear whether there is a benefit to resection of primary gastrointestinal carcinoid neoplasm with hepatic metastases. We investigated whether primary tumor resection in this setting led to a significant difference in outcomes.

A retrospective review of patients with abdominal carcinoid neoplasms between 1995 and 2006 was performed. Data collected on patients with proven carcinoid liver metastases at initial diagnosis included whether the primary neoplasm was resected, time to progression of liver metastases, and status at last follow-up. Progression-free survival and survival were calculated by the method of Kaplan-Meier and compared by the log-rank test.

There were 84 patients, 60 of whom had their primary neoplasm resected. The resected group had a greater median progression-free survival of 56 months, compared with 25 months for the primary nonresected group (P < .001). Median survival time for the resected group was longer at 159 months, compared with 47 months for the nonresected group (P < .001).

Resection of the primary neoplasm is associated with better progression-free survival and overall survival in patients with abdominal carcinoid neoplasms. Therefore, localization and resection of the primary neoplasm should be considered, even among patients in whom the primary neoplasm is asymptomatic.

Carcinoid tumors of the duodenum are rare, and their natural history has not been defined. Consequently, there is no consensus on the optimal extent of surgical treatment.

The authors reviewed the records of all patients with primary carcinoid tumors of the duodenum treated at their institution from 1969 through 2004. Patients with primary periampullary tumors and gastrinomas were excluded.

Twenty-four patients had a pathologic diagnosis of duodenal carcinoid tumor. The majority (89%) of tumors measured less than 2 cm in diameter, and most (85%) were limited to the mucosa or submucosa. Lymph node metastases were identified in the surgical specimen in 7 (54%) of 13 patients in whom lymph nodes were examined, including 2 patients with tumors smaller than 1 cm and limited to the submucosa. At a mean follow-up of 46 months, the disease-specific survival rate was 100%, and only 2 patients have had recurrences in regional lymph nodes. No patient has had distant metastases or the carcinoid syndrome.

Carcinoid tumors of the duodenum are indolent. The presence of regional lymph node metastases cannot be predicted reliably on the basis of tumor size or depth of invasion, and their impact on survival is uncertain.

Gastrointestinal carcinoid tumours are notoriously difficult to diagnose in the absence of the carcinoid syndrome. The clinical presentation is typically non-specific, and patients often go undiagnosed for years. Recent advances in computed tomography (CT), magnetic resonance (MR), endoscopic ultrasound, and nuclear scintigraphy have combined to improve the diagnosis and staging of this fascinating tumour. In this chapter the applications of cross-sectional imaging in patients with gastrointestinal carcinoid tumours is presented.

Neuroendocrine tumors (NETs) are rare neoplasms. Approximately 75% of all cases manifest in the gastroenteropancreatic (GEP) system. Because of the low incidence of NETs, limited data about the clinical outcome and prognostic variables are available. In an attempt to identify prognostic parameters, we investigated the distribution of primary tumors, pattern of metastasis formation, clinical presentation, histological classification, and outcome of therapeutic interventions in a large patient cohort cared for in a German referral center. In 254 patients with GEP-NETs, the primary tumor was of foregut, midgut, or hindgut origin in 44.1% (28.7% pancreas), 43.7% (34.7% jejunoileum), and 4.3%, respectively. No primary tumor was found in 7.9%. Metastases occurred preferentially in lymph nodes and the liver. The overall 5-year survival rate was 57.1%. In the absence or presence of metastases at initial diagnosis the 5-year survival rate was 80.0% and 51.7%, respectively. The 5-year survival rate was related to the localization of the primary and was 75.0% and 42.9% for jejunoileal and pancreatic tumors, respectively. The size of the primary tumor (<2 cm) and histological grading as low-grade malignant were both associated with a significantly longer survival. Surgery with curative intent was attempted in 141 patients. However, an R(0) resection was achieved in only 66.0% of these patients. Five-year survival rate in the latter group was significantly higher (77.3%) as compared with all surgical patients (55.4%). Long-term tumor-free survival was obtained in only 53.7% of successfully resected patients. Palliative medical treatment, either with chemotherapy (i.e., especially for foregut NETs) or biotherapy (especially for midgut NETs), was only moderately effective for both therapeutic regimens.

Neuroendocrine tumors (NETs) constitute a heterogeneous group of neoplasms that originate from endocrine glands such as the pituitary, the parathyroids, and the (neuroendocrine) adrenal, as well as endocrine islets within glandular tissue (thyroid or pancreatic) and cells dispersed between exocrine cells, such as endocrine cells of the digestive (gastroenteropancreatic) and respiratory tracts. Conventionally, NETs may present with a wide variety of functional or nonfunctional endocrine syndromes and may be familial and have other associated tumors. Assessment of specific or general tumor markers offers high sensitivity in establishing the diagnosis and can also have prognostic significance. Imaging modalities include endoscopic ultrasonography, computed tomography and magnetic resonance imaging, and particularly, scintigraphy with somatostatin analogs and metaiodobenzylguanidine. Successful treatment of disseminated NETs requires a multimodal approach; radical tumor surgery may be curative but is rarely possible. Well-differentiated and slow-growing gastroenteropancreatic tumors should be treated with somatostatin analogs or alpha-interferon, with chemotherapy being reserved for poorly differentiated and progressive tumors. Therapy with radionuclides may be used for tumors exhibiting uptake to a diagnostic scan, either after surgery to eradicate microscopic residual disease or later if conventional treatment or biotherapy fails. Maintenance of the quality of life should be a priority, particularly because patients with disseminated disease may experience prolonged survival.

Gastrointestinal (GI) carcinoids are neuroendocrine tumors originating in multiple locations throughout the GI tract. The prognosis for patients with GI carcinoid tumors is diverse. To determine the factors that significantly affect prognosis, we reviewed our experience. Between 1992 and 2000 a total of 70 patients with GI carcinoid tumors underwent surgical resection at our institution. The patients were grouped into three categories based on the origin of the carcinoid tumor: foregut, midgut, hindgut. The mean age of the patients was 56 +/- 2 years. All patients with foregut carcinoids had symptoms upon presentation, whereas 61% of those with midgut carcinoids and only 37% of those with hindgut carcinoids had symptoms ( p < 0.001). The factors that most strongly affected survival on univariate analysis were a symptomatic presentation and the site of origin. Patients with foregut or midgut lesions had lower 5-year disease-free survivals than those with hindgut tumors. Moreover, the size of the primary tumor and the presence of liver metastases were not independent predictors of survival. Despite the larger tumor size and the higher incidence of liver metastases, patients with foregut carcinoids appear to have the same prognosis as those with midgut carcinoids. These data therefore suggest that the outcomes of patients with carcinoid tumors are highly dependent on the presence of symptoms and the site of origin.

A subset of gastrointestinal neuroendocrine tumours (carcinoids and pancreatic endocrine tumours) show aggressive growth. Early identification of this subset is essential for management; however, clinical, laboratory and histologic features frequently fail to achieve this. Currently, there is an increased understanding of the molecular pathogenesis/changes in neuroendocrine tumours and this may identify important prognostic factors and possibly, new treatments. Recent findings and progress in this area are briefly reviewed in this article.

To describe a large series of patients with carcinoid tumors in terms of presenting symptoms, hormonal data, stage at diagnosis, pathologic features, and survival.

Published series have described significant prognostic features of carcinoid tumors as site of origin, age, sex, stage at diagnosis, presence of high hormone levels, and increased T stage. Of these, stage at diagnosis and T stage seem to emerge most often as independent predictors of survival in multivariate analyses. Of carcinoid tumors, those arising from a midgut location have higher levels of serotonin and serotonin breakdown products, as well as more frequent metastatic disease at presentation, than those arising from either foregut or hindgut locations.

A prospective database of carcinoid patients seen at Duke University Medical Center was kept from 1970 to the present. Retrospective medical record review was performed on this database to record presenting symptoms, hormonal data, pathologic features, and survival. Statistical methods included analysis of variance, Kaplan-Meier analysis, and Mantel-Cox proportional hazard survival analysis, with P <.05 considered significant for all tests.

Carcinoids arising in different locations had different presentations: rectal carcinoids presented significantly more often with gastrointestinal bleeding, and midgut carcinoids presented significantly more often with flushing, diarrhea, and the carcinoid syndrome. Patients with midgut tumors had significantly higher levels of serotonin and serotonin breakdown products, corresponding to higher metastatic tumor burdens. Although age, stage, region of origin, and urinary level of 5-hydroxyindoleacetic acid predicted survival by univariate analysis, only the latter three were independent predictors of survival by multivariate analysis. Of the patients with metastatic disease at diagnosis, those with midgut tumors had better survival than those with foregut or hindgut tumors.

Although region of origin is certainly an important factor in determination of prognosis, stage of disease at presentation is more predictive of survival. Pancreatic and midgut carcinoids are metastatic at diagnosis more often than those arising in other locations, leading to a worse overall prognosis. Among patients with distant metastases, patients with midgut primary tumors have improved survival despite increased hormone production compared with patients with tumors arising in other primary sites.