Capsule endoscopy to detect primary tumour site in metastatic neuroendocrine tumours

BackgroundIn patients with metastatic neuroendocrine tumours, primary tumour localisation is often difficult with morphological and/or functional imaging. Although utilised in investigating various small bowel pathologies, evidence for using video capsule endoscopy to identify suspected small bowel primaries in patients exhibiting metastatic neuroendocrine tumours is limited.AimsTo assess the role of video capsule endoscopy in locating primary small bowel neuroendocrine tumours when conventional imaging fails to identify the origin of metastatic disease.MethodsWe retrospectively compared our institutional database of patients presenting with metastatic neuroendocrine tumours between January 2010 and December 2013 with an analogous database of patients undergoing video capsule endoscopy for various indications. Patients whose primary tumours were not located radiologically and also underwent capsule endoscopy were identified.Results390 patients with metastasised neuroendocrine tumours presented within the study period. In 11 (2.8%) the primary tumour was not located radiologically. Video capsule endoscopy identified lesions suggestive of small bowel primary in 8/10 patients in whom it was successful. Small bowel primary was confirmed by histological analysis of surgical specimens.ConclusionsOur study supports the use of video capsule endoscopy as part of the diagnostic work-up in selected patients presenting with metastatic neuroendocrine tumours of unknown primary. The clinical utility of this technology requires clearer definition.     

New treatment strategies in advanced neuroendocrine tumours

Malignant well-differentiated neuroendocrine tumours of the pancreas and the gastrointestinal tract are rare and clinically challenging heterogeneous neoplasms. This review focuses on neuroendocrine tumours grade 1 and grade 2 (new WHO classification 2010), in comparison to the neuroendocrine tumours grade 3 group, corresponding to poorly differentiated neuroendocrine carcinomas. Surgical resection of the primary and metastases remains the only curative treatment, however many patients with neuroendocrine tumours are diagnosed once unresectable metastases have occurred; management of functioning syndromes with somatostatin analogues remains the priority. Pasireotide, a new somatostatin analogue, is currently undergoing evaluation for carcinoid syndrome. Treatment options for advanced neuroendocrine tumours differ from pancreatic gastrointestinal tract neuroendocrine tumours: (a) in pancreatic neuroendocrine tumours, streptozotocin-based chemotherapies are challenged by other cytotoxic agents (dacarbazine, temozolomide and oxaliplatin); two randomized, placebo-controlled phase III studies have demonstrated that everolimus and sunitinib significantly improved progression-free-survival; (b) in midgut neuroendocrine tumours, octreotide improved time-to-progression in patients with a low proliferation index and low liver burden; preliminary data suggesting efficacy of bevacizumab are still to be confirmed; the effect of everolimus associated with octreotide was almost significant on progression-free-survival in a phase III trial. Liver-directed therapies are effective in both tumour types. New techniques of embolization need further evaluation and must be formally compared to other therapies. Finally, peptide receptor radionuclide therapy has shown promising activity in non-comparative studies in advanced neuroendocrine tumours.     

The importance of the measurement of circulating markers in patients with neuroendocrine tumours of the pancreas and gut

The measurement of general and specific biochemical markers in patients with neuroendocrine tumours assists with diagnosis and gives an indication of the effectiveness of treatment and they may be used as prognostic indicators. There is much agreement that chromogranin A is the most universally helpful marker; it is found to be elevated in the circulation of about 90% of patients with metastatic neuroendocrine tumours and there are several excellent commercially available kits which give reliable estimations. Specific markers are useful for diagnosis also, and are helpful indicators of the effectiveness of treatment, particularly where tumour bulk may not change as much as tumour activity. Sporadic pancreatic neuroendocrine tumours may secrete more than one peptide and this indicates a worsening prognosis. Because of the wide variation in the progression of neuroendocrine tumours, a prognostic indicator gives a significant advantage to the clinician in order to facilitate optimum treatment at the optimum stage of disease. Both chromogranin A and neurokinin A have been used as powerful prognostic indicators for midgut carcinoid tumours.     

The role of somatostatin analogues in the treatment of neuroendocrine tumours

Neuroendocrine tumours belong to a heterogeneous family of neoplasms, originating in endocrine glands (such as the pituitary, parathyroid or the neuroendocrine adrenal glands), in endocrine islets (within the thyroid or pancreas) as well as in endocrine cells dispersed between exocrine cells throughout the digestive or respiratory tracts. The clinical behaviour of neuroendocrine tumours is variable; they may be functioning or not functioning, ranging from well-differentiated slow growing neuroendocrine tumours to poorly differentiated neuroendocrine tumours, which are highly aggressive malignant tumours. The development of somatostatin analogues as important diagnostic and treatment tools have revolutionised the clinical management of patients with neuroendocrine tumours. However, although symptomatic relief and stabilisation of tumour growth for various periods of time are observed in many patients treated with somatostatin analogues, tumour regression is rare. Development of new somatostatin analogues and new drug combination therapies should further improve the clinical management of these patients.     

Neuroendocrine tumours

Neuroendocrine tumours are a heterogeneous group including, for example, carcinoid, gastroenteropancreatic neuroendocrine tumours, pituitary tumours, medullary carcinoma of the thyroid and phaeochromocytomas. They have attracted much attention in recent years, both because they are relatively easy to palliate and because they have indicated the chronic effect of the particular hormone elevated. As neuroendocrine phenotypes became better understood, the definition of neuroendocrine cells changed and is now accepted as referring to cells with neurotransmitter, neuromodulator or neuropeptide hormone production, dense-core secretory granules, and the absence of axons and synapses. Neuroendocrine markers, particularly chromogranin A, are invaluable diagnostically. Study of several neuroendocrine tumours has revealed a genetic etiology, and techniques such as genetic screening have allowed risk stratification and prevention of morbidity in patients carrying the particular mutation. Pharmacological therapy for these often slow-growing tumours, e.g. with somatostatin analogues, has dramatically improved symptom control, and radiolabelled somatostatin analogues offer targeted therapy for metastatic or inoperable disease. In this review, the diagnosis and management of patients with carcinoid, gut neuroendocrine tumours, multiple endocrine neoplasia types 1 and 2, and isolated phaeochromocytoma are evaluated.     

Feasibility of the new WHO classification of pulmonary neuroendocrine tumours

Primary pulmonary neuroendocrine tumours present a heterogeneous group of tumours causing problems in diagnosis and treatment. The new WHO classification of lung tumours was published in 1999 in order to improve this situation by combining morphology, immunohistochemistry and clinical background for diagnosis. The aim of our study was to evaluate the feasibility of this classification and to discuss the consequences of modified diagnostic criteria. 50 cases of neuroendocrine tumours and 50 poorly differentiated lung tumours diagnosed in the years 1981-1994 were independently evaluated by three pathologists. The diagnosis of all 27 typical carcinoids (TC) was given by all authors, however, no unanimous agreement was achieved in one of three atypical carcinoids (AC) and two of four large cell neuroendocrine carcinomas (LCNEC). While typical and atypical carcinoids can be distinguished by the number of mitoses or presence of necrosis it was found that the most difficult diagnostic factor for large cell neuroendocrine carcinoma is the recognition of its light-microscopic neuroendocrine features. In consequence it must be distinguished not only from atypical carcinoid or small cell lung carcinoma (SCLC), but also from poorly differentiated carcinoma. Immunohistochemistry is important for the diagnosis of this entity but also for nonsmall cell lung carcinoma with neuroendocrine differentiation (of which 1 case was detected in our series) There was agreement on the diagnosis of small cell carcinomas in all but one case. The results indicate the excellent reproducibility of the WHO classification.     

Endocrine tumours of the gastrointestinal tract: Chemotherapy

Malignant neuroendocrine tumours are less sensitive to chemotherapy than other epithelial malignancies. If chemotherapy is considered, tumours of pancreatic origin have a higher sensitivity than tumours from the gastrointestinal tract ('carcinoids'). Chemotherapy with streptozocin combinations and with dacarbazine should be considered in patients with progressive malignant neuroendocrine tumours of the pancreas. A favourable response to chemotherapy can be expected in up to 60% of patients receiving a combination of streptozocin plus doxorubicin, and in up to 40% of patients receiving dacarbazine. A survival benefit has been shown for streptozocin combinations. Treatment regimens are effective in functioning and non-functioning tumours. The response to treatment cannot be predicted. Poorly differentiated neuroendocrine tumours, independent of their origin, respond to a combination of etoposide plus cisplatin. Chemotherapy is, however, almost ineffective in patients with well-differentiated neuroendocrine tumours originating in the gastrointestinal tract ('carcinoids').     

An overview of the current diagnosis and recent developments in neuroendocrine tumours of the gastroenteropancreatic tract: the diagnostic approach

Neuroendocrine tumours of the gastroenteropancreatic tract (GEP-NETs) comprise a group of very heterogeneous neoplasms, which are considered 'rare diseases'. Epidemiological studies on the incidence of GEP-NETs worldwide have reported a remarkable increase in the detection of these tumours. In a recent study, based on pathology reports (PALGA) to investigate the incidence of pancreatic and duodenal neuroendocrine tumours in the Netherlands from 1991 until 2009, we also noticed a significant increase in the incidence of these tumours. In particular, the incidence of non-functioning neuroendocrine tumours had significantly increased over this period. Remarkably, a substantial discrepancy was observed between the numbers of neuroendocrine tumours diagnosed in the clinical as opposed to the pathological setting, emphasising that these tumours provide a real diagnostic challenge. To improve the diagnosis of GEP -NET s, we advocate that these complex neoplasms should receive more specialised attention. In this mini-review we provide an overview of the current diagnostic approach to GEP-NETs, and add the recent developments in establishing the diagnosis of these tumours, in order to increase knowledge and awareness of GEP-NETs among clinicians and pathologists. Early detection in order to prevent morbidity from GEP-NETs is advocated.     

Tumour markers in neuroendocrine tumours

Most of the neuroendocrine tumours produce and secrete a large number of peptide hormones and amines. Each of these substances cause a specific clinical syndrome: carcinoid, Zollinger-Ellison, hyperglycaemic, glucagonoma and WDHA syndrome. Specific markers for these syndromes are basal and/or stimulated levels of: urinary-5-HIAA, serum or plasma gastrin, insulin, glucagon, and VIP, respectively. About 1/3 of neuroendocrine tumours belong to the so-called "non-functioning" tumours. Therefore, general markers such as chromogranin A, pancreatic polypeptide, serum neuronspecific enolase and subunit of glycoprotein hormones have been used for screening purposes in patients without distinct clinical hormone related syndromes. Among these general tumour markers chromogranin A, although its precise function is not yet established, has been shown to be a very sensitive and specific serum marker for various types of neuroendocrine tumours. This is because it may also be increased in many cases of less well differentiated tumours of neuroendocrine origin that do not secrete known hormones. Then chromogranin A is considered the best general neuroendocrine serum or plasma marker available at the moment and is increased in 50-100% of patients with various neuroendocrine tumours. Chromogranin A serum or plasma levels reflect tumour load and may be an independent marker of prognosis in patients with midgut carcinoids.     

Diagnostic value of plasma chromogranin A in neuroendocrine tumours

AIM: The aim of this study was to assess the value of plasma chromogranin A (CgA), a protein produced by neuroendocrine cells, in the diagnosis of neuroendocrine tumours. METHODS: Eighty subjects with neuroendocrine tumours were studied. Thirty-four had carcinoids, 21 nonfunctioning endocrine pancreatic tumours, 17 multiple endocrine neoplasia type 1 (MEN 1) (six of these also had gastrinomas), and eight had functioning pancreatic tumours (four gastrinomas, two glucagonomas, two somatostatinomas). Twenty-eight healthy subjects were studied as controls. A fasting plasma sample was obtained from each subject, and CgA plasma levels were measured by the ELISA method using a kit (Dako A/S, Denmark). RESULTS: In control subjects, plasma CgA values were below 5 U/l. Among the patients, 20 of the 34 with carcinoid tumours, 12 of the 21 with nonfunctioning pancreatic tumours, nine of the 17 with MEN 1 (including the six with gastrinomas), and the four gastrinomas of the eight functioning pancreatic tumours, i.e. overall, 45 of the 80 patients (56.3%) had abnormally high CgA values (22-961 U/l). Most of the patients with elevated CgA values, except nine of the 10 with gastrinomas, had multiple liver metastasis. CONCLUSIONS: The results show that the diagnostic value of plasma CgA in neuroendocrine tumours is relatively low; it may be of some interest only in patients with advanced disease and liver metastasis. Gastrinoma seems to be an exception, because in this tumour high CgA values are generally found even in the absence of liver metastasis.     

Ghrelin in neuroendocrine organs and tumours

Ghrelin is a 28 amino-acid hormone with multiple functions. It is predominantly produced by the stomach but has also been detected in other organs, including the small intestine, pancreas, hypothalamus and pituitary, as well as in the immune system and almost every other normal human tissue examined. It is also present in neuroendocrine tumours, pituitary adenomas, endocrine tumours of the pancreas, breast tumours, and thyroid and medullary thyroid carcinomas. Ghrelin is a brain-gut peptide with growth hormone-releasing and appetite-inducing activities, and is the endogenous ligand of the G protein-coupled growth hormone secretagogue receptor (GHS-R). In this review we comprehensively summarize the available data regarding (a) the expression of ghrelin and the GHS-R in normal endocrine tissues and in pituitary adenomas and neuroendocrine tumours, (b) the levels of circulating ghrelin in patients with pituitary adenomas and neuroendocrine tumours and (c) the effects of ghrelin administration in these patients on the levels of other hormones and on the rate of proliferation of the tumour. It is clear that ghrelin has many more functions and is involved in many more processes than was initially postulated, and its endocrine, paracrine and autocrine effects play a role in its physiological and pathophysiological functions. C. Leontiou and G. Franchi contributed equally to this work.     

Proliferative activity of neuroendocrine tumours of the gastroenteropancreatic endocrine system: DNA flow cytometric and immunohistological investigations.

The proliferative activity of 16 tumour specimens from 13 patients with neuroendocrine tumours of the gastroenteropancreatic endocrine system was studied by DNA flow cytometry and immunohistology for the nuclear Ki67 proliferation antigen. Equivalent results were obtained with both methods, which showed the proliferative activity of gastroenteropancreatic neuroendocrine tumours to be heterogeneous. In four malignant small intestinal carcinoids and one extravisceral carcinoid localised in the retroperitoneum the percentage (index) of proliferating tumour cells as measured by DNA flow cytometry ranged from 2.9 to 36.2% corresponding to low, moderate, or high proliferative activity. In four malignant pancreatic endocrine tumours and their metastases indices ranged from 8.7 to 18.3%, corresponding to low, moderate, or high proliferative activity. In four benign pancreatic endocrine tumours indices ranged from 4.3 to 7.7%, all corresponding to low proliferative activity. This heterogeneity of proliferative activity may in part explain the heterogeneous results reported of chemotherapy treatment. As chemotherapy of tumours is largely affected by favourable cell cycling kinetics, individual diagnostic investigations of the proliferative activity of these neuroendocrine tumours may be of value for identifying patients suitable for this treatment.     

New therapeutic options for metastatic malignant insulinomas

Insulinomas are the most common, functioning, pancreatic neuroendocrine tumours. The great majority (>90%) of insulinomas are nonmetastatic at presentation and can be surgically cured. The <10% patients with distant (liver-bone) metastases have a median survival of < 2 years. Everolimus and sunitinib have been recently introduced as targeted therapies for metastatic pancreatic neuroendocrine tumours. An additional advantage of everolimus in the treatment of patients with metastatic insulinomas is its capability to increase blood glucose levels. Peptide receptor radiotherapy using radiolabelled somatostatin analogues has also been shown to be successful in controlling tumour growth of metastatic pancreatic neuroendocrine tumours. In patients with metastatic insulinomas, this therapeutic modality was also effective in controlling hypoglycaemia, even in the presence of tumour regrowth. With the introduction of these new therapeutic modalities, the therapeutic arsenal for the 'tailor-made' approach of patients with metastatic insulinomas is further expanded.     

Requiem for the term 'carcinoid tumour' in the gastrointestinal tract?

Use of the term 'carcinoid tumour' to describe a unique type of tumour in the gastroenteropancreatic system is endemic in the medical literature and in daily clinical and pathological parlance. However, it is a somewhat misleading moniker because a spectrum of histopathological changes and hence, biological outcomes may occur in these tumours. The World Health Organization classification scheme recommends the use of the terms neuroendocrine tumours or carcinomas, which may be stratified as well-differentiated neuroendocrine tumours with benign or uncertain behaviour, well-differentiated tumours with low-grade neuroendocrine carcinoma behaviour and high-grade neuroendocrine carcinomas. These categories may be applied within different sites in the gastrointestinal tract and pancreas, and convey a sense of biological behaviour. In addition, a recently suggested tumour-node-metastasis scheme has been proposed and awaits clinical validation and acceptance. Thus, the term 'carcinoid' has served its purpose well, but its use should be phased out in favour of 'neuroendocrine tumour' or 'neuroendocrine carcinoma'.     

Synchronous well differentiated neuroendocrine tumour and gastrointestinal stromal tumour of the stomach: a case report

Background  

Well differentiated neuroendocrine tumours (carcinoids), arising from cells of the diffuse neuroendocrine system, represent the most commonly encountered gastric endocrine tumours. Gastrointestinal stromal tumours (GISTs), which stem from interstitial Cajal cells located within the wall of the gastrointestinal tract and have a characteristic immunoreactivity for CD117 (c-kit protein), account for the majority of gastrointestinal mesenchymal neoplasms. Simultaneous occurrence of a GIST with a well differentiated neuroendocrine tumour in the stomach is very rare.     

Endoscopic ultrasound-guided ethanol ablation of pancreatic neuroendocrine tumours: A case study and literature review

Here we offer a review of the literature regarding endoscopic ultrasound-guided ethanol ablation for pancreatic neuroendocrine tumours and describe the case of a cystic tumour completely ablated after a multisession procedure. A total of 35 PubM ed indexed cases of treated functioning and non-functioning pancreatic neuroendocrine tumours resulted from our search, 29 of which are well-documented and summarised. Endoscopic ultrasound-guided ethanol ablation appears as a local, minimally invasive treatment of pancreatic neuroendocrine tumours, suitable for selected patients. This technique appears feasible, relatively safe and efficient, especially when applied to symptom relief in functioning tumours, aiming at loss of endocrine secretion. For non-functioning tumours, where the goal is complete tissue ablation, eus guided ethanol ablation can provide good results for patients who are unfit for surgery or for those who refuse surgical resection. Its role in "fit for surgery" patients requires assessment through further studies.     

Somatostatin receptor expression in multiple endocrine neoplasia and in von hippel–lindau disease

Lamberts SWJ, Hofland LJ, Lely AJVD, de Herder WW (Erasmus University Rotterdam, The Netherlands). Somatostatin receptor expression in multiple endocrine neoplasia and in von hippel– lindau disease (Minisymposium: MEN & VHL). J Intern Med 1998; 243 : 569–71.
Somatostatin receptors are expressed on the majority of neuroendocrine tumours. The presence of these receptors is clinically useful. First, long-term treatment with somatostatin analogues controls hormonal hypersecretion, which controls flushing attacks, watery diarrhoea, hypoglycaemia and electrolyte disorders in patients with carcinoids and islet cell tumours. Secondly, somatostatin receptor imaging is used to localize primary neuroendocrine tumours and to visualize the spread of the disease. Thirdly internalization of somatostatin receptors by primary neuroendocrine tumours opens the possibility of carrying out radio- and chemotherapy with somatostatin analogues coupled to beta-emitting radionuclides and chemotherapeutic drugs. The presence and role of somatostatin receptors on the tumours which occur in multiple endocrine neoplasia and von Hippel–Lindau disease are discussed.     

Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract

The diffuse neuroendocrine cell gives rise to a heterogeneous population of tumours which differ in their morphological and functional features. The term 'carcinoid', although well established in medical terminology, is therefore no longer adequate to cover the entire spectrum of neuroendocrine neoplasms. Here we use the term neuroendocrine tumours (NET), which was suggested in the WHO classification of 2000, and review the most important NET entities that are currently recognised in the gastrointestinal tract, highlighting their distinguishing features.     

Pancreatic neuroendocrine tumours

Pancreatic neuroendocrine tumours are rare tumours ( approximately 1/100,00 population/year) of which 60% are non-functioning. Except for insulinoma all types are malignant in >50% of cases. In multiple endocrine neoplasia (MEN)1, pancreatic neuroendocrine tumours occur in 40-80% of patients and are mostly non-functioning tumours or gastrinomas. Insulinomas are benign in approximately 90%, solitary in 95% of sporadic cases whilst multiple in 90% of MEN1 patients. In contrast approximately 50% gastrinomas and the majority of non-functioning pancreatic neuroendocrine tumours are malignant. Pancreatic neuroendocrine tumours occur in 10-15% of patients with Von Hippel-Lindau (VHL) and are frequently multiple (>30%). Surgical excision is a key aspect of treatment for all cases of sporadic gastrinoma and if >2.5 cm in MEN1. Insulinomas are enucleated if solitary and may require pancreatectomy if multiple. Non-functioning tumours should also be resected if sporadic and if >2 cm in MEN1 or if >2-3 cm in VHL. Tumours <1cm require yearly follow-up by CT or MRI from an early age in VHL. The local treatment for liver metastases is now well established and options include liver resection, chemoembolisation and radiofrequency ablation. Systemic therapies have also been better defined and include radionuclide therapy against somatostatin receptors or MIBG and chemotherapy especially for poorly differentiated tumours. A number of novel agents are currently in clinical development.     

Improvements in small bowel carcinoid diagnosis and staging: 18F-DOPA PET,capsule endoscopy and double balloon enteroscopy

Carcinoid tumours are rare, slow growing tumours, originating from cells of the neuroendocrine system. Staging of the disease is of paramount importance to determine the optimal treatment strategy but is notoriously difficult. A case of a 45-year-old male who presented with abdominal pain and flushes is presented. An abdominal computerised tomography-scan was performed which showed a solitary liver lesion, consisting of neuroendocrine tumour cells. Further staging with ¹⁸F-DOPA PET, capsule endoscopy and double balloon enteroscopy revealed the localisation of the primary tumours in the small bowel, and the patient subsequently underwent surgery. The recent introduction of ¹⁸F-DOPA PET, capsule endoscopy and double balloon enteroscopy in the diagnosis and staging of carcinoid tumours has made significant contributions to the management of this disease.