The ABCs of NETs
australian NET Preceptorship Meeting
OVERVIEW
Neuroendocrine tumours (NETs - also known as "carcinoids") of the gastrointestinal (Gl) tract, are ill-understood, enigmatic malignancies which, although slow-growing as compared to most adenocarcinomas, can behave aggressively. Currently, they are classified based upon organ site and cell of origin. In recent years, it has become apparent that the term "carcinoid" (a derivative of the German term karzinoide) represents a spectrum of different neoplasms originating from a variety of different neuroendocrine cell types. In addition, the term gastro-entero-pancreatic (GEP) tumour has been used in conjunction with the acronym NET to designate these lesions. Overall, NETs occur most frequently in the Gl tract (67%) and the most common sites are the small intestine (25%), rectum (14%) and colon (12%). Clinically, their local manifestations include bleeding and obstruction or perforation due to either direct tumour invasion or as a consequence of fibrosis engendered by the tumour. Systemic manifestations (flushing, sweating, diarrhoea, bronchospasm) are often paroxysmal and are the result of the secretion of biological mediators by either the primary lesion or metastases. Except in the case of direct access into the systemic venous system (e.g. ovary, pulmonary), the presence of a "syndrome" indicates metastatic (usually hepatic) disease. The clinical manifestations of NETs are often vague, absent or misdiagnosed as irritable bowel syndrome, dyspepsia, food allergy, anxiety attacks, neurosis, or menopausal symptoms in females. In many instances, NETs are detected incidentally at surgery undertaken for other Gl disorders or during emergency surgery for appendicitis or obstruction, bleeding or perforation. Diagnosis is established by classical symptomatology and confirmed biochemically by elevations of plasma chromogranin A (CgA) or serotonin and elevated urinary 5-hydroxyindole acetic acid (5-HIAA). Topographic localisation is achieved by somatostatin receptor scintigraphy (SRS; Octreoscan®), computerised axial tomography (CT) scan or endoscopy with or without ultrasound. Histological identification is by general neuroendocrine markers (e.g. CgA, synaptophysin), or more specifically by immunocytochemistry using antibodies against specific cellular secretory products (gastrin, glucagon, serotonin). The tendency for metastatic spread correlates with tumour size, increased mitotic index and cellular atypia. An association with non-NET neoplasms occurs in 8-17% of lesions and may represent the effect of growth factors secreted by the lesion. Initial therapy consists of wide surgical excision of the tumour (if technically feasible) to avert the development of local complications (obstruction, perforation, bleeding), and cytoreductive hepatic surgery, if possible. In the case of gastric (type I and II) and rectal carcinoids, local endoscopic excision may be adequate. For all other NETs, formal excision of the primary is mandatory followed by hepatic cytoreduction if clinically feasible. In the past, NETs were arbitrarily divided into functional and non-functional tumours. Current evaluation of the cellular biology and pathology of NETs indicates no basis for this distinction and all should be treated alike. Somatostatin analogues effectively ameliorate symptoms and are the principal medical therapy although interferon exhibits some utility, albeit with the caveat of significant adverse effects. Conventional chemotherapy and classical radiotherapy either alone, or in combination, are of minimal efficacy and any usage should be balanced against the major decrease in quality of life (QOL) engendered by such agents. The recent publication of the PROMID study demonstrating the efficacy of Sandostatin LAR in increasing progression free survival provides good evidence of the clinical antiproliferative effectiveness of the agent. The RADIANT1 studies combining the mTOR kinase inhibitor (everolimus) and LAR have demonstrated the key role of the mTOR kinase pathway in tumour metabolism as well as the efficacy of combination therapy. Similarly, the introduction of novel therapeutic agents targeting angiogenesis and cell proliferation (bevicuzameb, temazolamide, sunitinib) has provided good evidence of the effectiveness of targeted therapeutic strategies. Peptide receptor targeted radiotherapy is also under evaluation for treatment of advanced NETs and metastases (that express sst2 or sst5) using radiolabeled octapeptide analogs including 111 In-pentetreotide [90Y-DOTAO,Tyr3]octreotide (OctreoTher®), [177Lu-DOTAOTyr3] octreotate, [111 ln-DOTAO]lanreotide and [90Y-DOTAO]lanreotide. Results are encouraging but the status of the modality is investigational. Hepatic metastatic disease may be amenable to surgery, radiofrequency ablation, embolisation, either alone or in combination with chemotherapeutic agents or isotopically loaded microspheres. Ideally, decreasing hepatic tumour burden to <10% optimises the outcome and the efficacy of antiproliferative therapy In rare circumstances, hepatic transplantation has benefit. Overall 5-year survival is excellent for NETs of the appendix (98%), stomach (type I and II; 81%) and rectum (87%), whereas small intestinal (60%), colonic carcinoids (62%) and gastric type III/IV (33%) exhibit a worse prognosis.