Endocrine-Related Cancer (2010) 17 R173–R193 REVIEW Paraneoplastic syndromes secondary to neuroendocrine tumours Gregory Kaltsas, Ioannis I Androulakis, Wouter W de Herder1 and Ashley B Grossman2 Endocrine Unit, Department of Pathophysiology, National University of Athens, Mikras Asias 75, 11527 Athens, Greece 1Department of Internal Medicine, Sector of Endocrinology, Erasmus MC, 3000 DR Rotterdam, The Netherlands 2Department of Endocrinology, St Bartholomew’s Hospital, London EC1A 7BE, UK (Correspondence should be addressed to G Kaltsas; Email: [email protected]) Abstract Neuroendocrine tumours may be either benign or malignant tumours, and have the ability to synthesise and secrete biologically active substances characteristic of the cell of origin that can cause distinct clinical syndromes. The term ‘paraneoplastic syndromes’ (PNSs) is used to denote syndromes secondary to substances secreted from tumours not related to their specific organ or tissue of origin and/or production of autoantibodies against tumour cells; such syndromes are mainly associated with hormonal and neurological symptoms. Appreciation of the presence of such syndromes is important as clinical presentation, if not identified, may delay the diagnosis of the underlying neoplasia. Conversely, early recognition can allow for more rapid diagnosis, particularly as the coexistence of a neoplasm with a clinical or biochemical marker offers an additional determinant of tumour status/progression. PNSs can complicate the patient’s clinical course, response to treatment, impact prognosis and even be confused as metastatic spread. Their diagnosis involves a multidisciplinary approach, and detailed endocrinological, neurological, radiological and histological studies are required. Correct diagnosis is essential as the treatment of choice will be different for each disorder, particularly in the case of malignant tumours; it is therefore important to develop appropriate means to correctly identify and localise these tumours. Clinical awareness and the incorporation into clinical practise of 111In-octreotide scintigraphy, chromogranin A and other evolving biochemical marker measurement techniques have substantially contributed to the identification of patients harbouring such syndromes. Disease- specific medical therapies are mandatory in order to prevent recurrence and/or further tumour growth. Owing to their rarity, central registration of these syndromes is very helpful in order to be able to provide evidence-based diagnostic and therapeutic approaches. Endocrine-Related Cancer (2010) 17 R173–R193 Introduction Neuroendocrine tumours (NETs) are derived from 2004b, Modlin et al. 2008), although they may in fact cells that have the unique ability to synthesise, store also be secretory without causing any well-described and secrete a variety of metabolically active sub- syndrome. The universal non-specific immunohisto- stances, peptides and amines, which can cause distinct chemical markers, chromogranin A (CgA) and clinical syndromes. These secretory products are synaptophysin, have been used to substantiate the NE characteristic of the tissue of origin, and such secretory nature of these tumours, and in this context, tumours tumours are denoted ‘functioning’ in order to be expressing these markers are regarded as NETs, and as distinguished from tumours originating from NE cells such will be considered in the present review (Table 1). not producing any substances associated with clear The recently introduced WHO and European Neuro- clinical syndromes. The latter tumours are termed endocrine Tumour Society (ENETS) classifications ‘non-functioning’ and cause symptoms, along with have identified NETs as either benign, unknown functioning tumours, due to mass effects (Kaltsas et al. potential, well or poorly differentiated endocrine Endocrine-Related Cancer (2010) 17 R173–R193 Downloaded from Bioscientifica.comDOI: 10.1677/ERC-10-0024 at 09/29/2021 07:11:23AM 1351–0088/10/017–R173 q 2010 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.orgvia free access G Kaltsas et al.: Ectopic hormonal secretion Table 1 Tumours regarded as NETs on the basis of the Patients with neoplastic, mostly malignant, tumours immunohistochemical expression of markers of NE differentiation may occasionally present with symptoms that cannot CgA-positive neuroendocrine tumours by be explained by the presence of the neoplastic lesion in immunohistochemistry a specific anatomic site or by a clinical syndrome attributed to a secretory product derived from the Anterior pituitary tumours specific cell of origin (Keffer 1996). The term NFPA PRLoma (CgB positive) ‘paraneoplastic syndromes’ (PNSs) is used to denote GH an array of symptom complexes that are manifested ACTH systemically as the result of the production of TSH hormones, growth factors, cytokines and/or other FSH/LH Parathyroid tumours substances by the tumour cells (Baylin & Mendelsohn Medullary thyroid carcinoma 1980, Agarwala 1996). A significant number of these Merkel cell tumour syndromes are caused by the secretory products, Neuroendocrine gastroenteropancreatic tumours mainly peptide hormones, of NE cells that are widely (GEP tumours) dispersed throughout the lung, gastrointestinal (GI) Carcinoids (foregut, midgut and hindgut) ECL-oma tract, pancreas, thyroid gland, adrenal medulla, skin, Non-functioning pancreatic neuroendocrine tumours prostate and breast (Agarwala 1996, Modlin et al. Gastrinoma 2008). The clinical manifestations of these ectopic Insulinoma hormonal secretion syndromes are similar to those VIP-oma Glucagonoma caused when the secretory product is derived from the Somatostatinoma expected site of origin, eutopic hormonal secretion, Phaeochromocytoma and can cause diagnostic and therapeutic dilemmas Paraganglioma (Keffer 1996; Fig. 1). Additionally, symptoms may Neuroblastoma and ganglioneuroma Small/large cell lung carcinoma result from autoantibodies produced against the tumour cells that may cross-react with a variety of normal CgA, chromogranin A; NET, neuroendocrine tumours; NFPA, cellular constituents (Agarwala 1996). The majority of non-functioning pituitary adenoma; PRL, prolactin; CgB, chromogranin B; ECL, enterochromaffin-like. such PNSs are associated with ectopic hormonal and neurological symptoms due to the production of carcinomas; all these histopathological entities have autoantibodies against neurological tissues (Pierce the ability to synthesise and secrete characteristic 1993, Agarwala 1996, DeLellis & Xia 2003; Table 2). (of the cell of origin) biologically active products The overall prevalence is 15% of malignancies, mostly (Rindi et al. 2000, Modlin et al.2008). involving the lungs, GI system and breast (Pierce 1993, Hypercalcaemia (PTHrP, PTH) Cushing's Hyponatraemia (ACTH, CRH) (ADH, ANP) Paraneoplastic Acromegaly endocrine syndromes Gynaecomastia (GHRH, GH) secondary to hCG neuroendocrine tumours Other peptidic Hypoglycaemia pituitary hormones (insulin, IGF1, big IGF) Diverse symptoms CT, VIP, LH/FSH, TSH, renin, CGRP, GLP-1, PRL Figure 1 Spectrum of paraneoplastic humoral syndromes secondary to NETs. CT, calcitonin; PTHrP, parathyroid hormone related peptide; CGRP, calcitonin gene related peptide; GLP, glucagon like peptide; ANP, atrial natriuretic peptide; VIP, vasointestinal peptide. Downloaded from Bioscientifica.com at 09/29/2021 07:11:23AM via free access R174 www.endocrinology-journals.org Endocrine-Related Cancer (2010) 17 R173–R193 Table 2 Pathophysiology of common NET-related paraneo- the underlying NET for which updated and consistent plastic syndromes guidelines have recently been formulated (Falconi Tumour production and secretion of biologically active peptide et al. 2006, Pacak et al. 2007, Ahlman et al. 2008, hormones/endocrine diseases Eriksson et al. 2008, Kloos et al. 2009). Where specific Tumour production of cytokines/fever, fatigue, weight loss PNS-directed therapy is required, this will be outlined. and cachexia Tumour stimulation of antibody formation/neurological syndromes Classification NET, neuroendocrine tumour. Based on clinical presentation, the great majority of Agarwala 1996, Bollanti et al. 2001). It is therefore NET-related PNSs are classified as follows: critical to recognise the presence of a PNS as it may 1) lead to the diagnosis of an underlying, previously 1) Humoral PNSs 2) Neurological PNSs unsuspected neoplasm, 2) dominate the clinical 3) Other less common manifestations of PNSs. picture and therefore be misleading in terms of tumour origin and type, and 3) be useful in following and monitoring the clinical course of the underlying disease (Pierce 1993, Bollanti et al. 2001). Pathogenesis Following the continuing rise in the prevalence of NETs, it is expected that the prevalence of PNSs The exact pathogenesis that leads to the development related to such tumours will also rise (Modlin et al. of these syndromes is not known. All cells in the 2008). However, to date, there has been no systemic human body contain the same genetic information, of documentation of the PNSs related to NETs. The body which only a proportion is expressed under normal of literature and medical knowledge relevant to the situations (Pierce 1993, Agarwala 1996). It is clear that PNSs secondary to NETs is widely dispersed, and has neoplastic transformation is linked or caused by the long been the subject of personal experience more than activation of certain cellular events that control cell coordinated reports (Keffer 1996, Bollanti et al.