Review article Radionuclide imaging of neuroendocrine tumours: biological basis and diagnostic results Ettore Seregni, Arturo Chiti, Emilio Bombardieri Division of Nuclear Medicine, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy

&p.1:Abstract. Neuroendocrine tumours have been defined as APUD-omas in the past by authors who identified common metabolic characteristics (amine precursor uptake and decarboxylation) in a group of tumours thought to originate from cells of the neural crest and to be able to produce biogenic amines. The identification of neuroendocrine tumours with APUD-omas was not confirmed by subsequent investigators. At present it is known that a group of neuroendocrine tumours derive from pluripotent stem cells or from differentiated neuroendocrine cells, and that they have a particular pattern of histology due to the presence of some secretory products and particular cytoplasmic proteins. Many radiopharmaceuticals have been successfully used in nuclear medicine to visualise neuroendocrine tumours; most of them are based on specific uptake mechanisms, but some are non-specific probes. This review is focussed on the clinical application of radiolabelled metaiodobenzylguanidine, indium-111 pentetreotide, radiolabelled vasointestinal peptide, radiolabelled monoclonal antibodies and positronemitting tracers. While many different types of neuroendocrine tumours are identified today, only the most common histotypes and those tumours of major relevance for nuclear medicine are considered in this review (anterior pituitary tumours and neuroblastoma are excluded). New knowledge in molecular biology, relevant biological and histological patterns, and the physiological and clinical behaviour are described for neuroendocrine tumours of the lung, tumours of the gastroenteropancreatic tract, medullary thyroid carcinoma, tumours of sympatho-adrenal lineage, and multiple endocrine neoplasia. The nuclear medicine results in diagnostic imaging are presented, and the major comparative studies with different tracers are reported. The study of further possible diagnostic approaches addressing the biological characteristics of these tumours could open the way to various new therapeutic options. &kwd:Key words: Radionuclide imaging – Gastroenteropancreatic tract tumours – Medullary thyroid carcinoma – Mul-

Correspondence to: E. Bombardieri, Division of Nuclear Medicine, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via G. Venezian 1, I-20133 Milano, Italy&/fn-block:

tiple endocrine neoplasia – Tumours of the lung and of sympatho-adrenal lineage Eur J Nucl Med (1998) 25:639–658

Introduction and general characteristics Neuroendocrine tumours have been defined as APUDomas in the past. The designation “APUD” (amine precursor uptake and decarboxylation) was originally proposed in 1969 by Pearse, who observed that cells of neural crest origin migrate during the embryonal development into different tissues including the intestinal tract, pancreas and several endocrine glands [1]. Their peculiar biological characteristic is the property of accumulating DOPA or 5′-hydroxytryptophan and decarboxylating these compounds to produce catecholamines or serotonin. In addition, these cells synthesise and release several bioactive peptides (e.g. hormones, growth factors, regulatory peptides). However the APUD theory, and the identification of neuroendocrine tumours with APUD-omas, was not confirmed by subsequent experimental studies and this concept is being abandoned by most investigators. It is now acknowledged that a group of neuroendocrine tumours do not derive from neural crest cells but rather from pluripotent stem cells of the organ in question or from differentiated neuroendocrine cells deriving from the former. Several observations support this new view [2, 3]. In this review the term “neuroendocrine” will be used to define cells and tumours with a characteristic pattern of histology, particularly of histopathological staining, secretory products and some cytoplasmic proteins, rather than their localisation and embryological derivation. They generally have uniform nuclei and granular and clear cytoplasm when routine haematoxylin-eosin staining methods are used. The silver staining techniques, i.e. argyrophil staining as developed by Grimelius [4] and argentaffin staining according to Masson [5], help to identify these cells. At the ultrastructural level, the neuroendocrine cells are characterised by the presence of large dense-core secretory granules (diameter >80 nm) in the cytoplasm which represent the storage organelles European Journal of Nuclear Medicine Vol. 25, No. 6, June 1998 – © Springer-Verlag 1998

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for hormones and other polypeptides [6]. Besides these granules, neuroendocrine cells and tumours derived from them have another secretory pattern that utilises small clear vesicles (diameter 40–80 nm) resembling the synaptic vesicles of neurones [7]. The functions of these small vesicles are still unknown, but recent evidence seems to indicate that they may store amino acid transmitters such as γ-aminobutyric acid (GABA) [8, 9]. In recent years a number of general and specific components of neuroendocrine cells have been identified by means of monoclonal or polyclonal antisera. These neuroendocrine markers are associated with cytosolic proteins, dense-core secretory granules or small secretory vesicles. Among the cytosolic markers, neuron-specific enolase (NSE), the protein gene product 9.5 (PGP 9.5) and the protein 7B2 are the most widely utilised for the diagnostic characterisation of neuroendocrine tumours. NSE, the gamma-gamma dimer of the glycolytic enzyme enolase, is the best known marker of neuroendocrine differentiation [10]. However, NSE expression is not restricted to neuroendocrine tumours as it is also detectable in non-neuroendocrine tissues including solid-cystic tumours of the pancreas, schwannoma, renal cell carcinoma, chordoma and malignant lymphomas. PGP 9.5, a protein originally extracted from brain tissue, has been discovered to be a marker of neuroendocrine tumours even if its physiological function is still entirely unknown [11, 12]. Similar considerations also pertain for 7B2, a 179-amino acid protein extracted from human pituitary which appears to be unrelated to NSE or PGP 9.5 [13]. Another interesting group of molecules comprises the proteins associated with large dense-core granules. The granin family is the most extensively investigated among these [6, 14, 15]. Granins constitute a family of watersoluble acidic glycoproteins localised in the matrix of secretory granules including at least three members, namely chromogranin A (CgA), chromogranin B (CgB) and C (secretogranin II). The physiological role of these proteins is still not completely understood but there is evidence that they are involved in hormone secretion and hormone packaging within secretory granules. Furthermore, the recent demonstration of potential cleavage sites in their structure seems to indicate that they represent the precursors of other bioactive products. Cleavage products from CgA identified so far include pancreastatin (CgA249-301) [16], β-granin (CgA1-114) [17], chromostatin (CgA124-143) [18] and vasostatin (CgA176) [19]; from CgB the peptides CgB420-493 [20] and CgB580-593 [21]; and from CgC the peptide secretoneurin (CgC154-186) [22]. The best characterised among all these cleavage products is pancreastatin (PST). This 52-amino acid peptide seems to have a general modulator control on endocrine and exocrine secretion acting via autocrine and paracrine mechanisms [23]. It has been demonstrated that PST is a negative regulator of parathyroid hormone (PTH), insulin, and glucagon release and it also displays an inhibitory effect on exocrine pancreatic and gastric secretions.

Among the small vesicle-associated proteins, different markers have been identified including synaptophysin, synapsin, synaptotagmin, and synaptobrevin [24–26]. They represent a group of membrane-bound proteins that are involved in the regulation of the secretory pattern of neuroendocrine cells. The somatostatin network: an example of neuroendocrine cell dispersion Somatostatin (SST) is a multifunctional peptide that is synthesised in neuroendocrine and other cells present in many districts and organs including the central and peripheral nervous systems, gastrointestinal tract, endocrine pancreas, thyroid, adrenals, genitourinary tract and lymphatic tissue. This diffuse network is a good example of neuroendocrine cell dispersion [27]. Endogenous bioactive peptides are the tetradecapeptide SST-14 and the N-terminally extended form SST-28, which display a variety of biological functions including the negative modulation of endocrine and exocrine pancreatic secretion, smooth muscle contractility, neurotransmission and cell proliferation [28]. These peptides exert their central and peripheral actions through G-protein-coupled receptors. Recent molecular studies have revealed the existence of five distinct SST receptor (sstr) subtypes with different tissue distribution. These receptors have been cloned and chronologically termed sstr1, sstr2, sstr3, sstr4 and sstr5. For sstr2 two splice variants, sstr2A and sstr2B, have been identified [29–31]. Structural analysis has shown that all of these receptor subtypes contain the seven putative transmembrane domains characteristic of other G-proteincoupled receptors. Pharmacological studies have demonstrated that sstr2A, sstr2B, sstr3 and sstr5 display a high affinity for the synthetic SST agonist MK678 and octreotide (type 1 receptors), whereas sstr1 and sstr4 have lower affinity for MK678 and octreotide (type 2 receptors). The same subdivision can be obtained from structural analysis, which demonstrates a marked sequence similarity (more than 80%) within the two groups of receptors. In contrast, homology between any of the receptors across the two groups does not exceed 60%. Furthermore, type 1 and 2 receptors also can be distinguished on the basis of the ligand-receptor interaction outcome [32]. SST binding to sstr2 receptors results in internalisation of the receptor-ligand complex, followed by intracellular degradation of the ligand into its target cells. By contrast, SST is not internalised in cells expressing sstr1 receptors. The causes and the biological significance of this different behaviour are not yet clear, but it may reflect different modalities of sensitisation and desensitisation of the receptors and of transmembrane signalling. Independently of the ligand-receptor interaction, all five cloned human SST receptors are coupled with Giproteins which determine the inhibition of the adenylyl

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cyclase [33]. The antiproliferative effects of SST, however, seem more closely related to the stimulation of enzymatic molecules with tyrosine phosphatase activity or via a phospholipase C/inositol phospholipid/calcium pathway [34, 35]. The first pathway was demonstrated for sstr1 and sstr2, and the second for sstr5. SST receptor subtypes seem to be expressed with a certain degree of tissue specificity [36–38]. In fact sstr1–4 subtypes are variably expressed in tumours or cancer cell lines from central nervous system, colon, liver, pancreas, lung, breast and skin. Among them, sstr2 is the most frequently represented, especially in neuroendocrine cells or tumours. sstr5 appears to be predominantly expressed in the anterior pituitary, smooth muscle and gastrointestinal tract. Recently, sstr5 expression has been found in human thyroid cancer [39]. New biological and clinical concepts in neuroendocrine tumours Neuroendocrine tumours of the lung Neuroendocrine lung tumours are characterised by a broad spectrum of histology and biological behaviour ranging from indolent tumours to the very aggressive small cell lung cancer. These tumours have recently been classified into three different types on the basis of their histological characteristics, i.e. benign (typical carcinoid), low-grade malignant (atypical carcinoid) and high-grade malignant tumours [40]. Well-differentiated neuroendocrine tumour, the typical carcinoid, has an excellent prognosis after radical surgery (>95% 5-year survival) and histological examination shows only a minor degree of cellular atypia, no necrosis, and no or very few mitoses. The diameter of these tumours is usually below 3 cm. Atypical carcinoids are generally larger than 3 cm in diameter and have a 60% 5-year survival after radical resection. They are characterised by a minor or moderate degree of cellular atypia, presence of cellular necrosis and mitoses. Atypical carcinoids represent the most controversial group of neuroendocrine tumours of the lung in terms of both histological diagnosis (absence of unequivocal morphological criteria) and prognosis. To improve the biological characterisation of these tumours, a variety of tissutal (e.g. proliferation markers, p53, expression of cell-adhesion molecules, etc.) and genetic (e.g. K-ras-2, c-raf-1, etc.) markers have been proposed in recent years [41]. Immunohistochemical detection of p53 seems to offer an interesting aid in predicting the clinical behaviour of atypical carcinoids. In a recent study, patients showing p53-positive immunostaining had a shorter survival than p53-negative patients [42]. However, these interesting findings need to be confirmed by further investigations. Neuroendocrine high-grade malignancies of the lung are subdivided into “large cell neuroendocrine carcinoma”, “mixed small cell-large cell neuroendocrine carci-

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noma” and “small cell carcinoma”, depending on cell size and nuclear morphology. Such tumours are among the most aggressive malignancies and are associated with a very short survival. Several hormonally active peptides can be produced by neuroendocrine lung tumours; among these gastrinreleasing peptide (GRP) seems to be the most relevant. In fact, the production of GRP has been demonstrated to be a feature of neuroendocrine tumours of the lung, particularly of small cell carcinoma [43–45]. This 27-amino acid peptide not only represents an important autocrine growth factor for neuroendocrine tumours but also plays a fundamental role in the growth and development of the lung. Besides GRP, neuroendocrine lung tumours can be associated with the production of other hormones including vasopressin, calcitonin, calcitonin gene-related peptide (CGRP), adrenocorticotropic hormone (ACTH), parathyroid hormone (PTH), PTH-related peptide, Leuencephalin and substance P. Related secretory syndromes including Cushing’s syndrome, the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and non-metastatic hypercalcaemia are observed with a variable incidence (up to 5%) in patients with neuroendocrine lung cancer [46]. However, it is important to remember that the incidence of these syndromes is much lower than the frequency of radioimmunological demonstration of the corresponding hormones in the bloodstream. This is due to the fact that tumours frequently release biologically inactive but immunologically detectable forms of these hormones such as large molecular weight precursors, fragments and subunits. Neuroendocrine tumours of the gastroenteropancreatic tract Endocrine tumours of the digestive tract are an uncommon clinical entity accounting for about 2% of all malignant gastrointestinal neoplasms with an incidence of about 0.7 cases per 100000 per year [47]. These tumours are believed to arise from the endocrine cells of the gastrointestinal tract (Table 1) and have been collectively termed carcinoids. However, their heterogeneity in terms of histological differentiation, hormone production and biological and clinical behaviour make the term carcinoid even more inadequate. A more articulate classification is that proposed by Solcia et al. [48, 49]; being based on the site of origin and biological behaviour of the tumour, this classification seems to be more closely related to the clinical history of such neoplasms. Neuroendocrine tumours of the pancreas, stomach, duodenum, jejunum and ileum, as well as colon and rectum, are included in this classification. Furthermore, for each site the neoplasms are subdivided into tumours with benign behaviour, low-grade malignancies (i.e. the classical carcinoids with slow growth and relatively good prognosis) and highly malignant neoplasms (undifferentiated neuroendocrine carcinomas). However, the term “carcinoid”

642 Table 1. Endocrine cells of the human gastroenteropancreatic apparatus&/tbl.c:&

Cell

P EC D L A PP B X ECL G CCK S GIP Mo N

Hormone(s)

Preferential site

Unknown 5-Hydroxytryptamine, P-peptide, opioids Somatostatin Glycentine, PP-like peptide Glucagon Pancreatic peptide Insulin Endotheline-like peptide Histamine Gastrin Cholecystokinin Secretin Gastric inhibitory peptide Motilin Neurotensin

Pancreas

Stomach

Upper Lower intestine intestine

+ +

+ +

+ +

+ +

+

+

+ +

+ +

+ + +

+ + + + +

+ + + + + +

&/tbl.:

and the classification of these tumours according to Williams and Sandler are still much used in clinical practice [50]. According to this classification the neuroendocrine gastrointestinal tumours are divided into two main groups, carcinoids and endocrine pancreatic tumours. The carcinoids are subdivided into foregut (respiratory tract, thymus), midgut (jejunum, ileum, right colon) and hindgut (left colon, rectum) carcinoids, whereas pancreatic tumours are classified on the basis of hormonal production and the related clinical syndrome, e.g. insulinomas, gastrinomas, VIPomas, glucagonomas, somatostatinomas and non-functioning islet cell tumours. Pancreatic endocrine tumours Among the pancreatic endocrine tumours, gastrinomas (G-cell tumours), insulinomas (B-cell tumours) and PPomas (PP-cell tumours) represent the most frequent entities. Less frequent tumours are VIPomas, glucagonomas (A-cell tumours), somatostatinomas (D-cell tumours) and the recently described tumours that release growth hormone releasing factor (GRF) (GRFomas). Furthermore, these tumours can also be classified as functional if they are associated with a clinical secretory syndrome due to hormone release and as non-functional if they are not associated with a clinical syndrome. The latter category includes tumours secreting pancreatic polypeptide (PP; PPomas) and endocrine tumours not causing highly elevated hormonal levels. Prognostic and clinical evaluation of neuroendocrine pancreatic tumours can be performed on the basis of the differentiation grade and the functional activity of tumour cells. Many studies have demonstrated the benign behaviour of well-differentiated non-angioinvasive endocrine tumours less than 2 cm in size that are either non-functioning or causing the insuli-

noma syndrome. Insulinomas and non-functioning tumours have a high rate of malignant behaviour only when above 3 cm in size. By contrast, more than 50% of tumours causing the gastrinoma, VIPoma, glucagonoma or carcinoid syndrome are malignant. Gastrinomas. &p.1:These tumours are classically characterised by severe ulcer and persistently elevated basal gastric acid secretion due to hypergastrinaemia. About twothirds of gastrinomas are sporadic and the remaining third are associated with MEN-1 syndrome (see below) [51]. As regards the anatomical location, gastrinomas were thought to occur most frequently in the pancreas; however, in a recent large study only 30% of gastrinomas were located in the pancreas and 40% and 20% in the duodenum and in the pancreatic head area lymph nodes, respectively [52]. Insulinomas. &p.1:The prevalence of these neoplasms is lower than that of gastrinomas, but unlike gastrinomas virtually all insulinomas are located within the pancreas [53]. The clinical symptoms of insulinomas are related to hypoglycaemia and include visual disturbances, confusion, altered consciousness and weakness. VIPomas. &p.1:The syndrome was first described by Verner and Morrison in 1958 and it is associated with watery diarrhoea, hypokalaemia, hypochlorhydria and acidosis (WDHHA syndrome) [54]. In adults, more than 90% of VIPomas are found in the pancreas, whereas characteristically in children the VIPoma syndrome is sustained by ganglioneuroma and ganglioneuroblastoma. VIP (vasointestinal peptide) represents the mediator of this syndrome and receptors for this hormone have been identified on intestinal epithelial cells [55]. VIP receptor stimulation leads to intestinal electrolyte and fluid secretion

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that is mediated by adenylate cyclase activation and cyclic AMP production. VIP receptors are also present on exocrine pancreas cells and they are responsible for the neurally mediated pancreatic ductal bicarbonate secretion [56]. Glucagonomas. &p.1:About 2% of gastroenteropancreatic tumours are glucagonomas. These tumours are generally large and 60% of them are metastatic at the time of diagnosis [57]. The glucagonoma syndrome is characterised by a typical rash (necrolytic migratory erythema), weight loss, diabetes, deep vein thrombosis and psychiatric disturbances [58]. Somatostatinomas. &p.1:These neoplasms are the least common of the endocrine pancreas tumours (less than 150 cases reported in the literature) and patients characteristically suffer from diabetes mellitus, diarrhoea, steatorrhoea, gallbladder disease, weight loss and hypochlorhydria [59]. Stomach Neuroendocrine tumours with different cell origins (ECL, G, D and PP cells) and different clinical behaviours can arise from the stomach [60]. Tumours deriving from argyrophil ECL cells are the most common (about 85% of all gastric neuroendocrine tumours). Physiologically, the ECL cells of the gastric mucosa are responsible for the paracrine secretion of histamine in response to gastrin and play an important role in the peripheral regulation of gastric secretion [61]. Gastrin stimulates histamine release via a cholecystokinin-B receptor subtype activating an intracellular calcium-dependent pathway. While the stimulatory role of gastrin on ECL is now generally accepted, some uncertainty still exists about molecules able to inhibit the ECL functions. Somatostatin is the best-known inhibitor of histamine release from ECL cells, but recently this role has also been attributed to the peptide YY (PYY) [62]. PYY is a 36amino acid peptide released from the small intestine under the influence of intraluminal nutrients. Various inhibitory actions have been assigned to PYY including inhibition of gastric acid secretion, pancreatic secretion, gastrointestinal motility, mucosal blood flow and mucosal ion transport. Specific receptors for PYY have recently been demonstrated on the ECL surface and their stimulation determines a marked inhibition of histamine from these cells and, consequently, of gastric acid secretion. Well-differentiated ECL tumours measuring up to 1 cm, confined to the mucosa or muscularis mucosae and without cytological atypia, are considered to be benign tumours [60]. These tumours often arise as multiple growths in severely atrophic corpus-fundus mucosa due to autoimmune destruction of acidopeptic glands (type A gastritis) [63]. Besides gastritis A, other background

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conditions favouring the development of multiple ECLcell tumours include combined multiple endocrine neoplasia type 1 (MEN-1) and Zollinger-Ellison syndrome (ZES) [64]. Hypergastrinaemia (secondary to achlorhydria as in the case of chronic gastritis or primary as in ZES) seems to be the causative event in these tumours. In this regard it has been demonstrated that gastrin not only represents a secretory stimulus for ECL cells but is also a stimulatory growth factor. The relation between hypergastrinaemia and ECL-cell hyperplasia is also confirmed by the frequent presence of the latter condition in patients undergoing long-term treatment with proton pump inhibitors or H2-blockers [65]. Invasive ECL-cell tumours arising sporadically in the gastric mucosa and independently from conditions causing hypergastrinaemia are tumours of more than 2 cm in size. These tumours produce metastases in more than 60% of cases, with liver metastases in about one-half of the patients. The mean survival is about 4 years. ECL cells synthesise and release mainly histamine, which is responsible for a secretory syndrome present in about one-fourth of the patients. The clinical manifestations of this syndrome (atypical) are quite different from those of the classic carcinoid syndrome and include generalised flush, headache, lacrimation, cutaneous rash, facial and skin swelling, hypotensive attacks and rhinorrhoea [66–68]. In addition to the well-differentiated neuroendocrine carcinoma, also poorly differentiated neuroendocrine tumours exist in the stomach. Like similar tumours of other sites, these tumours have a very poor prognosis, with most patients dying within 1 year from diagnosis. Duodenum Five major types of neuroendocrine tumours can be distinguished in the duodenum: gastrin-producing tumours (G-cell tumours), somatostatin-producing tumours (Dcell tumours), gangliocytic paragangliomas, serotoninproducing tumours (EC-cell tumours) and poorly differentiated carcinomas. Gastrin-producing tumours are the most frequent and represent two-thirds of all cases. They occur in the proximal duodenum. Although usually small (<1 cm), most of them have already metastasised to the regional lymph nodes at the time of diagnosis [40]. These lymph node metastases may be much larger than the primaries in the duodenum. Spread to the liver, however, is a rare and late event. About one-third of the tumours are associated with a ZES which may be part of the MEN-1 syndrome. Forty percent of patients with sporadic ZES have duodenal gastrinomas and in the remaining patients the tumour is found in the pancreas. In MEN-1 patients with ZES the incidence of duodenal gastrinoma is even higher and may reach 90%. Another characteristic of MEN-1-associated duodenal gastrinoma is their frequent multicentricity.

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Somatostatin-producing tumours are second in frequency and account for about 15%–20% of all neuroendocrine tumours of the duodenum. They occur almost exclusively in the ampulla of Vater and are usually malignant. Although they are strongly positive for somatostatin, they are non-functioning. However, about onethird of them are associated with neurofibromatosis type 1 (von Recklinghausen’s disease). Third in frequency are gangliocytic paragangliomas. They occur in the ampullary-periampullary region. Histologically these tumours are composed of three different components including cuboidal endocrine cells (D cells and to a lesser extent PP cells), mature ganglion cells and Schwann-like cells. Although often of large size (>2 cm) and showing involvement of the muscularis propria, they usually have a benign behaviour. Duodenal neuroendocrine tumours producing serotonin or other hormones (EC-cell tumours) are uncommon and poorly differentiated neuroendocrine carcinomas are extremely rare. Jejunum, ileum, appendix and caecum The vast majority of tumours of this tract are the classical carcinoids with production of serotonin and substance P [66–68]. These tumours derive from the enterochromaffin cells (EC cells or Kulchitsky cells) at the base of the crypts of Lieberkühn. They occur preferentially in the second part of the ileum and from a clinical point of view tumours larger than 2 cm in diameter must be considered malignant. In fact, in this group of neoplasms the incidence of lymph node metastases is very high and approximately 20% of the patients suffer from a carcinoid syndrome, which implies the presence of liver metastases. The classical carcinoid syndrome is characterised by the presence of different signs and symptoms including diarrhoea, weight loss, sweating, facial flushing, right-sided cardiac valve disease and bronchoconstriction. Colon and rectum Three main types of neuroendocrine tumours have been identified: L-cell tumours, EC-cell tumours and poorly differentiated small cell carcinoma. L-cell tumours are the most frequent. These endocrine cells have the property of secreting a large amount of products including glycentin, PP, PYY, glucagon-37, glucagon peptide 1 (GLP-1) and GLP-2 [69–71]. Despite their secretory behaviour, these tumours generally produce no related clinical symptoms. With regard to the natural history of these tumours it has been demonstrated that the risk of metastatic spread depends on the size of the tumour, being 3% for tumours smaller than 1 cm and 8% for tumours between 1 and 2 cm. The clinical manifestations of large tumours include bleeding and intestinal obstruc-

tion, and they cannot be distinguished from those of colorectal cancer. In these patients, skeletal and other distant metastases are often observed. Medullary thyroid carcinoma Medullary thyroid carcinoma (MTC) is a tumour which develops from the calcitonin (CT)-producing parafollicular cells of the thyroid (C cells). MTC represents 5%–10% of all thyroid malignancies [72]. About 80% of cases are sporadic and the remaining 20% are familial (MEN-2 syndromes) [73]. In addition to CT, various other bioactive products are thought to be released by MTC. Among them gastrin-releasing peptide (GRP) has recently been implicated in the aetiology of the diarrhoea that is present in about 30% of patients [74]. From a biological point of view one interesting finding, which is also peculiar to the other neuroendocrine tumours, is the presence, on the surface of malignant cells, of receptors for different hormones and regulatory peptides. The best characterised among these are the cholecystokinin-B (CCK-B) receptors, which display high affinity for CCK and gastrin, and the receptors for GLP-1, glucagon, VIP and SST [75–77]. The demonstration of receptors for these enteric hormones offers an insight into the physiological mechanisms sustaining CT secretion. In fact, it is now accepted that in addition to hypercalcaemia, which is the main stimulus for CT secretion, gastrin, GLP-1, glucagon and probably also VIP are able to potentiate the calcium-induced CT secretion. These findings corroborate the hypothesis of the existence of a gastroentero-parafollicular axis. This implies that peptides released from the gut during the absorption of calcium stimulate the parafollicular cells, alerting them to an influx of calcium so that they can respond early enough to prevent subsequent hypercalcaemia [78]. Clinically these tumours almost always present as a mass in the neck, and metastases to lymph nodes in the neck are frequently present at the time of diagnosis. The presence of lymph node involvement greatly influences the prognosis: the 10-year survival rate of patients with tumour-free lymph nodes can be as high as 85%–90% (similar to that of an otherwise healthy control group), falling to about 40% in patients with positive neck nodes. After primary surgery for sporadic MTC elevated plasma CT levels are frequently seen. All patients with a preoperative diagnosis of MTC should be screened for MEN-2 to exclude the presence of hyperparathyroidism (measurements of serum PTH and calcaemia) and phaeochromocytoma (24-h urine collection for determination of catecholamines and their metabolites). It is very important to exclude the diagnosis of a MEN-2-associated phaeochromocytoma because of the life-threatening consequences of operating on a patient with an undetected phaeochromocytoma.

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Tumours of sympatho-adrenal lineage The sympatho-adrenal stem cell derives from the neural crest and gives rise to sympathetic neurones, neuroglia, paraganglion cells, sympathetic ganglion cells (small intensely fluorescent cells) and chromaffin cells of the adrenal medulla [79, 80]. A common feature of these cells is the use of catecholamines as transmitters. Sympathetic neurones produce noradrenaline, paraganglion and ganglion cells produce noradrenaline and dopamine, and adrenal chromaffin cells produce predominantly adrenaline [81]. Three tumour types, phaeochromocytoma, paraganglioma and neuroblastoma, are considered to be derived from the sympatho-adrenal cell system. Phaeochromocytoma The most important neoplasm of the adrenal medulla is phaeochromocytoma, which occurs in approximately 0.1% of patients with hypertension [82]. In addition to hypertension, the classic symptoms of this disease include paroxysmal headaches, pallor, palpitations and diaphoresis. The pathological distinction between benign and malignant phaeochromocytomas is imprecise and ultimately based on the extent of local invasion, local recurrence, and the presence of nodal or distant metastases. About 20% of phaeochromocytomas are malignant. Phaeochromocytoma can be either sporadic or familial. Familial phaeochromocytomas include simple familial tumours without other disease manifestations, MEN-2 syndromes and neuroectodermal syndromes including neurofibromatosis type 1 and von Hippel-Lindau disease. Adrenal medulla hyperplasia is considered to be the precursor of these tumours and often coexists with phaeochromocytoma. In addition to catecholamines, these tumours can secrete a number of substances including ACTH, atrial natriuretic peptide (ANP) and CGRP. Interesting secretion products are adrenomedullin (AM) and neuropeptide Y (NPY). AM, recently isolated from a human phaeochromocytoma, is a 52-amino acid peptide that displays a potent vasodilator action [83]. Expression of AM has also been detected in cardiac ventricles, kidney, lung and, recently, in the human brain (thalamus and hypothalamus), suggesting that the molecule may act as a neurotransmitter, neuromodulator or neurohormone [84]. Cloning of cDNAs coding for AM has revealed that AM is processed starting from a 185-amino acid residue precursor (preproAM), in which another unique 20-residue sequence exists in the N-terminal region. This peptide has been termed propro N-terminal 20-peptide (PAMP) [85, 86]. Compared with AM, PAMP has been shown to have less hypotensive effects and its physiological function currently remains undetermined. NPY is a tyrosine-rich peptide distributed throughout the central and peripheral nervous system [87]. In sympathetic nerves and in the adrenal medulla NPY is co-

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stored and co-released with noradrenaline. Recent findings indicate that NPY expression is increased in adrenal phaeochromocytomas: high plasma levels of this hormone have been detected in these patients [88]. NPY has potent direct and indirect (catecholamine-mediated) cardiovascular effects including increase in the coronary and peripheral vascular resistance and inhibition of the parasympathetic stimulation on atrioventricular nodes. Thus, NPY released from phaeochromocytoma may be responsible, both by itself and by potentiating the effects of catecholamines, for the cardiovascular symptoms in these patients. The mechanisms causing the catecholamine release from phaeochromocytoma cells, and consequently the hypertensive crises, are still largely unknown. Interesting clues to the comprehension of this process are derived from the demonstration of the presence of type I angiotensin II receptors on the surface of adrenal medulla and phaeochromocytoma cells. In a recent experimental study it has been unequivocally demonstrated that angiotensin II increases intracellular calcium and induces a dose-dependent secretion of noradrenaline and NPY by phaeochromocytes [89]. Paragangliomas Paragangliomas are rare catecholamine-producing tumours that arise from extra-adrenal chromaffin tissue [90]. These tumours most frequently arise from aorticosympathetic and viscero-autonomic paraganglia. The aorticosympathetic paraganglia are found along the aorta, between the renal arteries and around the iliac bifurcation, and include the organs of Zuckerkandl. The viscero-autonomic ganglia occur in association with blood vessels or visceral organs such as the bladder and the heart. In about one-third of cases multiple paragangliomas may be present or may be associated with phaeochromocytoma. From a clinical point of view, these tumours are often malignant, being associated with a high incidence of persistent or recurrent disease with a significant mortality. Multiple endocrine neoplasia The multiple endocrine neoplasia (MEN) syndromes comprise an uncommon group of proliferative disorders that selectively target specific sets of endocrine glands, dispersed endocrine cells and in some cases, neurones and their supporting elements [91]. The tumours in affected individuals are typically multicentric and are preceded in their development by phases of endocrine cell hyperplasia. The major MEN syndromes include MEN-1 and the three variants of MEN-2 (MEN-2A, MEN-2B, FMTC). Despite their rare incidence these syndromes represent a fascinating group of diseases because of their genetic transmission, molecular biology, and clinical implications.

646

Multiple endocrine neoplasia type 2 The multiple endocrine neoplasia type 2 (MEN-2) syndromes are dominantly inherited diseases of tumour formation and disordered development that involve principally four tissues: the C cells of the thyroid, the adrenal medulla, the parathyroid and the intestinal autonomic nerve plexus. There are three distinct varieties of MEN-2 syndromes: MEN-2A, MEN-2B and Familial medullary thyroid carcinoma (FMTC) [92]. MEN-2A syndrome. &p.1:This syndrome is characterised by the presence of medullary thyroid carcinoma (MTC), phaeochromocytoma and hyperplasia or benign tumour of the parathyroids. The yearly incidence of MTC is about 1 per million. MTC is the most relevant and precocious expression of the MEN-2A syndrome. About 50% of the patients develop phaeochromocytoma and about 10% symptomatic parathyroid disease. FMTC. &p.1:This form is characterised by the presence of MTC only and its particular feature is the late onset and the low mortality. MEN-2B syndrome. &p.1:Among the three variants, MEN-2B syndrome is the most aggressive with the earliest age at onset. MEN-2B is recognised by developmental abnormalities, which are not seen in MEN-2A or FMTC, while parathyroid involvement is rare or absent. Disorganised peripheral nerve tissue gives rise to “neuromas”, and lip, tongue and musculoskeletal abnormalities result in a long, thin body type resembling Marfan’s syndrome. Furthermore an increase in the number of intrinsic autonomic ganglia is present and there is hyperplasia of extrinsic autonomic nerve fibres in the intestinal wall leading to disturbances of intestinal motility (diarrhoea or constipation). Other musculoskeletal abnormalities such as pes cavus, pectus escavatus, bifid ribs and slipped femoral epiphysis may also be present. All forms of MEN-2 syndrome are inherited in an autosomal dominant manner with a high degree of penetrance. Early molecular genetic studies showed that the genes for each of the three MEN-2 syndromes were localised in the same chromosomal region, suggesting that the syndrome might be sustained by one single gene mutation. This hypothesis was confirmed in 1993 when germline mutations in the RET proto-oncogene were demonstrated in the majority of families with the three syndromes [93, 94]. In addition to the MEN-2 syndromes, RET is implicated in familial Hirschsprung’s disease, which is characterised by a varying degree of loss of the enteric nervous system [95]. In recent years, important advances have been made in the understanding of the molecular and physiological characteristics of the RET proto-oncogene and of its molecular changes during the oncogenetic processes [92]. Cloning of the normal RET gene has shown that it encodes a transmembrane receptor-tyrosine kinase named

Ret. Like other receptor tyrosine kinases, wild-type Ret requires ligand binding for dimerization and subsequent activation, leading to autophosphorylation and phosphorylation of specific downstream targets. The ligand of the receptor has recently been identified in the glial cellline-derived neurotrophic factor (GDNF) [96]. This factor is a member of the TGF family and represents a potent survival factor for several neuronal populations. Furthermore, the signal transduction initiated by GDNF stimulation seems a more complex process requiring the presence of other molecules. One of them, called GDNFR, has been identified recently and one hypothesis is that GDNF binds directly to GDNFR and indirectly to Ret, forming a trimolecular signalling complex. The presence and the role of GDNFR in tissues involved in MEN-2 syndromes are still largely unknown. The RET proto-oncogene is located on chromosome 10q11.2 and the coding sequence consists of 21 exons in a genomic region of approximately 55 kb. The protein contains an extracellular domain, a transmembrane domain and a tyrosine kinase domain with a short interkinase region of 27 amino acids. The main features of the extracellular domain are a cysteine-rich region close to the cellular membrane and a more distal region that shows homology to members of the cadherin family of cell adhesion molecules. In more than 90% of MEN-2A families germline mutations in one of five cysteine codons (609, 611, 618, 620 and 634) within RET exons 10 and 11 have been described [97,98]. Codon 634 mutations in exon 11 are the most frequent with substitution of cysteine with arginine (80% of cases). Mutations outside codon 634 occur more often in FMTC than in MEN-2A and in this form germline mutations are also found in exons 13 and 14. Almost all the MEN-2B families reported so far have the same mutation, consisting of the replacement of methionine with threonine at codon 918 of exon 16. The knowledge of the site-specific mutations in MEN-2 syndromes has a number of important implications. From a biological point of view, it offers an insight into the different molecular pathogenetic events sustaining the MEN-2 disorders (see below). Furthermore, it is extremely relevant for the development of molecular genetic screening tests useful for early disease detection and improvement of prognosis. Regarding the molecular mechanism at the basis of MEN-2A, it is now accepted that cysteine mutations can lead to Ret activation by inducing covalent dimerization of receptors. In a normal situation these cysteines are paired in intramolecular disulphide bonds. By contrast the loss of one cysteine by mutation gives rise to an intermolecular bond with the corresponding free cysteine on an adjacent Ret molecule resulting in covalent dimerization and constitutive activation of the Ret tyrosine kinase domain [99]. A different scenario is valid for MEN-2B. In this case, replacement of methionine at position 918 with threonine in the intracellular domain alters the spatial

European Journal of Nuclear Medicine Vol. 25, No. 6, June 1998

647

configuration of this domain, and hence the substrate specificity and the pathway of downstream signalling [100].

only on the clinical results obtained with the most widely studied radiotracers in clinical practice: radiolabelled metaiodobenzylguanidine, indium-111 pentetreotide, radiolabelled vasointestinal peptide, some monoclonal antibodies and some positron-emitting tracers.

Multiple endocrine neoplasia type 1 MEN-1 syndrome is characterised by the development of hyperplasia or neoplasia involving the anterior pituitary, parathyroid glands, and duodeno-pancreatic endocrine system [91]. Neuroendocrine tumours of the lung, thymus and gastrointestinal tract may also be present. In addition, an increased frequency of adenomas or hyperplastic nodules of the adrenal and thyroid glands and multiple soft tissue lipomas has been reported. Hyperparathyroidism is the most common manifestation of MEN-1 (occurring in more than 95% of patients older than 30 years), and it is more frequently sustained by hyperplasia. Pancreatic endocrine abnormalities including gastrinoma and insulinoma are the second most common manifestation of MEN-1 (up to 75% of patients). Pituitary neoplasms occur in approximately 15% of patients with MEN-1 syndrome; most are prolactinomas, with a smaller number being growth hormone-secreting tumours or ACTH-secreting tumours. In 1988 the gene responsible for MEN-1 syndrome was mapped on chromosome 11q13 by linkage analysis but the precise nature of this gene has remained elusive for nearly a decade [101]. Very recently the MEN-1 gene has been cloned, revealing that it contains ten exons and extends across 9 kb. It codes for a 610-amino acid protein named “menin”, the function of which is still completely unknown [102]. Nuclear medicine approaches for imaging of neuroendocrine tumours The different metabolic pathways determine the choice of tracers for visualisation of neuroendocrine tumours. In fact various radiopharmaceuticals have been proposed in nuclear medicine; some of them are based on specific uptake mechanisms, others are non-specific probes. It should be stressed, however, that even if a specific uptake mechanism exists, this does not belong selectively to a particular tumour type, as the neuroendocrine cells are distributed all over the body. In fact, from a histological and anatomical point of view, neuroendocrine cells form either small organs, distinct cell clusters within other tissue or a network of cells dispersed in the thymus, thyroid, lung and gut. This is the reason why each tracer has many clinical applications, there being a great overlap among the clinical experiences with the individual radiopharmaceuticals in the different neuroendocrine types. In addition, the majority of the studies published in the literature do not take into account the modern classification criteria for neuroendocrine tumours described above. Therefore our attention will be focussed

European Journal of Nuclear Medicine Vol. 25, No. 6, June 1998

Radiolabelled metaiodobenzylguanidine Radiolabelled metaiodobenzylguanidine (MIBG) was developed in the early 1980s to visualise diseases arising from the adrenal medulla [103]. Chemically it is a combination of the benzyl group of bretylium and the guanidine group of guanethidine, the end product being a structural equivalent of noradrenaline [104]. At the concentrations used in diagnostic procedures it is taken up by the neoplastic cells through the type 1 amine uptake mechanism, which is an active mechanism dependent on energy and sodium concentration. After entering the cell, the molecule is transported to the catecholamine storage vesicles. Obviously, drugs which interfere with the uptake-1 mechanism or vesicular storage may alter MIBG uptake and retention; therefore it is essential to withdraw these drugs before injecting the tracer. For diagnostic purposes MIBG can be labelled with either iodine-131 or iodine-123. The physical characteristics of 123I make 123I-MIBG the molecule of choice for clinical applications. Nonetheless, 131I-MIBG is still widely employed due to its lower cost, its easy availability and the possibility of acquiring delayed images. The radiation dose from 131I-MIBG is not different to that from other diagnostic modalities, so 123I-MIBG is more favourable in this respect [105]. This radiopharmaceutical allows also good-quality single-photon emission tomography (SPET) images to be acquired [106]. Phaeochromocytoma and paraganglioma A large number of patients have been studied with MIBG scanning and the overall sensitivity and specificity are high, approximately 88% and 99%, respectively (Table 2). There is evidence that MIBG uptake is proportional to the quantity of neurosecretory granules in the tumour. This radiopharmaceutical is able to detect both primary tumours and metastases (Figs. 1, 2). Several reports describe the visualisation of non-functioning paragangliomas [107, 108]. The sensitivity of the test increases in malignant phaeochromocytoma, rising to 92.4% [109]. As expected,123I-MIBG has proved to have a higher sensitivity than the 131I-labelled compound. 123I-MIBG can visualise lesions with a low tracer concentration because of the better physical characteristics of the labelling isotope. Moreover, 123I-MIBG SPET imaging yields a better spatial definition of the lesions. The sensitivity of 123I-MIBG has been reported to be similar to or lower than that of morphological techniques like

648 Table 2. Results of MIBG and somatostatin receptor imaging (SRI) in phaeochromocytoma&/tbl.c:&

Author

No. of patients

Radiopharmaceutical

Sensitivity (%)

Tenenbaum F et al. (1995) [139] Hoefnagel CA [112] (review) Krenning EP et al. (1993) [136] Hoefnagel CA [112] (review) Fischer M et al. (1984) [140] Jakubowski W et al. (1985) [141] Troncone L et al. (1990) [142] Welchik MG et al. (1989) [143] Warren MJ et al. (1989) [144] Maurea S et al. (1993) [145]

7 10 14 1396 129 16 74 19 45 36

111In-pentetreotide

100 100 86 88 95 94 92 94 82 83

No. of patients

Radiopharmaceutical

Sensitivity (%)

111In-pentetreotide

60

111In-pentetreotide 111In-pentetreotide 123I-, 131I-MIBG 131I-MIBG 131I-MIBG 123I-, 131I-MIBG 131I-MIBG 131I-MIBG 131I-MIBG

&/tbl.: Table 3. Results of different radiopharmaceuticals in MTC&/tbl.c:&

Author

Baudin et al. (1996) [146] Ugur et al. (1996) [147]

24 14

Kwekkeboom et al. (1996) [148] Kurtaran et al. (1996) [149]

21 12

Eising et al. (1995) [150]

24

Behr TM et al. (1997) [124]

16

Hoefnagel CA [112] (review)

275

201Tl

19 99mTc-sestamibi 99mTc-DMSA(V) 111In-pentetreotide 123I-VIP 111In-pentetreotide 123I-Tyr3-octreotide 111In-pentetreotide 99mTc-DMSA(V) 99mTc-, 111In-, 131I-Anti-CEA 111In-pentetreotide 131I-MIBG

47 95 67 0 63.5 68 23 86 47 70

&/tbl.:

computed tomography (CT) and magnetic resonance imaging (MRI), while 131I-MIBG has shown still lower figures [105, 110]. On the other hand radionuclide scans have the advantage of imaging the whole body with a single examination. Therefore, MIBG imaging plays an important role in the clinical management of phaeochromocytoma, especially in the assessment of extra-adrenal neoplastic sites. The best combination of diagnostic modalities appears to be CT and 123I-MIBG, but the experience of individual centres may lead to different choices. MIBG diagnostic imaging becomes essential when evaluating the feasibility of 131I-MIBG therapy, to establish the biodistribution of the radiopharmaceutical before administering the therapeutic activities. Medullary thyroid carcinoma The use of MIBG scans in the clinical management of MTC has limited value. Although the specificity is higher than 95%, the sensitivity is only 35%, with a range between 6% and 55%, depending on the author. Hoefnagel reports cumulative results on the use of MIBG in

MTC [111] (Table 3). To date there is no clear explanation for these results. It has been suggested that the histological heterogeneity and the anaplastic transformation of the distant lesions may play a role [112]. However, MIBG uptake may be high enough to allow radionuclide therapy. In this setting MIBG imaging should be performed to assess such a therapeutic possibility. Neuroendocrine tumours of the gastroenteropancreatic tract and of the lung Since the introduction of somatostatin receptor imaging, the role of MIBG imaging in these neoplasms has been limited to a selected group of patients who can successfully undergo palliative therapy courses with 131I-MIBG. However, some authors report that 70% of neuroendocrine tumours of the gastroenteropancreatic (GEP) system and of the lung are able to take up MIBG (Table 4). Delayed images may reveal unknown lesions, particularly if 123I-MIBG is used with SPET [112]; therefore MIBG imaging should be employed when other diagnostic modalities give inconclusive results.

European Journal of Nuclear Medicine Vol. 25, No. 6, June 1998

649 Table 4. Results of MIBG and SRI in neuroendocrine tumours of the gastroenteropancreatic system and of the lungs&/tbl.c:&

Author

No. of patients

Radiopharmaceutical

Sensitivity (%)

Hoefnagel CA [112] (review) Hoefnagel CA [112] (review)

275 451

123I-MIBG, 131I-MIBG

70 86

123I-Tyr3-octreotide, 111In-pentetreotide

Modlin IM et al. (1995) [151] Jamar F et al. (1995) [152] Bombardieri E et al. 1997 [116] Lebtahi R et al. 1997 [153]

28 17 120 160

111In-pentetreotide 111In-pentetreotide 111In-pentetreotide 111In-pentetreotide

75 97 82 78

&/tbl.:

Radiolabelled somatostatin analogues Octreotide, a somatostatin analogue, binds to somatostatin receptors type 2 and, probably, 5. Somatostatin receptors are expressed on many neuroendocrine tumours; radiolabelling the analogue allows visualisation of these tumours. The first clinical research using radiolabelled somatostatin analogues was performed by Lamberts et al. [113], who used 123I-Tyr3-octreotide to localise somatostatin receptor-bearing tumours. After promising initial results this tracer revealed some problems which influenced its application in clinical practice. The major drawbacks were the cumbersome labelling of the radiopharmaceutical, the limited availability and high cost, and the high intestinal radioactivity due to the hepatobiliary clearance of 123I-Tyr3-octreotide [114]. Consequently a new tracer was developed by binding diethylene triamine penta-acetic acid (DTPA) with octreotide, resulting in DTPA-octreotide (pentetreotide), which is labelled with 111In. Although there is considerable overlap in the spectrum of neoplasms that can be detected with 111In-pentetreotide and radiolabelled MIBG, most studies suggest that the indications may be different, depending on the tumour type and the clinical setting. When used correctly, somatostatin receptor imaging (SRI) with 111In-pentetreotide can have a high sensitivity for both primary and metastatic tumour lesions. The patient requires bowel preparation before acquisition of the images. Usually a low-fibre diet is suggested for 3 days before administration of the radiopharmaceutical; polyethylene glycol laxative is given afterwards to reduce the abdominal radioactivity when the first set of images is acquired. To obtain good SRI, at least 220 MBq of 111Inpentetreotide should be injected. Medium-energy collimators should be employed, although in our experience it is possible to perform successful imaging with 111Inpentetreotide, using low-energy high-resolution collimators and acquiring the 171-keV photopeak only. This method can yield a higher resolution at the cost of a lower count rate. High-count whole-body images should be acquired 24 and 48 h after the injection. Localised highquality SPET is mandatory to detect small lesions and to better localise foci of uptake on whole-body scans. Seventy-two-hour planar images of the thorax or the abdo-

European Journal of Nuclear Medicine Vol. 25, No. 6, June 1998

men may be required in selected cases. Physiological radioactivity is seen in the liver, spleen, kidneys and bladder. The thyroid and the pituitary are often seen as well. Attention must be paid to gallbladder radioactivity, which may mimic a hepatic lesion. In these cases a fatty meal should be given to empty the gallbladder before repeating the acquisition. It must be stressed that activated lymphocytes express somatostatin receptors, so any inflammatory site or recent surgery wounds should be carefully evaluated. Neuroendocrine tumours of the gastroenteropancreatic (GEP) tract and of the lungs The available literature is not homogeneous as far as the classification of neuroendocrine tumours of the GEP tract and of the lungs is concerned. In fact bronchial carcinoids are often reported together with carcinoids of the GEP system: the classification based on embryological origin (foregut, midgut and hindgut carcinoids) is still widely used. The reported sensitivity is as high as 90% for the localisation of secondary lesions and above 80% for primary tumours (Table 4). The most common indications for SRI are the localisation of unknown primary tumours in patients with metastases (most often in the liver), the localisation of the primary tumour in symptomatic patients and staging in patients with known disease. Other indications include (a) post-surgical staging in patients in whom a neuroendocrine tumour is diagnosed after pathological examination and (b) selection of those patients with extensive disease who can benefit from palliative therapy with somatostatin analogues. In our preliminary data the major results of SRI were a change in the therapeutic planning in 24% of patients after the scan and the detection of previously unknown lesions in 31% of the patients. Moreover, SRI proved to have superior sensitivity for the detection of primary tumours and metastases compared with CT, ultrasound and other diagnostic modalities [115]. A low sensitivity has been reported for the use of SRI to detect insulinomas due to the low density of somatostatin receptors of type 2 in these tumours [116]. Although some of the first published studies reported a low sensitivity for liver metastases of neuroendocrine

650

GEP tumours, this is not a matter of debate as the low sensitivity reported may be explained by the fact that SPET was not employed [111]. In fact, a recent paper demonstrates that tomographic SRI visualises more lesions than planar imaging or radiological procedures [117]. An interesting study reported that elevated 5-hydroxyindole acetic acid and chromogranin-A levels correlate with positive SRI, so the latter may also be considered a prognostic indicator [118]. The authors also observed a higher hormone production in lesions with an elevated tumour/background ratio. The same study reported that the tumour/background ratio increases when the scan is acquired during treatment with unlabelled somatostatin analogues or interferon. The authors believe the treatment induces up-regulation of the somatostatin receptors, allowing better visualisation of high receptor density tissues such as tumours and lowering the uptake of low receptor density tissues. This phenomenon has already been reported in a limited number of patients affected by neuroendocrine tumours. It appears worthwhile to investigate this issue as the current explanation for the up-regulation of the receptors is not fully convincing [119, 120]. An interesting method has recently been proposed to evaluate somatostatin receptor density in vivo using 111In-pentetreotide [121]. The method is based on the biodistribution characteristics of the radiopharmaceutical. Patients with GEP tumours, neuroblastoma, small cell lung cancer and MTC were studied. The basis of this method is the tumour/background ratio calculated on SPET transaxial slices acquired 4 and 24 h after administration of the radiolabelled analogue. If the tumour/background ratio increases in the interval between 4 and 24 h, the tumour is assumed to have a high receptor density and vice versa. The initial study was based on a wash-out test. Patients were administered unlabelled octreotide after the 24-h SPET and another SPET was acquired 2 h later. At present the receptor density is measured by means of the polymerase chain reaction, which is an in-vitro test. The prognostic implications of this study are very interesting and the method, which facilitates patient selection, could be an aid in the choice of treatment. Promising results have recently been obtained using a technetium-labelled somatostatin analogue, 99mTc-P829

[122]. This radiopharmaceutical is of great interest because 99mTc labelling signifies lower cost and increased availability, although a radioisotope with a longer halflife such has 111In may be better suited for the biodistribution and kinetics of the somatostatin analogues. Small cell lung cancer SRI of small cell lung cancer is reported to have high sensitivity for the primary tumour, varying from 86% to 100%. On the other hand the sensitivity for metastases is quite low, varying from 45% to 60% (Table 5). An explanation for this phenomenon could be that secondary lesions have a lower receptor density. Moreover, many of these studies use data from planar imaging and the sensitivity may be improved by using SPET. At the moment it is not possible to establish a definite role for SRI in the management of small cell lung cancer. Considering the high cost of this technique, one should demonstrate that SRI gives more information than the standard diagnostic procedures before considering it as a routine diagnostic procedure for this tumour. This can be achieved on the basis of a proven high sensitivity for distant metastases with the use of high-quality SPET images. It may then be postulated that by using SRI some other procedures can be eliminated, thus equalling, or even lowering the total cost of patient staging or restaging. Another possibility is the evaluation of SRI as a prognostic indicator and an indicator of successful therapy. Phaeochromocytoma and paraganglioma MIBG imaging is the technique of choice for phaeochromocytoma because adrenal lesions are difficult to visualise with 111In-pentetreotide due to the high renal activity. The published data report a comparable sensitivity for both tracers, although the number of patients who have undergone SRI is very low compared with the patient numbers in MIBG studies (Table 2). At present SRI should be limited to those cases in which imaging with other nuclear medicine or radiological procedures produces inconclusive results, and to the assessment of response to treatment. Prognostic stratification may be indicated as more aggressive tumours can lose somatostatin receptors.

Table 5. Results of SRI in small cell lung cancer&/tbl.c:& Author

No. of patients

Radiopharmaceutical

Sensitivity (%) (primary tumour)

Sensitivity (%) (metastases)

Bohuslavizki et al.(1996) [154] Kirsch et al. (1994) [155] Bombardieri et al. (1994) [156] Krenning et al. (1993) [117] Leitha et al. (1993) [157] Maini et al. (1993) [158] O’Byrne et al. (1994) [159] Kwekkeboom et al. (1991) [160]

20 25 21 34 20 15 13 8

111In-pentetreotide

90 96 95 100 84 86 100 63

<26 45 – – 60 – 50 57

111In-pentetreotide 111In-pentetreotide 111In-pentetreotide 123I-Tyr3-octreotide 111In-pentetreotide 111In-pentetreotide 123I-Tyr3-octreotide

&/tbl.: European Journal of Nuclear Medicine Vol. 25, No. 6, June 1998

651

a

a

b Fig. 2a, b. Transaxial slices acquired soon after the whole-body scans in Fig. 1. The different distribution is striking in SPET studies. While 111In-pentetreotide is taken up in the major part of the lesion, leaving only a central area of reduced activity (a), 131IMIBG is intensively taken up only in two peripheral areas (b). The intense spot on the right side is due to activity in the right colon, as in whole-body imaging

The sensitivity of SRI in paragangliomas is superior to that of any other nuclear medicine or radiological procedure, although MIBG imaging displays a good specificity (Figs. 1, 2). Although a limited number of patients have been studied, this technique has a unique value in defining the disease extent, with a reported sensitivity of 97% (Table 6). The diagnostic approach should include

b

European Journal of Nuclear Medicine Vol. 25, No. 6, June 1998

Fig. 1a, b. Twenty-five-year-old male patient affected by a retroperitoneal paraganglioma. The tumour was unresectable due to the anarchic distribution of its blood supply. Whole-body scan 48 h after the administration of 200 MBq of 111In-pentetreotide (a) and 4 days after a therapeutic course with 5550 MBq of 131I-MIBG (b). Note the different distribution of the two radiopharmaceuticals in the same lesion. High activity in the right colon can be seen on 131I-MIBG imaging&ig.c:/f

652 Table 6. Results of MIBG and SRI in paraganglioma&/tbl.c:&

Author

No. of patients

Radiopharmaceutical

Sensitivity (%)

Hoefnagel CA [112] (review) Lamberts SWJ et al. 1990 [161] Hoefnagel CA [112] (review)

38 20 18

111In-pentetreotide

97 93.5 89

123I-Tyr3-octreotide 131I-MIBG

&/tbl.:

SRI as a staging procedure after locoregional examination with CT. Medullary thyroid carcinoma Many tracers have been employed to visualise MTC, but none of them has shown good sensitivity. Radionuclide imaging techniques are normally used in post-thyroidectomy follow-up if the calcitonin or CEA levels rise. Most of the diagnostic techniques, morphological as well as functional, fail to detect lesions smaller than 10 mm, which are often responsible for the elevated tumour marker levels. Although in vitro studies demonstrated the presence of somatostatin receptors in only 30% of MTCs [123], many investigators have reported on the use of SRI in this tumour, but the sensitivity was always unsatisfactory. Comparative studies using thallium-201, 99mTc-sestamibi, 111In-pentetreotide, 99mTc-(V)dimercaptosuccinic-acid [99mTc-(V)-DMSA] and radiolabelled antibodies against CEA demonstrate a higher sensitivity for 99mTc-(V)-DMSA (Table 3). At present it is not possible to indicate an ideal tracer for the followup of MTC patients. The diagnostic approach, based on tumour marker measurements, should be focussed on radiological imaging with CT and MRI. Radionuclide imaging plays an auxiliary role, depending on each single patient’s history. Radiolabelled monoclonal antibodies Controversial results have been reported regarding the utility of monoclonal antibody imaging in neuroendocrine tumours. Nonetheless, some interesting findings have been described. The combined use of radiolabelled anti-CEA antibodies and SRI has been reported to have a high sensitivity in MTC [124]. Their use was also proposed in the prognostic assessment of the disease, as better detectability using anti-CEA antibodies may be associated with aggressive tumours, while somatostatin receptor expression with low CEA levels and weak anti-CEA targeting seems to be associated with a more benign course. Promising results have been reported using three-step monoclonal antibody targeting in 29 patients with known or suspected neuroendocrine tumours other than pituitary adenomas [125]. In 26 patients, ten primary tumours and 16 recurrences were detected, while ten tumour sites were missed with conventional imaging. In this small series, this immunological approach showed a

higher diagnostic accuracy than conventional imaging techniques (93.1% vs 65.5%). These data need to be evaluated in a larger series of more selected patients as they seem to be complementary to data from trials using 111In-pentetreotide in the assessment of the biological behaviour of neuroendocrine tumours. Radiolabelled vasointestinal peptide Over recent years a cross-reactivity has been observed between vasointestinal peptide (VIP) and somatostatin analogues binding to VIP binding proteins and vice versa [126]. In support of the significant role of these receptors in oncological imaging, somatostatin receptor type 3 has been demonstrated to be the site of this interaction [127], and expression of binding sites for both VIP and somatostatin receptors on tumour cells has been shown. Successive studies validated the clinical applications of the radiolabelled peptide [128, 129] for the localisation of adenocarcinomas and neuroendocrine GEP tumours. This approach has led to a change in the clinical management of roughly 10% of patients. VIP scintigraphy uses natural VIP labelled with 123I. A highly specific preparation of 123I-VIP (150–300 MBq/g) is obtained by preparative high performance liquid chromatography. The biological activity of 123I-VIP and VIP is identical [126]. The radiopharmaceutical is injected as a single intravenous bolus injection in 3 ml of 0.9% NaCl solution. All patients are given sodium perchlorate and potassium iodide prior to injection of 123IVIP. After administration of the radiopharmaceutical a moderate fall in blood pressure may occur. Whole-body and SPET images are acquired 2–4 h after the injection with a gamma camera equipped with low-energy collimators. In most patients sequential abdominal images are recorded every 30 min. A sensitivity of 85% was obtained in neuroendocrine tumour imaging with 123I-VIP, for both primary tumours and metastases (Table 7). A study of the University of Vienna [130] reported that both 123I-VIP and 111In-pentetreotide are superior to CT in the visualisation of extrahepatic metastatic spread. In the same series insulinomas and VIPomas were successfully visualised by both tracers, including about 25% of patients with clinical signs of hyperfunctioning tumours. The 123I-VIP scan has a lower sensitivity than 111In-pentetreotide for gastrinoma, phaeochromocytoma, unclassified neuroendocrine tumours and glucagonoma. MTC is not visualised with this tracer. In order to image tumours bearing somatostatin receptors type 2, 5 and 3, a cocktail

European Journal of Nuclear Medicine Vol. 25, No. 6, June 1998

653 Table 7. Results of 123I-VIP scan in neuroendocrine tumours&/tbl.c:& Tumour

No. of patients

Sensitivity (%)

Primary or recurrent carcinoid Sites of metastatic spread Carcinoid syndrome Insulinomas Insulinoma syndrome VIPomas VIPoma syndrome Primary or recurrent MTC Phaeochromocytomas Gastrinomas Zollinger Ellison syndrome Glucagonomas NET, unclassified

38/45 76/92 4/16 14/17 2/5 5/5 2/7 1/17 3/7 2/7 0/1 0/2 4/12

84 82 25 82

5

33

&/tbl.:

scan using both 123I-VIP and 111In-pentetreotide has been proposed. In this type of scintigraphy injection of 200 MBq of 123I-VIP and 150 MBq of 111In-pentetreotide is employed to visualise the in-vivo binding of both tracers. Planar and SPET images are acquired 6 and 24 h after the injections. Positron-emitting tracers Positron emission tomography (PET) has proven useful in several differential diagnostic indications, i.e. for initial staging of cancer, differentiation between scar and residual disease, demonstration of suspected recurrences and follow-up of therapy. Tumour imaging is based on the metabolic uptake of different precursors by cancer cells and thus gives information on tissue metabolism. Its value can be best appreciated in oncology, where tissue characterisation is often the most important aspect of the diagnostic procedure. Although a very large number of positron-emitting radioisotopes may be employed to label radiopharmaceuticals, in current clinical oncology only fluorine-18 and carbon-11 are used. Most studies have employed 18F-fluorodeoxyglucose (18F-FDG), a glucose analogue which is phosphorylated after entering the cells via a diffusion mechanism. The neuroendocrine neoplastic cells may be characterised by increased glucose transport through the cell membrane which results in an increased uptake of 18F-FDG [131]. It should be mentioned that also inflammatory cells, such as macrophages and leucocytes, may display an increased uptake of 18F-FDG. For this reason great care is required in the acquisition, analysis and interpretation of the 18F-FDG PET data; in addition, at present it is only available in a limited number of nuclear medicine facilities [132]. However, this technique has potential advantages over traditional nuclear medicine imaging as far as patient management and drug development are concerned. Data on the application of 18F-FDG in neuroendocrine tumours of the pancreas and in MTC are still limitEuropean Journal of Nuclear Medicine Vol. 25, No. 6, June 1998

ed but they suggest that 18F-FDG uptake may be related to the metabolic activity of the lesions [133]. Wholebody imaging is often mandatory in oncology. Phaeochromocytomas and paragangliomas have been successfully detected with 18F-FDG and two cases of MIBGnegative phaeochromocytomas with 18F-FDG uptake have been described [134, 135]. Interesting results have been published regarding the use of 11C-labelled L-dopa and 5-hydroxytryptophan to visualise functioning tumours of the pancreas and the intestine [136]. The major drawback of the use of these radiotracers is the low sensitivity reported for non-functioning neoplasms. Other authors have proposed 11C-labelled hydroxyephedrine [137] and 18F-fluoroiodobenzylguanidine [138] to visualise neuroendocrine tumours. These new approaches have great potential value, but at present their use in clinical practice seems to be inhibited by the cost and the limited number of PET centres. It is likely that in the near future 18F-FDG will be proposed as the tracer of choice for PET imaging of neuroendocrine tumours. At the moment no data are available comparing 18F-FDG PET with gamma-emitting tracers. Conclusions There are a number of radiopharmaceuticals available today for the visualisation of neuroendocrine tumours. Their uptake is dependent upon various biological mechanisms that characterise the physiology of this particular neuroendocrine system: the capacity to take up and store amines, the expression of hormone receptors on their surface, the presence of antigenic structures detectable by antibodies and the enhanced glycolytic metabolism. The choice of radiopharmaceutical to be adopted in clinical routine should be guided by various considerations. Very important in this respect is the frequency of the presence of a specific pathway shared by the majority of endocrine cells. In this regard MIBG is a suitable tracer for those tumours characterised not only by the uptake of amines but also by the presence of specific storage vesicles, such as phaeochromocytoma. Somatostatin receptors are present on almost all neuroendocrine cells. As a consequence 111In-pentetreotide scintigraphy has shown a high sensitivity for the diagnosis of both primary and metastatic tumour lesions. However, somatostatin receptors are expressed with different degrees of intensity; high levels are mainly found in GEP tumours, while in other cancers there is a weaker expression (e.g. medullary thyroid tumours). The antigen structures may be displayed by all neuroendocrine tissues, but in this case a limitation is the poor bioavailability of the immunological detection probes, which do not exhibit any relevant clinical utility in this setting. The metabolic activity of neuroendocrine tumour cells does not seem very conspicuous, compared with that of their normal counterparts, and for this reason FDG PET has not yet been as extensively studied as in other oncological indications. From these biological observations, one can understand why

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MIBG and 111In-pentetreotide are the tracers currently used mostly for neuroendocrine tumour scintigraphy. It is obvious that, besides the mechanisms of uptake, other factors can be taken into account in the choice of radiopharmaceuticals, including dosimetry, cost-effectiveness, radioisotope availability, patient preparation, methodological aspects, and instrumentation facilities. The most promising research approaches are: (a) study of different subtypes of somatostatin receptors or receptors for other ligands; (b) development of new immunological reagents; (c) synthesis of positron-emitting tracers that explore other metabolic pathways of neuroendocrine cells. The first approach has been adopted to evaluate the potential clinical applications of VIP analogues. VIP receptors are localised only in the intestinal tract, and this could be of interest to obtain a radiopharmaceutical useful for all intestinal tumours, whether of the neuroendocrine type or not. The second approach aims at targeting neuroendocrine markers such as protein gene products or proteins of the granin family. The third approach involves radiopharmaceutical investigation into positron-emitting tracers for PET. Encouraging results have been obtained in this field with 11C-labelled precursors of catecholamine and serotonin. This perspective is dependent on the availability of PET facilities in individual countries and on the financial investment by the health authorities. It is important to realise that all these efforts to investigate possible diagnostic approaches may also open the way to new therapeutic options. References 1. Pearse AGE. The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series, and the embryologic, physiologic and pathologic implications of the concept. J Histochem Cytochem 1969; 17: 303–313. 2. Sosa-Pineda B, Chowdhurry K, Torres M, Oliver G, Gruss P. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature 1997; 386: 399–402. 3. Solcia E, Capella C, Fiocca R Cornaggia M, Bosi F. The gastroenteropancreatic endocrine system and related tumors. Gastroenterol Clin North Am 1989; 18: 671–693. 4. Grimelius L. A Silver nitrate stain for a2 cells in human pancreatic islet. Acta Societatis Medicorum Uppsaliensis 1968; 75: 243–270. 5. Masson P. La glande endocrine de l’intestin chez l’homme. Comptes Rendus de l’Academie des Sciences 1914; 158: 52–61. 6. Wiendenmann B, Huttner WB. Synaptophysin and chromogranins/secretogranins – widespread constituents of distinct types of neuroendocrine vesicles and new tools in tumor diagnosis. Virchows Arch B Cell Pathol 1989; 8: 95–121. 7. Anhert-Hilger G, Grube K, Kvols L, Lee I, Monch E, Riecken EO, Schmitt L, Wiedenmann B. Gastroenteropancreatic neuroendocrine tumours contain a common set of synaptic vesicle proteins and amino acid neurotransmitters. Eur J Cancer 1993; 9: 1982–1984. 8. Ahnert-Hilger G, Wiedenmann B. The amphicrine pancreatic cell line AR42 J secretes GABA and amylase by separate regulated pathways. FEBS Lett 1992; 314: 41–44.

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