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Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom
Correspondence: Address all correspondence and requests for reprints to: Prof. A. B. Grossman, Endocrine Oncology, Department of Endocrinology, St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom. E-mail: a.b.grossman{at}qmul.ac.uk
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Abstract |
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 Top Abstract I. IntroductionII. Histopathological...III. Tumor BiologyIV. Tumor Markers in...V. Natural History of...VI. Clinical Presentation,...VII. Medical Management of...VIII. Summary and Final...References |
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-interferon, with chemotherapy being reserved for poorly differentiated and progressive tumors. Therapy with radionuclides may be used for tumors exhibiting uptake to a diagnostic scan, either after surgery to eradicate microscopic residual disease or later if conventional treatment or biotherapy fails. Maintenance of the quality of life should be a priority, particularly because patients with disseminated disease may experience prolonged survival.
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I. Introduction |
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TopAbstractI. IntroductionII. Histopathological...III. Tumor BiologyIV. Tumor Markers in...V. Natural History of...VI. Clinical Presentation,...VII. Medical Management of...VIII. Summary and Final...References |
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This review will focus on the gastroenteropancreatic (GEP) NETs, NETs originating from chromaffin cells, and NETs originating from C (parafollicular) cells of the thyroid. The particular features of NETs that have recently been incorporated into their classification will be covered in an attempt to combine accurate diagnosis with biological behavior and prognosis. Recent developments involving the pathogenesis, earlier diagnosis, and screening for NETs, particularly in familial forms, will also be discussed. Classical symptoms of specific syndromes related to humoral secretion or other clinical presentation of such tumors and recent advances in their biochemical confirmation and localization methods will be presented, and a diagnostic algorithm will be formulated. Finally, evidence-based current medical therapeutic approaches aiming at humoral control and prevention of further tumor growth will be reviewed, and a possible therapeutic algorithm for each of these tumors will be proposed.
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II. Histopathological Classification and Variables Used to Predict Biological Behavior |
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TopAbstractI. IntroductionII. Histopathological...III. Tumor BiologyIV. Tumor Markers in...V. Natural History of...VI. Clinical Presentation,...VII. Medical Management of...VIII. Summary and Final...References |
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The differentiation is based on histomorphology, tumor size (in general larger tumors are more aggressive), and the presence or absence of gross local invasion and/or metastasis, thus reflecting biological behavior (2, 3). Most NETs are well-differentiated tumors that are characterized by a solid trabecular or glandular structure, tumor cell monomorphism with absent or low cytological atypia, and a low mitotic (<2 mitoses/mm2) and proliferative status (<2% Ki-67 positive cells) (3). Such tumors are slowly growing but can occasionally exhibit more aggressive behavior (>2 mitoses/mm2 and/or proliferation index >2% Ki-67 positive cells); however, only in the presence of metastasis and/or invasiveness is the tumor defined as a well-differentiated NE carcinoma (2, 18). Poorly differentiated NETs are invariably malignant, are defined as poorly differentiated NE carcinomas, and are characterized by a predominantly solid structure with abundant necrosis, cellular atypia with a high mitotic index (
10 mitoses/mm2) and proliferative status (>15% Ki-67 positive cells), diffuse reactivity for cytosolic markers, and scant or weak reactivity for granular markers or neurosecretory products (3). Mixed exocrine-endocrine carcinomas are epithelial tumors with a predominant exocrine component admixed with an endocrine component comprising at least one third of the entire tumor cell population. Their biological behavior is essentially dictated by the exocrine component, which may be acinar or ductal type (18). It is hoped that, in the future, other factors such as the angiogenic capacity of tumor cells and specific genetic changes may prove to be valuable tools in determining prognosis, biological behavior, and response to therapy (10).
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III. Tumor Biology |
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TopAbstractI. IntroductionII. Histopathological...III. Tumor BiologyIV. Tumor Markers in...V. Natural History of...VI. Clinical Presentation,...VII. Medical Management of...VIII. Summary and Final...References |
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Most NET-predisposing diseases have been related to inactivation of tumor growth suppressor genes, except in MEN II and the inherited form of MTC, which occur through dominant activation of the RET protooncogene (19, 21). The RET protooncogene encodes a transmembrane tyrosine-kinase receptor that causes cellular proliferation, differentiation, and increased cell motility (8, 21). MEN II comprises three clinical subtypes, MEN IIA, MEN IIB, and familial MTC (FMTC) (21); in MEN IIA, all patients develop MTC, about 50% pheochromocytoma, and about 15% primary hyperparathyroidism (21, 22). Patients with MEN IIB may have a marfanoid habitus and mucosal neuromas but not hyperparathyroidism; in these patients, MTC occurs at a younger age and behaves more aggressively compared with MEN IIA (19, 21). Approximately 95% of MEN II cases are accounted for by germline RET mutations (
98% of MEN IIA cases, 97% of MEN IIB cases, and 85% of FMTC cases) (21, 23). MEN I is an autosomal dominant syndrome characterized mainly by hyperplasia and/or multiple tumors of the parathyroid, endocrine pancreas, anterior pituitary, foregut-derived NE-tissues, and adrenocortical glands (24). Somatic mutations of the MEN Igene have been reported in sporadic forms of endocrine tumors with a variable incidence of 20–30% in parathyroid (25), endocrine pancreas (33% gastrinomas, 17% insulinomas) (26), 25% of lung carcinoids (27), but less than 1% in pituitary and adrenocortical tumors (4). In clinical practice, genetic analysis is useful to assess the syndromic diagnosis of MEN I, but the diagnosis cannot be excluded with certainty when a mutation is not found (8). Therefore, the clinical screening of patients remains a prerequisite for genetic analysis. The three major features of VHL disease are retinal angiomas, central nervous system hemangioblastomas, and clear cell renal cell carcinomas; the lifetime risk for each of these tumors has been estimated as greater than 70% (21, 28, 29). Other VHL-related lesions include pheochromocytomas, pancreatic islet cell tumors, and papillary cystadenomas of the pancreas, epididymis, the broad ligament, and the lymphatic sac of the middle ear (29). However, the incidence of specific tumors depends on the phenotypic class of VHL, of which four have been described (type 1 and types 2A, 2B, and 2C). The Carney complex is an autosomal dominant disease predisposing to various types of tumors, including cardiac and cutaneous myxomas, spotty pigmentation of the skin, and nonneoplastic hyperfunctioning endocrine states, such as nodular adrenocortical hyperplasia associated with Cushing’s syndrome and pituitary and thyroid adenomas (30, 31). Approximately 1% of patients diagnosed with pheochromocytomas may have NF1, a dominantly inherited disorder with complete penetrance but highly variable expressivity (32). Diagnostic criteria for NF1 include cutaneous or sc neurofibromas, café-au-lait spots appearing early in life, optic glioma, benign iris hamartomas (Lisch nodules), and specific dysplastic bone lesions (32). Digestive tract carcinoid tumors have rarely been described in patients with NF1 and tuberous sclerosis (8, 33). Knowledge of the particular genetic defects in these familial syndromes is essential for the early screening and counseling of other family members.
B. Apoptosis
The protein product of the bcl-2 oncogene is an important modulator of apoptosis because it blocks programmed cell death without affecting cell proliferation (34, 35, 36), whereas the c-myc protooncogene, which inactivates key tumor suppressors such as p53 and retinoblastoma gene product, also plays a central role in some forms of apoptosis (36, 37). Coexpression of bcl-2 and c-myc leads to a synergism that may result from the ability of bcl-2 to directly interfere with the apoptotic cell death resulting from the dysregulated expression of c-myc (34, 35, 36). Such an association has recently been described for a number of NETs including MTC, pheochromocytomas, carotid body tumors, and some carcinoids (34).
C. Growth factors
Malignant progression of NETs may also be triggered by overexpression of growth factors involved in endocrine and endothelial cell proliferation such as TGF, endothelial growth factor, nerve growth factor, and vascular endothelial growth factor (VEGF)/VEGF-related factors (19). Among various growth factors promoting angiogenesis, VEGF was found to be overexpressed, mainly in midgut carcinoid and some pancreatic tumors, suggesting that it may be involved indirectly in the growth of these tumors (38).
The genetic markers so far identified in various sporadic types of NETs are not specific enough to be used for diagnostic purposes, but they provide some clues as to the genetic mechanism of tumor development.
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IV. Tumor Markers in Neuroendocrine Tumors |
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TopAbstractI. IntroductionII. Histopathological...III. Tumor BiologyIV. Tumor Markers in...V. Natural History of...VI. Clinical Presentation,...VII. Medical Management of...VIII. Summary and Final...References |
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). A number of other components specific for all NE cells and associated with secretory granules or cytosolic proteins can also be used as tumor markers; among these, the chromogranin family is the one most commonly used (see Section IV.A.2) (6, 39).
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- and ß-subunits of human chorionic gonadotropin (- and ß-hCG) have been shown to be markers of nonfunctioning GEP tumors, as well as MTC and small-cell lung carcinoma (SCLC) (6, 40).
2. Nonspecific tumor markers.
In addition to specific hormones secreted by NE cells, other proteins that exert regulatory activities on the packaging, processing, and secretion of hormones are increasingly recognized as NET markers (6, 39, 41). CgA, CgB, and CgC form a group of acidic monomeric soluble proteins that are localized within secretory granules in which they are costored and cosecreted with the locally present peptides (39, 42). CgA is the granin mostly used in clinical practice, although the other chromogranins are relevant, particularly as CgA-negative, but CgB-positive tumors are increasingly being recognized (39, 43). Plasma CgA levels may be elevated in a variety of NETs, including pheochromocytomas (43, 44, 45), paragangliomas (40, 46), carcinoid and pancreatic islet cell tumors (43, 46, 47), MTC (43), parathyroid and pituitary adenomas (48), although much less (<60%) in SCLC (40, 44). The highest CgA levels have been found in metastatic carcinoids and GEP tumors (44, 45, 49, 50). Both tumor burden and secretory activity should be considered when interpreting CgA results, with a sensitivity and specificity varying between 10–100% and 68–100%, respectively (5, 43, 50). Renal insufficiency and hypergastrinemia are the main causes of false-positive CgA results (40, 43). Several assays for the measurement of intact CgA and the different cleavage products have been developed using either monoclonal or polyclonal antibodies, and thus exhibiting substantial differences in sensitivities and specificities (51). This must be taken into consideration until a recognized international standard for CgA is established (51). Comparative studies have shown that the sensitivity of CgA in relation to the reference biological specific markers is higher in foregut carcinoids, comprising bronchial, thymic, head and neck primaries (5, 40, 43), and comparable to specific tumor marker sensitivities in patients with ileal carcinoids and pheochromocytomas (43, 50). In addition, CgA has been shown to be an independent prognostic factor for midgut carcinoids because it correlates not only with tumor burden but also with biological activity (46, 47).
Synaptophysin and NSE are present diffusely in the cytoplasm of NETs, so they are consistently positive in most NETs (6). NSE is only present in neurons and NE cells and can also serve as a circulating marker for NETs (6). NSE is most frequently elevated in patients with SCLC (74%) but has also been found to be elevated in 30–50% of patients with carcinoids, MTC, islet cell tumors, and pheochromocytomas (40). Elevated levels of NSE are also roughly correlated with tumor size, although the specificity is lower than that of CgA; however, the combination of both CgA and NSE has a higher sensitivity than either parameter separately (40). Some oncogenic proteins are not specific for NETs but are frequently synthesized in these tumors, i.e., carcinoembryonic antigen (CEA) in MTC (6).
3. Tumor markers and stimulation tests.
When patients present with a high clinical suspicion of a functional syndrome but with normal basal measurements of specific tumor markers, a dynamic test can be used to increase sensitivity (39). Although the rationale of employing such tests has recently been questioned, several dynamic tests have traditionally been used (52). The dynamic tests that are still in use will be discussed later with reference to individual tumor types.
B. Amine and peptide receptor expression and visualization
The demonstration of the presence of amine uptake mechanisms and a high density of peptide receptors on several NETs, as well as their metastases, has been used for both diagnosis and monitoring of these tumors using radionuclide techniques (6, 53).
Metaiodobenzylguanidine (MIBG) is a guanidine derivative that exploits the specific type 1 amine uptake mechanism at the cell membrane and the subsequent uptake from the cytoplasm and storage within the intracellular storage vesicles (54). It shows little binding to postsynaptic receptors and has minimal or no intrinsic pharmacological effect (54, 55). MIBG localizes to adrenomedullary tumors, hyperplastic adrenal medulla and, to a lesser degree, in the healthy adrenal medulla (54, 56). In addition, several other NETs including carcinoids and MTC exhibit this specific uptake mechanism and can thus accumulate MIBG (54).
SS is a 14-amino acid peptide that is widely expressed throughout the central nervous system as well as in peripheral tissues including the endocrine pancreas, gut, thyroid, adrenals, and kidneys (57, 58). SS acts mostly as an inhibitory factor on neurotransmission, intestinal mobility, absorption of nutrients and ions, vascular contractility, and cell proliferation (57). Owing to its short half-life (1–2 min), many SS long-acting analogs have been synthesized, among which octreotide and lanreotide are the ones most commonly used in clinical practice (59, 60). These analogs are cyclic octapeptides that have a more prolonged half-life (1.5–2 h), and thus, biological activity (6, 59, 60, 61). The biological effects of SS are mediated by five specific SS receptors (1, 2, 3, 4, 5) that all bind the native peptide but show major differences in their affinities for SS analogs; the currently used analogs exhibit a very low affinity for SS receptors 1 and 4 but bind with high affinity to SS receptors 2 (predominantly) and 5 and with moderate affinity to SS receptor 3 (6, 57, 62, 63). Each receptor subtype is coupled to multiple intracellular transduction pathways, but all five are functionally coupled to inhibition of adenylate cyclase and decreased calcium influx, and thus generally inhibit hormonal secretion and intestinal mobility (57). SS also inhibits the proliferation of both normal and tumoral cells as a result of hypophosphorylation of the retinoblastoma gene product and G1 cell cycle arrest (64). The antiproliferative effects of SS can also result from apoptosis through SS receptor 3 induced by p53 and Bax (39). The SS effect on tumor growth may also be the result of indirect effects through the inhibition of growth factors (65) and angiogenesis (66, 67).
SS receptors are found mainly in well-differentiated rather than poorly differentiated tumors and thus may exert prognostic significance as markers of differentiation (Table 1
) (67, 68, 69). The high frequency of SS receptor 2 mRNA in NETs allows the localization of various human tumors and metastases using 111In-labeled octreotide (57, 66); there is a close correlation between the presence of SS receptor 2 mRNA, tracer uptake using SS receptor autoradiography, and the therapeutic response to SS analog treatment (6, 39, 70). In addition, specific polyclonal antibodies against SS receptor 2 have been developed that correlate with 111In-labeled octreotide uptake (71). Tumors and metastases that harbor uptake mechanisms and/or peptidic receptors can be visualized in vivo using a 
-camera after the injection of 123I-MIBG and/or 111In-pentetreotide (72, 73). In addition, other small peptidic receptors that are expressed in cell membranes of NE tissues include vasointestinal peptide (VIP), bombesin, cholecystokinin (CCK), gastrin and/or substance P (6, 67, 68, 69). Labeled analogs/peptides can also be used as markers for putative receptors for in vivo tumor visualization (69, 74).
C. Radionuclide imaging
Radionuclides provide a diagnostic modality in which radiolabeled amines or peptide analogs, based on their ability to bind to suitable ligands, are used for the identification and localization of NETs (7, 62, 63, 75).
1. Scintigraphy with MIBG (123I-MIBG).
The prolonged storage of MIBG within secretory vesicles permits high specific uptake and imaging after labeling with both 131I- and 123I-MIBG; however, imaging quality with 123I-MIBG is superior, and it is currently the radiopharmaceutical of choice (76, 77, 78, 79). The efficiency of 123I-MIBG is excellent for the visualization of intraadrenal and extraadrenal sites of benign and malignant pheochromocytomas, showing a diagnostic sensitivity and specificity above 80 and 90%, respectively (80). Radiolabeled MIBG facilitates in the diagnosis of multiple tumors and paragangliomas, in the detection of suspected malignant chromaffin tumors, for the screening of individuals at risk in familial forms of the disease, and for the selection of patients for therapeutic MIBG based on a positive diagnostic scan (72, 78). It also has a complementary role in the diagnosis of other NETs such as carcinoids and MTC (78, 79, 80) (Fig. 1); its sensitivity is said to be enhanced with the preimaging administration of MIBG, but this remains controversial (81).
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). Scintigraphy with 111In-octreotide has been shown to have a detection rate of 67–91% for all NETs and is used both for diagnosis and staging, and also in the follow-up of patients (7, 53, 59, 70, 83). In addition, it also exhibits high specificity (88, 89, 90, 91, 92), although occasional false-positive localizations may occur because uptake is also demonstrable in many other tumors, granulomas, and autoimmune diseases (7, 53, 54, 83, 86). A recent systematic study prospectively assessing the specificity of scintigraphy with 111In-octreotide in patients with gastrinomas revealed an overall specificity of 86% (93, 94). Evidence from in vitro studies has shown increased uptake of radiolabeled octreotide in the presence of low concentrations of unlabeled octreotide (95, 96). During octreotide treatment, the uptake of 111In-octreotide in SS receptor-positive tumors and the spleen is diminished (95). In general, NETs remain visible during treatment with octreotide, although tumor uptake may be less than without octreotide treatment (95).
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3. PET imaging.
PET utilizes the ability of radiolabeled tracers to be taken up by certain tumors and can thus selectively measure the function of different metabolic pathways of the specific tissue (104). The first tracer used in oncology was 18F-labeled deoxyglucose (FDG); however, because NETs are mostly well-differentiated and slow-growing tumors, they have a low metabolic rate and cannot be visualized efficiently with this tracer, which is more useful in less-differentiated NETs without SS receptors (78, 105, 106). The metabolic pathway synthesizing 5-hydroxytryptamine (5-HT) from 5-hydroxytryptophan (5-HTP) occurs in carcinoid and other NETs and can thus also be used for PET imaging (105, 106). 11C-5-HTP is specifically trapped by serotonin-producing tumors, and this can be further enhanced by the concomitant administration of carbidopa (107). PET imaging using 11C-5-HTP as a tracer is overall more sensitive compared with the other NE tracer 11C-labeled-L-DOPA, and can be used as a universal tracer for these tumors (104, 108). PET imaging using 11C-5-HTP has been shown to be superior to computed tomography (CT) scanning in diagnosing GEP tumors and monitoring their response to therapy; for poorly differentiated tumors, FDG-PET can be used instead (106, 107). Because scintigraphy with 111In-octreotide fails to visualize 10–20% of GEP tumors, PET may prove to be superior, although this needs to be formally assessed by a prospective trial (78).
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V. Natural History of Neuroendocrine Tumors |
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TopAbstractI. IntroductionII. Histopathological...III. Tumor BiologyIV. Tumor Markers in...V. Natural History of...VI. Clinical Presentation,...VII. Medical Management of...VIII. Summary and Final...References |
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Once an NET has been diagnosed, three main factors have to be considered: recognition of the possibility of a familial syndrome, "disease spread" assessment, and the tumor’s biological behavior (109, 112). Screening for MEN and other related familial syndromes is a fundamental step in the management of NETs, because prognosis and treatment may differ from the sporadic cases and there is the issue of familial screening in patients with familial syndromes (109, 113). The diagnosis of MEN is based on the presence of other MEN-related endocrinopathies in a patient or relatives. Occasionally, when the clinical suspicion is high without unequivocal biochemical confirmation, dynamic endocrine tests and more recently genetic screening may be needed (109). The association of MEN with NETs renders treatment more difficult, because MEN-related tumors may be multiple and diffusely spread (113). Hepatic and bony metastases are the major causes of death, with a less than 50% probability of 5-yr survival in patients with metastatic GEP tumors (109). Similarly, the liver is the most frequently involved organ in the metastatic process in MTC and malignant chromaffin cell tumors (114, 115, 116). The usually small difference between the 5- and 10-yr survival rates indicates that there are probably two subsets of patients with liver metastases (109, 117): 1) patients in whom there is a rapid tumoral evolution, who die relatively early, the median interval between progression of liver metastases (>25% growth within 6–12 months) and death being relatively short, 6 months (range, 1–24 months); and 2) patients with slow tumoral evolution who usually have prolonged survival (109, 114, 116). The routine use of the previously described variables to predict the biological behavior of the tumor probably discriminates well-differentiated from poorly differentiated NETs and the subset of well-differentiated tumors that may follow a more aggressive course. Among these variables, tumoral staining for Ki-67 and vascular and/or perineural invasion exhibit the highest sensitivity and specificity (112).
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VI. Clinical Presentation, Biochemical Confirmation, and Imaging of NETs |
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TopAbstractI. IntroductionII. Histopathological...III. Tumor BiologyIV. Tumor Markers in...V. Natural History of...VI. Clinical Presentation,...VII. Medical Management of...VIII. Summary and Final...References |
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The exact etiology of carcinoid tumorigenesis is unknown, although experimental studies have shown that in contrast to a number of nonendocrine tumors, neither common oncogenes (ras, myc, fos, jun, src) nor common tumor suppressor genes (p53, retinoblastoma) are generally important in the molecular pathogenesis of most, except possibly the more atypical forms (122). Recently, the amine handling of carcinoid tumors was highlighted with the finding of vesicular monoamine transporter in endocrine gut cells and carcinoid tumors (123, 124).
1. Clinical presentation
a. Classification.
Carcinoid tumors have traditionally been classified further according to the anatomic site of origin (52, 118, 121): foregut (including respiratory tract, thymus, stomach, duodenum, and pancreas), midgut (including small intestine, appendix, right colon), and hindgut (including transverse colon, sigmoid, and rectum). Within these subgroups, the biological and clinical characteristics of the tumors vary considerably (2, 5, 119). Foregut carcinoids have a low content of serotonin (5-HT) and often secrete the serotonin precursor 5-HTP, histamine, and a multitude of polypeptide hormones causing characteristic clinical syndromes (121). Foregut carcinoids are associated with an atypical CS and have the potential to metastasize to bone (118, 121). Midgut carcinoids have a high 5-HT content (118, 121), rarely secrete 5-HTP or peptide hormones, but do release 5-HT and other vasoactive compounds such as kinins, prostaglandins, and substance P (52, 119, 121); they are more likely to cause the classic CS with the development of hepatic metastases and rarely metastasize to bone (109, 118). Hindgut carcinoid tumors rarely contain 5-HT, secrete 5-HTP, and/or cause the CS; however, they can contain numerous GI hormones and very infrequently metastasize to bone (118).
b. Incidence, epidemiology, and prognosis.
Carcinoids are relatively rare tumors with an annual incidence of 0.8–2.1 cases per 100,000 per year (125, 126, 127), although autopsy series have found an incidence of 8.4 cases per 100,000 population per year (128). Analysis from Cancer Registries of several countries has recently highlighted the distribution of carcinoid tumors in the gut and other areas throughout the body (125, 129, 130). Carcinoid tumors, mainly foregut carcinoids, are associated with MEN I in about 10% of cases (20, 52), but can also occur in MEN II or NF1 and occasionally in familial polyposis coli; however, the great majority are sporadic (33, 52, 131, 132, 133, 134). Non-MEN familial carcinoid tumors are rare, most being GI in five families and pulmonary in the other family described to date (132, 135). Recent epidemiological studies have shown a small increased familial risk for midgut and hindgut carcinoids in offspring of parents affected with carcinoids, bladder cancer, or other endocrine gland tumors (129, 136). Overall, approximately 1% of patients with carcinoid tumors appear to have a positive family history in first-degree relatives, which is therefore associated with a relative risk of 3.6; this is much higher if both parents are affected (129, 136).
A cumulative analysis of all types of carcinoid tumors showed that in 45% of cases metastases were already evident at the time of diagnosis and that the 5-yr survival rate of all carcinoid tumors regardless of site was approximately 50% (126). The highest metastatic percentages were noticed for pancreatic (76%), colonic (71%), and small bowel carcinoids (71%), corresponding to their poor 5-yr survival rates (34, 42, and 55%, respectively) (126, 137). Among patients with distant metastases, those with midgut primary tumors have improved survival compared with patients with tumors arising from other primary sites (126, 137). Synchronous or metachronous adenocarcinomas, particularly of the large bowel, are found in 13% of patients, particularly males, with mainly midgut tumors (52, 130, 131). Occasionally, carcinoid tumors may secrete one hormone, whereas at other times the peptide or amine secreted may differ and yield an entirely different clinical syndrome or, more rarely, metastases may secrete different hormones from the original tumor (121).
c. CS.
The CS is usually a consequence of a synergistic interaction of tumor factors (5-HT, kinins, kallikrein, prostaglandins) gaining access to the systemic circulation, thus circumventing metabolism in the portal or pulmonary arterial circulation (52, 118, 121, 138, 139). Patients with the more common (95%) classic (typical) CS usually present with flushing (90%), diarrhea (70%), abdominal pain (40%), valvular heart disease (40–45%), telangiectasia (25%), wheezing (15%), and pellagra (5%) (52, 118, 121, 138, 139).
The principal features of CS are diarrhea and flushing (139). In the early phases of the disease, the major mechanisms of diarrhea are secretory and GI dysmotility factors, whereas the later phases are also associated with gut lymphangiectasia and bacterial overgrowth (60, 121, 139). The flush found in patients with the classic CS (midgut carcinoids) is usually of a pink to red color and involves the face and upper trunk, lasting for a few minutes and occurring many times per day without leaving a permanent discoloration (121). This type of flush is triggered by alcohol or tyramine-containing foods, chocolate, walnuts, and bananas (121, 138, 139). The atypical syndrome, which is much less common (5%), consists in a flush that tends to be of protracted duration lasting for hours, of a purplish rather than the usual pink-red color. It frequently leaves telangiectasia and hypertrophy of the skin of the face and upper neck but also involves the limbs, which may become acrocyanotic; this type of flush occurs in the absence of triggering foods (10, 52, 121, 139). In addition, headache, lacrimation, hypotension, cutaneous edema, and bronchoconstriction may occur (10, 139). It is usually found in patients with foregut carcinoid tumors, and it is thought to be mediated by 5-HTP, histamine, and other biogenic amines (121, 139). In a recent analysis of 8876 patients with carcinoid tumors, 8.4% of patients developed the CS; these patients were older, had higher serotonin activity, and a higher incidence of hepatic metastases compared with patients without CS (138).
Carcinoid crisis is the most immediate life-threatening complication of the syndrome; it is mostly observed in patients with foregut and midgut carcinoid tumors (139). Hypotension, very rarely hypertension, tachycardia predisposing to arrhythmias, bronchial wheezing, flushing, and central nervous system dysfunction are the main features (52, 118, 121). It can occur spontaneously or, more commonly, can be precipitated after anesthesia, interventional procedures, or medication (chemotherapy, or radiopharmaceuticals causing tumor lysis and releasing large amounts of amines into the systemic circulation) (139).
d. Pulmonary carcinoids.
Pulmonary carcinoids account for approximately 1–2% of primary lung tumors (140, 141) and are classified along a spectrum of pulmonary NETs with different biological characteristics such as typical carcinoid tumor, atypical carcinoid tumor, large-cell NE carcinoma, and SCLC (142, 143). Typical bronchial carcinoids are generally more benign than atypical carcinoid tumors, but both types can metastasize to regional lymph nodes or to the liver, bones, and brain (143, 144). Typical carcinoid tumors (well-differentiated NETs) are mostly located centrally close to the hilum, are associated with symptoms suggestive of a mass effect (119, 145), and often develop clinical syndromes secondary to secretion of other hormones that are nontypical to the tissue of origin, such as Cushing’s syndrome from ectopic secretion of ACTH (120), acromegaly due to ectopic secretion of GHRH, or the syndrome of inappropriate antidiuretic hormone secretion (ADH) due to ectopic ADH secretion (52, 119). The CS occurs in less than 5% of cases, although it may be found in up to 50% of patients with disseminated disease (144, 145). Some tumors produce histamine, and these patients may experience an atypical CS (146). Well-differentiated pulmonary tumors are usually indolent, associated with metastases in less than 15% of cases (119, 147, 148). The presence of lymph node metastases and symptoms at the time of diagnosis are considered adverse prognostic factors (140, 144, 145); most studies have shown 5- and 10-yr survival rates of around 90% (140, 144, 145, 147, 148).
Approximately 20–30% of pulmonary carcinoid tumors have atypical histological features and are more accurately classified as well-differentiated pulmonary NE carcinomas (119, 140, 144, 145). The combination of carcinoid morphology and the presence of two or more mitoses per square millimeter or necrosis is diagnostic of atypical carcinoids (143). Atypical carcinoids have a more aggressive clinical course, metastasize to lymph nodes in 30–50% of cases, and have a 5- and 10-yr survival rate of 40–60% and 35–49%, respectively (140, 141, 143, 144, 148, 149). Large-cell NE carcinoma are closely related to smoking and, although less aggressive, have a similar clinical course and prognosis to SCLC (Refs. 143 and 149 ; also see Ref. 150).
e. Thymic carcinoids.
Thymic carcinoids are a rare type of tumor with approximately 150 cases reported (151). MEN I-related thymic carcinoids constitute approximately 25% of all cases of thymic carcinoids, although rarely these tumors may be encountered in MEN IIA (151, 152). Thymic carcinoids frequently develop metastases and have a poor outcome; there is commonly an association with ectopic ACTH production, but not with the CS (152, 153, 154). In patients with MEN I, this is an insidious tumor associated with neither Cushing’s syndrome nor the CS, typically developing in males (>95%), aged over 40 yr (>70%), with a history of tobacco smoking (>70%) (151, 152, 155). Local invasion, recurrence, and distant metastasis are common; there is no effective treatment available (152, 153). Its male predominance, the absence of loss of heterozygosity in the MEN I region, clustering in some MEN I families, and the presence of different MEN I mutations in these families, suggest either haploid insufficiency or the involvement of other etiological factors, probably a putative tumor suppressor gene on 1p (151, 152).
f. Gastric carcinoids (GC).
GC are separated into three distinct groups: GC associated with chronic atrophic gastritis (CAG) type A, GC associated with the Zollinger-Ellison syndrome (ZES), and sporadic GC (119, 156, 157). The prevalence of CS is 4% (158), whereas the majority of cases (
75%) are associated with CAG (119, 156, 157, 158, 159); these latter patients have hypochlorhydria and hypergastrinemia that results in ECL cell hyperplasia (119, 156, 157), and approximately 50% have associated pernicious anemia (119, 156, 159). Most of these tumors are less than 1 cm in diameter, and approximately 60% are multifocal (160). CAG type A-associated carcinoids are usually indolent, metastasizing in 8–23%, with distant metastases in 3–5%, and although a few deaths have been described, the overall mortality is minimal (156, 158, 159, 161). Between 5 and 10% of GC are associated with the ZES and occur almost exclusively in the context of the MEN I syndrome (119, 156, 162). These tumors are thought to arise from hyperplastic ECL cells, they are not associated with the CS, and their prognosis is similar to CAG type A-associated carcinoid tumors (119, 156, 157). Sporadic GC tumors account for 15–25% of GC tumors, are usually solitary and greater than 1 cm in diameter, and in approximately 30% are associated with an atypical CS mediated via histamine release (119, 156, 157, 159, 160). These tumors are highly aggressive, the great majority being metastatic at diagnosis, and are associated with a high mortality rate particularly in the presence of atypical histology (156, 158, 160). Regional lymph node metastases have been described in 20–50% of patients, and liver metastases ultimately develop in two thirds of patients (160). Occasionally, poorly differentiated cases of NE carcinomas, particularly in elderly patients, have been described with an overall mean survival of 7 months (Refs. 156 and 163 ; also see Refs. 164, 165, 166, 167).
g. Duodenal carcinoids.
Duodenal carcinoids are relatively uncommon tumors (18) that are usually of small size (2 cm) and are found during endoscopic procedures; such small tumors are not associated with metastases and appear to have a good prognosis (168). Duodenal carcinoids exhibit significantly lower serotoninergic hormone levels than other foregut carcinoids, but up to 20% stain for SS, and rarely for calcitonin and pancreatic polypeptide (PP) (160, 168). When these tumors are of larger size (>2 cm), they may develop metastases to regional lymph nodes or the liver in 45% of patients (160). Approximately 30% may be associated with neurofibromatosis, occasionally MEN I and/or pheochromocytomas, and may display reactivity for other hormones (160). These various tumor entities are important to recognize because of possible associations with hormonal or hereditary syndromes and a distinctly variable aggressive behavior (160, 168). Overall survival is similar to GC (including sporadic cases) (168). Such tumors should be distinguished from duodenal gastrinomas, particularly in MEN I patients. A recent analysis has revealed a high typical/atypical ratio, a relatively low metastatic rate of 27%, and a 3% incidence of CS (169).
h. Pancreatic carcinoids.
Primary pancreatic carcinoids (serotonin-producing tumors of the pancreas) are a rare subtype of pancreatic tumors with approximately 100 cases reported (160, 170). These tumors are relatively large with a high rate of metastasis (69–88.4%) at the time of diagnosis (168, 170, 171). Pancreatic carcinoid tumors produce higher levels of serotoninergic hormones and are commonly associated with the CS (65%), which may be atypical because the most common symptoms are pain, diarrhea, and weight loss, whereas flushing is encountered in only approximately one third of such patients (168, 171). The diagnosis is based on a demonstrable pancreatic NET plus elevation of plasma serotonin and/or elevation of 5-HIAA (86%) in the urine; however, not all tumors result in recognizable hyperserotoninemia (170). These tumors have a poor prognosis due to delayed diagnosis, which precludes extensive resection, and a poor response to other therapeutic modalities; a single reported patient has been associated with MEN I (168, 170, 171, 172).
i. Small intestine carcinoids.
The small intestine is the most common site for carcinoid tumors, which are thought to arise from serotonin-producing intraepithelial endocrine cells; they make up approximately one third of small bowel tumors, are mostly located in the distal ileum, and are often multicentric (119, 126, 173). The majority of patients present with abdominal pain, small bowel obstruction, and metastases to the lymph nodes and the liver; 7–28.6% of them may present with the CS (119, 173). In this group of patients, tumor size is an unreliable predictor of metastatic disease, although tumors larger than 2 cm are more likely to metastasize (119, 174, 175). However, metastases have been reported even from tumors measuring less than 0.5 cm in diameter; approximately 65% of small gut carcinoids (<1 cm) show microscopic spread to lymph nodes and almost half have liver metastases (10, 173). These tumors are frequently associated with an extensive mesenteric reaction fibrosis leading to bulking of the intestine and mesenteric ischemia (10). Long-term survival correlates closely with the stage of the disease, 5-yr survival being 65–73% among patients with localized or regional disease and 36–79% among patients with liver metastases; the lowest survival is found in patients with more than four distinct liver metastases and the presence of the CS (47, 126, 173, 176). Synchronous and metachronous malignancies were found in approximately 14–16.6% of patients in recent series (126, 173, 177). The diagnosis of the primary site of these tumors may occasionally be quite difficult, and thus many cases of small bowel carcinoids may present as disseminated carcinoid tumors of unknown primary (177, 178).
j. Appendiceal carcinoids.
Carcinoid tumors are the most common tumors of the appendix and are thought to arise from subepithelial endocrine cells of the lamina propria and submucosa of the appendix wall (119, 179). They are more common in women than in men and may be found in 0.3% of patients undergoing appendectomy (52, 119, 129, 180). The majority are located in the distal third of the appendix and are unlikely to cause obstruction (181, 182). Besides location, the size of the tumor is the best predictor of prognosis, particularly because more than 95% of appendiceal carcinoids are less than 2 cm in diameter (119). Patients with such small tumors only rarely metastasize, in contrast to approximately 30% of patients with larger tumors who may have either nodal or distant metastases (119, 182). The 5-yr survival rate is 94% for patients with local disease and 85% for patients with regional metastases (119, 126). In the presence of hepatic metastases, which can be associated with the CS, the 5-yr survival rate is 34% (119, 126). Goblet cell carcinoids of the appendix possess morphological features suggestive of both carcinoid and glandular differentiation (183). Recent studies have suggested an aggressive behavior with a 20–56% incidence of metastases, whereas tumor size is not an accurate guide to further management (5, 183). However, survival rates can show wide variation, indicating unpredictable malignant behavior (5, 184).
k. Carcinoids of the colon.
Carcinoid tumors of the colon are thought to arise from serotonin-producing epithelial endocrine cells and account for less than 1% of colonic malignancies; however, only 60–70% of these tumors show positive serotonin immunohistochemistry (119, 126, 185). These tumors are mainly located in the cecum, followed by the ileocecal region (185). Most patients present with symptoms of pain, anorexia, and weight loss (119, 186) and have clinically palpable tumors (185), whereas less than 5%, mainly with tumors of the proximal colon, present with the CS (119, 186, 187). In more than 90% of patients, tumor size is greater than 2 cm, and over two thirds of patients have either nodal or distant metastases at presentation; even lesions of less than 1 cm are associated with metastases in 22% (119, 185, 188). The 5-yr survival rates are 70% for patients with local disease, 44% for patients with regional metastases, and 20% for those with distant metastases (126).
l. Rectal carcinoids.
Rectal carcinoids account for 1–2% of all rectal tumors (119, 126, 189), although most contain glucagon, PP, and glicentin-like peptides rather than serotonin (189, 190). The CS is very rare, and although patients can present with rectal bleeding, pain, or constipation, approximately 50% of tumors are asymptomatic and are found on routine endoscopy (119, 189, 191). The size of the primary lesion correlates closely with the probability of metastases that occur in less than 5% of patients with tumors less than 1 cm in diameter, but in most patients with tumors more than 2 cm in diameter; other important prognostic features are infiltration of muscularis propria and atypical histology (119, 189, 190, 191). However, the majority of patients with tumors between 1 and 2 cm and atypical histology may have developed metastases at diagnosis (191). Approximately 10% of rectal carcinoids may be associated with another colonic neoplasm (126). The 5-yr survival rates are 81% for patients with local disease, 47% for patients with regional disease, and 18% for patients with distant metastases (119, 126).
m. Ovarian carcinoids.
These tumors are rare, ranging from 0.52–1.7% in different series (126, 192), and usually present with either pain in the pelvic area or pain with defecation (193). They can be divided into cystic teratoma/dermoid and those without such lesions (192). The former tumors follow a more benign course with less incidence of regional and hepatic metastases and a 5-yr survival of almost 100%, compared with 84% for the latter; for patients with disseminated disease (30%), the overall 5-yr survival is 33% (192, 193). The CS is present in approximately 30% of patients (192, 193).
n. Carcinoids of unknown primary.
Carcinoids of unknown primary site have not been defined in detail, even in studies including a large number of patients with carcinoid tumors (126, 177). A recent analysis of 434 carcinoid tumors revealed an unexpectedly high number of carcinoids of unknown primary that were clinically and biochemically similar to midgut metastatic carcinoids (177). In addition, their survival rate was shorter than carcinoids with identified primaries and similar to that of patients with midgut carcinoids with distant metastases (22 vs. 28%) (177).
o. Less common primaries and metastatic locations.
After the publication of studies including large numbers of patients, it became obvious that carcinoid tumors may develop in virtually any organ; however, relatively few have been reported arising from the esophagus, liver or gall bladder, middle ear, testis, and the heart (98, 126, 129, 194, 195, 196, 197, 198). More recently, the application of more sensitive techniques including radionuclide imaging with MIBG and octreotide has demonstrated unusual areas of metastases and remote primaries in patients with carcinoid tumors, such as the breast and orbit (98, 194).
p. Carcinoid heart disease (CHD).
CHD occurs in 57–77% of patients with the CS but is hemodynamically significant in a much smaller percentage (199, 200). Carcinoid heart lesions are characterized by plaque-like, fibrous endocardial thickening that classically involves the right and, in approximately 10% of patients, the left side of the heart, the most common valvular lesion being tricuspid regurgitation (119, 199, 201, 202). Patients with the CS and CHD have significantly higher levels of 5-HIAA and other vasoactive substances, suggesting that higher serotonin levels may be responsible (118, 126), although the great majority of them have previously received chemotherapy (200). This view is also supported by the finding that anorectic drugs that interfere with serotonin metabolism can produce valvular lesions similar to those seen in CHD (118, 119, 203, 204). Patients with CHD also exhibit high levels of plasma vasopressin (205, 206). Right-sided heart disease is associated with substantial morbidity and mortality in such patients, and nearly half of the patients who die of CS succumb to heart failure (118, 119); a recent analysis revealed that at least in some patients SS analogs did not prevent progression of cardiac lesions (207). Although valvular replacement in patients with symptoms of CHD has been associated with high perioperative morbidity and mortality in elderly patients, surviving patients appear to have substantial improvement of symptoms and quality of life and probably an improvement in survival (199, 201, 208). It should therefore be seriously considered in all patients with otherwise controllable disease, but significant cardiac impairment due to the valvular disease, who present reasonable operative risks.
q. Carcinoid fibrosis.
In midgut carcinoid tumors, mesenteric metastases are common even with the smallest primary tumors (174). A larger size primary tumor may occasionally coalesce with lymph gland metastases in the mesentery that can grow further and are characterized by marked mesenteric fibrosis (174, 182, 208). This fibrosis, which can occasionally be extensive, probably results from the effects of growth factors and other substances released from the carcinoid metastases (209). The fibrosis causes shrinkage and fixation of the mesentery and mesenteric root to the retroperitoneum, such that fibrous bands may obstruct the duodenum and, occasionally, parts of the colon (174). This may cause partial or complete small bowel obstruction, although the primary tumor is not large enough to obstruct the intestinal lumen (174, 209). The mesenteric vessels may also become entrapped or occluded, with resulting venous stasis and ischemia and occasionally impairment of the arterial circulation (174). In terms of therapy, in such cases extensive surgical intervention and debulking of the tumor mass from the mesenteric root with preservation of the main intestinal vascular supply and important collaterals are required (174). This approach will generally allow more limited small intestinal resection, minimize the risk of further intestinal complications, and probably avoid a bypass procedure (174).
2. Biochemical diagnosis.
In all three tumor subgroups, high levels of CgA, PP, and /ß-hCG subunit may be found (5, 6, 131, 178). High levels of -subunit are often found in patients with hindgut and midgut carcinoid tumors, whereas both - and ß-subunits may be increased in midgut carcinoid patients (146). Patients with midgut carcinoid tumors have increased rates of serotonin production; elevated serotonin levels can be measured either in the plasma or as the serotonin metabolite 5-HIAA (52, 146). Determination of serotonin is associated with a poor specificity, due to significant variations over time, and thus 5-HIAA levels are usually measured instead (178). Measurement of urinary 5-HIAA levels is used for confirming the diagnosis and monitoring patients with metastatic disease; in such patients, elevated 24-h urinary 5-HIAA levels were associated with a 73% sensitivity and a 100% specificity in predicting the presence of a tumor (210). Patients with midgut carcinoids also exhibit increased tachykinin levels (neurokinin A and K) that can also be used for diagnosis and evaluation of responsivity during treatment (211). Patients with foregut carcinoid tumors rarely secrete serotonin, and only the rare existence of CS justifies measurement of 5-HIAA (178). Patients with hindgut tumors rarely present with elevated levels of tumor markers, even in the presence of metastatic disease, and thus measurement of 5-HIAA or other hormones and peptides is mainly indicated in the presence of a hypersecretory syndrome (178).
Levels of serum CgA are raised in 80% of patients and also seem to correlate with tumor load and predict prognosis, particularly in patients with midgut carcinoids, because elevation of CgA levels can precede radiographic evidence of recurrence (52, 118, 146). Although the routine measurement of CgA has not been established as yet, it has been suggested that it should also be used in foregut carcinoids because CgA may be elevated in 93% of patients with metastatic pulmonary carcinoids and patients with gastric and thymic carcinoids (5, 161, 178). However, its low specificity makes it unreliable for the differential diagnosis of a lung tumor found on chest radiology (161). Using patients with metastatic carcinoid tumors and patients in remission, a cut-off discriminatory level of CgA has been suggested with a 92% sensitivity and a 96% specificity (212), whereas CgA was found to be more sensitive than either NSE or -hCG when directly compared in the same group of patients (40). Although a recent study failed to confirm the same results of CgA measurement, this has been attributed to the methodology used (6, 51, 213). Increased CEA levels are a poor prognostic factor and raise the possibility of a tumor with adenocarcinoma differentiation (119). Determination of other hormones is recommended in the presence of a functional syndrome (178). In patients with the atypical CS, the diagnosis can be established by analysis of the main metabolite of histamine, methylimidazole acetic acid in the urine (10). Our current policy is to routinely measure CgA in all patients with carcinoid tumors and 5-HIAA levels in patients with midgut carcinoids, the CS, and/or liver metastases; measurement of other markers is performed in the presence of a relevant hypersecretory syndrome. The differential diagnosis of the CS is considerable and will include various types of inflammatory bowel disease, gut neoplasia, and diverticular disease in older patients, and irritable bowel syndrome in younger patients. It should be emphasized that normal barium contrast studies of the bowel do not confirm the diagnosis of irritable bowel syndrome, and plasma CgA and/or urinary 5-HIAA levels are simple screening techniques.
3. Imaging carcinoid tumors and diagnostic workup.
The determination of tumor extent (localization and metastases) as well as primary tumor location is an essential aspect of the management of carcinoid tumors because it facilitates possible resection, which remains the only treatment that can actually cure the patient, i.e., remove all evidence of tumor with no recurrence (214, 215). Currently, 111In-pentetreotide is used by many in the routine staging of GEP tumors to demonstrate diagnostic uptake and in the follow-up of such patients to detect regrowth or newly occurring metastases at an early stage, and we believe it should be used in all such cases; a negative scan in the presence of proven disease should alert the physician to the possibility of a poorly differentiated tumor (62, 69).
a. Foregut carcinoid tumors.
Chest radiography may occasionally detect bronchial carcinoids, mainly as opacities with notched margins (62). However, thin-section CT and magnetic resonance imaging (MRI) allows greater resolution of bronchial carcinoids, identifies lymph node involvement, and can also facilitate tissue diagnosis with fine-needle aspiration cytology (178). Scintigraphy with 111In-octreotide may identify previously unrecognized lesions, particularly in patients with the possibility of ACTH-dependent Cushing’s syndrome, but may be negative in up to 30%, although a recent study suggested that the majority of such patients will eventually develop a positive scan (216, 217, 218, 219). Although PET with FDG is usually of limited value in the diagnosis of bronchial carcinoids, PET with radiolabeled-5-HTP may be more useful in detecting occult bronchial carcinoid tumors (104, 105). Similarly, although chest radiography may demonstrate a thymic mass, CT and/or MRI is further required to evaluate the presence of metastases and plan surgery and may be more sensitive than scintigraphy with 111In-octreotide (151, 152, 155, 220). Most GC are usually diagnosed on endoscopy or endosonography, because upper GI contrast studies are often nonspecific or fail to visualize the lesion (221). The investigation should be concluded by performing CT of the abdomen (178).
b. Midgut carcinoid tumors.
In general, midgut carcinoid tumors, regardless of their functional state, are diagnosed when they have already metastasized (178, 222). Scintigraphy with 111In-octreotide is extremely helpful and is used for staging and identification of the primary lesion (178, 222). SS scintigraphy has an 83% diagnostic accuracy and a positive predictive value of 100%, and can also identify lesions that are not seen by other imaging modalities; it is also very sensitive in identifying bone deposits from carcinoids (53, 118). The superiority of SS scintigraphy to other diagnostic modalities has been demonstrated by several recent studies (92, 223, 224, 225). Transabdominal ultrasound identifies approximately one third of small bowel carcinoids and two thirds of liver metastases (226), and may also be used to guide percutaneous biopsies of liver tumors (227). CT and MRI are less sensitive than scintigraphy with 111In-octreotide because they identify only approximately 50% of the primary tumors, although they are reliable methods for monitoring responsiveness to treatment (99, 118) (Figs. 3–6). For identification of the primary tumor, classic double-contrast barium GI studies (enteroclysis) are generally used, although recently CT-enteroclysis may offer diagnostic advantages (228, 229). Probably the most important reason to use this technique is to assess the possibility of imminent small bowel obstruction. However, approximately 40% of primary and metastatic tumors may not be visualized by the usual techniques (118).
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d. Carcinoids of unknown origin.
In cases where the metastases are detected first, it may be of prognostic significance to try and identify the primary origin of the tumor in either the abdomen or chest or in unusual locations such as testes, ovaries, and breast (98, 194). Using radiological and/or nuclear imaging methods, the primary tumor was localized in 96 and 81% of cases of nonfunctioning and functioning NETs, respectively, in one series (232).
We currently perform scintigraphy with 111In-octreotide in all of our patients with carcinoid tumors and use conventional imaging to clarify the exact morphology of the tumor and follow the response to treatment; in cases of a negative scan (particularly foregut carcinoid tumors), we use 123I-MIBG. The latter radionuclide is also used as a guide to therapy (see Section VII.C). SPECT/CT hybrid imaging with 111In-octreotide is used by some in the assessment of NETs (233). PET imaging is not routinely performed and is reserved only for patients in which all other imaging modalities are negative; however, we and others are currently evaluating the routine use of this form of imaging in all patients with carcinoid tumors.
4. Screening.
Clinical examination to exclude NF1 and an extended family history should be taken in all patients with carcinoid tumors. Patients with sporadic or familial bronchial or GC should be evaluated for germline MEN I mutations; in the presence of a mutation, these cases should be treated as MEN I families. Management of MEN I families includes screening for parathyroid and enteropancreatic tumors from late childhood, with predictive testing of first-degree relatives of known mutations. Patients with mid- and hindgut carcinoid tumors should be screened for another neoplasm (usually within the GI tract), particularly if they are males, in the presence of relevant family history and during the first year after initial diagnosis (129, 136). Counseling should be readily available in case of positive findings.
B. Islet cell tumors
A variety of clinical syndromes are found in patients with islet cell tumors, reflecting the potential of endocrine cells to secrete both peptides and amines (1, 234). However, about 20% of islet tumors secrete no detectable hormones and may remain clinically silent until detected at an unresectable stage with symptoms due to the mass effect of the tumor or metastatic disease (1, 234). The initial concern with islet cell tumors is an awareness of the multitude of clinical syndromes that they may cause (Table 2).
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The tumor is characterized by hypersecretion of insulin and the subsequent development of symptoms of neuroglycopenia and symptoms resulting from the catecholaminergic response, which may not always be present (236, 243, 244). Patients with neuroglycopenia may complain of headache, lethargy, dizziness, diplopia, blurred vision, and amnesia; rarely, hypoglycemia may result in seizures, coma, or permanent neurological deficit (236, 244). The catecholaminergic response is associated with tremor, anxiety, palpitations, nausea, hunger, and sweating (236, 245, 246). Hypoglycemic episodes occur early in the morning and may be triggered by exercise (244). Because occasionally symptoms are not specific and insulinoma can mimic several pathological conditions, a broad differential diagnosis should be considered. More importantly, the diagnosis should be considered in any patients presenting with unexplained paroxysmal episodes, including those associated with abnormalities in behavior and/or seizures (242, 247).
The diagnosis of insulinoma is based on demonstrating Whipple’s triad [symptoms of hypoglycemia, concomitant plasma glucose of <45 mg/dl (<2.2 mmol/liter), and relief of symptoms with sugar intake] (236, 245, 246). Fasting therefore is the major maneuver used in the diagnosis of insulinoma and has two important purposes: the first is to document hypoglycemia (glucose levels < 45 mg/dl), and the second is to demonstrate hypoglycemia-associated, inappropriate insulin (>6 µU/ml or 30 pmol/liter) and C-peptide (>300 pmol/liter) concentrations. The absence of sulfonylurea or related drug in the plasma or urine should be sought in relevant cases (236, 244, 248). Exogenously administered insulin is associated with raised insulin plasma but low plasma C-peptide levels (236, 247, 249). Proinsulin levels have been shown to be of diagnostic value because more than 90% of patients with insulinomas have a plasma proinsulin component of at least 25% of the total immunoreactive insulin (247, 248, 249, 250). When an insulinoma seems highly likely, the 72-h fast is considered as the investigation of choice (240, 248, 249). In most series, 30% of patients develop symptoms by 12 h into the fast, 80% within 24 h, and almost 100% at 72 h (240, 246). Normal subjects may lower their glucose levels below 45 mg/dl in 48 h, but the corresponding insulin levels should be very low or undetectable (240). More recently, it has been suggested that a 48-h fast may be as sensitive as the 72-h fast in demonstrating the presence of an insulinoma (248). Not all patients with insulinoma will develop diagnostically reduced glucose levels; in these cases, measuring insulin surrogates (ß-hydroxybutyrate and the response of plasma glucose to iv glucagon at the end of the prolonged fast) can be valuable (240, 246, 247). Rarely, patients with insulinomas may suppress their insulin levels below 10 µU/ml because their glucose levels fall at the end of the fast; however, these patients still have elevated proinsulin concentrations (240, 248, 251). Because of the reliability of the 72-h fast, provocative tests are only rarely used, and shorter fasts (such as three sets of 15-h fasts) are of lower reliability (242). Occasionally, it may be helpful to provide the patient or their partner with home glucose monitoring to assess blood glucose levels during an attack. When serum chromogranins are used as tumor markers, CgB should be measured instead of CgA because these tumors preferentially secrete CgB (39, 252). Selective intraarterial calcium gluconate injection into the various arteries supplying the pancreas and hepatic venous sampling [arterial stimulation venous sampling (ASVS)], with calcium acting as an insulin secretagogue, may be extremely helpful in the diagnosis and localization of these tumors (253, 254). The differential diagnosis of an insulinoma is large and will include a variety of cerebral and cardiac dysrhythmias (249). We generally include a 24-h electrocardiogram and an electroencephalogram in the diagnostic workup of such patients, except where the diagnosis of hypoglycemia is quickly confirmed. With confirmation of hypoglycemia as the cause of the attacks, certain rare metabolic syndromes may need to be considered, as well as factitious hypoglycemia and ectopic secretion of pro-IGF-II by certain tumors (Ref. 255 ; also see Ref. 256).
Only approximately 5–10% of insulinomas are truly malignant, presenting with similar clinical symptoms to patients with benign disease, namely symptoms of hypoglycemia (236, 242, 257). These tumors are usually single and large, averaging 6 cm in diameter with a median survival of 4 yr (240). Recently, patients with mainly postprandial hypoglycemia, noninsulinoma pancreatogenous hypoglycemia (NIPH), have been reported (258). These patients characteristically present with neuroglycopenic symptoms within 4 h of meal ingestion, have negative 72-h fasts, and harbor islet hypertrophy or nesidioblastosis rather than insulinomas (258). In contrast to NIPH, patients with nesidioblastosis develop fasting hypoglycemia within 8–14 h; however, nesidioblastosis per se constituted only 0.7% of the causes of endogenous hyperinsulinism in one big series (259). In both of these entities, ASVS can be extremely helpful to differentiate this condition from the presence of an islet cell tumor (258), although the diagnosis usually requires histopathological verification. Successful excision of a benign lesion is associated with normal life expectancy (240), whereas a 10-yr survival of 29% has been described for malignant insulinomas (249).
b. Gastrinomas.
Gastrinomas are gastrin-secreting tumors derived from either the duodenum or the pancreas, causing the ZES by producing hypergastrinemia, which results in hyperchlorhydria and gastric mucosal thickening (139). The majority occur in or near the head of the pancreas; less frequent sites are the small intestine and the stomach (162, 260). Gastrinomas, after insulinomas, are the second most frequent endocrine tumors of the pancreas that occur in either the sporadic form or in up to 25% in association with MEN I (139, 162). A duodenal localization is mainly associated with the MEN I syndrome when gastrinomas are usually small and frequently multifocal, and may therefore be difficult to detect either by traditional imaging methods or at surgery (139, 162). Although the majority of gastrinomas run a malignant course (162, 260, 261), neither their size nor their histological appearance accurately reflects their biological behavior (260, 262). Lymph node and liver metastasis is present in 70–80% at diagnosis, and bone metastases in 12% (139, 162). Previous studies have shown that after the excision of lymphoid tissue containing gastrinoma there was cure of the disease, implicating the presence of primary gastrinoma in lymph nodes; even more rarely, ovarian and heart tumors that release gastrin have been described (94, 162, 260, 261, 263).
Except for the symptoms due to the effects of widespread metastases, the clinical manifestations of the ZES are due almost entirely to the effects of elevated gastrin levels and hypersecretion of gastric acid (162, 260). In a recent review of 261 patients, the mean age at presentation was 41 yr, and there was a 5.2-yr delay between the onset of the symptoms and the time of diagnosis (264). Ulceration of the upper GI mucosa develops in more than 90% of patients; less frequent sites are the distal duodenum or the jejunum (139, 162, 260, 264). Esophageal involvement is increasingly recognized, occurring in 10–60% of patients, and includes heartburn and dysphagia due to gastroesophageal reflux and its complications (162, 264). Diarrhea is the second most common symptom, developing in 50–65% of patients, and it can precede, accompany, or follow the ulcerous disease; in 7–35%, it may be the only initial symptom (162, 260). Cushing’s syndrome occurs with an incidence of 6% in sporadic gastrinomas, mainly due to ectopic ACTH production, and is usually severe and associated with a worse prognosis (265). Coexisting pheochromocytomas have also been described rarely in patients with the ZES (266). Duodenal gastrinomas comprise 60% of all duodenal NETs and are located in the first and second portion of the duodenum (160). They are frequently small (<1 cm) and thus difficult to detect, but can metastasize to regional lymph nodes in 30–70% of patients (160, 162). Approximately 40% of gastrinomas are located within the duodenal submucosa, and in MEN I patients with ZES this prevalence may reach 90% (160). Patients with ZES and MEN I are clinically different from patients with the sporadic form of the disease in that they characteristically present at an earlier age, and although the gastrinoma can be the presenting lesion, most patients have hyperparathyroidism or pituitary disease at the time of presentation of the ZES (162, 267). Duodenal and pancreatic gastrinomas differ both in biological behavior and their cells of origin (268). Approximately 25% of gastrinomas are associated with MEN-I, and 19% of them can also have mild Cushing’s syndrome secondary to a pituitary tumor secreting ACTH (162, 260, 265). In patients associated with MEN I, the trophic effects of prolonged hypergastrinemia on ECL cells lead to the formation of GC, mainly involving the body and fundus of the stomach; these cases demonstrate loss of heterozygosity on chromosome 11q13 (162). Patients with MEN I have a 20–30 fold higher chance of developing an ECLoma than patients with the sporadic form (269).
One should always consider the presence of ZES in cases of an unusual ulcer location or ulcers refractory to treatment, unexplained diarrhea and weight loss, and prominent gastric folds at endoscopy. The basic investigations for establishing the diagnosis of ZES are a fasting serum gastrin concentration, the secretin stimulation test, and gastric secretion studies. Measurement of serum gastrin is not interpretable in the presence of drugs that inhibit gastric acid output. Although an occasional patient with the ZES may have normal serum gastrin levels, the great majority (>90%) do have fasting hypergastrinemia and a gastric fluid pH lower than 2.5 (162, 260). A serum gastrin level of 1000 pg/ml or greater is diagnostic of ZES as long as the patient is normocalcemic and free of pyloric obstruction, has normal renal function, and secretes gastric acid (270). However, many patients with gastrinomas may have nondiagnostic serum gastrin levels (260, 270). In such cases, a gastric analysis and a secretin provocative test may be performed to establish the correct diagnosis (162, 260). Two units per kilogram of secretin are given iv, and serum gastrin is measured before and 2, 5, 10, and 20 min afterward; a positive response is considered an increase of at least 200 pg/ml in serum gastrin and is found in 87% of patients (271, 272). Approximately 30% of those with an equivocal secretin test will have a positive calcium infusion test (272). Gastric acid perfusion studies are rarely used (273). - and ß-Subunits of hCG are elevated in 30–40% of patients; however, their association with malignancy is not fully established (40, 50). Prominent gastric folds are apparent in 94% of patients at endoscopy (264). When measuring serum gastrin, we stop H2-antagonists for a minimum of 1 wk and proton pump inhibitors for at least 3 wk. The presence of liver metastases at the time of diagnosis is the most important determinant of survival, mostly found in patients with pancreatic rather than duodenal lesions; the incidence of lymph node metastases is similar in patients with duodenal and pancreatic gastrinomas but does not exert a significant influence on survival (268, 274). Approximately 25% of patients with ZES follow an aggressive course with development of liver metastases and an overall 10-yr survival of 30% (268). The overall survival of MEN I-related gastrinomas is similar to the sporadic form and is largely determined by the presence of liver metastases (20, 275).
c. Glucagonoma.
Glucagonomas are rare slow-growing tumors arising from the pancreatic -cells, commonly associated with a characteristic syndrome as the result of excessive secretion of glucagon and other peptides (276). The majority of cases are sporadic, but between 5 and 17% are associated with MEN I or, rarely, familial adenomatous polyposis (276, 277, 278). However, glucagonomas may be more common because autopsy series have demonstrated 0.8% occurrence rates of microglucagonomas in adult-onset diabetics (278, 279). Patients with the sporadic disease present in their fifth decade of life with lesions mainly located in the tail of the pancreas, whereas patients with MEN I present at the younger age of 33 yr (277, 280). Glucagonomas can be as large as 6 cm, are highly malignant, and over 80% of the sporadic tumors have documented mainly hepatic metastases at diagnosis (277, 278, 279, 281).
The most common symptoms are weight loss (70–80%), rash (65–80%), diabetes (75%), cheilosis or stomatitis (30–40%), and diarrhea (15–30%), the most characteristic being the rash, necrolytic migratory erythema (NME) (277, 278, 279, 281). This dermatitis-looking lesion typically evolves over 7–14 d, beginning as small erythematous lesions in the groin and extending to the perineum, lower extremities, and perioral regions (276, 277). These areas then blister, and central erosions develop in the epidermis, followed by secondary infection with Candida albicans and Staphylococcus aureus (278, 282). There are only a few sporadic reports of patients with glucagonomas who never develop NME (277, 278). Other dermatological manifestations of glucagonoma are dystrophic nails, angular cheilitis, atrophic glossitis, and buccal mucosal inflammation (277, 282). Fatty acid, zinc, and amino acid deficiency and hepatic impairment have been implicated as causes of NME, but the exact etiology is unknown; serum glucagon levels do not correlate with the presence or the severity of the rash (276, 277, 278). Diabetes may precede the NME by several years, but NME can occur alone (283). Once the combination of NME and diabetes develops, the diagnosis of glucagonoma is usually made rapidly (276, 277, 278). Other common manifestations are psychiatric disorders and an increased incidence of thromboembolism (30%), manifest as deep venous thrombosis and pulmonary embolism (276, 277, 278).
Patients with glucagonomas often develop a normochromic normocytic anemia and hypoalbuminemia, hypocholesterolemia, and hypoaminoacidemia (277). The diagnosis is based on clinical suspicion and the demonstration of raised fasting plasma glucagon levels (>50 pmol/liter) in the presence of a pancreatic tumor (278). Fasting plasma glucagon levels may be elevated to between 1.5 and 150 times the upper limit of normal (276, 278). It is therefore important to maintain a high index of suspicion in patients with clinical features suggestive of a glucagonoma, but in whom only marginally elevated glucagon levels are found, especially when a glucagonoma is suspected in a patient with MEN I at an earlier stage as a result of screening (276). Approximately 20–40% of patients with glucagonomas may also have raised fasting gastrin levels and VIP levels; these may be associated with secondary endocrine syndromes, particularly ZES, and warrant further follow-up (276, 277, 278). Patients without established metastases have a good outcome after surgery alone, with an over 85% survival rate at a mean follow-up of 4.7 yr, whereas this rate falls to 60% in patients with malignant disease (276, 277, 278). Thromboembolic events may account for over 50% of all deaths directly attributed to the glucagonoma syndrome (Ref. 280 ; also see Ref. 284).
d. VIPoma.
Most VIPomas are sporadic, and approximately 70–80% originate from the pancreas, mostly from the pancreatic tail (139, 285). Other, less common sites of origin are the adrenal, retroperitoneum, mediastinum, lung, and jejunum (285, 286). Primary tumors are usually large, greater than 2 cm, and 50–60% of pancreatic VIPomas have already developed metastases, mainly to the liver and lymph nodes, at the time of diagnosis (285). VIPomas can also be of neural origin (10–12%), mostly in children as ganglioneuromas, ganglioblastomas, or neuroblastomas (139, 287). In contrast to pancreatic VIPomas, in neurogenic VIPomas the presence of metastases is much less common (29%) and mainly involves the lymph nodes (285). Occasionally carcinoid tumors, pheochromocytomas, and bronchogenic carcinomas may be associated with VIP secretion (287). VIPomas can be multifocal in 4%, and in 8.7% there is an association with MEN I (285).
Severe watery diarrhea is a universal symptom of the syndrome (285, 286). The diarrhea is secretory in nature, typically unremitting with fasting, intermittent in 53%, and continuous in 47% of cases (139). When the diarrhea is intermittent, there is usually a delay in making the diagnosis (286). Patients typically produce more than 3 liters of watery stool per day with a range up to 30 liters/d. Chronic diarrhea is associated with severe fluid and electrolyte (mainly potassium and bicarbonate) loss with subsequent marked asthenia, cramps leading to tetany and cardiac alterations, and even sudden death (139). Hypokalemia is often severe (K+ < 2.5 mEq/liter, losses > 400 mEq/d), paradoxically associated with low bicarbonate levels due to severe intestinal loss; this results in severe hyperchloremic acidosis (286). Hypophosphatemia and hypomagnesemia are also apparent, although a number of patients have associated hypercalcemia (285). Other symptoms include carbohydrate intolerance (50%) and facial flushing in up to 20% of patients, secondary to a direct vasodilatory action of VIP (285, 287). Achlorhydria or hypochlorhydria is present in over two thirds of the patients (285). The diagnosis is based on the presence of secretory diarrhea in association with raised fasting VIP levels in the presence of a pancreatic or other lesion associated with VIP production (285). In the early stages of the disease or in the presence of intermittent symptoms, random VIP levels may be normal (288). In these instances the diagnosis is obtained when VIP measurements are performed in the presence of diarrhea; in addition, other endocrine causes of secretory diarrhea, such as the CS, gastrinoma and MTC, or laxative abuse, should be considered (Ref. 286 ; also see Ref. 289).
e. Somatostatinoma.
Somatostatinomas are rare tumors of either the pancreas or the small intestine, mainly the duodenum, with an estimated incidence of one in 40 million per year; approximately 200 cases have been reported according to a recent review (290). SS exerts a general inhibitory function on exocrine and endocrine secretions and bowel motility, which is shown as suppression of hormonal secretion and bowel-related functions (transit, motility, and absorption), a so-called inhibitory syndrome (139, 290). In contrast to other functional pancreatic tumors, somatostatinomas are characterized by a relatively low incidence of a hypersecretory syndrome and association with the MEN I syndrome, whereas they are more commonly associated with NF1 and pheochromocytomas, suggestive of an inherited endocrinopathy (139, 290).
Pancreatic somatostatinomas are usually large (85.5% greater than 2 cm; average diameter, 5.1 cm) and associated with local symptoms and/or symptoms of excessive SS secretion; commonly, these tumors may demonstrate features of multisecretory activity (33.3%) (290). Symptoms related to SS hypersecretion are found in approximately 11% of patients with somatostatinomas: hyperglycemia (95%), cholelithiasis (68%), diarrhea (60%), steatorrhea (47%), and hypochlorhydria (26%) (290). Abdominal pain, weight loss, and anemia are nonspecific symptoms most probably related to the size of the tumor and its malignant potential (290, 291). These tumors, when not specifically looked for, are usually found late between the fifth and sixth decades of life, either at the time of exploratory laparotomy or during various imaging studies (290, 291).
The majority of extrapancreatic somatostatinomas are found in the duodenum but can also occur in the jejunum, cystic duct, colon, and rectum (290, 291, 292). Their presenting features are mostly related to local effects of the mass rather than the systemic effects of SS, whereas the majority are diagnosed serendipitously during endoscopic procedures (290, 292). Most duodenal tumors are located near the ampulla of Vater and may be associated with obstruction of the bile duct (39%), pancreatitis, and GI bleeding (292). These tumors usually are not associated with a secretory syndrome (2.5% compared with 18.5% of pancreatic tumors), although diabetes and cholelithiasis have occasionally been described (292, 293). Duodenal somatostatinomas tend to be smaller (58.6% smaller than 2 cm), with psammoma bodies and multisecretory activity when they are associated with von Recklinghausen disease in 43.2% (290). The diagnosis is established by demonstrating elevated SS levels in a patient with a relevant history and the presence of a pancreatic mass; duodenal somatostatinomas may not be associated with abnormal SS levels or secrete abnormally high molecular weight forms of SS (294). In a review of 173 cases reported in the literature (290), no statistically significant difference in the rate of metastases and malignancy was detected between pancreatic and extrapancreatic tumors. The overall 5-yr survival rate is 75%, or 60% when metastases are present (Ref. 290 ; also see Ref. 295).
f. Rare forms of islet cell tumors.
Other rare tumors have also been reported (109). Most prevalent among them are ACTHomas (110 cases reported), GRFomas that can be associated with acromegaly (50 cases), neurotensinomas (50 cases), and parathyrinomas (35 cases) (109). Very rarely, pancreatic tumors secreting calcitonin, enteroglucagon, CCK, gastric inhibitory peptide, LH, gastrin-releasing peptide (GRP), and ghrelin have also been described (109, 296, 297). Rare forms of islet cell tumors may raise diagnostic difficulties due to their multiple and occasionally fluctuating hormonal production and release (109).
g. Nonfunctioning tumors and PPomas.
These tumors account for about 20% of all endocrine pancreatic tumors and are not associated with clinical syndromes caused by hormonal hypersecretion (298). They are most often diagnosed in the fifth to sixth decades of life and are mainly situated in the pancreas rather than the duodenum (139, 298, 299, 300). Their clinical silence may be related to inactive hormonal production, cosecretion of peptide inhibitors, or down-regulation of peripheral receptors (139, 301). These tumors are usually large and are diagnosed either as incidental findings or by symptoms caused by an expanding mass or metastases because approximately two thirds are truly malignant; except when associated with MEN I in approximately 20–30% of cases, nonfunctioning pancreatic tumors are generally unifocal (178, 299, 300, 302). Histologically, they demonstrate positive immunohistochemistry for insulin (50%), PP (40%), glucagon (30%), or SS (13%) (139, 301). Recently, it has been shown that two subgroups of nonfunctioning tumors exist, each accounting for 50% of cases; one shows a large number of chromosomal derangements, which are a strong independent adverse prognostic factor, whereas the other lacks any (188, 303). Overall 5- and 10-yr survival rates of 65 and 49%, respectively, have been described (299, 300, 302). Although tumors derived from PP cells are clinically silent, there are rare exceptions of PPpomas associated with diarrhea, diabetes mellitus, and weight loss; 55 of such cases have been described (109). Because the majority of these tumors are clinically silent, differentiation from the more aggressive pancreatic adenocarcinomas should always be considered. Lack of tumor hypervascularization with resulting contrast enhancement on CT scanning and negative scintigraphy with 111In-octreotide are more in favor of adenocarcinomas (304). Histopathology is usually diagnostic, but in cases of doubt specialist pathological advice should be sought. It should be noted that pancreatic adenocarcinomas may occasionally have NE elements intermingled with more typical adenocarcinoma cells (see Section II).
h. Pancreatic islet cell tumors in MEN I.
The prevalence of enteropancreatic tumors in MEN I varies from 30–75% and approaches 80% in necropsy series (20, 275). These tumors can be found in any part of the pancreas or at the duodenum; they are multicentric, benign or malignant, micro- or macroadenomas, and less often present as hyperplastic lesions (20, 305). Although patients usually present with hormonal symptoms by the age of 40 yr, they can be diagnosed earlier during screening of individuals at risk; however, malignancy (although it may be present in an occult form) rarely presents before the age of 30 yr (20, 275). These tumors display a variety of elevated tumor markers that can change with time (275) but cannot reliably identify the patients at risk for the development or progression of malignant disease (20). Gastrinomas, followed by insulinomas, are the most common functioning pancreatic islet cell tumors related to MEN I, and approximately 50% may have metastasized before diagnosis (20, 305, 306). However, in younger patients, an insulinoma may be more frequently seen. Pancreatic primary lesions, the presence of metastases or ectopic Cushing’s syndrome, and the height of gastrin level are correlates of a poor prognosis (20, 305, 306). Nonfunctioning tumors occur in virtually all patients who have had adequate screening; at the time of the onset of symptoms, half of the patients have malignant disease (307). Early tumor recognition depends on biochemical screening; however, there is a wide variation of investigations that may be performed (20). Measurement of gastrin, insulin/proinsulin, PP, glucagon, and CgA is associated with a sensitivity of approximately 70%; this can be further increased with - and ß-hCG subunits and VIP and measurement of gastrin and PP after a meal stimulation test (20, 275, 308, 309). It has been shown that lesion size is not a useful indicator of malignant transformation, although patients with larger tumors are more likely to harbor liver metastases; furthermore, survival in ZES patients with MEN-I is closely similar to survival in sporadic cases, suggesting that the malignant potential is the most important cause of death-related disease (113, 275). Therefore, it has been suggested that early surgical resection may reduce the risk for malignant progression and future dissemination (307, 310). Patients with MEN I should always be investigated for the presence of a thymic carcinoid (155).
2. Imaging islet cell tumors.
Recently, several prospective studies have investigated the relative utility of currently available techniques and helped to establish a diagnostic work-up on evidence-based information (93, 105, 178, 222, 224, 311, 312, 313, 314). Because of its high sensitivity and its ability to obtain whole body images, we consider that scintigraphy with 111In-octreotide is the initial imaging procedure of choice for GEP tumors; however, conventional noninvasive and occasionally invasive diagnostic modalities may still be required (6, 118, 162).
a. Radionuclear imaging.
Several studies, including some prospective ones, have shown that 111In-octreotide is more sensitive than any other single conventional method used to localize a gastrinoma or identify hepatic metastases (93, 223, 224, 315, 316, 317, 318), although even this may still miss up to 30% of gastrinomas ultimately detected on surgical exploration (53, 93, 162, 316). In another prospective study, 111In-octreotide altered the management in many patients with gastrinomas by successfully locating the primary tumor and clarifying equivocal localization results obtained by other imaging modalities (224). The ability of all conventional imaging modalities to visualize primary lesions is limited when the tumor size is less than 1 cm, and they will thus miss many duodenal gastrinomas (162, 268). Scintigraphy with 111In-octreotide detects 30–75% of gastrinomas measuring less than 1.1 cm, primarily small duodenal gastrinomas, and almost all that are larger than 2 cm (316, 317). A negative scan in the presence of a visible tumor suggests either a poorly differentiated NET or a pancreatic adenocarcinoma (304). Imaging with 123I-MIBG has a poor sensitivity in identifying islet cell tumors and should not generally be used in cases with negative 111In-octreotide scintigraphy (99). PET using 11C-5-HTP, due to selective uptake in tumor tissue compared with surrounding tissue, produces very good tumor visibility; it can be used for the examination of both the thorax and abdomen and has been shown on several occasions to be superior to scintigraphy with 111In-octreotide (104). However, the lack of general availability and the high cost limit its extensive use (104, 319). Intraoperative radionuclear imaging can be used to help define the exact location of a biochemically proven NET and aid in its complete resection (319).
b. Ultrasonography.
Transabdominal ultrasound exhibits a detection rate for insulinomas and gastrinomas between 25–70% and 30%, respectively (240, 313, 320, 321). Detection rates are better for lesions greater than 3 cm in diameter and are relatively poor for lesions smaller than 1 cm; however, these rates may improve considerably with the application of modern high-resolution real-time ultrasound (313, 321).
EUS allows the positioning of a high-frequency (7.5–10 MHz) transducer in close proximity to the pancreas (313). Lesions as small as 5 mm and gastrinomas located in the bowel can be detected with this technique (322). Although there is a potential "blind-spot" at the splenic hilum, sensitivities as high as 79–82% have been obtained (235, 239, 240, 322, 323). A recent single-center prospective study revealed a sensitivity of 93% and a specificity of 95% in the localization of intrapancreatic lesions (324); EUS detected all tumors visualized by any other conventional technique (excluding scintigraphy with 111In-octreotide), calling into question the necessity for these other imaging modalities (162, 325). EUS can identify approximately half of these tumors and, in combination with 111In-octreotide, up to 69%, although it may still miss up to 50% of duodenal gastrinomas (162, 326). Particularly for gastrinomas, a negative EUS of the pancreas invariably predicted an extrapancreatic location (324).
Intraoperative ultrasound (IOUS) also allows direct high-resolution examination of the pancreas (313); the combination of IOUS and surgical palpation has led to 97% cure rates in patients with benign insulinomas (240). The overall sensitivity for gastrinomas is 83%, with 100% of intrapancreatic and 58% of extrapancreatic lesions detected in a large series (162). Although IOUS does not substitute for preoperative localization of islet cell tumors, it facilitates surgical resection and, in patients with MEN I, can help define the appropriate plane of resection by identifying multiple small tumors (313).
c. CT and MRI.
The majority of islet cell tumors are isodense on unenhanced CT and will not be seen without iv contrast enhancement, appearing then as hypervascular lesions (93, 235, 313). Dual-face helical CT scan allows multiphase imaging during a single bolus of contrast administration and can achieve sensitivities in the range 82–92% (320, 327, 328). Reviewing most recently published series using T1-weighted fat suppression images, MRI identified 71 of 78 lesions, a 91% sensitivity in 57 islet cell tumors (311, 312, 329, 330). A comparative study showed that the sensitivity of T1-weighted MRI is equivalent to delayed dynamic CT (311). MRI is considered the most sensitive technique for demonstrating liver and bone metastases in patients with NETs and is recommended for precise monitoring of response to therapy (331).
d. Invasive imaging techniques.
In cases of small insulinomas not detected with the previously mentioned imaging modalities, invasive procedures may still be necessary to achieve preoperative localization (332). Sensitivities between 77 and 100% have been described for transhepatic portal venous sampling, but this technique is associated with a not inconsiderable morbidity (332, 333). Selective arterial calcium stimulation and hepatic venous sampling (ASVS) using calcium as the insulin secretagogue is a powerful tool for the preoperative localization of occult insulinomas and can also help distinguish the rare forms of NIPHs (240, 247, 249, 254, 257). In particular, it allows for correlation of anatomical imaging abnormalities with functional changes and is particularly helpful in MEN I when several anatomical changes may be identified and it is vital to know which are functionally relevant. After successful catheterization of gastroduodenal (supplying the head of the pancreas and uncinate process), superior mesenteric (supplying the body and tail), splenic (tail of pancreas), and hepatic (supplying the liver) arteries, a greater than 2-fold rise in insulin is required to localize an insulin-secreting tumor in the portion of the pancreas supplied by the artery studied (253). In a recent series of 11 patients, a sensitivity of 100% was obtained with this technique, which may also identify rare extrapancreatic insulin-secreting NETs, mainly of the liver (93, 332). Hepatic venous sampling after selective injection of secretin is a more sensitive study than portal venous sampling in localizing extrapancreatic and duodenal gastrinomas (334), but will probably now be replaced by calcium stimulation.
3. Diagnostic protocols.
Because of its sensitivity and high specificity, its ability to alter management and image all areas of the body at once, we consider that the initial investigation of choice for the diagnosis of functional (except insulinomas) and nonfunctional endocrine pancreatic tumors should be scintigraphy with 111In-octreotide (53, 89, 99, 178, 222, 223, 224). When a gastrinoma is suspected, endoscopy or EUS should also be performed to identify duodenal as well as pancreatic gastrinomas, especially when multiple lesions are suspected as in MEN I (139, 162). In patients with positive 111In-octreotide scintigraphy, further imaging may be applied to delineate the exact anatomic margins of the tumor and local spread of the disease (178, 222). CT and MRI are also very sensitive and specific methods in demonstrating hepatic metastases and pancreatic tumors, and they show specific advantages in routine tumor staging and monitoring of therapy (178, 222, 223). EUS is the most sensitive method for the precise delineation of pancreatic lesions (317, 326). For MEN I patients with positive scintigraphy with 111In-octreotide, further investigation for other associated lesions is warranted (222, 335). Because fewer than 60% of insulinomas express SS receptors and the great majority are located in the pancreas, endoscopic ultrasonography is regarded as the most sensitive method for tumor (324, 336) localization; helical CT and MRI may also be helpful (325). However, scintigraphy with 111In-octreotide may also be needed in cases of malignant insulinomas because these tumors more often demonstrate SS receptors (222). When scintigraphy with 111In octreotide is negative, areas within a high prevalence of metastases should be investigated (222). Currently, the intraarterial calcium stimulation test remains the only invasive functional study in frequent use: it may help recognize sporadic or MEN I-related occult tumors, it aids in the correlation of anatomic abnormalities with functionality, and it facilitates the differential diagnosis from NIPH (247, 333, 337).
C. Chromaffin cell tumors (pheochromocytomas and paragangliomas)
Pheochromocytomas and paragangliomas are NETs arising from chromaffin cells that can occur in either sporadic or familial forms. Pheochromocytomas are chromaffin cell tumors arising from the adrenal medulla (338, 339). Paragangliomas are chromaffin cell tumors derived from the paraganglia that can be of either sympathetic (localized mainly in the retroperitoneum and thorax) or parasympathetic origin (occurring adjacent to the aortic arch, neck, and skull base); approximately 5% of head and neck paragangliomas and 50% of abdominal paragangliomas are hormone-producing (340). Pheochromocytomas occur with an estimated incidence of one to eight cases per million per year; they represent 0.5% of patients tested for hypertension and suggestive symptoms and 4% of patients presenting with adrenal incidentalomas (115, 341, 342, 343). However, the incidence of pheochromocytomas increases continuously with advancing age, although a significant number (>50%) are first diagnosed at autopsy, a prevalence of pheochromocytoma of about 0.1%, having escaped diagnosis in life (342, 344).
Chromaffin cell tumors generally obey the rough rule of 10: about 10% are malignant, 10% are familial, 10% are not associated with hypertension, 10% are extraadrenal, 10% are bilateral, and 10% occur in children (344, 345, 346). However, with more extended follow-up, the application of sensitive biochemical tests, and scintigraphy with MIBG, it has been established that the number of malignant chromaffin cel1 tumors is probably higher, ranging from 13–26% (347, 348, 349, 350). In addition, using genetic analysis, it has been suggested that the incidence of patients with familial disease may also be higher than previously considered (21). Bilateral or multifocal chromaffin cell tumors are found most frequently in familial syndromes, either as an isolated trait with an autosomal mode of inheritance or in association with other tumors in the autosomal dominant MEN syndromes (351). In the MEN IIA and MEN IIB syndromes, there is a roughly 30–50% prevalence of pheochromocytomas and chromaffin cell tumors (352, 353). There is also an association of pheochromocytomas with the VHL syndrome (15–20%), NF1 (1–5%), and possibly also with Carney’s syndrome (344, 354). The catecholamines (epinephrine, norepinephrine, and dopamine), widely distributed biogenic amines, are the main secretory products of chromaffin cells (115). Patients with chromaffin cell tumors present with a diversity of symptoms that have been attributed to the catecholamine release as well as to a variety of cosecreted active metabolic substances (115, 342). Pheochromocytomas primarily secrete norepinephrine and sometimes epinephrine; however, dopamine-secreting and nonfunctioning pheochromocytomas have also been described (355). The only definite criterion to ascertain malignancy is the presence of metastases at sites where chromaffin tissue is normally absent; the most common metastatic sites are the skeleton (>50%), liver (50%), and lung (30%) (Refs. 111 , 115 , 344 , and 355 ; also see Refs. 342 , 343 , and 356).
1. Clinical presentation and biochemical diagnosis.
Many patients with a functioning chromaffin-secreting tumor present with the classic triad of episodic headache, palpitations, and profuse sweating (111, 357). Hypertension is the foremost clinical manifestation and presents either as sustained, with or without paroxysms, or paroxysmal hypertension with intervening normotension (111, 357). The presence of hypertension with the classic triad of symptoms should suggest the diagnosis of a catecholamine-secreting tumor (115, 355). Other common but less characteristic clinical symptoms and signs include tremor, nervousness and anxiety, weakness, nausea, vomiting, flushing, paresthesia, constipation, weight loss, fever, and chest or abdominal pain (357). However, a considerable number of chromaffin cell tumors may be asymptomatic with a normal blood pressure and may be diagnosed either at autopsy or while investigating an incidentally discovered adrenal mass (358). Attacks can occur spontaneously or be precipitated by exercise, increases of intraabdominal pressure, medication, or general anesthesia (115, 355). The pressor crises are associated with a significant morbidity and occasionally mortality (359). In a proportion of patients, cardiac manifestations predominate, with chest pain, angina pectoris, myocardial infarction, and myocarditis (Ref. 344 ; also see Ref. 342).
The diagnosis is usually established with the documentation of high catecholamine levels. In the past, this was sought through the measurement of elevated urinary catecholamine metabolites, vanillyl mandelic acid, and metanephrines. Vanillyl mandelic acid measurement has a sensitivity of only 63% but can be useful in detecting large tumors with abnormal catecholamine metabolism such as neuroblastomas or malignant chromaffin cell tumors (360, 361). Urinary metanephrine excretion has a higher sensitivity and specificity (76 and 94%, respectively), but measurement of urinary free catecholamines offers more than 90% sensitivity, although with some loss in specificity, and is currently widely used (360). Adjustments have to be made with respect to renal function; multiple urine collections have to be undertaken, particularly if the patient is suffering from intermittent symptoms (344, 360). Elevated plasma catecholamines have a sensitivity of 85% and a specificity ranging from 80–95%, according to the threshold taken, whereas CgA has been reported to exert a sensitivity of 83% with an acceptable specificity for the diagnosis of a chromaffin cell tumor (344, 360, 361). The combination of urinary free catecholamines and metanephrines usually suffices to diagnose most patients (355, 357), although the combination of resting plasma catecholamines and total urinary metanephrines gives a false negative rate of 2.7% (115). Recently, measurement of plasma metanephrines was claimed to offer a 99% sensitivity in detecting a secretory chromaffin cell tumor, and it is also associated with the highest sensitivity at 100% specificity in reaching such a diagnosis (360), although this is not universally accepted (342, 343). The catecholamine response to the combination of glucagon stimulation and clonidine suppression tests that have been used to increase the sensitivity in the presence of equivocal results are currently used very seldom (115, 342, 360). A number of hormones have been described in patients with functioning catecholamine-secreting tumors. Secretion of ACTH is associated with Cushing’s syndrome; substance P, tachykinins, and histamine with hypotension; VIP and calcitonin gene-related peptide (CGRP) with flushing; and opioids with constipation (Ref. 344 ; also see Refs. 342 and 361).
Malignant chromaffin cell tumors are larger than benign ones (average diameter, 8.8 cm vs. 4.2 cm, respectively) (355), and although traditionally the extraadrenal forms were considered more malignant than adrenal tumors, this has recently been questioned (351, 355). Chromaffin cell tumors are less likely to be malignant in patients with familial syndromes, whereas they are more likely to be malignant in patients with a family history of a malignant tumor (20, 355). However, the clinical behavior of malignant chromaffin cell tumors may be highly variable, with 5-yr survival rates ranging from 36–74% (353, 362). The 3-yr survival rate was found to be 73%, with the majority of cases diagnosed at first presentation (363). Markedly elevated CgA levels point toward malignant chromaffin cell tumors (Ref. 364 ; also see Refs. 365 and 366).
2. Localization studies: screening in familial forms
a. Imaging of pheochromocytomas and paragangliomas.
Having established the diagnosis of a chromaffin cell tumor, the next step is to document the extent of the disease and whether the tumor occurs as part of a familial or a sporadic form of the disease, and then to determine tumor biology and extent. Because more than 90% of chromaffin cell tumors are intraabdominal, approximately 90% are located in the adrenals, and the great majority are larger than 2 cm, CT imaging demonstrates a 93–100% sensitivity for detecting adrenal tumors and 90% sensitivity for detecting extraadrenal tumors (351, 357, 360). Most tumors enhance markedly after iv contrast medium; nonionic contrast medium does not usually require previous -adrenoceptor blockade (367). MRI exerts equal sensitivity to CT in detecting adrenal tumors but is superior in detecting extraadrenal tumors (351, 368). Most pheochromocytomas are hypointense on T1-weighted images and markedly hyperintense on T2-weighted images; although typical, these appearances on T2-weighted images are not specific (368). However, both techniques have inferior specificity, which is particularly important due the high frequency of non-pheochromocytoma-related adrenal masses (369). Scintigraphy with 123I-labeled MIBG offers superior specificity, especially for familial and malignant lesions (95–100%), and a sensitivity approximating 90%; however, more than 10% of tumors can still be nondemonstrable with this technique (360). Because chromaffin cell tumors often express SS receptors, scintigraphy with 111In-octreotide can be used to increase sensitivity, particularly in cases of 123I-MIBG negative lesions (99). In cases where clinical and biochemical suspicion is high and all imaging studies have failed to demonstrate a lesion, venous catheterization of the adrenal or other suspected sites is performed with sampling for measurement of both epinephrine and norepinephrine, and their ratio is calculated; high epinephrine/norepinephrine levels suggest a normal adrenal (344, 370). PET, originally with FDG and 11C-hydroxyephedrine and more recently with 6-[18F]-fluorodopamine, has been shown to be highly sensitive, and on several occasions better than other established methods, demonstrating almost 100% sensitivity and specificity; when widely available, it has been claimed that PET will become the imaging modality of choice (22, 371).
b. Familial chromaffin cell tumors and genetic screening.
Recent advances in genetics have contributed to early diagnosis and screening in cases of familial chromaffin cell tumor manifestation in MEN types IIA and IIB by early screening of the relatives; VHL kindreds are absent in the type I phenotype but are the sole manifestation in type 2C families (21, 28). Recently, it was shown that germline mutations in three of the succinate dehydrogenase (SDH) mitochondrial complex II subunits (SDHD, SDHB, and SDHC) cause susceptibility to chromaffin cell tumors (372). It has been reported that 84% of all multifocal tumors (including bilateral tumors) and 59% of tumors with onset at the age of 18 yr or younger, particularly extraadrenal pheochromocytomas, may be associated with hereditary disease (21); in such cases counseling should be readily available. Somatic RET mutations have been described in 10% of sporadic pheochromocytomas and VHL mutations in approximately 3% (28, 373, 374). Although it has recently been suggested that RET, VHL, and SDHD mutations together may account for 15–24% of nonfamilial presentation of pheochromocytoma (21, 352), this is not widely accepted (28, 373), and we therefore cannot recommend their routine screening in apparently sporadic chromaffin cell tumors. When uncertainty regarding the malignant nature of the tumor remains, elevated telomerase and/or c-myc and decreased or absent neuropeptide Y activity and inhibin/activin ß-subunit have been suggested to be indicative of malignant pheochromocytoma (355, 375, 376, 377, 378).
D. Medullary thyroid carcinoma
MTC is a rare calcitonin-secreting tumor of the parafollicular or C cells of the thyroid (110). MTC occurs in both sporadic and hereditary forms; although it accounts for only 3–10% of all thyroid carcinomas, it is responsible for up to 13.4% of all deaths (110, 379, 380, 381). The familial (hereditary) variety of MTC is inherited as an autosomal dominant trait with a high degree of penetrance (379). There are three distinct hereditary varieties of MTC: 1) MEN IIA syndrome (90% of the cases of MEN II syndromes), characterized by MTC in combination with pheochromocytoma and tumors of the parathyroids; 2) MEN IIB syndrome, characterized by MTC, pheochromocytoma, ganglioneuromatosis, and a marfanoid habitus; and 3) FMTC, without any other endocrinopathies.
A germline mutation in the RET protooncogene predisposes individuals to develop MEN II and FMTC (381). These varieties of FMTC are clinically distinct from each other with respect to incidence, genetics, age of onset, association with other disease, histopathology, and prognosis. The majority of patients (75%) have sporadic MTC (379), which usually occurs in the fifth decade of life, whereas hereditary disease is usually diagnosed earlier, depending on biochemical or genetic screening (379, 381). MTC synthesizes and secretes large amounts of calcitonin as well as a number of other substances such as CGRP, CEA, NSE, CgA, and ACTH (382, 383); however, none of these tumor markers has the sensitivity and specificity comparable to calcitonin. Calcitonin is secreted in all cases of clinically palpable MTC, whereas normal basal calcitonin levels are usually found in very small tumors and cases of C cell hyperplasia (382). Pentagastrin has been used extensively as a provocative agent for calcitonin secretion for the identification of both subclinical MTC and gene carriers in families at risk (379, 381); in addition, the combined calcium and pentagastrin infusion test has been proposed to potentiate the secretagogue stimulus for calcitonin (384). Recently, however, genetic screening has been progressively replacing biochemical tests (Refs. 379 and 381 ; also see Refs. 385 and 386).
1. Clinical presentation and biochemical diagnosis.
The majority of patients with sporadic MTC (70%) initially present with a thyroid nodule or mass, occasionally accompanied by cervical lymphadenopathy; when a thyroid nodule is palpable, cervical lymph node metastases are present in at least 50% of patients (355, 387). Occasionally, there may be symptoms of ectopic hormone production such as diarrhea, facial flushing, and (rarely) Cushing’s syndrome (379, 381). The correct diagnosis is usually obtained from cytological diagnosis or by plasma calcitonin measurements (383). Preoperative calcitonin levels correlate with tumor size (388) and are usually above 100 pg/ml in the presence of clinically significant disease; a stimulation test may be used in suspicious cases with normal calcitonin levels (388, 389). Although routine measurement of serum calcitonin has been advocated in all patients presenting with thyroid nodules, it is not yet clear whether this represents a cost-effective method (390). Variable loss of calcitonin synthesis and secretion with or without an increase in CEA may indicate a dedifferentiation and a more aggressive form of MTC (6, 40). The discovery of a MTC in a patient has several diagnostic implications involving a specific strategy: these include preoperative evaluation of the extent of the disease, classification of MTC as sporadic or hereditary by DNA testing, and screening for associated endocrinopathies in hereditary MTC.
2. Screening of familial forms and localization studies
a. Screening.
Traditionally, first-degree relatives of patients with MTC were tested with the pentagastrin stimulation test to identify asymptomatic members necessitating prophylactic thyroidectomy; however, calcitonin results were occasionally borderline and difficult to interpret (383). The preferred current method is genetic screening; if a RET mutation is identified, then all family members should be offered testing for the same mutation (20, 391). Family members without the RET mutation are reassured and informed that no further tests are necessary for either them or their offspring (20, 383). When FMTC is suspected and no mutation is detected in a given patient, genetic linkage analysis may be performed to evaluate family members at risk (391). Once gene carriers are identified, prophylactic thyroidectomy can be offered, which, in these patients, is curative if carried out at a young enough age.
b. Disease localization after initial diagnosis.
Before surgery, ultrasound of the neck or MRI of the neck and mediastinum should be performed (381). A CT scan of the liver and the lung is also needed before surgery to identify any evidence of metastases, although these may be miliary (381). MTC is characterized by its early lymph node metastatic spread, in approximately 50%, and even micro-MTC (<10 mm) may cause clinically detectable cervical lymph node metastasis in 10% of cases (388).
c. Localization of residual or recurrent disease.
After thyroidectomy, patients are initiated on T4 replacement therapy and have their calcitonin levels assessed within the next few months. Ideally, patients who have been treated with total thyroidectomy with neck dissection should have low or undetectable calcitonin levels (392, 393), using the more sensitive immunoradiometric assay methods (392). Patients with postoperative normalization of calcitonin and/or CEA levels are commonly considered surgically cured (110, 382). However, stimulated peak plasma calcitonin levels are more useful than basal levels in detecting occult disease after thyroidectomy (379, 381). Using molecular detection of disseminated tumor cells in cervical lymph nodes with cytokeratin 20 RT-PCR, a higher percentage of involved lymph nodes was detected compared with immunohistochemistry, suggesting more extensive residual disease (394). However, the prognostic value of minimal residual disease in MTC has yet to be confirmed in prospective studies.
In patients with residual or recurrent disease, further evaluation should be performed by means of high-resolution ultrasonography with or without fine-needle aspiration, CT, and/or MRI; however, their sensitivity in detecting minimal residual disease is substantially reduced (383). Scintigraphy with 131I-MIBG and 111In-octreotide has shown a sensitivity of 35–50% and 50–75%, respectively (54, 72, 99); 111In-octreotide has been shown to be more sensitive than MRI scanning in detecting occult MTC recurrence (395), and scintigraphy with these radionuclides will also visualize chromaffin cell tumors in MEN patients (396). Although it was originally suggested that scintigraphy with 99m-technetium-dimercaptosuccinic acid is sensitive in identifying both bone and soft tissue metastases, these results have not been consistently reproduced (382). Similarly, immunoscintigraphic procedures using radiolabeled monoclonal antibodies, with either calcitonin or CEA, have been reported to show considerable sensitivity but are still considered experimental investigations (382, 397). Selective venous sampling catheterization with or without pentagastrin stimulation has shown encouraging results for the localization of occult disease in individual patients (398). Diagnostic laparoscopy of the liver may demonstrate small deposits of metastatic MTC in a number of patients with negative imaging studies, but this procedure is not widely used (399). More recently, FDG PET has been shown to be promising, although comparisons with other imaging techniques are still lacking (400).
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VII. Medical Management of Advanced Neuroendocrine Tumors |
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TopAbstractI. IntroductionII. Histopathological...III. Tumor BiologyIV. Tumor Markers in...V. Natural History of...VI. Clinical Presentation,...VII. Medical Management of...VIII. Summary and Final...References |
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Before applying any kind of therapy, the possibility of an MEN I syndrome should always be considered in patients with GEP, particularly pancreatic tumors, whereas the possibility of MEN II syndrome should be entertained in patients with chromaffin cell tumors and MTC (113, 344, 383). Such an approach is important because there is considerable difference in the management of these tumors when they occur as part of the MEN syndromes (20, 109, 113, 383). In addition, tumor biology is currently becoming a powerful determinant of the form of medical treatment because it may correlate with the natural history of the disease (109). Uniform criteria to assess responses to treatment are also necessary to establish specific management guidelines (5, 404).
Patients’ responses to therapy should be divided into symptomatic, hormonal, and tumor responses (59, 409, 410). Tumor responses are classified according to WHO criteria as: 1) complete response, complete regression of all clinical and hormonal evidence of tumor, including radiological abnormalities; 2) partial response, a 50% or greater reduction of all measurable tumor and no appearance of new lesions, including hormonal and symptomatic improvement; 3) stable disease, a less than 50% reduction or no greater than 25% increase of tumor size, hormonal measurements, and symptoms; and 4) progression, appearance of new lesions or an increase of 25% or more of tumor size, and hormonal and symptomatic deterioration. Patients are reviewed at 3- to 6-month intervals; review assessment comprises clinical, biochemical, and radiological evaluation. The rationale of applying further treatment at these time intervals is contingent upon the relative prolonged replication period of these tumors (79, 116).
B. Symptomatic treatment of GEP tumors
GEP tumors associated with clinical syndromes related to specific hormonal production are currently best managed with SS analogs (61, 411, 412). Before the availability of SS analogs, several therapies directed to specific hormonal production were used, with the goal of improving symptoms and the quality of life (413). Some of these therapies may still be necessary either when symptoms become refractory to SS analogs or in combination with them (61, 401, 405, 414).
1. CS.
Because flushing and diarrhea may be associated with particular precipitants, lifestyle adjustments may be required; patients should avoid known precipitants such as alcohol, spicy foods, and strenuous exercise (52). Diarrhea in patients with CS is not always the consequence of excessive hormonal secretion because occasionally it may deteriorate or even start after surgical resection of the primary tumor, mainly in the terminal ileum (59, 405). In such cases, the diarrhea is secondary to bile acid loss and/or increased bacterial contamination of the small intestine with subsequent deconjugation of bile acids; cholestyramine is the treatment of choice for the former case, and antibiotics for the latter (405, 411). Patients with histamine-producing tumors and the atypical CS should avoid histamine-liberating drugs and optimally be pretreated with SS analogs, blockade of histamine receptors, and possibly corticosteroids (405, 411). A number of other agents active in the CS were used in the pre-SS analog era; their mode of action has been extensively reviewed in the past (60, 402, 413). Among them, loperamide, mainly in combination with SS analogs, may still be of great value (59). Combination vitamin B replacement should be administered in patients with severe disease and suspicion of pellagra, and indeed we use compound vitamin B replacement in all patients with CS.
2. Pancreatic tumors
a. Insulinoma.
These tumors are the least sensitive to treatment with SS analogs (61). Diazoxide at doses of 50–300 mg/d (but up to 600 mg/d) usually diminishes insulin secretion and is the most effective drug for controlling hypoglycemia; it can cause marked edema, renal impairment, and hirsutism (59, 405). Verapamil (a Ca+2 blocker), glucocorticoids, and phenytoin have also been used, although less effectively (60, 246, 250). In refractory cases, glucocorticoids such as prednisolone or high doses of synthetic GH can be effective (255).
b. Gastrinoma.
The introduction of H2-receptor antagonists and, later, H+-K+-ATPase (proton pump) inhibitors has replaced surgery in many cases and has markedly improved the therapeutic strategies for the management of gastric acid secretion and its sequel in patients with ZES (59, 60, 405). Proton pump inhibitors are currently the therapeutic agents of choice for short- and long-term control of gastric acid secretion (59, 61, 405, 415). Gastric acid secretion is best controlled by a mean morning dose of 40–80 mg of omeprazole or an equivalent dose of other similar compounds; if higher doses are required, they should be given every 12 h (415), and patients should be on these medications indefinitely (59, 61, 405, 411). Although H2-blockers are also capable of controlling gastric acid hypersecretion effectively, they have for the most part been superseded by proton pump inhibitors (59, 61, 405).
c. Glucagonoma.
NME responds to SS infusion irrespective of alterations in glucagon levels or normalization of previously low amino acid levels (416). Because surgical resection may be considered even if the tumor is metastatic, it is important to correct hypoaminoacidemia and mineral deficiency, control diabetes, and administer low-dose heparin to decrease the risk of thrombosis; SS analogs preoperatively have also been advocated (277).
d. VIPoma.
Several antidiarrheal drugs, indomethacin, and lithium can be used, but they seldom control the diarrhea effectively. Glucocorticoids are usually highly effective, however, and can produce a 40–50% reduction in VIP levels (286, 405). They may best be used for acute exacerbations, with SS analogs being the mainstay for chronic control (286, 405).
e. Somatostatinomas.
There is no specific treatment for somatostatinomas besides administration of SS analogs that inhibit SS secretion from the tumor.
C. Systemic treatment of GEP tumors
Systemic medical treatment of GEP tumors includes treatment with biological agents [SS analogs, interferon (INF)-], chemotherapy, and variations of these forms of therapy (5, 417, 418, 419). However, the results of published trials are often obscured by the rarity of GEP tumors, a lack of precise knowledge of the natural history, a paucity of prospective studies with large numbers of patients, and the lack of uniform criteria for assessing response to treatment (59, 113, 420, 421). GEP tumors can exhibit long phases of spontaneous tumor standstill, spontaneous regression even without treatment, or explosive growth (405). Once progression of disease becomes clinically detectable, however, the pace of clinical deterioration appears to increase (420). It is hoped that the incorporation of markers of tumor biology in the diagnostic workout of these tumors will successfully identify the more aggressive subset of tumors and direct treatment accordingly.
1. Biotherapy: SS analogs and/or INF-
a. SS analogs in GEP tumors.
SS analogs can reliably control hormone-mediated symptoms, may exert an antiproliferative effect and thus control tumor growth, and can also have vascular and immune system modulatory effects (59, 404, 405). SS analogs are poor tumoricidal agents (59, 122, 404, 405, 422) but may show tumoristatic effects and retard further NET growth, resulting in tumor stabilization (59, 122, 404, 405, 422). Regular octreotide at a daily dose of 200–450 µg is associated with a median 60% symptomatic, 70% biochemical, and 5–11% tumoral response (59, 404, 405, 423). The highest response rates are obtained using octreotide in daily doses greater than 30,000 µg or lanreotide in doses greater than 5 mg/d (and up to 15 mg) (421); such high doses may also induce tumor cell apoptosis (421, 423, 424). More than 30 patients with partial tumor regression to SS analogs have been reported, the majority of whom had also received other treatment modalities; very few cases have shown complete tumor regression with octreotide monotherapy, and some of these were in the context of an MEN I syndrome (421, 425, 426, 427, 428, 429). However, a great number of patients achieve disease stabilization (59, 404, 405, 417, 420, 421, 424, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438) (Table 3). This has also been clearly demonstrated in prospective studies, in which only patients with substantial tumor progression (>25%) were treated with 450–750 µg of octreotide daily; 36.5–50% of these patients obtained radiographically proven disease stabilization with a median duration of 5–18 months (405, 420, 431). Slow-release formulations of octreotide (Sandostatin LAR, Novartis) administered at doses of 20–30 mg/month or lanreotide at 30 mg every 10–14 d are now available and have achieved better or similar response rates with a more convenient administration scheme (5, 59, 439, 440, 441). Lanreotide Autogel (Ipsen, Paris, France) appears to be at least as effective as conventional lanreotide at a monthly dosage of 60–120 mg, given by deep sc injection (74, 116). Although most data are derived from retrospective studies, there seems to be no major difference between octreotide and lanreotide in terms of receptor affinity or biological activity (59, 432, 434), as also shown by a prospective study (437). In a recent as yet unpublished study, Lanreotide Autogel appeared to be highly effective in controlling CS-associated flushing but was apparently less effective against diarrhea; however, it is probable that this relates to patient selection criteria, and it seems unlikely that there will be major differences in symptomatic control between the currently available long-acting SS analogs. The quality of life was substantially improved after treatment with long-acting SS analogs (435, 437). When octreotide LAR is prescribed, concomitant treatment with short-acting octreotide should be initiated for the first 2–3 wk (59, 423).
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b. High-dose treatment/continuous infusion treatment.
A number of studies have examined the effect of treatment with high doses of SS analogs (octreotide, 6 mg/d, and lanreotide, 9–15 mg/d) in patients with progressive GEP tumors on conventional doses of octreotide, showing a further tumoral response (421, 449). One study using high doses of lanreotide was unique in that patients who obtained disease stabilization underwent serial tumor biopsies over a period of 12 months, showing an increased number of apoptotic cells; it was postulated that this was achieved through induction of apoptosis via SS receptor subtype 3 (449). This extra antiproliferative effect of ultra-high doses has also been demonstrated in studies in which only progressive tumors were included (421). It is possible that high-dose octreotide/lanreotide can produce additional antiproliferative effects in patients failing on standard doses of octreotide (412). More recently, the administration of 1.5 mg/d of octreotide was associated with substantial tumor responses in two patients with disseminated atypical carcinoid lung tumors (450). Although the continuous infusion of SS analogs was not associated with any side effects, there was no improvement in the tumoral response; however, this form of treatment can be considered in acute and life-threatening crises (449). Currently, our own position is to use doses of Sandostatin LAR up to 30–60 mg every 3–4 wk, and Lanreotide Autogel up to 120 mg monthly. However, it is reasonable to consider additional "top-up" doses of sc octreotide, using 50 or 100 µg from time to time if required. Alone, sc octreotide can be used up to 1000 µg daily, either as regular intermittent doses or by continuous sc infusion, for short times during acute exacerbations. We do not at present recommend the regular use of doses above these levels outside of controlled clinical trials.
c. Tachyphylaxis.
Eventually, the great majority of patients escape from SS analog therapy; the median duration of response is around 12 months with regard to both hormonal production and tumor growth; increased doses may be required initially to maintain symptomatic control, but eventually dose escalation can no longer control the clinical symptoms (61, 412, 451, 452). Although the majority of these data are derived from studies that have used octreotide and fewer are from studies that have used lanreotide, this phenomenon probably reflects a drug class rather than a specific compound effect (432). The mechanism behind this tachyphylaxis is not yet known, although early down-regulation of SS receptors (restorable transiently by a drug-free interval or dose increment) and development of receptor-negative clones has been considered (132, 452); this issue has recently been extensively reviewed (452). However, tachyphylaxis does not occur when patients with acromegaly are treated with octreotide, and it is more likely to be caused by changes in tissue-specific regulation of cellular SS receptors rather than simply differential patterns of SS receptor subtype expression (62, 63, 452). Tachyphylaxis may also be related to the frequency and form of SS analog administration (453). In recent studies using long-acting formulations of SS analogs, tachyphylaxis has not been so commonly described (424, 435, 436, 438, 441). We would generally increase the dose of long-acting SS analog as required for symptom control, adding top-up doses of short-acting drugs to the long-acting analogs where these provide additional clinical benefit. Experience with drug-free "holidays" is limited, and we tend not to use this technique. As noted above, we would not normally go above a Sandostatin LAR dosage of 30–60 mg every 3–4 wk or Lanreotide Autogel dosage of 120 mg monthly.
d. Adverse effects of treatment with SS analogs.
Adverse effects to treatment with SS analogs do occur but are usually mild and very rarely require discontinuation of the treatment (59, 60, 412, 431, 432, 437, 438). Approximately half of the patients on long-term SS analog treatment develop gallbladder dysfunction and a predisposition to biliary sludge or gallstone formation, although this is rarely clinically significant (454). Other side effects are discomfort at the injection sites, nausea, flatulence, diarrhea, steatorrhea and fat malabsorption, abdominal pain, and (rarely) hyperglycemia and a rash (59, 60, 412, 431, 432, 437, 438).
Currently, slow-release SS analogs are regarded as the gold standard treatment for the management of hormone-related symptoms in patients with GEP tumors, because they improve patient compliance and satisfaction (5, 419). Of interest, some preliminary data have shown a significant efficacy of Sandostatin LAR in terms of objective response rate and biochemical and symptomatic control in patients with progressive metastatic disease after therapy with lanreotide (440, 455). This possible lack of cross-resistance between different SS analogs might be due to different pharmacokinetic and pharmacodynamic properties of the compounds leading to different receptor desensitization mechanisms, and this may lead to the development of new therapeutic strategies in the management of NETs (440, 455, 456). There is no direct evidence that treatment with SS analogs prolongs survival in patients with GEP tumors (122). However, retrospective comparison with a cohort of patients treated with chemotherapy has shown that octreotide was associated with around 3-fold improved survival, whereas the overall survival of patients with GEP tumors has probably increased after the introduction of SS analogs (130, 444). This awaits confirmation from prospective studies.
e. Newer SS analogs.
SOM-230 (Novartis) is a new SS analog that has a more prolonged half-life (23–24 h) and exerts a more potent inhibitory effect than current available compounds, because it binds with much higher affinity to several subtypes of SS receptors (457). SOM-230 binds with high affinity to SS receptors 1, 2, 3, and 5, but hardly at all to subtype 4, but in this sense represents a near-universal ligand (457, 458). Initial studies have revealed no desensitization of the suppressing effect of SOM-230, in contrast to octreotide, due to the different intracellular dynamics of SS receptor subtypes 2 and 5 (459). The introduction of SOM-230 into clinical practice will also address the long-standing question as to whether SS receptor subtypes 1 and 3, which mediate antitumor effects (cell cycle inhibition, induction of apoptosis), exert a clinical beneficial effect in inoperable carcinoid and islet cell tumors (457, 460). Early phase I clinical trials using SOM-230 have been initiated recently (457, 458).
f. Future prospects.
The potential value of high-dose SS analog therapy and novel SS subtype specific analogs is currently under extensive investigation. There may be certain types of tumors that preferentially express subtypes of SS receptors that have little or no affinity for current SS analogs, and agents such as SOM-230 may increase the proportion of NETs able to respond to SS therapy. This is also currently being explored with the availability of the slow-release formulations that allow the administration of even higher doses. The SS receptor status, tumor biology, and growth pattern of each patient are included in the prior-to-treatment analysis to optimize treatment and provide new insights into the mechanisms of action of SS analogs (412). In addition, the incorporation of SS analogs with other therapeutic modalities is currently under investigation.
g. INF- therapy in GEP tumors.
INFs are compounds known to exert a combination of effects directed to several groups of tumors and are considered as biological response modifiers because they interact with other soluble or cell-associated regulatory factors (172, 404, 461). INF has been used either alone or in combination with chemotherapy and SS analogs in various, but mainly carcinoid, endocrine tumors (172, 404, 461). The antitumor action of INF-, produced by leukocytes, includes direct effects on proliferation, apoptosis, differentiation, and angiogenesis (461). INF- also exerts an immunomodulatory effect and induces fibrosis in metastatic, particularly hepatic lesions (461, 462).
Initial studies used human leukocyte INF, but currently recombinant INF is the major agent in use (63, 64). The recommended doses are 3–9 MU daily or every other day, with a median dose of 5 MU every other day sc, but treatment should be titrated individually according to sex, weight, and age (463, 464). The leukocyte count can also be used to determine INF dose titration, aiming at reducing the number of leukocytes to below 3.0 x 109/liter (463, 464). From data derived from studies summarized in Table 4 (including carcinoid and pancreatic tumors separately), the median symptomatic and biochemical response rates to INF are 40–70% and 44%, respectively, and the median tumoral response is 11% (422, 463, 465, 466, 467, 468, 469, 470). Disease stabilization is noticed in a further 35% of patients, and tumor progression in approximately 15–20%; the median duration of response was 32 months (463). It has been postulated that INF induces apoptosis and that tumor cells are replaced by fibrotic tissue, which could explain the increased intratumoral fibrosis observed in carcinoid metastases without a significant change in tumor size; this could theoretically account for the discrepancy between biochemical and tumoral results (5, 227, 423, 461, 464, 471, 472). In patients with low proliferative endocrine pancreatic tumors, a response rate of approximately 50%, lasting for more than 2 yr, has been observed (5, 227, 423, 461, 464, 471, 472). Both retrospective and prospective studies have shown that INFs, with or without SS analogs, should be the medical treatment of choice, particularly in patients with midgut carcinoids (5, 227, 423, 461, 464, 471, 472). There seems to be no clear dose-response relationship, and higher doses were not associated with an improved response (465). Oberg and co-workers (5, 47, 172, 461) have treated more than 300 patients with GEP tumors with INF- and have suggested that a limited tumor burden may be associated with a better therapeutic response. Although retrospective data suggest a prolongation of survival, there are only a few randomized control studies demonstrating a better outcome of patients treated with INF compared with patients treated with chemotherapy or SS analogs (172, 404, 461). In another randomized study, discontinuation of successful INF therapy was associated with shortening of life expectancy (468).
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, second line (salvage) therapy with 131I-MIBG or STZ -based chemotherapy was not proven to be effective, although the number of patients treated was small (476). Recently, intralesional INF administration was associated with tumor necrosis and significant clinical improvement in a patient with metastatic carcinoid tumor (477). In contrast to the above findings, a small number of studies have suggested that the effects of INF are often suppressed as a result of adverse effects that limit continuous treatment and can affect its efficiency (465, 478, 479). Similarly, in bronchial carcinoids neither SS analogs, INF, or their combination was found to be effective (480). The development of neutralizing antibodies to recombinant INF may also limit its clinical efficiency, although change to human INF may restore some of these effects (481). Recently, it has been speculated that the activation of phospholipase A2, which may provide some of the antitumor effects of INF, might also contribute to the clinical side effects (481).
h. Adverse effects.
Flu-like symptoms are almost universal but short-lived, lasting approximately 1 wk (404, 461, 471). Chronic fatigue and mild depression may develop in up to 50% of patients, occasionally leading to discontinuation of the treatment. Autoimmune reactions (thyroid dysfunction, a systemic lupus erythematosus syndrome, and polymyalgia) appear in approximately 30% of patients. The presence of these reactions does not, however, appear to influence tumor responsiveness (482).
i. Future prospects.
It is expected that newer INFs, particularly the longer-acting polyethylene glycosylated recombinant formulations, will soon be available, leading to better patient compliance and less side effects. In addition, the induction of INF regulatory factors might be used to indicate the response of carcinoid tumors to treatment with INF (483). Pegylated INF- has come into clinical use at doses of 50–100 µg sc once a week (461, 471).
j. Combination of SS analogs and INF-.
After a dramatic response was obtained following treatment with the combination of INF- and SS analogs, it was hypothesized that patients resistant to either medication alone might respond to that combination (473, 484), and the problem of tachyphylaxis of analog treatment alone could be postponed without any additional cross-resistance between the two biotherapies (146, 473, 484, 485). This original observation was reinforced further when the application of INF- and SS analogs in patients with malignant midgut carcinoid tumors was shown to improve prognosis and offer good symptomatic relief (146, 485). In a further study, the addition of INF to patients with progressive carcinoid and pancreatic islet cell tumors, besides treatment with octreotide alone, was associated with significant symptomatic and biochemical improvement, inhibition of tumor growth, and probably prolongation of survival in the responder group (473) (Table 5; Refs. 473 , 484, 485, 486). Although the objective tumor responses obtained from that study are difficult to compare to other studies, because a greater than 30% reduction of tumor size was accepted as indicative of a radiological tumor response, similar findings were obtained in a recent study in which the combination of INF and SS analogs was used in patients with pancreatic islet cell tumors who developed progression of their disease after becoming refractory to the administration of each drug alone; however, the value of sequential treatment was not considered in that study (486). Similarly, this combination has been shown to be effective in liver metastases from pernicious anemia-related ECL-GC tumors (161, 487), but not in patients with pulmonary carcinoids suffering from CS (although there was some symptomatic relief) (161). However, the results of a prospective study evaluating the effect of this combination vs. each drug alone in 80 therapy-naive patients with verified metastatic NETs showed that SS analogs (lanreotide), INF, or the combination of the two had comparable antiproliferative effects (474). Response rates were relatively lower than those of nonrandomized studies, similar for functional and nonfunctional NETs, whereas side effects leading to discontinuation of the therapy were more frequent in the group that received the combination treatment (474). Currently, we rarely find an occasion to add INF when treatment with SS analogs is no longer effective.
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a. Chemotherapy for GEP tumors.
Chemotherapy has been used extensively in the past for the management of disseminated GEP tumors; however, it was only after each group of tumors was separately analyzed that its efficacy was shown to depend on primary site and histological differentiation (404, 488). Currently, the indications for chemotherapy need to be very carefully reconsidered, because biotherapy with SS analogs and/or INF can control the symptoms of humoral syndromes and may also affect tumor growth (5, 116, 488). However, chemotherapy may be beneficial for selected cases of advanced, especially pancreatic, tumors that do not respond to other forms of therapy, and for poorly differentiated GEP tumors (5, 52, 116, 423, 488). One of the most commonly used drugs is STZ (182, 412, 489). STZ and its related compound chlorozotocin are glucose molecules with a nitrosurea substitute in the C2 position; this is likely to be the actual toxic part of the molecule (481).
b. Chemotherapy for well-differentiated pancreatic tumors.
Chemotherapy is currently considered for progressive tumors (>25% increase in size of main tumor mass over 6–12 months) and is not usually appropriate in the early management of the disease when application of biotherapy is more advisable (116, 488, 490). Several chemotherapy regimens, initially with single drugs and later on with combinations of drugs, have been used and extensively reviewed in the past (172, 182, 404, 412, 423, 443); however, there are very few prospective studies confirming their efficacy (491). The combination of STZ and doxorubicin has been superior to other regimens, mainly STZ and 5-fluorouracil (5-FU), and has been associated with a 69% objective response lasting for 18 months and an overall median survival of 2.2 yr (491) (Table 6; Refs. 489 , 491, 492, 493, 494, 495, 496, 497, 498). In cases where the use of doxorubicin is limited due to its potential cardiotoxicity, the traditional combination of STZ and 5-FU can be used as an alternative (116, 464, 488, 498). Patients with functioning tumors respond better than those with nonfunctioning tumors (423, 443, 489). Patients who respond may also be good candidates for secondary surgical excision (113).
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). In two randomized studies, the combination of 5-FU and STZ produced 33 and 22% response rates, respectively, while using non-WHO criteria (182, 492). The response duration is unpredictable and often short lasting, in the region of 3–8 months (182, 413, 499, 500, 501); although individual cases of much longer responses have also been described (116, 503, 504), there is no unequivocal evidence that chemotherapy improves survival, and it can certainly induce unpleasant adverse effects and be associated with a poor quality of life (172, 423, 443). In patients with typical pulmonary carcinoids, the combination of etoposide and cis-platinum, particularly if used as first-line chemotherapy, may be of value, in contrast to previous findings in patients with typical pancreatic carcinoid tumors (144, 307, 505). In this group of patients with lung tumors, conventional chemotherapy using STZ and 5-FU failed to control the disease (144, 480). We consider the use of systemic chemotherapy for well-differentiated GEP tumors when the general condition of the patient is good enough and after an observational period to appreciate the rate of tumor growth. Similarly, because these tumors are relatively slow-growing, antitumor efficacy should be evaluated after 6 months unless further tumor progression has occurred (5, 488, 490, 506). In cases of substantial tumor regression, the possibility of surgical resection of the main residual disease should be considered; this can occasionally be associated with prolonged tumor control (488, 490). Chemotherapy has to be weighed against potential side effects but may be the only alternative, particularly in poorly differentiated tumors.
d. Chemotherapy for poorly differentiated GEP tumors.
A high (overall 67% regression rate with a 17% complete regression rate) but short-lasting response, similar to the one described in SCLC, has been obtained in poorly differentiated GEP tumors using the combination of etoposide and cis-platinum (491, 507). In addition, there was a tendency for more prolonged survival compared with the 6-month survival reported in a small group of poorly differentiated carcinoid tumors (508). Although the activity of this regimen for poorly differentiated GEP tumors has subsequently been confirmed in phase II studies (505, 507, 509), results concerning the response rate in well-differentiated GEP tumors have been contradictory, with some studies demonstrating a poor response (505, 507, 509) while others have achieved significant responses in heavily pretreated patients (505) (Table 7; Refs. 505 , 507 , 509). However, the response to treatment may be limited due to potential nephrotoxicity, particularly in previous heavily pretreated patients; currently, coadministration of amifostine as a means to reduce chemotoxicity is being evaluated (505).
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f. Future prospects.
To improve response rate and find novel chemotherapeutic regimens, new agents with antitumor activity in NETs are being tried. Phase II trials have shown that high-dose paclitaxel in patients with advanced NETs was associated with minimal antitumor activity with considerable hematological toxicity (510). More recently, a novel specific cytotoxic treatment for serotonin-producing tumors has appeared (511). This treatment is based on the inherent ability of serotonin-secreting cells to take up the inactive compound 5-hydroxy-tryptophan, which is then metabolized via tryptophan hydroxylase to the toxic compound 5,7-dihydroxy-tryptophan (511). In addition, a cytotoxic hybrid between the SS analog vapreotide and doxorubicin has been shown, at least in animal studies, to increase the dose and effect of doxorubicin without increasing the toxicity because it is directed to the tumor cells (512, 513). There are also anecdotal reports of the use of thalidomide, as an antiangiogenic agent, and antagonists of the epidermal growth factor in the therapy of NETs (514). The results of controlled trials with the use of newer antiangiogenic agents will be of considerable interest.
3. Treatment of hepatic metastases.
Liver metastases in GEP- and other NETs carry a poor prognosis, with a 5-yr survival rate of less than 50%, and are associated with deterioration in the patient’s quality of life (126, 515, 516, 517). In one small study of untreated patients, progression of tumor was observed in all, with almost a doubling of tumor mass after 1 yr, although there were individuals with disseminated disease who experienced prolonged survival (10, 518). Treatment directed against the hepatic metastases is either surgical (selective segmental liver resection, liver transplantation, and ablative therapy) or medical (vascular intervention leading to ischemia of the area occupied by the tumor) (10, 517, 518). The medical-ischemic treatment of NETs relies on the exclusive blood supply of tumoral tissue from the hepatic artery, in contrast to normal liver parenchyma that mainly relies on portal venous perfusion (10, 518). Ischemia can be achieved by several techniques directed to the hepatic artery, such as ligation, selective embolization, or temporary occlusion (10).
a. Surgical therapy of hepatic metastases.
This form of treatment relies on the predilection of most NETs for developing liver metastases that rarely progress to liver dysfunction and failure despite gross tumor load (516, 517, 519). Because of their slow tumor growth and often incapacitating symptoms related to tumor bulk and hormone production, solitary metastases or multiple lesions confined to one lobe can be surgically resected, aiming either at cure or at removal of at least 90% of tumor burden (516, 517, 519, 520). In patients with GEP tumors, surgical resection was associated with significant prolongation of survival and symptomatic improvement, although it was rarely curative; patients with bilobar disease or more than 75% liver involvement were the least likely to benefit (516, 517, 519, 521). The location and removal of the primary tumor before hepatic resection also contributed to improved survival (517). The introduction of more specific local ablation techniques, which achieve tumor destruction in situ, has widened the possibilities for treating liver metastases and has potentially extended the indications for surgery (e.g., by resecting a tumor in one lobe and local ablation in the other, with or without chemoembolization) (520). Several ablative techniques are currently used, including ethanol injections (520); cryosurgery, where tumor cells are killed after injection of liquid nitrogen (–196 C) (522); or radiofrequency ablation, a slow wave diathermy technique that destroys tumor cells by protein coagulation caused by heat (520). Hepatic radioembolization has also been tried, although in a limited number of patients (523). All of these techniques, while promising, still need to be tested prospectively in a large group of patients. Currently, only a small number of retrospective reviews provide some indirect evidence suggesting that surgical resection of hepatic metastases may prolong survival in selected cases, although this is rarely curative (406, 516, 517).
b. Invasive medical therapy of hepatic metastases (hepatic artery embolization-chemoembolization).
Selective embolization of the hepatic arteries causes a temporary but complete ischemia (10, 524), with objective symptomatic and hormonal responses of 65 and 81%, respectively (525). Chemoembolization is embolization combined with liver-targeted intraarterial administration of chemotherapy; initially, small particles of iodized oil containing a chemotherapeutic agent are injected and, to obliterate peripheral arterial branches, are followed by sponge particles to embolize larger proximal feeding tumor arteries (10, 515). Contraindications include complete portal vein obstruction and hepatic insufficiency (515, 526). Initial studies showed a symptomatic improvement and significant tumor reduction in response to 5-FU in carcinoid tumors, with a mean duration of 2 yr (527). Similar results were obtained from both prospective and retrospective studies for several types of NETs using other chemotherapeutic agents; in such studies, it has been reported that more than 35% of patients showed objective tumor responses (525, 527, 528, 529, 530, 531, 532, 533) (Table 8). During these procedures, SS analogs may be coadministered to avoid life-threatening crises (10). Chemoembolization is more efficient if the bulk of tumor mass, and particularly the primary tumor, has been resected (532). Therefore, chemoembolization is an alternative to chemotherapy for progressive hepatic metastases in patients with NETs, although it is not clear whether this treatment should be used early or late in the course of the disease (506). However, as other therapies for GEP and other NETs become available, its role needs to be reevaluated (506). The side effects of the procedure are usually mild and transient and mainly constitute the postembolization syndrome (nausea, vomiting, abdominal pain, fever up to 37.5 C, and raised transaminases); major complications (acute renal failure and bleeding peptic ulcers) are extremely rare (515). However, when they do occur they can be life threatening, and we would advise that the procedure is only carried out in major centers with the relevant experience and expertise (534).
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4. Treatment of NETs with radiopharmaceuticals (endoradiotherapy).
Radioiodine for the treatment of thyroid disorders has been the best example of a radionuclide-targeting agent; with the introduction of 131I-labeled MIBG, the field of radionuclide treatment has been extended to a wide range of NETs because more than 90% of chromaffin cell tumors, 70% of carcinoids, and around of 35% of MTC concentrate MIBG (87, 99, 319, 425, 537). The use of this therapy can be considered either early in an adjuvant setting, after surgery to eradicate occult disease, or later for treatment of disseminated disease (538).
a. 131I-MIBG therapy for malignant NETs.
Potential advantages of 131I-MIBG therapy are that it is a treatment targeting both primary tumors and distant metastases, it has a preferential radiation delivery to tumoral lesions with relative sparing of normal tissues (mainly ß-emission with only a 10% -emission contribution), and it has little pharmacological toxicity (55). Most of the patients treated so far had no other therapeutic options or were refractory to conventional treatment strategies, with only a few prospective trials incorporating treatment-naive patients. Usually, patients had multiple sites of disease as evidenced by scintigraphic 123I-MIBG appearance, a prerequisite for the initiation of treatment (79) (Fig. 7). 131I-MIBG is administered as a slow iv infusion over a period of 60–90 min, and patients are kept in an isotope treatment unit for 4–6 d; to minimize thyroidal 131I uptake, potassium iodide 120–150 mg/d is given starting 2 d before therapy and continued for 8–21 d after therapy (76, 79, 347, 539, 540).
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Hematological toxicity is the main significant side effect of 131I-MIBG therapy (mainly leucopenia and thrombocytopenia (339, 545). Severe myelosuppression is mainly seen in patients with widespread bone metastases and diffuse bone marrow involvement, and in patients heavily pretreated with chemotherapy (347, 546). Transient hepatic failure, presumably secondary to widespread hepatic lesion necrosis, has also been described (79, 547). We have also reported premature ovarian failure (Ref. 79 ; also see Ref. 548).
b. Radiopharmaceutical therapy with 111In octreotide.
111In emits mainly -radiation, Auger and conversion electrons, and exerts an antiproliferative effect in malignant tumors if their principal target, cellular DNA, is within the particle range (54, 83, 549). Thirty end-stage patients with NETs, including 20 patients with GEP tumors, were treated with [111In-DTPA] octreotide; 21 of these patients, all with progressive disease, received a cumulative dose of 20 GBq (83). Of these 21 patients, six showed an antiproliferative effect demonstrated as shrinkage of the tumor, whereas in another eight patients there was stabilization of disease; there was a tendency toward better results in patients with high tumor uptake (83). In 27 additional patients treated with two doses of 111In pentetreotide, an objective partial response occurred in two (8%), whereas significant tumor necrosis occurred in seven (27%) patients without any major side effect; the median survival was 18 months, compared with 6 months expected (550). However, in recent studies it was shown that the response may not be sustained in time, probably due to the preferential survival of resistant clones (551, 552), and that its efficacy in large tumors and end-stage patients is limited (551, 552). Therefore, it was suggested that 111In-pentetreotide should be given either in combination with ß-emitters or to eradicate micrometastases (553). Toxicity of the treatment was generally low, with 100 GBq being the maximum tolerable dose (553).
c. Radiopharmaceutical therapy with 90Y octreotide/DOTATOC.
Radionuclides emitting ß-radiation have greater therapeutic potential because the particles they emit have sufficient energy to cause cell damage, and they deliver higher radiation doses in a larger part of the tumor without penetrating very far into surrounding tissue (54, 83, 554). The same SS analog (Tyr3-octreotide) used for diagnosis has been coupled to a bifunctional chelating agent (DOTA) for the complexing of 90Y, a pure energetic ß-emitter well suited for internal radiotherapy, 90Y-DOTA-D-Phe1-Tyr3-octreotide (90Y-SMT487, OctreoTher, Novartis, Basel, Switzerland) (83, 99, 555). Concomitant iv administration of amino acids reduces renal radioactivity uptake without altering tumor uptake (73, 554, 555). Thirty-nine patients with a variety of tumors received OctreoTher in an escalating dosage with minor toxicity, whereas the objective response rate (complete and partial responses) was 23% and disease stabilization 64% (80, 556). A Novartis-sponsored phase II study is currently ongoing to test the efficacy of OctreoTher in patients with a variety of disseminated NETs (also see Refs. 73 , 554 , 555) (Fig. 8). There is also experience using 90Y-DOTATOC, a compound similar to OctreoTher (554, 557); of 10 patients with metastatic NETs treated with 90Y-DOTATOC, six reported improvement in tumor growth, hormonal secretion, and symptoms, with minimal side effects, whereas the others showed stable disease (84, 554, 557). Another 29 patients were treated with 90Y-DOTATOC, six of whom obtained a remission, whereas 20 had disease stabilization (543, 557). In a more recent phase II nonrandomized study involving 37 patients with progressive GEP tumors, an objective tumor response of 24% (36% for pancreatic tumors) was noted, without serious toxicity; there was also a suggestion of a more favorable long-term outcome (542).
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e. Radionuclear therapy with [177Lu-DOTA Tyr3]-octreotate.
To overcome the limitations of administering tumoricidal doses of radiotherapy to nonoctreotide avid lesions and the lack of uptake to certain areas due to tumor heterogeneity, several ß-emitters, in addition to 90Y, such as 153Sm, 177Lu, and 186Re are also being considered, along with the newest SS analog Tyr3-octreotate, which exhibits the highest affinity for SS receptor type 2 (553). 177Lu-DOTA-Tyr3-octreotate shows a very high tumor uptake with a very good ratio of tumor-to-kidney uptake, thus suggesting an ideal compound for radionuclide therapy (553). Radiotherapy with 177Lu-DOTA-Tyr3-octreotate has recently been used in 18 patients with a variety of progressive NETs, with 39% of patients showing a partial remission (560). It has also been suggested that in patients with tumors of different sizes, including small metastases, the administration of combinations of different radionuclides, e.g., 90Y, which is optimal for larger tumors, and 177Lu, which is optimal for smaller tumors, coupled to octreotide and/or octreotate may be particularly useful (553).
f. Future prospects.
It is likely that "endoradiotherapy" for the treatment of NETs will develop considerably within the next few years. Until now, indications for 131I-MIBG have been limited to palliative treatment of malignant chromaffin cell and occasionally carcinoid tumors, most often at an advanced disease stage. The recent application of 90Y-labeled SS analogs represents a major advantage, because these radionuclides can be taken up by a wider number of NETs (99). Ideally, these radionuclides should be used in patients with small tumor targets (not more than 1–2 cm in diameter) (561). Combination therapy with both 131I-MIBG and OctreoTher or 111In/90Y/177Lu-octreotide remains an attractive theoretical option, after as complete a surgical resection as possible to ensure good uptake of the radiopharmaceutical by the remaining tumor target. If treatments are repeated regularly, it is likely that the disease can be at least stabilized for a period of several years, if not cured. In addition, newer SS analogs in combination with different emitters are in development that might show superior imaging and therapeutic properties. Finally, it may be hoped that the efficacy of endoradiotherapy will be improved by coadministration of chemotherapeutic drugs whose radiosensitizing properties may be synergistic with those of irradiation (80). Immune system activation for the control of micrometastatic disease may also be required to achieve complete control and eventual cure. Compounds antagonizing tumor angiogenesis by binding to vß3 receptors on newly formed blood vessels could be combined with DTPA-Tyr3-octreotate from hybrid peptides that can bind to both SS receptor 2 and vß3 receptors and can thus be used for both scintigraphy and radionuclide therapy (562). In addition, transfer of genes encoding for the expression of SS receptors 2 and 5 to receptor-negative tumors may render them responsive to treatment with these agents (563).
D. Multidisciplinary approach—quality of life
The increasing number of investigative procedures and therapeutic options for both the diagnosis and treatment of NETs is best dealt with by a multidisciplinary team. Such a team should include physicians with a special interest in NETs, pathologists, endocrinologists, gastroenterologists, interventional radiologists, surgeons, oncologists, and a nuclear medicine expert (52, 131). Diagnostic procedures should be critically reviewed to help establish a consensus on the best evidence-based management, including invasive procedures such as chemoembolization or repeated surgical procedures. Due to the relative rarity of such tumors, optimum management should be undertaken in centers with relevant experience and expertise (52, 131). Because the majority of these tumors are slowly growing and even patients with disseminated disease may have prolonged survival, early involvement in palliative team programs may be helpful. To evaluate the results of current management, establish guidelines, and develop new therapeutic trials, multicenter collaborations are particularly helpful. However, this does not always occur; a recent retrospective analysis from Italy reviewing all GEP tumors treated over the last 20 yr found that a such multidisciplinary approach was practiced in only a small proportion of patients (232). In addition, attempts to improve the quality of life should be sought because patients with metastatic disease may still experience prolonged survival, and this should be weighed against the potential side effects of any systemic treatment (116).
E. Symptomatic and systemic treatment of benign and malignant chromaffin cell tumors (pheochromocytoma and paraganglioma)
Surgery with complete resection, when possible, or debulking of the primary tumor should be as radical as possible to obtain disease-free, long-term survival (111). Antihypertensive drugs that block the effects of catecholamine and -methyl tyrosine, which inhibits catecholamine synthesis, are used for control of the symptoms, but these therapies do not inhibit the growth of these tumors (111, 344, 347).
1. Symptomatic therapy.
Surgical resection is the treatment of choice for isolated unilateral pheochromocytomas, and even cases of localized metastases should always be carried out as an elective procedure after careful preoperative preparation (115, 344). The resection of these tumors has great potential for intra- and postoperative complications, which are substantially minimized by adequate blood pressure control and close monitoring of fluid balance (115, 357). Blood pressure control is achieved preoperatively with the mixed 1/2 noncompetitive adrenoreceptor antagonist phenoxybenzamine, starting at a dose of 10 mg orally up to 10–20 mg four times daily (115, 357). After dose stabilization, the ß1/ß2 antagonist propranolol, at a dose of 40 mg three times a day, is given to avoid reflex tachycardia, although much higher doses may be required (344). Newer selective 1-antagonists such as terazosin, prazosin, and doxazosin can also be used, particularly because they may be less likely to produce reflex tachycardia (564). In addition, calcium-channel blockers can be used either alone or as an adjunct to -blockade in high-risk patients or where these drugs are contraindicated (115, 565). However, despite adequate -blockade, significant elevations of blood pressure and rarely hypertensive crises may still occur, particularly during manipulation of the tumor, followed by severe hypotension on tumor removal (115, 344). Although hypertensive episodes can be treated with intermittent iv injections of phentolamine, this drug can cause repeated cycles of hyper- or hypotension (344). Sodium nitroprusside should be used to obtain a gradual and controlled reduction of arterial blood pressure through continuous iv infusion. Nifedipine capsules taken sublingually have also been used with success (115). For patients with inoperable, malignant, recurrent, or multicentric tumors, long-term medical therapy using - and ß-adrenergic blockade is the treatment of choice (115). Another approach is to decrease catecholamine production from the tumor by using -methyl-p-tyrosine, which inhibits the rate-limiting enzyme tyrosine hydroxylase (566). Circulating catecholamine can be reduced up to 80%, but its use is occasionally associated with side effects (115). A case of an objective tumor response has been described with the use of metyrosine but has not been substantiated in other studies; however, metyrosine can be used as an adjuvant to chemotherapy (567, 568, 569). The combination of /ß blockers with metyrosine has been shown to exert a synergistic effect (Ref. 115 ; also see Ref. 342).
2. Systemic therapy.
The principal therapy for malignant chromaffin cell tumors is resection and catecholamine blockade (355). However, additional treatment will be required for inoperable symptomatic tumors or tumors with extensive disease after resection (355). This is particularly important because survival analysis in malignant pheochromocytomas has shown two subsets of patients; approximately 50% of patients have a more aggressive course and die within 4–5 yr, whereas the others show a more indolent course and survive for many years even without treatment (114, 116, 346). It has therefore been suggested that early mortality probably results from progression of the malignancy, rather than hormonal hypersecretion, thus necessitating further aggressive treatment (114). Tumor biology may be a powerful tool directing further management; however, there are not enough studies applying currently established or other markers of disease aggressiveness in chromaffin cell tumors.
Short-term or long-term administration of SS analogs has not shown any clinical benefit, although occasional biochemical responses have been obtained (570, 571, 572, 573). However, SS analogs may still be of value in individual patients (570, 574). INF has very rarely been used as the sole treatment in patients with pheochromocytomas with some success (575). Chemotherapy with either single agents or a combination of agents has also been tried as the last option in patients with malignant chromaffin cell tumors (345). Individual cases have been treated with a variety of chemotherapeutic agents that occasionally have shown clinically useful responses (345, 576). Due to the resemblance of these tumors to neuroblastomas, which have shown an overall response rate of 80% to the regimen of cyclophosphamide, vincristine, and dacarbazine (CVD), this regimen has been used more extensively in patients with malignant chromaffin cell tumors. The largest series of 14 patients showed a 79% hormonal and 57% tumor response with minimal side effects, mainly bone marrow toxicity and hypotension (114). This was not a randomized study, and there was no evidence of any prolongation of survival with this form of treatment (114). Several other reports have confirmed the efficacy of this regimen, including a large number of patients treated in Japan (364, 577). Although most responses are transient without any clear effect on long-term survival (114), occasional individual long-term survivors have also been described (578) (Table 9; see Refs. 114 , 345 , 568 , 569 , and 577, 578, 579, 580, 581, 582, 583, 584, 585, 586). Chemotherapy with CVD should be performed under adequate -blockade, because life-threatening hypertensive crises from excessive catecholamine release have been described, even in asymptomatic patients (584). The combination of CVD chemotherapy with -methyl-p-tyrosine has been shown to exert a synergistic effect in the control of excessive catecholamine release in individual cases (569). CgA and catecholamine measurements are the best biochemical markers, not only suggesting the diagnosis of malignant chromaffin cell tumors but also in gauging the response to treatment (364).
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(Refs. 590, 591, 592, 593, 594, 595, 596); see also Ref. 597). Although controlled studies are lacking, these data do suggest that 131I-MIBG treatment may be associated with increased survival with occasional sustained complete remissions or cures (79, 347). Occasionally, malignant pheochromocytomas may be octreotide but not MIBG avid; in such cases therapy with octreotide may be of value (544). A few patients with malignant chromaffin cell tumors have already been treated with 111In-octreotide and 90Y-octreotide (DOTATOC), with some obtaining disease stabilization (542, 598). In cases of malignant chromaffin cell tumors with liver metastases that are resistant to chemotherapy, transarterial embolization may be useful in achieving transient symptomatic and hormonal improvement in patients under close peri- and postoperative monitoring of blood pressure (569, 577, 599). Radiofrequency ablation of metastases may also be helpful in selected patients (600). The majority of pheochromocytomas with MEN II, NF1, and VHL disease are benign; in cases with a strong family history of malignant pheochromocytoma, earlier surgical intervention should be considered (Ref. 355 ; also see Ref. 548).
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F. Treatment of medullary thyroid carcinoma
Total thyroidectomy with central lymph node dissection with or without an ipsilateral modified neck dissection is the initial treatment of choice (383). Once gene carriers have been identified, prophylactic thyroidectomy at an early age should be offered: this may be curative and has significantly improved the prognosis of FMTC (20, 382).
1. Treatment of residual or recurrent disease.
In patients with postoperative persistent disease and positive imaging studies, there is increasing evidence that they should undergo a second operation (110, 380, 383). In patients with evidence of noncurable and inoperable disease or occult disease, close clinical observation and monitoring of changes in the serum calcitonin concentration are required. It appears that there are two subsets of patients; the great majority will remain stable for many years and will require no additional treatment, except for long-term follow-up (381). Persistent hypercalcitoninemia postoperatively in patients with sporadic and FMTC is associated with overall 90% and 86% 5-and 10-yr survival rates (362). The frequent long survival without symptoms or evidence of progression, even after the diagnosis of distant metastases, and the poor results of chemotherapy in patients with proven metastases (389) suggest that the option of no treatment is entirely reasonable if the disease does not progress while the patient is under careful observation (389). The presence of more than three metastatic lymph nodes at the time of the first operation is a major predictor of disease recurrence (389). However, for the minority of patients who have active hormonal secretion or in whom the disease progresses rapidly, further treatment will be required (110, 380, 381).
External beam radiotherapy was originally reported to be useful in selected groups with MTC, particularly in patients with large tumor load and worst prognostic factors (382, 604), although earlier studies considered that patients with MTC were relatively radioresistant (605). A recent retrospective analysis of patients with a high risk of recurrence (microscopic residual disease, extraglandular invasion, or lymph node involvement) who received external irradiation besides surgery showed that they developed less local/regional relapse compared with patients who were treated with surgery alone; however, no effect on survival was documented (382). Currently, there are no clear indications for the role of external radiotherapy in patients with postoperative high risks for recurrence or residual disease, mainly due to the lack of a randomized control trial. We therefore suggest that external radiotherapy can be used in patients with inoperable tumors and expanding postoperative lesions for palliation, whereas its application for local control in patients with residual disease should be decided individually, considering the presence of other risk factors (383, 605). Currently, there is no role of 131I for eradicating residual thyroid tissue in the treatment of MTC, because there was no difference in respect to recurrence, alterations in calcitonin levels, or 5- and 10-yr survival rates along patients who were treated with surgery alone and those who received adjunctive 131I therapy (606).
Because 131I-MIBG is taken up by a number of MTC tumors, its administration has been proposed as a radiometabolic treatment for those patients who present a significant scintigraphic uptake (10, 79, 99, 116). The worldwide cumulative experience was reported in 1991 and 1994 for 18 and 22 patients, respectively (10, 72, 590, 607). An objective tumor response was documented in approximately 30% of patients, with a symptomatic response in 50%. Since then, four additional reports including 17 patients have appeared demonstrating a complete response in one patient plus two partial responses, whereas no response was obtained in the rest of the patients (55, 79, 537). On several occasions, symptomatic and hormonal responses have been obtained irrespective of objective tumor responses (55, 79). Thus, although tumor disappearance is exceptional, there is considerable improvement in symptoms and beneficial effects on hormonal and tumor control in a substantial number of patients (79, 80). 131I-MIBG is an expensive and complex therapy, and the response is unpredictable, although occasional patients may show a therapeutic response. Radionuclide therapy with SS analogs has also been used occasionally. A few patients with MTC have also received 111In-octreotide or 90Y-lanreotide in the MAURITIUS trial (552, 558); although this was not a homogeneous group of patients, the initial results were encouraging, supporting further prospective studies for the use of this form of therapy in patients with advanced MTC disease.
Although a few studies have shown some hormonal improvement after treatment with SS analogs (608), biological or morphological parameters were not significantly improved in larger series (609). In occasional patients, continuous treatment with high-dose SS analogs can offer some improvement (69). Only a few series have formally assessed the effect of therapy with INF, and no major effect was found (470, 473). The combination of octreotide (0.3 mg/d) with INF, although well tolerated, was not associated with any tumor response and only a selective biochemical response; however, the combination of lanreotide with INF was associated with substantial biochemical response and stabilization of the disease in the majority of patients reported (382, 610, 611). The results of this treatment combination need to be assessed in a prospective study. Chemotherapy is usually restricted to a minority, less than 20%, of patients with MTC with rapidly progressive disease (382, 383). The most effective agent is doxorubicin, which has produced partial response rates up to 30% either alone or in combination (382). Responses have also been less than impressive in other small series using combination chemotherapy with agents including 5-FU and dacarbazine, cyclophosphamide, methotrexate, and cis-platinum (110, 116, 382, 612). In a recent review of the literature, Orlandi et al. (382) analyzed 144 patients treated with a variety of chemotherapeutic schemes and showed a 3% complete and a 27% partial tumor response; however, no clear benefit was demonstrated on survival. Comparing the results from different chemotherapeutic treatments, it seems that doxorubicin and the combination of doxorubicin and cis-platinum, or 5-FU and dacarbazine, produce similar response rates (382). Chemotherapeutic agents have also been used to enhance the tumoricidal activity of ionizing agents, but it is still difficult to reach firm conclusions regarding their efficacy because most series included only a limited number of patients (110, 613). However, mainly due to the low toxicity, regimens containing 5-FU and dacarbazine might be indicated as the first-line treatment of advanced MTC, although clearly controlled studies are indicated (498). Radiometabolic therapy with anti-CEA-labeled monoclonal antibodies has also been proposed. A few phase I/II trials have shown initially promising results but await confirmation from further studies (614, 615). Recent studies have shown that vaccination with calcitonin and/or CEA peptide-pulsed dendritic cells results in the induction of a cellular, antigen-specific immune response in patients with MTC, leading to beneficial responses in patients with residual or recurrent disease (Refs. 616 and 617 ; also see Refs. 618 and 619).
2. Future prospects.
Recently, in patients with RET gene-activated mutations and subsequent increased tyrosine kinase activity, treatment with specific RET oncoprotein inhibitors is undergoing clinical trial, offering an alternative treatment strategy for tumors sustaining oncogenic activation of RET (620).
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VIII. Summary and Final Conclusions |
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TopAbstractI. IntroductionII. Histopathological...III. Tumor BiologyIV. Tumor Markers in...V. Natural History of...VI. Clinical Presentation,...VII. Medical Management of...VIII. Summary and Final...References |
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alone or in combination, although our preference is to exhibit SS analogs at an early stage, and we rarely add INF. Chemotherapy should be considered for poorly differentiated and progressive GEP tumors. Therapy with radionuclides, 131I-MIBG for chromaffin cell tumors and treatment with radiolabeled SS analogs for other NETs, may be used for tumors exhibiting uptake to a diagnostic scan either after surgery to eradicate microscopic residual disease or later if conventional treatment or biotherapy fails. Alternatively, chemotherapy can be used in patients with GEP tumors and progressive disease, despite biotherapy or treatment with radiolabeled SS analogs, and in patients with disseminated chromaffin cell tumors and MTC. However, such an approach should always consider the patient’s performance and comfort status, the growth rate of the tumor, and the side effect profile. The possibility that these tumors may occur in the context of endocrine syndromes with the involvement of other tissues and other family members should always be considered, and treatment should be directed accordingly. Maintenance of the quality of life should be a priority, particularly because patients with disseminated disease may experience prolonged survival, and the expected efficacy of treatment should be weighed against possible adverse effects. Finally, a suggested flow-plan for the assessment and general therapeutic approach to these tumors, particularly in GEP tumors, is included in Fig. 9.
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Footnotes |
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Abbreviations: ADH, Antidiuretic hormone secretion; ASVS, arterial stimulation venous sampling; CAG, chronic atrophic gastritis; CCK, cholecystokinin; CEA, carcinoembryonic antigen; CgA, chromogranin A; CGRP, calcitonin gene-related peptide; CHD, carcinoid heart disease; CS, carcinoid syndrome; CT, computed tomography; CVD, cyclophosphamide, vincristine, and dacarbazine; DOTA, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DTPA, diethylene-triamine-penta acetic acid; ECL, enterochromaffin; EUS, endoscopic ultrasound; FDG, 18F-labeled deoxyglucose; FMTC, familial MTC; 5-FU, 5-fluorouracil; GC, gastric carcinoid(s); GEP, gastroenteropancreatic; GI, gastrointestinal; GRP, gastrin-releasing peptide; hCG, human chorionic gonadotropin; 5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5-hydroxytryptamine; 5-HTP, 5-hydroxytryptophan; INF, interferon; IOUS, intraoperative ultrasound; MEN, multiple endocrine neoplasia; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; MTC, medullary thyroid carcinoma; NE, neuroendocrine; NET, NE tumor; NF, neurofibromatosis; NIPH, noninsulinoma pancreatogenous hypoglycemia; NME, necrolytic migratory erythema; NSE, neuron-specific enolase; PET, positron emission tomography; PP, pancreatic polypeptide; SCLC, small-cell lung carcinoma; SDH, succinate dehydrogenase; SPECT, single-photon emission CT; SS, somatostatin; STZ, streptozotocin; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau; VIP, vasointestinal peptide; ZES, Zollinger-Ellison syndrome.
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References |
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-subunit of glycoprotein hormones. J Clin Endocrinol Metab 82:2622–2628-interferon. Acta Oncol 32:225–229[Medline]
