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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 o
