The distribution of carcinoids is Gaussian in nature. The peak incidence occurs in the sixth and seventh decade of life, but patients as young as 10 years of age and people in their ninth decade are also seen.

Carcinoid tumors are slow growing and may be present for years without overt symptoms, thus escaping attention. During the early stages, vague abdominal pain goes undiagnosed and invariably is ascribed to irritable bowel or spastic colon. Fully one-third of patients with carcinoid tumors present with years of intermittent abdominal pain. Carcinoid tumors can present in a variety of ways. For example, duodenal tumors are known to produce gastrin and may present with the gastrinoma syndrome.

An interesting association between pernicious anemia, atrophic gastritis, chronic thyroiditis, and gastric carcinoid tumors has been described (6) These tumors arise from the gastric enterochromaffin-like (ECL) cell and usually are small and multiple. Development of these tumors is believed to be secondary to longstanding basal hypergastrinemia, resulting in stimulation of ECL cells and the development of hyperplasia, nodularity, and, eventually, carcinoid tumors (7,8). The association between hypergastrinemia and the development of gastric carcinoids supports the hypothesis that growth factors are important in the genesis of endocrine tumors. Patients with carcinoid tumors of the thymus most often manifest ectopic Cushing’s syndrome or hypercalcemia. Bronchial carcinoids may be associated with MEN-1.

Figure 3. Natural History of Carcinoid Tumors.(9)

The major clinical manifestations of carcinoid tumors (Fig.3) include cutaneous flushing, which occurs in 84% of patients, gastrointestinal (GI) hypermotility with diarrhea (70%), heart disease (37%), bronchial constriction (17%), myopathy (7%), and an abnormal increase in skin pigmentation (5%) (8) When co-existence of the major symptoms of flushing and diarrhea is sought, it emerges that flushing and diarrhea occur simultaneously in 58%, diarrhea without flushing in 15%, flushing without diarrhea in 5%, and neither flushing nor diarrhea as a symptom complex in 22%. The natural history of these tumors is illustrated in Figure 3. Invariably there has been a long history of vague abdominal symptoms, a series of visits to the primary care practitioner and referral to a gastroenterologist and the diagnosis of irritable bowel syndrome (IBS) made. In our review of our own experience with midgut carcinoid patients the diagnosis of IBS at some point in time could always be found in the patient record. These symptoms persist and with a median latency to diagnosis of 9.2 years the correct diagnosis is arrived at by which time the tumor has metastasized, causing flushing and diarrhea and progressing on its slow but relentless course to demise. Clearly a greater index of suspicion is warranted on all patients presenting with “traditional irritable bowel symptoms”.

With metastases to the liver, the correct diagnosis generally is arrived at, but with a delay of many years. Even then, mistaken identity is not uncommon, and unless biopsy material is examined for the secretory peptide chromogranin, (10)synaptophysin, (11)or NSE, (12)tumors may be labeled erroneously as adenocarcinoma, with a negative impact on attitudes toward management and underestimation of prospects for survival.

Figure 4.  

Figure 5.  

Figure 6.  

The diagnosis of carcinoid tumors rests on a strong clinical suspicion in patients who present with flushing, diarrhea, wheezing, myopathy, and right heart disease, and it includes appropriate biochemical and localization studies along with immunohistochemical studies as shown in figure 6 and figure 7.

The rate-limiting step in carcinoid tumors for the synthesis of serotonin is the conversion of tryptophan into 5-HTP, catalyzed by the enzyme tryptophan hydroxylase. In midgut tumors, 5-HTP is rapidly converted to 5-HT by the enzyme aromatic amino acid decarboxylase (dopa-decarboxylase). 5-HT is either stored in the neurosecretory granules or may be secreted directly into the vascular compartment. Most of the secreted 5-HT is taken up by platelets and stored in their secretory granules. The rest remains free in the plasma, and circulating 5-HT is then largely converted into the urinary metabolite 5-hydroxyindoleacetic acid (5-HIAA) by the enzyme monoamine oxidase and by aldehyde dehydrogenase. These enzymes are abundant in the kidney, and the urine typically contains large amounts of 5-HIAA.

Figure 7. Immunohistochemistry of gastric mucosa with Synaptophysin, Chromogranin and Ki-67antigen in a gastric neuroendocrine tumor.

In patients with foregut tumors, the urine contains relatively little 5-HIAA but large amounts of 5-HTP. It is presumed that these tumors are deficient in dopa-decarboxylase, which therefore impairs the conversion of 5-HTP into 5-HT, leading to 5-HTP secretion into the vascular compartment. Some 5-HTP, however, is converted to 5-HT and 5-HIAA—thus, the modest increase in these metabolites. The normal range for 5-HIAA secretion is 2 to 8 mg per 24 hours, and the quantitation of serotonin and all of its metabolites usually permit the detection of 84% of patients with carcinoid tumors. No single measurement detects all cases of carcinoid syndrome, although the urine 5-HIAA appears to be the best screening procedure.

Other peptides involved include SP, neuropeptide K, PP, and chromogranin A (CGA). Neuroendocrine tumors are characterized by their capacity to synthesize, store and release hormonal products. These substances are store in neurosecretory vesicles together with CGA. The concentration of CGA in plasma is thought to reflect the neuroendocrine differentiation of the tumor, the total tumor burden and to be useful as a means of measuring response to treatment. Using nude mice with engrafted human ileal carcinoid tumors (13) a direct correlation between tumor weight and CGA levels was found. Octreotide treated animals had a significant reduction in plasma levels indicating that CGA does correspond with tumor burden and may be useful for monitoring the course of the disease but unfortunately the study did not define the action of Octreotide on secretion versus change in tumor bulk. TO determine the “interest” of CGA for diagnosis and follow up of neuroendocrine tumors Nehar et al (14) CGA levels were measured using an immunoradiometric assay in 124 sporadic neuroendocrine tumors, 34 MEN-1 and 127 controls. Serial measurements were done in 56 patients (212 visits). In secretory tumors the sensitivity was 62.9% with specificity of 98.4%. It was higher in secreting vs. non secreting tumors (73 vs. 45%) and related to the extent of metastases. In non secreting tumors the positive predictive value (PPV) for the presence of metastases was 100% but the negative predictive value was only 50%. In MEN-1 a high value predicted the presence of a pancreatic tumor with 100% specificity but the sensitivity was only 59%. During follow up the concordance e of tumor growth and CGA was 80%, indeed better than serotonin. (81 vs. 54%). Thus due to its high specificity, CGA determination may help to discriminate the endocrine character of a neuroendocrine tumor and to establish a pancreatic tumor in MEN-1 syndrome. Serial measurements are also useful for following responses to treatment. Figure X shows the percent positivity of CGA vs. 5 HIAA in the different carcinoids. CGA is positive 80-100% of the time in fore-mid and hind-gut tumors whereas 5HIAA detects a little over 70% of midgut tumors, only 30% of foregut and fails to recognize the presence of a hindgut carcinoid tumor(Figure 5).

The combined use of CGA and PP may further enhance this sensitivity. Both markers were measured in 68 patients, 28 functioning and 40 nonfunctioning tumors. CGA sensitivity was 96% in functioning tumors, 75% in non functioning, and 74% in pancreatic and 91 % in gastrointestinal tumors. Specificity was 89%. In contrast PP sensitivity for these tumors was approximately 50% but combining the two markers increased sensitivity for all tumors to >95%. More specifically the gain in pancreatic tumors was 93% vs. 68% using the one marker alone. It seems not unreasonable to recommend using both markers under these circumstances. There are however always caveats. Pelckmans and colleagues (15) examined the possibility that gastric parietal cell antibodies, which neutralize acid secretion, thereby unbridling the G cell to produce gastrin, which in turn is trophic to the gastric ECL cell, which can transform into the gastric carcinoid. Measurement of gastrin and CGA, but not NSE and 5HIAA is a means of evaluating the ECL mass. This is particularly useful in decision making with regard to doing an antrectomy or simply following conservatively and removing the carcinoid polyps as they arise. Of course this raises the issue of whether or not the reported elevations in CGA in people taking proton pump inhibitors are truly false positive or reflect ECL hyperplasia! Nonetheless all evidence point to the combined measurement of CGA, PP and gastrin as being a very effective means of discovering a neuroendocrine tumor, identifying its probable site of origin and monitoring response to intervention.

Figure 8.  

Figure 9. Parting Pearls on Chromogranin A (CgA)(16).

In carcinoid tumors, neurotensin is elevated in 43%, SP in 32%, motilin in 14%, somatostatin in 5%, and VIP rarely. In miscellaneous illnesses, there may be elevation of the following hormones: neurotensin, SP, and motilin in 35, 7, and 5%, respectively. Up to one-third of people with idiopathic flushing who do not have carcinoid syndrome, however, have elevated levels of a number of neuropeptides. Furthermore, we have examined the relationship between the products of the preprotachykinin gene, SP, and neurokinin A in healthy subjects and in patients with carcinoid tumors. SP was elevated 80% of the time in patients with carcinoid tumors, whereas neurokinin A was raised in all patients. Why there should be a discrepancy in these two peptides that derive from a common precursor gene product remains unclear. Measurement of circulating levels enhances the ability to identify more patients with carcinoid tumors.

Figure 10.  

Figure 11.  

Figure 12. Ki-67 therapy ((17)

Figure 13. Value of measurement of Neurokinin A(18).

A number of techniques have been used to identify the primary site of the tumor and to evaluate the extent of the disease and presence of metastases. Chest radiography or computed tomography (CT) usually suffices to detect bronchial carcinoids. In contrast, carcinoids of the cecum, right colon, and hindgut carcinoids usually are demonstrable by endoscopy or barium enema examination. The greatest problems encountered are in localizing small bowel carcinoids, which may be small, and carcinoids in extra-intestinal sites. These tumors usually are not identified by upper or GI roentgenographic studies. Abdominal CT scans and ultrasound usually are not helpful because the primary tumors are below the resolution capacity of even the most sophisticated scanning apparatus. Shown in figure 6 is an abdominal CT san in a patient with a malignant metastatic neuroendocrine tumor producing predominantly pancreatic polypeptide. The tumor metastases are not evident in the scan. A T2 weighted image may have revealed the tumors becaue of their vascular nature. However, Octreotide scintigraphy and superior mesenteric angiography are usually of help. Contrast the abdominal CT with the Octreoscan of the same patient in figure 14.

Figure 14. Positive angiogram with Negative CAT scan in a patient of NET.

Figure 15. Different modalities of localization of NET.

Figure 16. Ability to identify the NET lesion using endoscopic

Figure 17. Ultrasound. Computed Tomography (CT) or CAT scan: CT scan of Abdomen and pelvis showing liver metastases of carcinoid tumor and desmoplastic reaction with spiculae of surrounding mesenterial fat and central calcification.

Figure 18. MRI image of a neuroendocrine tumor(19).

Figure 19. Positron Emission Tomography (PET) Scan

Figure 20.  

Figure 21. Octreoscan

Figure 22.  

Figure 23.  

Figure 24.  

Several other diagnostic methods have been evaluated for the diagnosis of carcinoid tumors, including barium examinations, ¹³¹I-metaiodobenzylguanidine (MIBG) scanning, angiography, and venous sampling with radioimmunoassay of hormones. Barium examinations rarely are diagnostic, but they may demonstrate fixation, separation, thickening, and angulations of bowel loops. CT is the primary diagnostic procedure for tumor staging; it allows assessment of the extent of tumor spread to the mesentery and bowel wall as well as metastases to the lymph nodes and liver. The typical appearance of mesenteric invasion by carcinoid tumor on CT is a mesenteric mass with radiating linear densities representing thickened neurovascular bundles. Liver metastases appear as focal, hypodense lesions on non-enhanced CT scanning(20). The advantage of CT is its ability to localize the tumors precisely in relation to the adjacent structure. CT also remains the most useful roentgenographic method for localization of metastatic carcinoid tumors and evaluation of the response of metastatic carcinoid tumors to therapy. Magnetic resonance imaging (MRI) is a very sensitive technique for the detection of liver metastases, but it appears to be less sensitive for the diagnosis of extra-hepatic disease. MRI needs further evaluation, however, before it is used as primary modality for the diagnosis and staging of carcinoid tumor, (21)but, overall, it appears to have little advantage over CT.

The role of angiography in the diagnosis of carcinoid tumor has been decreased by the availability of the newer imaging methods. Diagnostic angiography generally is employed when noninvasive imaging studies are equivocal and surgery or chemoembolization is contemplated (Figure 29). Figure 14 illustrates the highly vascular nature of neuroendocrine tumor metastases to the liver. It is this hypervascularity of the tumor that distinguished it from other non-endocrine tumors that metastasize to the liver as well as providing insight into the availability of “feeder vessels” for chemoembolization for the reduction of tumor burden. This is particularly helpful in restoring responsiveness to octreotide, reducing tumor load and lessening the biochemical deviations, which in the case of serotonin for example may reduce the risk of development of carcinoid heart disease. Liver metastases from carcinoid tumors vary in size and usually are vascular, with abundant neovascularity demonstrable on angiography. Percutaneous transhepatic portal and systemic venous sampling with hormone assay is not a very useful technique for the localization of carcinoid tumors. Positron emission tomography (PET) has been used to image neuroendocrine gastrointestinal tumors, but experience thus far is very limited. Most patients who have been studied had classical midgut tumors and the carcinoid syndrome. Both tryptophan and 5-HTP have been used as tracer substances, but initial studies showed that only 11C-5-HTP was taken up in serotonin-producing tumors(22). PET has been shown to be capable of identifying midgut carcinoid tumors that have metastasized to a variety of sites, and it may be of value in monitoring the effects of treatment(23).

Figure 25. Angiography of a neuroendocrine tumor(19).

Figure 26. Retrospective Image Fusion: CT and Scintigraphy (SRS): Enhanced ability to identify NET by image fusion technique using CT and Scintigraphy.

The first report of ¹³¹I-MIBG for the imaging of a carcinoid tumor was that of Fischer and colleagues in 1984, in which hepatic metastases that were seen as photopenic areas on a 99mTc-phytate liver scan concentrated (24) ¹³¹I-MIBG(25). Since this initial description, there have been a number of reports of successful imaging of carcinoid tumors using ¹³¹I-MIBG. The number studied are far less than those reported for pheochromocytomas or neuroblastoma, however, but it probably is fair to say that the sensitivity is significantly lower(134-137). The overall sensitivity is calculated to be 55%. Because MIBG is taken up by a wide variety of neuroendocrine tumors, specificity depends on the certainty of the clinical and biochemical diagnosis. In the correct clinical context, this is well over 95% for pheochromocytomas (26) and neuroblastoma, (27-29)but it is clearly less for carcinoid tumors.

Recently, somatostatin receptors have been identified on most endocrine tumors, including carcinoid tumors, which generally express a high density of the receptors. Five human somatostatin receptor subtypes have been cloned so far, and the binding affinity of octreotide may depend on the subtype(s) expressed(30). SOM-230 is a new somatostatin analogue with potency to bind SSTR2,SSTR3 and SSTR5.

Figure 27. Summary of the expression of the SSTR subtypes analysed by Reverse transcription Polymerase Chain Reaction (RT-PCR) SSTR 2 are expressed in majority or neuroendocrine tumors and shows high binding affinity to somatostatin analogues. SSTR5 are rarely expressed by neuroendocrine tumors.(30).

Tumors that express sst₂ or sst₅ can be visualized in vivo after injection of the radio-labeled compound. Several different imaging agents that bind to the receptor have been studied(31). I-Tyr3-octreotide was the agent initially used, but it has several disadvantages, including a short half-life, biliary excretion obscuring potential tumor sites, with liver accumulation and difficulties with conjugation. The development of(32). In-DTPA octreotide, with a half-life of 3 days and renal excretion, has obviated many of these difficulties. The most widely used analogue for scintigraphy is currently(32). In- DTPA⁰ octreotide,( Octreoscan, Tyco healthcare, Mallinckrodt, St Louis USA,(33). Apart from this, In pentreotide [In-DOTA⁰] lanreotide can also be used(34),(35).

Figure 28.  

The efficacy of peptide receptor scintigraphy with(32). In-DTPA octreotide was evaluated in a European Multicenter Trial (EMT) in 350 patients with a histologically or biochemically proven neuroendocrine GEP tumor(36). Tumor sites were detected by conventional imaging methods in 88%, whereas somatostatin receptor scintigraphy was positive in 80%. The highest success rates of somatostatin receptor scintigraphy were observed with glucagonomas (100%), Vipomas (88%), carcinoids (87%), and nonfunctioning islet cell tumors (82%). The low detection rate (46%) noted for insulinomas is related to the lower incidence of sst₂ somatostatin receptors on insulinoma cells. However, the overall 80% sensitivity found is somewhat lower than the 88% obtained by Krenning’s group (68) in Rotterdam, who studied 130 patients with GEP tumors. This may be related to important differences in scanning procedures such as the amount of radioligand administered (minimal dose of(32).In of 200 MBq and at least 10 mg of peptide by the Rotterdam group), the duration of the acquisition, and the use of single photon emission computed tomography (SPECT) (with a triple-head camera by Krenning and colleagues). The fact that abdominal SPECT was not systematically performed in all patients of the EMT may explain that only 73% of gastrinoma patients had a positive scan compared to the 90 to 100% sensitivity reported in other studies. In the EMT, a total of 388 sites were visualized with conventional imaging methods in 308 of the 350 patients. In addition to 297 known localizations, somatostatin receptor scintigraphy revealed another 166 unsuspected lesions. Forty percent of these unsuspected lesions were subsequently confirmed as true positive findings based on the results of additional imaging procedures or histology obtained during the 1-year follow-up period. The clinical relevance of detecting additional tumor localizations is very dependent on the clinical status of the patient. The demonstration of an unsuspected lesion in a patient with known metastatic spread usually has little impact on the management. In contrast, the detection of unsuspected tumor sites in patients with a single known lesion or without any known lesions is important in that it may affect patient selection for curative surgery, which remains the treatment of choice for patients with this type of tumor. In the cohort of 350 patients studied, 42 had no lesion detected by conventional imaging modalities (CIM) and 178 were known to have a single tumor localization prior to the study. Somatostatin receptor scintigraphy was positive in 11 of the 42 patients (25%), and 12 of 16 lesions revealed by somatostatin receptor scintigraphy were further confirmed as true positive. Somatostatin receptor scintigraphy demonstrated multiple tumor sites in 62 of the 178 patients (35%); 60% of these lesions were confirmed by follow-up (1-year) procedures. A reply to an impact questionnaire was obtained for 235 patients. Overall, the scintigraphic findings led to management changes in 40% of the 235 patients. One center extended their number of patients and reported the results separately in more detail (37) (38,39).

Gibril et al. compared in a prospective study the sensitivity of somatostatin receptor scintigraphy with that of CT, MRI, ultrasonography, and selective angiography in the detection of primary and metastatic gastrinomas(39). Their conclusion was that somatostatin receptor scintigraphy is the single most sensitive method for imaging either primary or metastatic liver lesions in patients with Zollinger-Ellison syndrome. The same group studied the effect of somatostatin receptor scintigraphy on clinical management based on the data of this comparative study (40,41). Since this technique altered management of 47% of the patients and because of its superior sensitivity, high specificity, simplicity, and cost-effectiveness, they concluded that somatostatin receptor scintigraphy should be the initial imaging modality for patients with gastrinomas. It is likely that the conclusion drawn from this study can also be extended to other pancreatic endocrine tumor syndromes except insulinomas(39).

Knowledge of the fact that other processes can be somatostatin receptor positive is crucial for interpretation of these scintigrams(36). This has been re-emphasized recently by Gibril et al.(41). They report on the sensitivity of this technique and the importance of (1) having a thorough understanding of diseases or circumstances that result in false-positive localization and (2) including the clinical context at the time of reading and interpretation. Unjustified alteration in management can be reduced to below 3% of all ¹¹¹In-DTPA octreotide scintigraphy studies in this way.

Figure 29. Octreoscan showing extensive metastases to sternum, clavicles, ribs and base of brain.

Thus, octreotide scintigraphy has benefit in identifying small primary tumors and liver metastases. This imaging technique is also valuable in identifying metastatic disease to extra-abdominal sites (Figure 29). Figure 30 demonstrates the Octreoscan finding in a patient with malignant metastatic disease to the base of the brain, sternum, clavicles and ribs. This turns out to be helpful from at least two points of view. Firstly, the fact that the metastases take up the tracer suggest responsiveness to treatment with octreotide. Secondly, the recognition that there are bony metastases using and octreotide tracer suggests treatment with bisphosphonates, which as in other malignancies involving bone appear to have a salutary effect on symptoms and may, although this has not been studied in detail, abrogate the rate of tumor growth in this site.

In addition to tumor imaging, octreotide scanning may be useful in predicting responses to octreotide. One recent study showed that 22 of 27 patients with carcinoid tumor and positive scans responded to octreotide, whereas all three patients with negative scans failed to respond(42). Other investigators have shown similar results(43).

In the remaining cases, in whom the tumor has not been identified by the above techniques, total-body venous sampling with measurement of a peptide hormone that is produced may be considered. Measurements of serotonin may be misleading, but those of SP may well direct attention to the source of overproduction of the peptide. This has proved useful in SP-producing tumors(44).

Figure 30.  

Figure 31.  

Carcinoid syndrome occurs in less than 10% of patients with carcinoid tumors. Principal features include flushing, sweating, wheezing, diarrhea, abdominal pain, endomyocardial fibrosis, and pellagra. Diarrhea is found in 76-83% of cases, flushing in 94%, (45), heart valvular disease and abdominal cramping each in about 50%, dyspnea in 20%, and bronchospasm in 6%. A variety of other symptoms such as wheezing, edema, cyanosis, pellagra and arthropathy occur much less frequently (Figure 10). The relationship between diarrhea and flushing is variable. One can occur without the other, and there may be no temporal relationship between the two. The specific etiologic agent or agents for each of the protean manifestations of the carcinoid tumors are not known. Serotonin, (45,46)prostaglandins, (46)5-HTP, (47,48)SP, (44,49), kallikrein, (50)histamine, (51)dopamine, (52)and neuropeptide K (53) are thought to be involved in the clinical manifestations of carcinoid tumors. In addition, symptoms may relate to overproduction of peptides in the pro-opiomelanocortin family (e.g., endorphin and enkephalin). Pancreatic polypeptide and motilin levels often are raised, (54)may be important markers of tumor activity, and may provide a means of monitoring tumor growth and response to therapy rather than contributing to specific symptomatology.

Feldman and O’Dorisio (55) (56) examined the proportion of 43 patients with carcinoid tumor having increased levels of serotonin and various other vasoactive peptides(56). Serotonin, measured either as its urinary metabolite 5-HIAA (57) or whole-blood serotonin, (58,59) was raised in 84% of patients with carcinoid tumors and within normal limits in patients having other tumors and miscellaneous illnesses. Urinary 5-HIAA alone had 73% sensitivity and 100% specificity. Seven of these patients had normal urinary 5-HIAA levels but other elevated indices of serotonin production. Neurotensin and SP were raised in 43 and 32% of patients and had specificity values of 60 and 85%, respectively. False-positive results occurred in 23 and 26%, respectively, of patients with conditions other than carcinoid tumors. Motilin and somatostatin were raised in 14 and 50%, respectively.

These humors may prove useful as an aid in the localization of ostensibly occult carcinoid tumors. Whole-body venous sampling with measurements of plasma serotonin erroneously localized the tumor to the neck, for which a negative exploration was carried out; however, SP levels correctly localized certain of these tumors(44).

Flushing, a cardinal symptom of carcinoid tumors occurs in a variety of other conditions that need to be distinguished (Fig.35). A good rule of thumb is that if the flushing is wet it is due to a cause other than carcinoid. Table 35 lists the variety of causes that are confounding and the features that help distinguish them from flushing de to carcinoid.

Figure 35. Various tests to identify the cause of flushing.

Flushing in carcinoid syndrome is of two varieties. First, with midgut carcinoid, the flush usually is of a faint pink to red color and involves the face and upper trunk as far as the nipple line. The flush is initially provoked by alcohol and food containing tyramines (e.g., blue cheese, chocolate, red sausage, and red wine). With time, the flush may occur spontaneously and without provocation. It usually is ephemeral, lasting only a few minutes, and may occur many times per day but generally does not leave permanent discoloration.

In contrast, in the second type, the flush of foregut tumors often is more intense, of longer duration, purplish in hue, frequently followed by telangiectasia, and involves not only the upper trunk but may also affect the limbs. The limbs may become acrocyanotic, and the nose resembles that of rhinophyma. The skin of the face often thickens, with the appearance of a leonine facies resembling that seen in leprosy and acromegaly.

Flushing cannot always be attributed to carcinoid syndrome. The differential diagnosis of flushing includes the postmenopausal state, simultaneous ingestion of chlorpropamide and alcohol, panic attacks, medullary carcinoma of the thyroid, autonomic epilepsy, autonomic neuropathy, and mastocytosis. (Table 35).

Flushing in carcinoid syndrome has been ascribed to prostaglandins, kinins, and serotonin (5-HT). With the advent of sophisticated radioimmunoassay methods and region-specific antisera, a number of neurohumors now are thought to be secreted by carcinoid tumors, including serotonin, (45)dopamine, (52)histamine, and 5-HIAA, (51)kallikrein, (48)SP, (47)neurotensin, (55)motilin, (44,55)SRIF,(169) VIP, (61)prostaglandins, (62)neuropeptide K, (53)and gastrin-releasing peptide (GRP)(55).

Feldman and O’Dorisio have previously reported the incidence of elevated levels of plasma neuropeptide concentrations(55). Despite the elevated basal concentrations of SP and neurotensin, these authors were able to document further increases in these neuropeptides during ethanol-induced facial flushing. We support this contention and hasten to add that neuropeptide abnormalities frequently occur in patients with other forms of flushing and may be of pathogenetic significance(63).

Several provocative tests have been developed for to identify the cause of flushing in carcinoid syndrome (Table 7). These tests are based upon the need to distinguish the flushing from that found in a host of other conditions particularly in panic syndrome in which the associate anxiety and phobias usually establish the cause but frequently the physician and patient need reassurance that there is no underlying malignancy.

Ahlman and colleagues (64) reported the results of pentagastrin (PG) provocation in 16 patients with midgut carcinoid tumors and hepatic metastases. All patients tested had elevated urinary 5-HIAA levels, and 12 had profuse diarrhea requiring medication. PG uniformly induced facial flushing and GI symptoms in patients with liver metastases, but it had no effect in healthy control patients. All patients with PG-induced GI symptoms demonstrated elevated serotonin levels in peripheral blood. Administration of a serotonin-receptor antagonist had no effect on serotonin release but completely aborted the GI symptoms. The authors emphasized the improved reliability of PG compared with calcium infusion, another provocative test popularized by Kaplan and colleagues, (65)and pointed out that PG provocation occasionally can be falsely negative in patients with subclinical disease. Our own experience is that PG uniformly induced flushing in 11 patients with gastric carcinoid tumors that was associated with a rise in circulating levels of SP in 80%(66). Thus, SP is one neurohumor that may be involved in the flushing of carcinoid syndrome.

Figure 36.  

Substance P has been found in tumor extracts and plasma from patients with carcinoid tumors and, in one reported case, was useful for tumor localization(44). Neurokinin A, its amino-terminally extended form, neuropeptide K, and SP are a group of peptides (i.e., tachykinins) with common biologic properties (67,68). Norheim and colleagues (68) measured peptide responses to PG or ingestion of food or alcohol in 16 patients with metastatic carcinoid tumors and demonstrated two-fold or greater increases in neurokinin A and neuropeptide K in 75% of patients, as well as variable increases in SP in approximately 20% of patients(69).

Conlon and colleagues (67) used region-specific antisera to SP and neurokinin A to measure circulating tachykinins during a meal-induced flush in 10 patients with metastatic carcinoid tumors. Five patients had undetectable levels of neurokinin A and SP after stimulation, thus suggesting that elevated tachykinin concentrations are not a constant feature of such patients. The authors also studied the effect of a somatostatin-analogue administration on meal-induced tachykinin responses in three patients with carcinoid tumors. Flushing was aborted in two patients, but tachykinin levels were only partially suppressed, indicating that these peptides cannot be solely responsible for the carcinoid flush. When the diagnosis of the underlying cause of flushing has been established, pathogenesis oriented treatment can be very helpful (Table 36).

Three cases presented with longstanding flushing, abdominal pain, diarrhea and facial telangiectasia (2-20 years). The only biochemical abnormalities were elevated calcitonin levels and positive Pentagastrin and calcium stimulation tests. Venous sampling localized the overproduction to the thyroid. Histology of the thyroid showed C cell hyperplasia. Symptoms improved to a large extend after subtotal thyroidectomy in one case and resolved in other two cases after total thyroidectomy. The condition may be a gene mutation but so far the site has not been identified. Ret Proto-oncogene evaluation came to be negative. All cases of flushing and diarrhea should have a calcitonin measurement. Total thyroidectomy is the treatment of choice for this syndrome. Histology of the thyroid of those cases can be seen with C cell hyperplasia shown by arrows in Figure 37.

Figure 37. C cell staining with H&E and Immunohistochemical method. C cells are identified with difficulty in sections stained with hematoxylin and eosin, where they appear polygonal and with a granular weakly eosinophilic cytoplasm that is larger and paler than that of follicular cells. (Fig 1a,c,e) (See arrow). When compared with sections from the same patients using immunohistochemical staining, C cells as more readily identified part of the follicular epithelium and as isolated cluster between follicles

The diarrhea syndrome that occurs with carcinoid tumors usually is of a secretory nature. In fact all endocrine diarrheas are secretory in nature and in the absence of this feature the usual cause is gastroenterological. Common secretory diarrheas are those found with the WDHHA syndrome, medullary carcinoma of the thyroid, Gastrinoma syndrome and villous adenomas of the rectum. Diarrhea persists with fasting or fails to disappear when feeding has been curtailed and sustenance given by the intravenous route. Perhaps one the most vexing problems is to exclude factitious diarrhea induced by for example laxative abuse. In this case measurement of stool osmolarity and electrolytes can be very revealing. An osmolar gap (i.e. there are osomoles not accounted for by the electrolytes) (Figure 38) suggests the presence of laxatives which can then be readily identified in the stool using KOH.

Figure 38.  

There are, however, a number of other causes of secretory diarrhea, but virtually all endocrine diarrheas are secretory in nature. A history of improvement in the diarrhea with administration of H₂-receptor antagonists is strongly suggestive of the gastrinoma syndrome. Hypercalcemia is frequent with VIP-secreting tumors and steatorrhea and, for all intents and purposes, occurs only with the Zollinger-Ellison syndrome. Figure 39 illustrates the essential differences in the mechanisms involved in generation of diarrhea that occurs in the VIPoma, PPoma, Medullary Carcinoma of the thyroid tumors and the Zollinger Ellison (Gastrinoma) syndrome (Figure 39). In essence the humors that stimulate gastrointestinal secretions such as VIP increase the rate of fluid delivery from the proximal to the distal small intestine that exceed the absorptive capacity of the distal intestine. The diarrhea is watery in nature and there is great loss of bicarbonate and potassium ions. Hence, the term: Watery Diarrhea, Hypokalemia, Hypochlorhydria, Acidosis syndrome (WDHHA). This form of diarrhea persists with fasting and in the absence of a history to support this contention placing the patient on NPO while giving fkuids IV rapidly establishes wheter the diarrhea is secretory in nature or malabsorptive.In contrast the gastrinoma diarrhea is due to stimulation of gastric acid secretion by the tumor. Acid in the duodenum and small intestine inactivates lipase, amylase and trypsin, damages the mucosa of the small bowel precipitates the succus entericus thereby decresing absorption of nutrients and imparing digestion leading to a secretory diarrhea with elements of malabsorptiuon and or steatorrhea. Clinically this can be distinguished by asking what happens to the diarrhea with the use of a proton pump inhibitor or an H₂ blocker. Also demonstration of the very acidic nature of gastric acid secretion can be helpful. Marked metabolic acidosis with bicarbonate wasting usually is only a characteristic of VIP-secreting tumors.

Figure 39.  

The villous adenoma of the rectum causing secretory diarrhea is notoriously rare, and although it is referred to in many texts, most physicians have yet to see a case. A disturbing cause that may be very difficult to differentiate is laxative abuse, and, in all circumstances, a KOH stool preparation to detect laxatives is mandatory. Measurement of intestinal secretion by passing a multilumen tube and quantifying electrolytes and water transport, in addition to the measurement of stool electrolytes, which should account for the total osmolarity, will help to exclude laxative abuse.

Figure 40.  

With the advent of modern therapy for carcinoid tumors, the longer survival is unveiling a high incidence of carcinoid heart disease. There is indeed a parallel with the idiopathic fibroelastosis found in Africa amongst consumers of the casava plant rich in serotonin precurors. Similarly the surge in interst in the cardiac fibroelastosis found in patients on long-term, high dose serotonin reuptake inhibitors has revealed a possible parallel pathogenesis to the carcinoid heart. All three condtions demonstrate the fibroproliferative endomyocardial changes found most commonly in the right ventricle and involving the tricuspid and pulmonary valves leading to stenosis or incompetence of these valves. Figure 40 indicates the difference in symptomtology between right heart failure and carcinoid symptoms. While there should be no mistaking these comditions it is not surprising that faced with a patient who is suffering from flushng, wheezing and bronchospasm the occurrence of dyspnea, fatigue and edema might go unnoticed. This can be particularly devastating since the advent of heart failure heralds a very poor prognosis. Its occurrence doses not appear to be predicated by the bulk of the tumor, the duration of symptoms, location of the primary tumor but rather the level of serotonin in the blood. Values greater than 1000pg/ml seem to consort with the development of carcinoid heart disease. Possibly for this reason alone, in treating these patients all attempts should be made to keep serotonin levels down in addition to relieving symptoms and slowing or abrogating tumor growth. Carcinoid heart disease is a unique heart disease associated with this cancer and may be seen in up to 60% of patients with metastatic carcinoid. Valvular disease is the most common pathologic feature and tricuspid damage is found in 97% and pulmonary valve disease in 88% with 88% displaying insufficiency and 49% stenosis. The distinctive carcinoid lesion consists of deposits of fibrous tissue devoid of elastic fibers known as carcinoid plaque. The deposits are found on the endocardial surface on the ventricular aspect of the tricuspid leaflet and on the arterial aspect of the pulmonary valve cusps(70). Most patients have the distinctive lesions on the right side of the heart. In the setting of bronchial carcinoid, the left-sided lesions on the mitral valve may be so extensive as to cause mitral stenosis. Ovarian carcinoids are the rare variety in which cardiac involvement occurs without metastases to the liver. No doubt because of the direct drainage of the ovarian veins into the systemic circulation. The consequence of the downstream deposition of plaque is to cause an adherence of the leaflet to the mural endocardium so as to cause tricuspid incompetence with a degree of narrowing of the ostium and stenosis. The pulmonary valve becomes narrowed and stenosis ensues. Carcinoid heart disease is the only condition in which both right-sided valves are involved and the combination of pulmonary stenosis and tricuspid regurgitation occur. The development of pulmonary stenosis favors the development of tricuspid regurgitation.

The condition can be diagnosed clinically. In approximately 20% of patients with carcinoid disease the presenting symptom may be attributable to heart failure(71). Ninety five percent of patients have the diastolic murmur of tricuspid incompetence and 13% the precordial systolic murmur of pulmonary stenosis. The chest radiograph may show an increase in the cardiothoracic ratio in 38% of cases and is not a sensitive measure(70). The electrocardiograph characteristically shows low voltage in that the sum of the QRS voltage in the standard leads 1, 11, and 111 is less than 15 mm, but evidence of right ventricular hypertrophy is rare. Transthoracic echocardiography, both M-mode and cross-sectional may show dilated right ventricular cavity and abnormal movement of the ventricular septum as well as thickened and retracted tricuspid leaflets with a fixed orifice but is not very sensitive, being positive only in only two thirds of (15/20) patients with clinical evidence of carcinoid heart disease at the time(72). Transesophageal echocardiography may be more sensitive than transthoracic (71% vs 57% of 31 patients with ileal carcinoid) and allows for measurement of the thickness of the A-V valves(73). Doppler echocardiography was examined by Pellika and colleagues (74) in 132 patients with carcinoid syndrome. They found 74 (56%) with Doppler echocardiographic features of carcinoid heart. Ninety seven percent had thickened and shortened tricuspid leaflets and 100% had tricuspid regurgitation. A dagger-shape spectral profile with an early peak pressure and rapid decline was characteristic. The pulmonary valves were thickened, retracted and immobile in 59% and of these regurgitation was present in 81% and stenosis in 53%. Left-sided lesions were found in patients with patent foramen ovale in 7%, metastasis to the myocardium in 4% and small pericardial effusions in 14%. The 3-year survival in their series was reduced from 68% to 31% in those with carcinoid heart disease. Hemodynamic tests show the expected pulmonary stenosis and tricuspid valve regurgitation and are only indicated for decision making with regard to possible valvulotomy. A Doppler gradient of >10mm Hg is considered by one group to indicate a need for pulmonary valvulotomy(75).

The pathogenesis of the plaque is not completely understood. The plaque is composed of smooth muscle cells, myofibroblasts and an overlying endothelial cell layer. The smooth muscle cells and the myofibrils are surrounded by an extracellular matrix of microfibrils, acid mucopolysaccharides, collagen fibers and basement membrane. Serotonin infusion in the presence of hepatic injury or tryptophan or niacin deficiency in animals leads to similar lesions(76). A similar condition is also observed in Uganda, with large consumption of the Cassava plant which is rich in tryptophan, the precursor of serotonin. Similarly the recent discovery of an analogous heart condition in obese patients taking phen/fen for weight reduction is thought to be due to the enhanced release of serotonin and decreased serotonin reuptake exposing the heart valves to much higher concentrations of 5 hydroxytryptamine(77). Fenfluramine and dexfenfluramine (Phentermine) are appetite suppressants that were in widespread use in the United States. On July 8th 1997, 24 case of valvular heart disease were reported in women who had been treated with the combination for about one year. Regurgitation was found in all cases. Both right and left-sided heart valves were involved. Eight women developed pulmonary hypertension. Cardiac surgical intervention was required in 5 patients at the time of reporting. The histological features were similar to those observed in carcinoid-induced valvular disease, a serotonin-related syndrome. Based on these observations the FDA issued a public health advisory and sent letters to 700,000 US health care practitioners advocating the immediate cessation of further prescriptions. The rarity of the syndrome in patients with bronchial carcinoids may be ascribable to the production only of 5 hydroxytryptophan rather than the amine, serotonin.

Lundin (78) and colleagues (1988) reported on 68 patients with midgut tumors 50 of who had carcinoid syndrome. Eighty nine percent had elevated 5HIAA and the patients with severe right sided heart disease had significantly higher mean values (9800 vs 2190 umol/day). Pellika et al (74) reporting on the Mayo experience found higher urinary 5HIAA in their 84 patients with carcinoid heart compared with the remainder of the 132 patients studied (270 vs 131 mg/day). Robolio et al (79) reported on the Duke carcinoid database of 604 patients found strikingly higher plasma serotonin (1130 vs 426 pmol/ml) and urinary 5HIAA (219 vs 55 mg/day) in 119 patients with carcinoid heart than in 585 patients with tumors. Thus there is considerable circumstantial evidence to implicate serotonin per se in the pathogenesis of carcinoid heart. Our own experience is that treatment of patients with carcinoid syndrome with Octreotide often ameliorates the clinical syndrome but does little to lower serotonin levels and the heart disease progresses while the condition appears to regress and(80). The finding by (78) in (1988) of higher levels of neuropeptide K and substance P in patients with midgut carcinoids and heart disease may simply reflect the advanced stage of the disease since these are potent vasodilators and are not known to be able to influence the development of the characteristic plaque. Similarly their report (81) of higher levels of Atrial Natriuretic Peptide (ANP) in patients with carcinoid heart may only reflect upon the development of failure, a known cause of increases levels of ANF.

Figure 41.  

The dismal prognosis of patient with carcinoid heart disease of < 20% 5 year survival compared with > 66% in patients with tumors treated with Octreotide dictates a much more aggressive approach to management. Up to 1995, 38 patients had been reported with either single case studies or small series of patients who had undergone valve replacement. There were no significant differences in survival of patients with bioprosthesis vs a mechanical prosthesis in the tricuspid valve position. The 4 year survival was improved to 48±13%.(77).In the Mayo and Duke experience (194) in 26 and 8 patients respectively, up to 30% die within the first 30 days of operation. Predictors of operative mortality are low voltage in the standard EKG leads (QRS in leads 1,11,111 <15mm), high preoperative serotonin and age > 60 years (>56% mortality). Long term survival was predicated by low serotonin values and none of the patients <60 years died early. All who survived had symptomatic improvement. Balloon valvulotomy has had mixed results. Somewhat surprisingly Rayson and colleagues report four patients with severe carcinoid heart disease who had regression of their metastatic tumors postoperatively.(82). Further descriptions of tumor status in patients who have had cardiac surgery to confirm or refute this observation are clearly necessary and it would be of considerable interest and therapeutic potential to determine the possible mechanism thereof.

Thus if the distinction between symptoms due to cardiac disease are recognized early, before there is marked elevation of the serotonin levels, especially in patients under the age of 60 years and without EKG evidence of low voltage, it is probably prudent today to aggressively replace the tricuspid and pulmonary valves. Since the long-term durability of bioprosthetic valves is > than the 20% 5 year survival of untreated patients this is not an issue. Prolongation of life can be achieved and more importantly the quality is greatly enhanced for the remaining years.

There are a number of skeletal complications of malignant neuroendocrine tumors which may be from the tumor itself which has metastasized to bone or paraneoplastic plows or be the results of therapy. The ramifications of NETs are listed below:

Metastses from NET are both lytic and osteoblastic.Meijer et. al study (83) showed osteolytic and osteoblastic bone metastases by plain radiography in carcinoid patients with bone metastases There may be an increased osteoclast activity contributing to lytic lesions and or an increase osteoblastic activity responsible for blastic metastases..

A possible explanation for the high rate of bone metastases could be due to the therapeutic use of various somatostatin analogs and interferon- . These agents relieve symptoms mediated by amines secreted by the tumor (84) but have only a limited effect on tumor growth(85). As a result, therapy with newer somatostatin analogs and interferon-alpha can lead to a prolonged survival and a greater impact of symptoms related to bone tumor growth. In such cases, bone metastases, associated with advanced disease, may increasingly cause symptoms in carcinoid patients related to bone such as pain, fractures, and spinal cord compression.

Figure 42. Bone metastases mechanism in neuroendocrine tumors showing the spread of neoplastic cells from the primary tumor invading blood vessels and spreading as emboli to distant regions like bone. Malignant tumor cells adhere to blood vessel at the distant capillary bed in bone to enter the bone matrix through extravasations and then they proliferate inside the bone matrix.

Another explanation for the high rate of bone metastases could be that the uses of imaging techniques like Octreotide scintigraphy which reveals asymptomatic bone metastases, leading to diagnosis of higher rate of bone metastases.

Figure 43. NETs with osteolytic and osteoblastic lesions. OCL:osteoclasts; OB:osteoblasts

NETs are renowned for their production of a host of peptides and amines as well as many cytokines. Thus, it appears that the tumor may foster in due growth as well as that of metastases to bone.

Figure 44. A vicious cycle, interaction between the tumor cells and bone cells.Osteoclastic resorption and osteoblast deposition of bone during mineralization causes stimulation of Bone derived Growth Factors which in turn stimulate the cancer cells which have capability to stimulate both osteoblast and osteoclast through osteoblatic and osteolytic chemokines and thus causing a vicious cycle. TGFβ: Tissue growth factor beta, PTHrP: Parathyroid hormone-related protein, IL: Interleukin, TNF: Tumor necrosis factor, ET: endothelin -1, PDGF: Platelet derived growth factor.

Shown in the figure 44 are some of the proposed mechanisms whereby NETs affect bone turnover. NETs cells are capable of producing both osteoblastic and osteolytic chemokines. The figure shows a partial listing which includes immunoreactive Parathyroid hormone related protein or PTHrp, endothelin -1 (ET-1) shown to bind to an Endothlein A and B receptor mediating osteolysis, various cytokine such as tumor necrosis factor ( TNF a) and interleukins 6 and 11. Perhaps the most significant of these is RANK which binds to its ligand RANKL thereby promoting osteoclastic activity. The natural antagonist is osteoprotegrin (OPG) which binds to RANK and precludes its binding to RANKL inhibiting osteocalstic activity.

While the standard means of detecting bone metastases is radiological e.g. X-ray, bone scan, Octreoscan, bone metastases can be sought with measurement of bone alkaline phosphatase levels along with N telopeptide and 25-OH Vitamin D, 1-25-OH Vitamin D. Following are the different assays for bone. A more complete listing of bone markers that may aid for tumor recognition as well as provide guidelines in therapy and decision making is shown in following figure.

Figure 45. Bone Metastases Screening for Bone Markers & Assays, Bone resorption markers, Markers of malignancy, Markers of cytokine excess and Vit D metabolism. IGF: Insulin like Growth Factor, IL:Interleukin, PTHrP: Parathyroid hormone-related protein, NTX: N-Telopeptide; TGFβ: Tissue growth factor beta.

Bone Markers in Lytic and Osteoblastic Metastases that may assist in the evaluation of stage as well as response to therapy include bone alkaline phosphatase an indicator of osteoblast function and urinary N –telopeptide which reflects osteoclast activity or bone resorption. Somewhat paradoxically only blastic metastases show and increase in both markers as indicated in the figure

Several studies have shown bone markers to be elevated in cancer patients who have documented evidence of metastatic bone disease. Increased levels are also observed in some patients without clinical evidence of bone metastases, when compared with normal subjects. (86)Rises in such markers may be the first indication of bone involvement and therefore may potentially be useful in early diagnosis of progression. Preliminary data suggest bone marker level correlates with the extent of metastatic disease and the number of skeletal sites involved. Markers of bone turnover may be helpful in identifying those patients likely to respond to bisphosphonates treatment.(86)

Figure 46. Bone markers in patients with lytic and blastic metastases. Note here that markers for bone formation-Alkaline Phosphatase and Bone lysis-N-telopeptide are both increased in blastic lesions.(86).

Therapeutic options are mainly based on the drugs, surgery, chemo and radiation therapy. Bisphosphonates, anti TGF beta, anti endothelin acting drugs, Denusumab human monoclonal antibody and antibody that binds RankL are major non invasive options. Surgery and external beam radiation are invasive approach towards the treatment for BM.

The management of bone metastases includes:

Bisphosphonates are effective for the prevention of skeletal complications secondary to bone metastases. IV pamidronate and zoledronic acid are FDA-approved for other malignancies but are in extensive clinical use in NET. There is however, a need for more safe and effective therapies. Renal toxicity and osteonecrosis of the jaw are potential complications associated with bisphosphonates and are of considerable concern in patients with NET(87), (88) ,(89) ,(90) ,(91) ,(92,93). All patients embarking the treatment with bisphosphonates should have an evaluation for possible complications.

Signs and Symptoms of Possible Osteonecrosis of Jaw:

1) Symptoms-

· “heavy jaw”, a dull aching sensation

· numbness/tingling of the jaw

· tooth pain

· undiagnosed oral pain

2) Signs

· rough area on the jawbone

· soft tissue swelling, drainage or infection

· exposed bone in the oral cavity

· sudden change in the health of periodontal tissue

· failure of oral mucosa to heal

· loosening of teeth

Figure 47. Different mechanisms of action of Bisphosphonates. They inhibit osteoclasts formation, migration, osteolytic activity and promotes apoptosis. They also modulate signalling from osteoblasts to osteoclasts.

The direct in vitro effects of bispohosphonates on bone include: Inhibition of growth,(94) ,¯ invasiveness(95),(96) ,­ apoptosis (Derenne et al., JBMR 1999; Senaratne et al., Br J Cancer 2000),¯ adhesion to bone (van der Pluijm et al., JCI 1996; Boissier et al., Cancer Res 1997), Inflammatory effects on T cells, Anti-angiogenic. None the less the clinical impression is that symptoms (pain) may be relieved, little is done in the growth of the tumor. While we have used pamidronate exclusively, a recent report (97) suggests that Zoledronate is the more preferred agent. Prospects for alternative therapies are in the research area.

1) TGFb:

TGF β is a Multifunctional Cytokine responsible for a number of effects in bone:

2) Endothelin Receptor ET-1:

Endothelin Receptors are responsible for a number of effects in bone:

Endothelin receptors are novel targets in the therapy for tumors with bone metastases. Phase II trials with Endothelin A Receptor (ETAR) antagonist, Atrasentan, in metastatic hormone resistant prostate cancer to bone, showed increased time for clinical progression of the disease as well as slow rise in PSA levels(98). In another Phase II trial with Atrasentan, they showed decreases levels of markers for bone remodeling after treatment with Atrasentan(99). Treatment with an orally active Endothelin A receptor antagonist dramatically decreased bone metastases and tumor burden in mice inoculated with ZR-75-1 cells(100). Tumor-produced endothelin-1 may have a major role in the establishment of osteoblastic bone metastases, and endothelin A receptor blockade represents effective treatment(100).

Outcome

Brown (2005) evaluated the outcome of the tumor metastases to bone and found that increased Osteoclast activity predicts a poor outcome(101).

(101)

The general prognosis in carcinoid tumor is excellent compared with that of other visceral cancers. Based on a world literature of some 2,837 cases, the median 5-year survival rate for all cases is 82%(102).

Figure 48.  

If, however, the tumor is localized, then the 5-year survival is 94%, decreasing to 64% with regional lymph node involvement and 18% with distant metastases. Davis and colleagues (3) reported a mean survival of 38 months from the first episode of flushing, with 25% of patients living for more than 6 years. With regional lymph node involvement, the figure falls to approximately 14 months,(103) and with urinary 5-HIAA in excess of 150 mg per 24 hours or inoperable tumors, median survival is only 11 months (102)(Table 12).

Surgical removal of the primary tumor is the treatment of choice for small and localized tumors as well as for the alleviation of any obstructive symptoms, but surgical cure of carcinoid tumor is almost impossible in the presence of intra-abdominal and hepatic metastases. Different chemotherapeutic agents (198) and surgery or arterial embolization (104) have been used with variable success, but eventual relapse with increasing resistance to the drugs is encountered(102). Because the carcinoid is a slow-growing tumor, even patients with extensive metastatic disease can enjoy a normal quality of life so long as the endocrine syndrome is quiescent. Different chemical agents such as methysergide, cyproheptadine, heparin, phenothiazines, a-adrenergic antagonists, corticosteroids, H₁ and H₂ antihistamine blockers, symptomatic treatment of diarrhea with opioids, and codeine have been tried with variable results(102). Because somatostatin has very broad inhibitory effects, somatostatin-14 has been used successfully to suppress diarrhea and flushing in patients with carcinoid tumors (105) but, its clinical use is limited by its short half-life (106) and the resulting need for continuous intravenous infusion. The advent of the long-acting somatostatin analogue octreotide, has resolved problems with short half life time and it has been used in the treatment of different neuroendocrine tumors, including carcinoid.

Various chemotherapeutic agents, including parachlorophenylalanine, cyproheptadene, methotrimeprazine, corticosteroids, aprotinin, phenoxybenzamine, and numerous antineoplastic agents have been used in carcinoid syndrome with variable success (61,107). These medications either, inhibit serotonin synthesis, or act as systemic antagonist of serotonin, or block kallikrein release. Most recently, somatostatin-14 and its long-acting analogue, octreotide, have been used successfully to control the symptoms of diarrhea and flushing (105) (108) (109) (4) in the carcinoid syndrome.

There is the potential to deliver therapeutic doses of radiation to those tumors in which there is intense and prolonged tumor uptake of tracer doses of MIBG. Target-to-background ratios with tracer doses that achieve diagnostic imaging may not, however, always permit the delivery of therapeutic radiation when large doses of activity are administered (127,128,128) (221-223).

At present, therapy for carcinoid tumor with MIBG is considered to be highly experimental. Possible guidelines for its employment based on the experience with other neuroendocrine tumors would include (a) lesions not readily treatable by alternative modalities, (b) patients with life expectancies sufficient to permit beneficial effects to become apparent (e.g., > 6 months or 1 year), and (c) undertaking dosimetric studies for whole-body and blood-absorbed radiation dose using tracer doses to guide the size of therapeutic administrations (24,127,128) (221-223). The bone marrow and, especially, the platelets appear to be the dose-limiting tissues for MIBG therapy. Typical doses to date have been in the range of 100 to 250 mCi per administration, with cumulative doses sometimes exceeding 600 mCi. In addition, if at all possible, the absorbed radiation dose to one or more representative tumors should be determined from serial scintigraphic images. From these, the initial uptake and biologic reaction time of retention can be determined; the use of conjugate view technique with the inclusion of standard sources may be especially helpful(12). Tumor volume also must be determined by CT or another modality. This can be used with Medical Internal Radiation Dose (MIRD) formulas to calculate the radiation-absorbed dose(129).

The ability of somatostatin analogues to bind to GEP tumors has suggested other novel therapeutic approaches. Conjugating somatostatin with high energy gamma-emitters, short-acting alpha-particle emitters, or tumoricidal toxins such as ricin or modified diphtheria toxin has been proposed.(130,131). Although similar strategies have been used to deliver tumoricidal agents to other types of tumors, there are few data thus far on the therapeutic effectiveness of such an approach in GEP tumors.

Today, angiography frequently is used for therapeutic purposes. Hepatic artery embolization has proved to be a relatively safe procedure for the palliation of carcinoid syndrome related to an excessive hormone production from hepatic carcinoid metastases (132)(Fig 12).

Figure 52.  

This method usually is beneficial to the patients whose hepatic metastases have failed to respond to chemotherapy and other pharmacologic therapy (87%). Gelfoam powder (particle sizes, 80–200µM) and Ivalon particles (sizes, 149–250 µM) are the agents frequently used for devascularization of the hepatic metastases.

Several authors have described their experience with hepatic artery ligation or embolization in patients with malignant carcinoid tumors(133,134). In one study, the former procedure resulted in objective tumor responses in 9 of 19 patients, stable disease in 5 of 19 patients, and progressive disease in 4 of 19 patients when they were assessed 6 and 12 months after the procedure(134). Two patients died 1 and 3 months postoperatively from complications including liver abscesses, and the remainder of patients experienced mild abdominal pain, fever, and fatigue that was self-limiting. Hepatic artery gelfoam embolization performed in eight patients resulted in three objective responses and five with stable disease. Toxicity from this procedure included fever, abdominal pain, nausea, and elevation of serum hepatic enzymes, which returned to normal within 12 days. Overall, the duration of palliation tends to be short-lived(135). Hepatic arterial occlusion combined with sequential chemotherapy has resulted in an 80% response rate, with a median duration of 18 months (232). Although hepatic artery occlusion may produce subjective and objective responses in the majority of highly selected patients, the toxicity and duration of responses resulting from this therapy generally do not support its routine use(135).

High dose ¹¹¹In-pentetreotide therapy is effective in stabilizing progression of disseminated neuroendocrine tumors (Delpassand, E.S., Safety and Efficacy of radionuclide therapy with multiple 500 mCi doses of In-111 Pentetreotide in patients with progressive NETs.)

No available data support the use of radiation therapy in patients with metastatic carcinoid unless they have symptomatic bone metastases, spinal cord compression, or bronchial obstructions that are all amenable to this modality of treatment.

There are two components: embolisation and brachytherapy. The embolisation procedure is defined with the angiographic endpoints of embolisation and stasis with the need to modify the delivery according to angiographic findings under fluoroscopy. Brachytherapy is defined as the administration and delivery of internal radiation with modification of dose based on tumor and target volume. (136)

Currently two different ⁹⁰Yttrium microsphere products, glass microsphere and resin microsphere are available. Resin microspheres have received FDA premarket approval for hepatic metastasis from colorectal cancer, concurrent with flurodeoxyuridine (FUDR). There has been no direct comparision of the efficacy of the two microsphere products. (136)

⁹⁰Yttrium microsphere therapy is a complex procedure that requires multidisciplinary approach management for safety and success as shown in Fig.55(136).

The benefits of internal radiation to the liver includes low toxicity, low amount of radiation used, and ability to retreat the liver for new lesions or incompletely destroyed original lesions .Extensive pior systemic and non-radioactive hepatic therapy did not interfere with the successful delivery of ⁹⁰Yttrium microspheres(137).

Figure 53. Treatment algorithm for 90yttrium microsphere brachytherapy(136).

In malignant carcinoid tumor, chemotherapy has not been shown to be effective for most patients, and this approach should still be considered investigational. The single agent most studied in carcinoid tumor is 5-fluorouracil, which accounted for observed response rates of 26 and 18% in single-institution and multi-institutional trials, respectively (138,139), (Table 85.10). Melia and colleagues (140)(229) reported a high complication rate with little benefit when 5-fluorouracil was administered by intra-arterial, portal, or peripheral intravenous routes. Few responses were observed following intravenous doxorubicin, 60 mg/m₂, every 3 to 4 weeks (102,135,141). Despite well-established activity in other GEP cancers, streptozotocin has not demonstrated significant efficacy in patients with carcinoid tumor (115); (196). Among other single agents, there have been anecdotal reports of objective responses to dacarbazine and dactinomycin (235;236), however, a study of 32 patients demonstrated that dactinomycin or dacarbazine had little activity against metastatic carcinoid tumor(142). A larger, more recent study confirmed the ineffectiveness of dacarbazine in carcinoid tumor. Phase II studies in evaluable patients with carcinoid tumor have shown rare objective responses to either cisplatin or etoposide (138,143,144). No responses to carboplatinum were seen in a series of 20 patients.

Initial experience with combination chemotherapy suggested that this modality might be effective against malignant carcinoid tumor. Early, nonrandomized studies of combinations of cyclophosphamide plus methotrexate, streptozotocin plus 5-fluorouracil, or weekly streptozotocin plus doxorubicin reported response rates in excess of 50%; however, rigid criteria for response were not always employed and complete responses were not seen (1,102,139,144,145). Based on these observations, the Eastern Cooperative Oncology Group conducted a series of multi-institutional, randomized trials of combinations that all contained streptozotocin, despite the low activity of this drug when used alone. In two studies of 170 evaluable patients, the response rates ranged from 23 to 33%, and there was no evidence for any difference between streptozotocin administered every 6 weeks or every 10 weeks plus 5-fluorouracil versus streptozotocin plus cyclophosphamide versus single-agent doxorubicin(102,139,146). In a prospective trial, the Southwest Oncology Group reported similar response rates of brief duration following a combination of 5-fluorouracil, cyclophosphamide, and streptozotocin with or without doxorubicin(147). Only 10% of 31 patients had objective response following streptozotocin and 5-fluorouracil in another prospective clinical trial reported by Oberg and colleagues(148).

Feldman (149) suggested that streptozotocin alone or in combination with 5-fluorouracil may be beneficial for patients with foregut carcinoid tumors, in contrast to patients with midgut carcinoid tumors. This contrasts with the Eastern Cooperative Oncology Group experience, (139)however, and remains unsubstantiated. Thus, in the absence of randomized trials that contain a no-treatment arm, there is no persuasive evidence that single-agent or combination chemotherapy provides any significant impact on disease progression or on survival in patients with malignant carcinoid tumor.

Receptor tyrosine kinases (RTKs) are transmembrane proteins containing extracellular ligand-binding domains and intracellular catalytic domains. RTKs are activated following binding of their cognate ligands and many of the processes involved in tumor growth, progression, and metastases are mediated by signaling molecules acting downstream from these proteins(150).

Figure 54.  

Several members of the split-kinase domain family of RTKs are implicated in deregulated/ autocrine proliferation and survival of solid and hematologic cancer cells. These include the platelet-derived growth factor receptors (PDGFRα and β); vascular endothelial growth factor receptors (VEGFR) Type 1 and 2 (FLT1 and FLK1/KDR); the stem cell factor (SCF) receptor, KIT; and the FLT3-ligand receptor. In addition, PDGFR and VEGFR are implicated in tumor-dependent angiogenesis(151).

Neuroendocrine tumors are characterized by abundant vasculature.Inhibition of angiogenesis would therefore be expected to result in growth inhibition and regression of these tumors. A number of tumors, including NET, aberrantly express both the vascular endothelial growth factor (VEGF) ligand and its Flk-1/KDR receptor (VEGFR), both of which play critical roles in tumor angiogenesis. Investigation of novel angiogenesis inhibitors such as sunitinib in patients with pancreatic islet cell tumors is therefore of great

Interest. Tyrosine kinase inhibitors like sutent acts through the receptors for VEGF and PDGF, and also blocks signalling through the KIT, FLT3 and RET pathways.

Figure 55.  

Figure 56. Actions of Tyrosine Kinase (TK) and potential inhibitor.

The mTOR pathway is a key regulator of proliferation and growth of cells. This pathway integrates signals from growth factors to regulate metabolism and ribosome synthesis and deregulation of mTOR is associated with diverse human diseases including cancer and diabetes(152). Rapamycin binds to the FKBP12 protein to form a drug–receptor complex that then interacts with and perturbs a large protein kinase called TOR (target of rapamycin)(152). Although the function of TOR is far from well understood, it is increasingly clear that TOR is the central component of a complex signaling network that regulates cell growth and proliferation. Rapamycin does not perturb all mTOR functions because mTOR exists in two distinct multi-protein complexes and only one binds to FKBP12–rapamycin (Figure 60). This complex is composed of mTOR as well as the GbL and raptor proteins, and rapamycin inhibits its kinase activity in vitro(152). The rapamycin-insensitive complex also contains mTOR and GbL, but, instead of raptor, a different protein called rictor.

FKBP12–rapamycin binds to a region adjacent to GbL and the mTOR kinase domain but >1000 amino acids away from where raptor binds to mTOR(152). Perhaps FKBP12–rapamycin induces a conformational change in mTOR that weakens the binding of raptor and perturbs its capacity to recruit substrates (see below). It is also unclear why FKBP12–rapamycin does not bind the rictor-containing mTOR complex. Rictor or an unidentified component of the complex may block or occupy the FKBP12–rapamycin binding site or allosterically destroy the FKBP12–rapamycin binding pocket. As the rictor–mTOR complex cannot bind FKBP12– rapamycin, it is unlikely to mediate mTOR functions discovered through their sensitivity to acute treatment with the drug. Akt/PKB is a key component of the insulin/PI3K signaling pathway and modulates cell survival and proliferation through downstream. Thus, through the rictor- and raptor-containing complexes, mTOR affects cell size, shape and number(152).

Figure 57. A model of the mTOR and PI3K/Akt signaling pathways and their interconnections. Two mTOR-interacting proteins, raptor and rictor, define distinct branches of the mTOR pathway. The raptor–mTOR pathway regulates cell growth (accumulation of cell mass) through S6K1 and 4E-BP1 as well as unknown effectors. It responds to nutrients and growth factors in part through the upstream regulators TSC1/2 and rheb. The rapamycin-insensitive rictor–mTOR pathway regulates Akt/PKB, PKCa, Rho/Rac to control cell survival, proliferation, metabolism and the cytoskeleton. The binding of growth factors to cell surface receptors activates PI3K to generate PtdIns P3 and recruits the PDK1 kinase and Akt/PKB to the plasma membrane. Akt/PKB is activated by its phosphorylation on two different sites. The rictor–mTOR complex phosphorylates Akt/PKB on Ser473 in the hydrophobic motif which may facilitate the phosphorylation by PDK1 of the activation loop of Akt/PKB on Thr308. How the rictor–mTOR complex is regulated is unknown. Dashed lines indicate interactions that are likely not direct.(152).

Figure 58. PI3K/Akt pathway integrates signals from growth factor receptors, stress and available nutrients. mTOR, an intracellular serine-threonine kinase is centrally located downstream of PI3K.mTOR is a master regulator involved in translation of proteins critical for cell growth, proliferation and angiogenesis in response to upstream signals.

Insulin like Growth Factor (IGF)-I is a potent growth factor, exerting its actions by both endocrine and paracrine/autocrine mechanisms. The action of the IGFs in both the circulation and tissues is tightly regulated by a family of high-affinity IGF binding proteins (IGFBPs)(153). The synthesis of the IGFBPs in various tissues is under partial control of IGF-I. IGF-I exerts its biological effect by binding to the transmembrane type 1 IGF receptor, whose activation leads to the extensive tyrosyl-phosphorylation of insulin receptor substrate-1, which acts as a docking protein for the downstream signal transduction pathways(153).

Angiogenesis, the formation of new blood capillaries, is an important component of embryonic vascular development, wound healing, and organ regeneration, as well as pathological processes such as diabetic retinopathies, atherosclerosis and tumor growth(154). Vascular endothelial growth factor (VEGF) is essential for many angiogenic processes both in normal and pathological conditions. The binding of VEGF to its cognate receptors induces dimerization and subsequent phosphorylation of the receptors leading to the activation of several intracellular signaling pathways. In particular, the angiogenic signals triggered by VEGF are mediated through the activation of phospholipase Cã (PLCã)(154), protein kinase C (PKC), and subsequently the extracellular regulated kinases 1 and 2 (ERK1/2)(154).

VEGF also regulates vascular permeability and endothelial cell migration by stimulating the Src family kinases, in particular c-Src, and the phosphatidylinositol 3’OH-kinase (PI3K)/Akt pathway-dependent endothelial nitric oxide synthase (eNOS) activation. The importance of VEGF-induced signaling is demonstrated in that the genetic inactivation of either receptor leads to a complete lack of development of blood vessels in the embryo, and inactivation of VEGFR2 function dramatically impairs the growth of cancer cells in vivo(154).

mTOR is a threonine kinase that mediates downstream signaling from IGFi/SSA, VEGFi and VEGF TKIs signaling pathways implicated in neuroendocrine tumor growth(155). Activation of PI3K/AKT/mTOR pathways has been shown to increase translation of protein regulating cell cycle progression, and inhibitors of mTOR have shown early activity in number of cancers including neuroendocrine tumors(156).

Figure 59. mTOR mediates downstreaming signaling from IGFi/SSA, VEGFi and VEGF TKIs which is responsible for angiogenesis, bioenergy, growth and proliferation of cell. Activation of mTOR pathway occurs through PI3K/AKT/RAS. While inhibitors of mTOR pathway includes PTEN/NF1. Inactivation of mTOR pathway alone or combined with RAD001 therapy is implicated in inhibition of neuroendocrine tumor growth.

Thirty seven patients with progressive neuroendocrine tumors were treated with mTOR inhibitor temsirolimus in one pahse II study. The response rate was 5.6% with 63.9% of patients showed partial response or stable disease(157). While study showed better outcomes with mTOR inhibitors alone, the combined effect of mTOR inhibitors RAD001(everolimus;5mg/day) and depot octreotide (30mg/4weeks) showed partial response of 12% in carcinoid patiets while 37% of patients had > 50% reduction in chromogranin A(158).

RAD001 (everolimus) is a novel agent that is being trialled in the treatment of neuro-endocrine tumours, and is known to interact with mTOR. Grozonsky-Glasberg S (2007) found that treatment with octreotide and RAD001 inhibited proliferation and attenuated phosphorylation of all downstream targets of Akt: TSC2, mTOR, and p70S6K(159). Octreotide and RAD001 appear to act through a similar pathway and inhibit the Akt-mTOR-p70S6 kinase pathway downstream of Akt(159). In another Phase I study by Awada (2008) showed that daily therapy with RAD001 plus letrozole suggest anti-tumor activity in breast cancers(160).

Several studies have used interferon against malignant carcinoid tumor. In the first, 17 of 36 patients (47%) with metastatic carcinoid tumor who were treated with human leukocyte interferon, 3 to 6 million units per day subcutaneously, had objective hormonal responses for a median duration of 34 months(148). Four patients had significant tumor regression, and two complete responses were noted. A second study randomized 20 patients to treatment with either a combination of streptozotocin and 5-fluorouracil or human leukocyte interferon, 6 million units five times per week(161). After 6 months, 50% of the patients treated with interferon had an objective hormonal response, and no patients treated with chemotherapy responded. Finally, Oberg and colleagues(148) conducted a study in 20 patients with malignant carcinoid tumor that suggested recombinant human interferon-α-_2b, 5 X 10⁶ U/m₂ three times a week subcutaneously for 6 months, was as active as leukocyte interferon, and that the two agents may not be cross-resistant. In this study, the development of neutralizing interferon antibodies correlated with a lack of response to interferon in three patients.

Additional positive outcomes using recombinant human interferon- α -_2b have been reported by several additional groups after small prospective trials (162,163). Hanssen and colleagues (162) also gave interferon following hepatic artery embolization, and they observed five of seven patients with objective tumor and hormonal responses after 12 months. A recent review by Oberg (164) of 300 patients with carcinoid tumor treated with interferon-α for a median of 2.5 years concluded that this agent has significant antitumor effects in 70 to 80% of patients, as manifested by biochemical control and inhibition of tumor growth. Tumor progression generally occurred within 3 to 9 months after cessation of the drug.

These encouraging results with interferon must be interpreted with caution, however, considering the results from another prospective study using interferon reported by Moertel and colleagues(165). In this study, 27 previously treated patients with malignant carcinoid tumors were treated with recombinant human interferon- α -2a, 12–24 X 10⁶ U/m₂ subcutaneously three times weekly for 8 weeks. Nine of 23 patients (39%) with elevated 5-HIAA had objective responses for a median of 40 weeks (range, 23–127 weeks), and 4 of 20 patients (20%) had objective tumor responses for a median of 7 weeks (range, 4–26 weeks). The flu-like syndrome and fatigue side effects from interferon were common in this study, requiring dose reduction in 10 patients and causing deterioration of performance status in 50% of all patients. In addition to differences in dose and observed toxicities, the variable response rates found in these reported studies may relate to the use of different recombinant interferon subtypes (alpha-2a vs. alpha-_2b) and the subsequent development of neutralizing antibodies(159). The role for the combination of recombinant human interferon- α -2a and doxorubicin in patients with advanced pancreatic endocrine or carcinoid tumors currently is under investigation(166). A series of 19 patients treated with interferon- α combined with octreotide showed a 92% median biochemical response rate for a period of 10 months(125).

Any suspected case of carcinoid needs proper evaluation for the diagnosis and management of the case. The schematic presentation of evaluation of carcinoid is described as follows in Fig.50.

Figure 60. Norfolk Algorithm for Neuroendocrine Tumor (NANET).

Figure 61.  

Figure 62. Management of metastatic tumor

Figure 63.  

Combined modality therapy, such as the use of adjuvant chemotherapy either before or following surgery, remains undefined for metastatic carcinoid. In the absence of well-established activity for chemotherapy in this disease, there is no rationale to support the use of adjuvant chemotherapy. In contrast, preliminary results of the prospective experience of sequential hepatic artery occlusion and alternating combination chemotherapy at the Mayo Clinic are of considerable interest (135,141,167). Following hepatic artery occlusion by surgical ligation or percutaneous embolization, 21 patients were treated with dacarbazine, 250 mg/m₂ daily for 5 days, plus doxorubicin, 60 mg/m₂, alternating every 4 to 5 weeks with 5-fluorouracil, 400 mg/m₂ daily for 5 days, plus streptozotocin, 500 mg/m₂ daily for 5 days until maximum response was observed. Using this combined-modality approach, Moertel (135) reported a hormonal response rate of 86%, with a median duration of response of 2 years. The toxicity of this approach notwithstanding, and pending publication of the Mayo Clinic experience or other confirmatory experience, sequential hepatic artery occlusion and combination chemotherapy may be considered for selective patients with symptomatic metastatic carcinoid refractory to somatostatin therapy. Timodar and Xeloda may have a slight benefit in patients with neuroendocrine tumors but more controlled trials are needed to see the role and benefits of them in NET.