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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 85Neoplasms of the Neuroendocrine System and Neoplasms of the Gastroenteropancreatic Endocrine System

, MD, , MD, , MD, , MD, ,  MD, , MD, and , MD.

Neuroendocrine Neoplasms of the Gastroenteropancreatic System


Endocrine tumors of the gastroenteropancreatic (GEP) axis consist of cells that are capable of amine precursor uptake and decarboxylation and therefore have been named APUDomas.1 The morphologic similarity of the APUD cells suggested a common embryologic origin, which was believed to be the neural crest but was later revised to include the neuroectoderm or, in the case of endocrine cells, the dorsal placoderm. Various studies have cast doubt on this hypothesis, however, and most workers agree that these tumors should be classified according to their secretory products (i.e., gastrinoma, insulinoma, somatostatinoma, glucagonoma, vasoactive intestinal peptide [VIPoma] and pancreatic polypeptide [PPoma]).2–4 The generally held belief that the neuronal characteristics of these cells indicate an ectodermal origin during mammalian embryogenesis largely has been abandoned.

Developmental Origin of Islets during Pancreatic Embryogenesis

The developing pancreas appears as a protrusion from the dorsal surface of the embryonic gut.5 The different islet-cell types appear sequentially during development in vivo. Therefore, it seems reasonable to propose that coordinated growth depends on the specificity of growth factors.

Rosenberg and Vinik6 used a model for new islet formation (i.e., nesidioblastosis) and showed that pancreatic ductal cells are capable of differentiating on stimulation into adult endocrine cells that are capable of secreting insulin in a fully regulated manner. This has led to the notion that endocrine tumors derive from a totipotential stem cell in the gut that is capable of differentiating into any one of a variety of cells that may be responsible for the clinical syndrome (Fig. 85.1).

Figure 85.1. Gastroenteropancreatic tumors.

Figure 85.1

Gastroenteropancreatic tumors. ACTH = corticotropin; EC = enterochromaffin; GHRF = growth hormone-releasing factor; GRP = gastrin-releasing peptide; HHM = humoral hypercalcemia of malignancy; PP = pancreatic polypeptide; Subst P = substance P; VIP = vasoactive (more...)

A great deal of interest is now being focused on the factors responsible for the initiation of growth, growth proliferation, differentiation into adult endocrine cells, and, in neuronal systems, for growth cessation and cell maintenance. Several models of pancreatic regeneration and tumor formation have been established.7–17

Growth Factors

Multiple growth factors and receptors are frequently expressed in GEP tumors. These growth factors may include insulin-like growth factor-1, platelet-derived growth factor, transforming growth factors (TGF)-α and -β, basic fibroblast growth factors, and nerve growth factor.18,19 The frequent co-expression of TGF-α and its corresponding receptor, the epidermal growth factor receptor, suggests the presence of autocrine regulatory mechanisms in these tumors.19 TGF-β has been implicated in the desmoplastic reaction associated with carcinoid tumors.19,20 Overall, the precise role of these growth factors and their importance in the growth and progression of GEP tumors is unknown.

Apoptosis (i.e., programmed cell death) has been shown to be an important process that may occur under normal physiologic conditions, including embryonic growth and development, the differentiation of B-cell populations, and the involution of cells deprived of necessary growth factors.21 Apoptosis may be induced by a variety of chemotherapeutic drugs and cytokines.22 Several growth factors and substances that are secreted by neuroendocrine tumors, including TGF-β1,23 glucocorticoids, and somatostatin,25 have been shown in other model systems to induce apoptosis. The importance of apoptosis in the normal growth and differentiation of neuroendocrine tissues, however, and the importance of apoptosis in the response of GEP tumors to chemotherapy remain unknown.

The multiple endocrine neoplasia (MEN) characterized by the combined occurrence of tumors of the pituitary, pancreas, and parathyroid glands is associated with the loss of a tumor suppressor gene on chromosome 11q13.26,27 This is the same chromosome on which the insulin gene has been located28; it has been linked to nesidioblastosis in certain families and parathyroid mitogenic activity can be identified in the plasma of patients with MEN-1.29,30 All of this suggests a genetic predisposition to tumor formation based on elaboration of a growth factor. Data from cell lineage analysis of pancreatic islet cells suggest that progenitor cells, which contain catecholamines, are present in pancreatic ducts and give rise to the glucagon and insulin cells of adult islets;31 and they can be stimulated to grow by plasma from patients with MEN-1. The findings that patients with MEN-1 also might elaborate into their plasma mitogenic factors for pancreatic islet cells led McLeod and colleagues to postulate a genetically determined, circulating growth factor in the initiation of GEP tumor growth (Table 85.1).32 It has been suggested, but not proven, that allelic loses in the MEN-1 tumor suppressor gene located in the 11q13 region also might be responsible for sporadic parathyroid, pituitary, neuroendocrine tumors of the stomach, pancreas, and intestine.33 The few cases of carcinoid tumors studied have not shown losses in this region.

Table 85.1. Characteristics of Neuroendocrine Tumors.

Table 85.1

Characteristics of Neuroendocrine Tumors.

In addition, MEN-2a,34,35 MEN-2b,36,37 and familial medullary thyroid carcinoma are associated with mutations of the RET proto-oncogene, which is a conventional dominant oncogene located on 10q11.2. Although mutations in this region have been associated with sporadic medullary thyroid carcinoma, the role, if any, of this gene in sporadic GEP tumors is not known.

Neuroendocrine Characteristics

A number of peptides originally isolated from gut endocrine tissues have been shown to occur in nerves. These include gastrin, cholecystokinin, vasoactive intestinal polypeptide (VIP), and substance P (SP). As a corollary, peptides that have been found primarily in nervous tissues have now been identified in gut endocrine cells and include somatostatin (SRIF), enkephalins, SP, neurotensin, and thyrotropin-releasing hormone (TRH).38–40 Because many of these peptides occur both in endocrine cells and nerves, “endocrine” tumors of the gut may, in fact, be endocrine or neurocrine. Unique to the GEP axis is the ability of the endocrine cell to secrete a variety of peptides and amines. Hormonal peptides not only have been found within the same cell (e.g., motilin and serotonin in the enterochromaffin [EC] cell), but they have also been localized to the same secretory granule. Whether these act within the secretory granule in a paracrine manner or are co-regulated in some way is not clear. At any one point in time, several hormones and amines are co-secreted; in individual instances, the symptom complex derives from one or more of the peptides and amines produced and cannot simply be ascribed to a single factor. Thus, a tumor may secrete one peptide, recur, and secrete yet another, and its metastases may secrete still other peptides. In the British National Supra-Regional Survey of National Health Service Hospitals, 58% of 353 patients with neuroendocrine tumors had increased serum levels of two or more hormones at diagnosis. Nine percent of patients had clinical symptoms related to different hormones, and four patients developed new symptoms from secretion of a second hormone after diagnosis.41

Anatomic Distribution

More than 50% of neuroendocrine tumors in clinical practice are of the so-called carcinoid variety and are found incidentally at operation, after metastasis has occurred, in the small intestine (especially the appendix). The remaining fraction comprises approximately 50% gastrinomas, 30% insulinomas, 13% VIpomas, 5 to 10% glucagonomas, and, rarely, less than 5% neurotensinomas, somatostatinomas, and etopic hormone-secreting tumors. Nonsecretory tumors were thought to make up the bulk of pancreatic tumors, but with better immunohistochemical stains for endocrine cells, especially for neuron-specific enclose (NSE), chromogranin, synaptophysin, and receptors for somatostatin,42 there is increasing recognition that tumors masquerading as carcinomas of liver, small cell carcinoma of the lung, and the like are endocrine tumors (Table 85.2). Most of these nonsecretory tumors actually store and secrete pancreatic polypeptide (PP), but because it has so little, if any, in the way of biologic activity, the tumor often remains silent until it is quite large.

Table 85.2. The Clinical Syndromes.

Table 85.2

The Clinical Syndromes.

Approximately 60% of pancreatic gastrinomas are concentrated in Pasarro’s Triangle, an area subtended by the head of pancreas, gastric antrum, and first portion of the duodenum. Other neuroendocrine tumors may be distributed more evenly across the pancreas or in ectopic sites such as the adrenal medulla, whereas carcinoid tumors most frequently occur in the appendix and small intestine.

The tumors are proliferative in nature and may take the form of hyperplasia or neoplasia (adenoma, adenomatous hyperplasia, microadenomatosis, nesidioblastosis, or carcinoma). Hyperplasia is relatively uncommon in benign sporadic tumors, but it is the rule in MEN-1 syndrome and often is present in the area of the pancreas surrounding a benign tumor.

The tumors may be further subdivided into (a) orthoendocrine, when they secrete the normal product of the cell type (e.g., α-cell glucagon), and (b) paraendocrine, when they secrete a peptide or amine that is foreign to the organ or cell of origin. Paraendocrine tumors are found in the adrenal medulla, kidney, lymph nodes, or liver and as a part of MEN-1 when a variety of peptides or amines are secreted. When tumors metastasize, they do so to local lymph nodes, liver, peritoneum, and, rarely, to bone. Metastases are notoriously highly vascular, which is a telltale sign of a GEP tumor. The occurrence of MEN-1 syndrome may be as frequent as one-third of the cases of GEP tumors, depending on the endemic area. In high-risk areas, measurements of ionized calcium, prolactin, and PP are important. The sections that follow focus on the specific syndromes that are ascribed to GEP hyperfunction.

Carcinoid Tumors

Carcinoid tumors are the most commonly occurring gut endocrine tumors. The incidence is estimated to be approximately 1.5 cases per 100,000 of the general population (i.e., approximately 2,500 cases/year in the United States). Nonetheless, they account for 13 to 34% of all tumors of the small bowel and 17 to 46% of all malignant tumors of the small bowel.43 They derive from a primitive stem cell and generally are found in the gut wall. Carcinoids may, however, occur in the pancreas, rectum, ovary, lung, and elsewhere. The tumors grow slowly and often are clinically silent for many years before becoming manifest after metastases have occurred. They frequently metastasize to the regional lymph nodes, liver, and, less commonly, to bone. The likelihood of metastases relates to tumor size. The incidence of metastases is less than 15% with a carcinoid tumor smaller than 1 cm but rises to 95% with tumors larger than 2 cm. These tumors may be symptomatic only episodically, and their existence may go unrecognized for many years. The average time from onset of symptoms attributable to the tumor and diagnosis is just over 9 years, and diagnosis is usually made only after the carcinoid syndrome occurs. However, it should be noted that the carcinoid syndrome occurs in less than 10% of patients with carcinoid tumors.44 It is especially common in tumors of the ileum and jejunum but also occurs with bronchial, ovarian, and other carcinoids.45 This section discusses the incidence, natural history, clinical presentation, diagnosis, and management of carcinoid tumors.

One of the more clinically useful classifications of carcinoid tumors is according to the division of the primitive gut from which the tumor cells arise. There are two types of foregut carcinoid tumors: (a) sporadic primary and (b) tumors secondary to achlorhydria. Sporadic primary foregut tumors include carcinoids of the bronchus, stomach, first portion of the duodenum, and pancreas. Midgut carcinoid tumors derive from the second portion of the duodenum, the jejunum, the ileum, and the right colon. Hindgut carcinoid tumors include those of the transverse colon, left colon, and rectum. This distinction assists in distinguishing a number of important biochemical and clinical differences between carcinoid tumors because the presentation, histochemistry, and secretory products are quite different (see Table 85.2).

Foregut carcinoids are argentaffin negative. They have a low content of serotonin (5-hydroxytryptamine [5-HT]). They often secrete the serotonin precursor 5-hydroxytryptophan (5-HTP), histamine, and a multitude of polypeptide hormones. Their functional manifestations include carcinoid syndrome, gastrinoma syndrome, acromegaly, Cushing’s disease, and a number of other endocrine disorders. Furthermore, they are unusual in that the flush tends to be of protracted duration, is often of a purplish or violaceous hue as contrasted with the usual pink or red, and frequently leaves results in telangiectasia and hypertrophy of the skin of the face and upper neck. The face may assumes a “leonine” characteristic after repeated episodes. It is not unusual for these tumors to metastasize to bone.

Midgut carcinoids, in contrast, are argentaffin positive, have a high 5-HT content, rarely secrete 5-HTP, and often produce a number of other vasoactive compounds, such as kinins, prostaglandins, and SP. The clinical picture that results is the classic carcinoid syndrome of flushing and diarrhea with or without wheezing. These tumors may produce adrenocorticotropic hormone (ACTH) on rare occasions and infrequently metastasize to bone.

Hindgut carcinoids are argentaffin negative, rarely contain 5-HT, rarely secrete 5-HTP or other peptides, and usually are silent in their presentation. However, they may metastasize to bone.

A further point of interest is that if a carcinoid tumor co-exists with MEN-1, more than two-thirds of the time in males the tumor is in the thymus, whereas in females, it is in the lung over 75% of the time.

Although carcinoids classically are tumors of enterochromaffin and argentaffin cells of the digestive tract, the term carcinoid tumor can be expanded to cover gut tumors of paracrine- and endocrine-like cells of unknown function.46,47 It now is established that these tumors are of neuroendocrine origin and derive from a primitive stem cell. They may differentiate into any one of a variety of adult endocrine secreting cells: B cell and insulinoma, A cell and glucagonoma, D cell and somatostatinoma, and the PP cell and PPoma, or cells capable of producing ACTH, growth hormone-releasing hormone, VIP, SP, gastrin-releasing factor, calcitonin, and the EC cell, with its ability to co-secrete amines such as serotonin and the peptide motilin (Fig. 85.2). At any one point in time, these cells may secrete one humor, whereas at others, the peptide or amine secreted may differ and yield an entirely different clinical syndrome. Indeed, metastases are known to secrete hormones that differ from the parent tumor, and different metastases may secrete different hormones. Symptoms may derive from secretion of one or more of the hormones secreted.

Figure 85.2. Ovarian carcinoid tumor stained positive for substance P.

Figure 85.2

Ovarian carcinoid tumor stained positive for substance P.

Age Distribution

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.

Natural History

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.48 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.41,49 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.

The major clinical manifestations of carcinoid tumors 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%).49 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%.

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,50 synaptophysin,51 or NSE,52 tumors may be labeled erroneously as adenocarcinomas, with a negative impact on attitudes toward management and an underestimate of survival.


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.

Biochemical Studies

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.

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 permits 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. 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.

Localization Studies

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 extraintestinal 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. Octreotide scintigraphy and superior mesenteric angiography, however, may be of help.

Several diagnostic methods have been evaluated for the diagnosis of carcinoid tumors, including barium examinations, CT, 131I-metaiodobenzylguanidine (MIBG) scanning, octreotide scanning, angiography, and venous sampling with radioimmunoassay of hormones. Barium examinations rarely are diagnostic, but they may demonstrate fixation, separation, thickening, and angulation of the 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 nonenhanced CT scanning.53 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 extrahepatic disease. MRI needs further evaluation, however, before it is used as primary modality for the diagnosis and staging of carcinoid tumor,54 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 is contemplated (Fig. 85.3). 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.55 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.56

Figure 85.3. Celiac-axis angiogram (Subtraction films) showing tumor in the head of the pancreas (arrow).

Figure 85.3

Celiac-axis angiogram (Subtraction films) showing tumor in the head of the pancreas (arrow).

Scintigraphic Detection with MIBG or Octreotide Scanning

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 131I-MIBG.57 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 pheochromocytoma or neuroblastoma, however, but it probably is fair to say that the sensitivity is significantly lower.59–62 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 pheochromocytoma29,63 and neuroblastoma,64–66 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.67 Several different imaging agents that bind to the receptor have been studied. 123I-Tyr3-octreotide was the agent initially used, but it has several disadvantages, including a short half-life, biliary excretion obscuring potential tumor sites, and difficulties with conjugation. The development of 111g-DTPA octreotide, with a half-life of 3 days and renal excretion, has obviated many of these difficulties.

The efficacy of peptide receptor scintigrahy with 111In-DTPA octreotide was evaluated in a European Multicenter Trial (EMT) in 350 patients with a histologically or biochemically proven neuroendocrine GEP tumor.68 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 group68 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 111In of 200 MBq and at least 10 μg 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.69–71

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.71 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.72,73 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.71

Knowledge of the fact that other processes can be somatostatin receptor positive is crucial for interpretation of these scintigrams.68 This has been re-emphasized recently by Gibril et al.73 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.

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 (Fig. 85.4). 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.74 Other investigators have shown similar results.75

Figure 85.4. Octreotide scan at 24 hours showing liver and pelvic metastases in a patient with malignant carcinoid tumor.

Figure 85.4

Octreotide scan at 24 hours showing liver and pelvic metastases in a patient with malignant carcinoid tumor.

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.76

Carcinoid Syndrome

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 83% of cases, flushing in 49%, dyspnea in 20%, and bronchospasm in 6%.77 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,78,79 prostaglandins,80 5-HTP,81–83 SP,76,84, kallikrein,85 histamine,83 dopamine,86 and neuropeptide K87 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,88 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’Dorisio89 examined the proportion of 43 patients with carcinoid tumor having increased levels of serotonin and various other vasoactive peptides.90 Serotonin, measured either as its urinary metabolite 5-HIAA91 or whole-blood serotonin,92–94 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 a 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.76


The diarrhea syndrome that occurs with carcinoid tumors usually is of a secretory nature. Diarrhea persists with fasting or fails to disappear when feeding has been curtailed and sustenance given by the intravenous route. 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. Marked metabolic acidosis with bicarbonate wasting usually is only a characteristic of VIP-secreting tumors. 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.


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.

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,78 dopamine,86 histamine, and 5-HIAA,83 kallikrein,82 SP,81 neurotensin,89 motilin,76,89 SRIF,89 VIP,95 prostaglandins,80 neuropeptide K,87 and gastrin-releasing peptide (GRP).89

Feldman and O’Dorisio have previously reported the incidence of elevated levels of plasma neuropeptide concentrations.89 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.96

Several provocative tests have been developed for carcinoid syndrome. Ahlman and colleagues97 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,98 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%.49 Thus, SP is one neurohumor that may be involved in the flushing of carcinoid syndrome.

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.76 Neurokinin A, its amino-terminally extended form, neuropeptide K, and SP are a group of peptides (i.e., tachykinins) with common biologic properties.99,100 Norheim and colleagues100 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.101

Conlon and colleagues99 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.


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 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 colleagues45 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 μg per 24 hours or inoperable tumors, median survival is only 11 months.102

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 agents104 and surgery or arterial embolization105 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, cyproheptadene, heparin, phenothiazines, α-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,106 but its clinical use is limited by its short half-life107 and the resulting need for continuous intravenous infusion. With the advent of the long-acting somatostatin analogue octreotide (SMS 201–995),108 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.77,95 These medications either inhibit serotonin synthesis, act as systemic antagonists 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 flushing46,106,109,110 in the carcinoid syndrome. We have had variable experiences with carcinoid syndrome and report here factors that determine responsiveness.

Responses to Octreotide

Frolich and colleagues111 also reported on the value of native somatostatin given by continuous infusion to reverse the PG-induced flushing in patients with carcinoid tumors. The initial patients treated with octreotide were a heterogeneous group with advanced carcinoid tumors refractory to conventional therapy who were tried on the somatostatin analogue with variable clinical and biochemical responses. Kvols and colleagues112 found that 19 of 24 patients with carcinoid tumors had a 50% reduction in flushing, 3 had a minor response, and the octreotide failed in 2 patients. Richter and colleagues113 showed that six of eight patients had improved symptoms.

Vinik’s experience110 was that 64% of his patients presented with flushing as their major symptom. In all instances, the symptom complex improved, with a clear decrease in the frequency of symptoms using doses of octreotide in the range of 450 to 1500 mcg/d. In no instance was there resistance to the drug. Tachyphylaxis did not occur, and withdrawal of the drug (or substitution with distilled water) was always followed by recurrence of the symptom complex. In contrast to another report,113 relapse of flushing did not occur with continued treatment once it was under control. However, in contrast to the reduction in a number of episodes, the severity in certain patients decreased only slightly, and the duration of each episode was essentially unchanged.

The extreme example of flushing is the carcinoid crisis with a profound fall in blood pressure. In the past, it was deemed unwise to submit a patient to anesthesia or operation without premedication using a combination of adrenergic blockade, steroids, thorazine, and aspirin. Currently, however, preoperative use of octreotide is the most important drug to prevent carcinoid crisis. Kvols and colleagues109 presented data on one such patient, who, soon after the induction of anesthesia, had a fall in blood pressure that was unresponsive to intravenous fluid, calcium, Neo-Synephrine, or epinephrine administration. Within 1 minute of 100 μg of octreotide given intravenously, blood pressure rose, and the patient made an uneventful recovery.

Thus, although the mechanism of action by octreotide and the factors mediating flushing and vasodilatation is unclear, octreotide no doubt is a potent antidote to the vasoactive humors participating in the flush and hypotension. The drug is a useful adjunct in the preparation of patients for operative procedures and should be available as a standby for the management of carcinoid crisis.


Diarrhea occurred in 86% of Vinik’s110 patients and responded variably to octreotide. Acute administration of octreotide normalized the water and electrolyte transport across the proximal intestine, as has been shown in patients with the watery diarrhea hypokalemia hypochlorhydria and acidosis (WDHHA) syndrome.110,114 The acute reduction in electrolyte secretion did not, however, predict the long-term response of diarrhea to octreotide therapy, but this needs to be further examined in a larger number of patients. Only 58% of his patients with diarrhea had complete remission, which differs from the improvement in 19 of 25 patients (76%) reported by Kvols and colleagues.112 This could result from the fact that diarrhea in patients with carcinoid tumors has multiple etiologies (i.e., secretory, increased motility, malabsorption, partial luminal lymphatic obstruction, bacterial overgrowth, and short bowel syndrome because of surgical resection). The diarrhea may even seem to worsen with the appearance of steatorrhea, and the physician not infrequently is faced with the confounding situation of not knowing to what to attribute the symptom. However, although octreotide does inhibit exocrine pancreatic secretion,115 addition of pancreatic enzyme supplementation has not uniformly decreased octreotide-induced steatorrhea.116 There are no consistent changes in frequency or consistency of bowel movements in response to pancreatic supplements in those patients with steatorrhea before treatment or the bowel habits after therapy with octreotide, which is compatible with the notion that the steatorrhea has a complex pathogenesis and may be contributed to by alterations in bile flow, the direct effects of octreotide on nutrient absorption, and intestinal motility.117

Effects of octreotide on pulmonary function

All three of our patients with wheezing had clinical improvement, and spirometric improvement was documented. Pulmonary function did not improve further after 3 months of treatment, indicating an irreversible component or small airway disease secondary to longstanding smoking.118

Effects of octreotide on myopathy

One patient in our series presented with severe proximal muscle weakness and normal muscle enzymes and nerve conduction studies, but electromyographic features of a proximal myopathy. Although a neurologic deficit secondary to metastatic carcinoid has been reported,119 metabolic-induced neuromuscular disease is very rare.120–122 Although our patient had a history of hypokalemia, his potassium was normal at the time of admission, with no biochemical evidence of thyrotoxicosis, ectopic ACTH production, or osteomalacia. We believe that his severe myopathy was caused by his carcinoid tumor, although it might have been aggravated by severe diarrhea, weight loss, and poor nutrition. Histologic changes can be induced in the skeletal muscle of mice by intraperitoneal injection of 5-HT,123 and 3 months after octreotide therapy, the patient had no clinical evidence of myopathy, with improvement in electromyographic features.118

Biochemical responses

Reports conflict regarding the biochemical responses of patients with carcinoid tumors to octreotide. Richter and colleagues113 reported a significant drop in 5-HT levels in eight patients treated with 150 mg/d of octreotide but no changes in urinary 5-HIAA; others have found a drop in urinary 5-HIAA.41 In prolonging their treatment of four patients to 15 to 30 weeks, blood serotonin remained unchanged.116

In our patients, urinary 5-HIAA dropped in almost all patients and normalized in one-third, and four of eight patients normalized their 24-hour 5-HIAA. Although few of our patients had a fall in their blood serotonin level, the overall postoctreotide values were not significantly lower than the pretreatment values.

There were no clinical correlations between the clinical responses and either urinary 5-HIAA or the blood serotonin level. In contrast, for patients in whom urinary 5-HIAA fell, there was clinical improvement in one or more of the symptoms. This may reflect that multiple etiologic factors are involved in the symptomatology of carcinoid tumors. In our patients, those who responded clinically required no more than 500 mg/d of octreotide to control their symptoms, although we have examined the response to higher doses in certain instances.

Responses of tumor growth and metastases to octreotide

Because of the slow growth of carcinoid tumors, it is difficult to assess the effect of octreotide on tumor growth or regression. Shrinkage of liver metastases in patients with carcinoid110,112 and other functioning pancreatic neuroendocrine tumors124 has been reported. We have had variable experiences. The relationship between tumor size and growth and the biochemistry is not a simple one. In one patient, the tumor clearly shrank, but ACTH levels rose to the 2,000 to 3,000 pg/mL range. On molecular sieve chromatography, the ACTH coeluted with native ACTH, but the patient has no clinical features of Cushing’s syndrome, is gaining weight, and has no diarrhea or flushing. Another patient had progression of tumor growth after 18 months of octreotide therapy, yet there was a dramatic fall in blood serotonin values and the patient is entirely asymptomatic. The opposite also is not unusual, wherein there is no change in tumor size, a very well patient, and hormonal levels that are unaffected by octreotide even at doses as high as 1,000 μg/d.84

We have follow-up CT data for 14 patients. Two showed some tumor regression, and, in one case, the tumor infarcted. Five cases showed progression and seven cases no changes on the CT scan when followed for up to 2 to 5 years. It appears that the cessation or reversal of growth occurs in about two-thirds of patients with carcinoid tumors who are treated with octreotide.

As a palliative agent, octreotide can control flushing, diarrhea, and wheezing in most patients with carcinoid tumors, with improvement in their general condition. The effects of octreotide on tumor growth need to be evaluated further in relation to the slow progression and indolent nature of these tumors. Octreotide increases the median survival of patients with metastatic carcinoid tumor from 11 to 33 months. Higher doses of octreotide may yield even better outcomes. A recent phase II study of apudomas showed no major tumor regressions but a 50% disease stabilization rate.125 A study of 14 patients with neuroendocrine tumor who received doses of octreotide of up to 9,000 μg/d showed partial responses in four patients (31%) and disease stabilization in two patients (16%).126 Radiographic evidence of tumor necrosis was seen in five patients, but this did not correlate with response. A larger study of 55 patients showed an objective response rate of 37%.127 It is reasonable to offer octreotide at initial doses of 150 μg subcutaneously t.i.d. for control of symptoms and palliation. Escalation of the dose to 250 to even 1000 μg t.i.d. may be necessary in patients with a large tumor burden, but there is no evidence that higher doses have a greater likelihood of inducing actual tumor regression. When there is clear evidence that tumor growth is not contained by octreotide, alternative forms of treatment should be considered.128 There are also experimental techniques that should be considered.

Internal Radiotherapy Delivered by MIBG

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.129–131

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.129–131 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.52 Tumor volume also must be determined by CT or another modality, and with the other parameters, this can be used with Medical Internal Radiation Dose (MIRD) formulas to calculate the radiation-absorbed dose.132

The ability of somatostatin analogues to bind to GEP tumors has suggested other novel therapeutic approaches. Conjugating somatostatin with high energy β-emitters, short-acting α-particle emitters, or tumoricidal toxins such as ricin or modified diphtheria toxin has been proposed.133,134 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.135 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, 80–200 μM) and Ivalon particles (sizes, 149–250 μM) are the frequently used agents for devascularization of the hepatic metastases.

Several authors have described their experience with hepatic artery ligation or embolization in patients with malignant carcinoid tumors.136–138 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.138 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.139 Hepatic arterial occlusion combined with sequential chemotherapy has resulted in an 80% response rate, with a median duration of 18 months.140 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.139

Radiation Therapy

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 obstruction that are all amenable to this modality of treatment.


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,141,142 (Table 85.10). Melia and colleagues137 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.102,139,143 Despite well-established activity in other GEP cancers, streptozotocin has not demonstrated significant efficacy in patients with carcinoid tumor.43,102 Among other single agents, there have been anecdotal reports of objective responses to dacarbazine and dactinomycin143,144; however, a study of 32 patients demonstrated that dactinomycin or dacarbazine had little activity against metastatic carcinoid tumor.145 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.141,146,147 No responses to carboplatinum were seen in a series of 20 patients.

Table 85.10. Systemic Anticancer Therapy for Malignant Carcinoid.

Table 85.10

Systemic Anticancer Therapy for Malignant Carcinoid.

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.43,102,142,146,148 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.102,142,149 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.150 Only 10% of 31 patients had objective response following streptozotocin and 5-fluorouracil in another prospective clinical trial reported by Oberg and colleagues.151

Feldman152 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,142 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.


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.153 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.154 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 colleagues151 conducted a study in 20 patients with malignant carcinoid tumor that suggested recombinant human interferon-α-2b, 5 × 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.155,156 Hanssen and colleagues155 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 Oberg157 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.158 In this study, 27 previously treated patients with malignant carcinoid tumors were treated with recombinant human interferon-α-2a, 12–24 × 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.160 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.127

Adjuvant Therapy

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.139,143,161 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, Moertel139 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.

Gastrinoma Syndrome

The gastrinoma syndrome is characterized by a severe ulcer diathesis and persistent basal gastric acid hypersecretion because of hypergastrinemia (Table 85.3). It has been increasingly recognized that this syndrome can exist in multiple forms: benign sporadic, malignant metastatic, and as part of the MEN-1 syndrome. The gastrinoma syndrome needs to be distinguished from the G-cell hyperplasia syndrome and from those rare cases in which acid hypersecretion cannot be ascribed to gastrin.88,162 From various series, it appears that approximately 66% of gastrinomas are sporadic.163 Most sporadic tumors in the pancreas are solitary and have been malignant in approximately 60 to 85% of cases. These usually are found in older subjects. Sporadic tumors generally occur in the pancreas, although primary tumors also may occur in the body of the stomach, duodenum, and jejunum, accounting for up to 23% of tumors found at operation.163 Less than 40% of these are malignant. Ectopic tumors also have been identified in peripancreatic lymph nodes,163–169 in the splenic hilum, root of the mesentery, omentum, liver, gallbladder, and the ovary.163,170 Solitary tumors in these sites are less likely to be malignant, and the overall cure rate is higher than that reported for pancreatic tumors.169 In the past, the likelihood of a surgeon finding the tumor in these sites, however, has been less than 50%, but there still are difficulties finding tumors in these locations, leading to operative failures.167,168,171

Table 85.3. Clinical Manifestations Suggestive of Gastrinoma.

Table 85.3

Clinical Manifestations Suggestive of Gastrinoma.

Because of the pioneering work of Debas and colleagues172 as well as Thompson and colleagues173 and others, the duodenum has been increasingly recognized as a site for gastrinomas. In several recent series, gastrinomas were located in extrapancreatic sites, including the duodenal wall, in 43 to 77% of patients.173–175

Approximately 33% of gastrinomas are associated with the MEN-1 syndrome.171,176–180 The problems attending gastrinoma in the MEN-1 syndrome are quite different from those associated with the sporadic variety, however. If patients with hyperparathyroidism are scrutinized carefully, up to 38% are found to have gastrinomas.178,181 Whereas 50 to 60% of patients with MEN-1 develop gastrinoma, over 90% have hyperparathyroidism. Refined testing is indicated to detect the presence of gastrinoma in patients with ulcer and hyperparathyroidism.182 Tumors in the MEN-1 syndrome usually are multiple, often small or undetectable, and less frequently (7–12%), malignant.176,177,179,183,184 Most cases, however, are discovered at a younger age than in the sporadic cases, and the frequency of malignancy may indeed be considerably higher. Both the multiplicity of the tumors and their small size may make it difficult to find the specific tumors that are secreting gastrin, and the likelihood of recurrence or persistence after excision militates against laparotomy without first identifying a specific site or sites of origin for the hypergastrinemia.

The G-cell hyperplasia syndrome has been considered by some to be part of the gastrinoma syndrome, but, in general, the distinction from a tumor can be made based on equivocal responses to secretin and an exaggerated response to food ingestion, thus directing attention to the appropriate site of gastrin overproduction.184 There seldom is a need to pursue localization procedures.

Metastases from gastrinoma predominantly are located in the liver. The presence of gastrinoma in peripancreatic lymph glands should not be taken to indicate incurability,167,168,184–186 because it does not preclude removal of nodes and the primary tumor for possible cure. Some have advocated resection or a debulking procedure169,185–187 or even gastrectomy, which has been reported to cause regression of the primary tumor.165,188 Nonetheless, it is vitally important to identify metastases because tumor-related mortality can be as high as 79%.167 High serum levels of gastrin-17 compared with gastrin-34 may be of value,189,190 or, if available, measurement of the NH2 to COOH-terminal gastrin ratio.191,192 Elevated circulating hCG subunits strongly favor the presence of metastases193; in such cases, curative surgical attempts are unlikely to succeed.


The possibility of gastrinoma syndrome should be entertained in all patients with ulcer disease and in those with unexplained secretory diarrhea. Before development of the radioimmunoassay, 80% of patients with gastrinoma presented with a severe ulcer diathesis, bleeding, intestinal obstruction, or perforation. Two-thirds had had at least one operation. Although this may seem extravagant, it can be calculated that one unnecessary operation costs at least 1,000 gastrin assays; thus, if the success rate is 1:1,000, it should more than compensate for the cost of the assay. Since 1970, only 20% of patients with Zollinger-Ellison syndrome have presented with serious ulcer complications (ulcer diabetes because of gastrinoma), and only one-third have had prior surgery.194 Today, the diagnosis of gastrinoma should be made even without ulcers, based on diarrhea or mild duodenitis.

Before carrying out an extensive work-up of hypergastrinemia, however, a careful family history inquiring for features of MEN-1 syndrome should be conducted. If this is positive or suspicious, then in most patients with MEN-1, hypercalcemia has developed before age 30. If present, this indicates autosomal dominant inheritance of the MEN-1 gene.29 Measurement of serum calcium corrected for albumin will suffice because esophagogastric duodenoscopy allows the examination of gastric juice for pH and visually identifies superficial ectopic lesions that are missed by barium studies. A urine testing tape is also useful because, in the absence of antisecretory drugs, a pH of 3.0 or higher excludes Zollinger-Ellison syndrome.

Studies of gastric acid secretion should include measurements of volume as well as basal and PG-stimulated acid secretion. The diagnosis is confirmed if (a) the volume of gastric secretion is large (typically > 10 L per 24 hours); (b) the basal acid output is over 15 mmol/h or, after vagotomy or gastrectomy, over 3 mmol/h (values in the 10–15 range are borderline, and < 10 mmol/h excludes Zollinger-Ellison syndrome); and (c) the ratio of the basal acid output to the maximum response to pentagastrin is greater than 0.6, because the gastrinoma cells are maximally stimulating acid secretion and pentagastrin can cause no further rise. Of great importance is the need to stop H2 blockers, K+1/H + 1 adenosinetriphophatase inhibitors, and octreotide at least 24 hours before the study because false-negative results may occur through iatrogenic inhibition of acid secretion.

Serum gastrin levels are usually greater than 150 pg/mL in patients with Zollinger-Ellison syndrome, except for the small proportion who secrete a biologically active variant not recognized by the antiserum used.191 Gastrin levels may be raised for other reasons.

As Table 85.4 shows, it is apparent that only during conditions in which there is increased acid should Zollinger-Ellison syndrome be considered. The most sensitive and accurate test remains the secretin stimulation test for gastrin secretion. Secretin, 2 μ/kg, is given intravenously and blood samples for gastrin drawn at 2, 5, 10, 20, and 30 minutes. A rise of more than 100 pg/mL is strongly suggestive of Zollinger-Ellison syndrome. No new test has emerged with a greater sensitivity or specificity. Although false-positive results do occur, they are rare and usually found in hypochlorhydric states.88 The presence of normal hyperfunctioning antrum usually can be identified by a gastrin response to a meal greater than that to secretin.

Table 85.4. Causes of Hypergastrinemia.

Table 85.4

Causes of Hypergastrinemia.

Gastrinoma Localization

Tumor localization is needed to make the best treatment decisions in individual patients; the sensitivity and specificity of various localization procedures is given in Table 85.5. Selective angiography achieves visualization of the tumor in a minority of patients,195–197 although it often is useful for the demonstration of hepatic metastases. CT198 and ultrasound,163,198 even with the use of contrast, have proven to be of limited value because the density of these tumors is within the limits of the surrounding pancreatic tissue or, as occurs not infrequently, the tumors are below the resolution capacity of the technique. Furthermore, the presence of small tumors in extrapancreatic sites and, even within the body of the liver, may go undetected by these means.168,184,186,199 A technique using intraoperative ultrasound of the exposed pancreas200–202 has been modestly successful, suggesting that this technique may be able to eliminate some of the artifacts created by external ultrasound. MRI was greeted with some enthusiasm, but apart from an enhanced capacity to visualize blood vessels, it generally has not been superior to previous techniques.203 A recent study of 11 patients with islet cell tumors showed that MRI combined with dynamic gadolinium scanning may be superior to CT.204

Table 85.5. Success of Tumor Localization in Gastrinoma.

Table 85.5

Success of Tumor Localization in Gastrinoma.

On occasion, a combination of techniques may be useful. Although both CT and selective visceral angiography were found to be effective in identifying nearly all patients with metastatic disease to the liver and, in some cases, to retroperitoneal lymph nodes, these studies failed to identify primary tumors in more than 50% of the patients seen with biochemical proof of gastrinoma syndrome. Recently, selective intra-arterial injection of secretin has been used to help localize gastrinomas either by enhancing tumor/background differences in gastrin levels or by causing a tumor blush on angiography.172,205 This technique has the advantage that it can be performed simultaneously with angiography with the addition of a catheter in a hepatic and a peripheral vein to sample gastrin levels. When secretin is injected into a vessel that supplies the gastrinoma, the hepatic vein levels of gastrin greatly exceed the peripheral levels. This technique may have a higher accuracy than percutaneous transhepatic venous sampling (PTHVS) alone.205

The use of percutaneous transhepatic portal, pancreatic, and hepatic venous gastrin sampling by Ingemansson and colleagues206 in 1977, Burcharth and colleagues207 in 1979, and subsequently by others208–210 suggested that this new technique was of value in those patients with gastrinoma syndrome without liver metastases or those with a primary gastrinoma that was not detected by conventional imaging methods. Our initial studies were undertaken in 1978.184,209,210 It soon became apparent that not only was a skilled angiographer imperative, but also expert technique, a detailed understanding of the variable venous anatomy, a sound and reliable assay method for gastrin, and thoughtful interpretation of the data in each case.184,209,210 The technique is both costly and time consuming.191 Gradients were determined by simultaneous measurements of gastrin in peripancreatic veins and central arterial samples to avoid the misinterpretations that the rapid changes in secretory rate often associated with gastrinomas can cause. Placement of cannulae without obstruction of the vessel and streaming of blood in the portal vessel had to be considered. Awareness of the peculiarities of the peripancreatic venous drainage was a prerequisite to avoid erroneous localization of tumors. Furthermore, hepatic venous sampling also was considered to be essential to detect occult liver metastases or the rare primary gastrinoma within the liver. In our experience, it has been possible to predict the presence or absence of liver metastases and, in two patients, to identify solitary resectable primary liver gastrinomas. Our results in 46 patients with gastrin hypersecretion indicate that the technique may be uniquely valuable in sporadic or ectopic gastrinomas,184,209,210 but false-negative results also have been reported.211

The most recent analysis of a 10-year experience supports PTHVS as a useful method to regionalize a tumor. Early results suggested that the technique was of limited value in patients with MEN-1 who were much less likely to benefit from localization and excision of the tumor.179,184 The results are based on the demonstration of tumors in the pancreas and in ectopic sites. Clearly, however, the surgeon would have found at least 50% of the tumors without the aid of PTHVS. Our approach has been aggressive: if there has been a gradient (by criteria that differ from those of others), the surgeon has pursued mobilization of the head of the pancreas and duodenotomy. These procedures have not been pursued by many other surgeons because of the relatively benign course of those patients in whom no tumor is found at standard laparotomy.

In experienced hands, endoscopic ultrasound may increase the ability to detect pancreatic gastrinomas, and localization rates of 80 to 100% have been reported.212,213 The ability of this technique to detect lesions less then 5 mm in size or occult duodenal lesions, however, is uncertain. A typical instrument consists of a side-viewing endoscope combined with a 7.5- and 12.0-MHz ultrasonic transducer distal to the side-viewing optics, giving an ultrasonic section of 360° perpendicular to the shaft axis of the scope.213 The pancreatic head is examined with the scanner positioned in the duodenum. The body and tail of the pancreas are studied with the scanner in the stomach. A special saline-filled balloon at the tip of the instrument and instillation of approximately 400 mL of saline into the stomach are used to provide an interface between the ultrasonic unit and the GI wall.212,213

With the aggressive approach, at least 30% of patients with sporadic gastrinoma syndrome can be cured by tumor resection. With recent advances in localization methods and operative techniques, the percentage of patients cured likely will increase. Thus, in appropriate cases, an aggressive approach is distinctly advantageous in the localization and selection of operative treatment. Failure to find a tumor carries a good prognosis, and no patient has died in an 8.5-year follow-up.179 This must be contrasted with the 29% perioperative morbidity and mortality rate resulting from explorations of the head of the pancreas reported by some,167,177,187,199,210 although one group has reported 37%.214 The ultimate answer to the vexing question of whether to explore the head of the pancreas will no doubt be determined by longer follow-up; the approach will be dictated by the available expertise and experience of those involved.


Treatment of the gastrinoma syndrome has undergone significant changes since the first case was described in 1955.169 Until the development of drugs to control excessive acid production,215–218 the purpose of operative intervention was to excise the acid-secreting stomach, which was the major cause of morbidity and mortality (from massive hemorrhage or perforation). These operations most frequently were done as emergency procedures under adverse conditions and were associated with a significant increase in mortality compared with elective partial or total gastrectomies. It soon was learned that partial gastrectomy with or without vagotomy usually was ineffective, and total gastrectomy became the standard operation in patients with an established diagnosis of gastrinoma.163,167,169,176 As experience accumulated, it became apparent that approximately 60% of patients with gastrinoma syndrome had malignant tumors, which, although relatively slow growing, became the major contributing factor to mortality after longer follow-up.163 Occasional cases were reported, however, in which the syndrome had been cured by tumor excision only, particularly when the primary neoplasm was in the duodenum and no metastases were found in either lymph nodes or the liver.167,199,219–221 In most of these cases, a total gastrectomy also was performed because the surgeon was rightfully concerned that occult metastases might be present and remain a cause of continued hypersecretion of gastrin.

Most authorities now recommend a combined medical and surgical approach to the management of these tumors. If patients with MEN-1 syndrome are excluded, the cure rate for excision of a gastrinoma is approximately 14%.168,179,181,222–225 These studies did not, however, define the nature of the primary disease. When only extrapancreatic tumors are examined, as many as 50% may be cured by excision of the tumor,163,167,168,219 especially those in the duodenum. Even excision of tumors in lymph nodes may result in cure.199,219,222 For the most part, unfortunately, various reports have grouped their patients together and not identified the subgroups defined earlier. Surgical exploration should include mobilization of the pancreas along its entire length, allowing careful bimanual palpation if regionalization has not been achieved preoperatively. A variety of intraoperative methods are helpful to the surgeon in identifying gastrinomas. Intraoperative ultrasound has been shown by some investigators to detect nonpalpable lesions, identify the relationship of the lesion to major structures such as the main pancreatic duct, and detect signs suggesting malignancy.226,227 The ability of this technique to detect duodenal lesions, however, is poor. Intraoperative endoscopy with transillumination of the duodenum has been shown to be capable of locating duodenal wall gastrinomas,228 but the most accurate method of detecting duodenal gastrinomas appears to be duodenotomy with careful palpation. Because the duodenum and extrapancreatic locations have been recognized increasingly as sites of gastrinomas,171,179,184,214,219 most experienced teams routinely employ duodenotomy during surgical exploration for gastrinoma.173,175 Such an aggressive approach has increased significantly the number of positive explorations, with one group increasing the percentage of positive explorations from 64 to over 90%, primarily through the identification and resection of duodenal wall gastrinomas.174,175

The current treatment of the patient with MEN-1 and gastrinoma remains controversial.176,180,229 The total number of patients with the MEN-1 and gastrinoma syndromes who have been carefully evaluated for possible palliative or curative pancreatic operations based on selective venous sampling has been so limited that a definitive statement about optimal management cannot be made at present. In these patients, both the functional (i.e., hypergastrinemia) and malignant potential of the disease should be considered in the individual case. When there is no evidence of metastatic disease and venous sampling demonstrates an anatomically localized source of gastrin, enucleation (i.e., pancreatic head) or resection (i.e., body or tail) may offer excellent palliation, if not cure. The low incidence of malignancy in the patients with MEN-1 should not dictate a more cavalier approach than in sporadic cases without evidence of MEN-1.

Accurate estimates for chemotherapeutic activity in metastatic gastrinoma are difficult to ascertain because most published series have studied chemotherapy for all histologic subtypes of pancreatic endocrine cancers pooled together. With respect to single-agent chemotherapy, streptozotocin probably is the most active antineoplastic drug in patients with metastatic gastrinomas.230–233 From their review, Maton and colleagues suggested that the drug appears to cause an objective response rate of 50% in patients with this disease. There is no evidence for improved outcomes when streptozotocin is used in combination with 5-fluorouracil with or without doxorubicin.234,235 Inconsistencies in the reported dose and schedule of administration of streptozotocin as well as in the criteria used for reported objective tumor responses preclude reliable recommendations for chemotherapy with this agent in patients with metastatic gastrinoma. Among six patients with advanced gastrinoma who received dacarbazine, none had an objective response.234,236

Similarly, there has been little experience in the use of adjuvant chemotherapy following surgical resection. In one report of four patients who underwent complete resection of locally advanced gastrinoma followed by chemotherapy with streptozotocin, doxorubicin, and 5-fluorouracil, two patients remained free of disease at 14- and 32-month follow-up evaluations.237 The small number of patients and relatively short follow-up period is insufficient to recommend that this approach be generally adopted, however, although it may be appropriate to consider it for selected patients.

As discussed later for other pancreatic endocrine tumors, there appears to be a role for interferon in management.151 The number of reported patients with gastrinoma treated with interferon, however, is too few to reach any firm conclusions regarding its effectiveness in this specific disease.


A firmly established diagnosis of an insulin-secreting lesion of the pancreas is essential to successful management. Therefore, it is critically important to rule out other causes of hypoglycemia associated with fasting.238 A detailed differential diagnosis may be found in Table 85.6. Nonislet cell neoplasms associated with hypoglycemia are given in Table 85.7.

Table 85.6. Classification of Hypoglycemia.

Table 85.6

Classification of Hypoglycemia.

Table 85.7. Nonislet Cell Neoplasms Associated with Hypoglycemia.

Table 85.7

Nonislet Cell Neoplasms Associated with Hypoglycemia.

An accurate diagnosis of organic hyperinsulinism can be established with near certainty in all cases.238 The specific causes of hyperinsulinism (see Table 85.7) usually can be made before exploration. There are syndromes of autoimmunity that may lead to hypoglycemia that must be considered.

Antireceptor antibodies usually occur in the presence of other autoimmune disease, with antireceptor antibodies mimicking the effect of insulin and reducing insulin clearance. Therefore, insulin levels may be normal or high, but C-peptide levels are low. This is because islet cells are suppressed. Titers fall with time, leading to remission, although corticosteroids have been used. Autoimmune hypoglycemic disease syndrome usually occurs in the presence of other autoimmune disorders (e.g., Graves’ disease, rheumatoid arthritis, lupus) and generally produces reactive hypoglycemia from prolongation of the half-life of circulating insulin. Insulin levels generally are extremely elevated, which may result from interference by antibodies with the particular insulin assay or, if C peptide also is increased, increased insulin secretion by the pancreas to compensate for inactivation of insulin by circulating antibodies. Glucose tolerance testing reveals that plasma glucose is elevated early and reduced late because of the buffering effect of antibodies on the action of secreted insulin. The disease usually is self-limited and may be precipitated in some patients by exposure to drugs containing sulfhydryl groups that react with sulfhydroyl groups on insulin and render it immunogenic.


The blood glucose level alone is not diagnostic of insulinoma, nor in general is the absolute insulin level elevated in all cases of organic hyperinsulinism. The standard test remains a 72-hour fast while the patient is closely observed.238,239 More than 95% of cases can be diagnosed based on responses to a 72-hour fast. Serial glucose and insulin levels are obtained over the 72 hours until the patient becomes symptomatic. Because the absolute insulin level is not elevated in all patients with insulinomas, a normal level does not rule out the disease; however, a fasting insulin level of greater than 24 μU/mL is found in approximately 50% of patients with insulinoma. This is strong evidence in favor of the diagnosis. Values of insulin greater than 7 μU/mL after a more prolonged fast in the presence of a blood glucose less than 40 mg/dL also are highly suggestive. A refinement in the interpretation of glucose and insulin levels has been established by determining the ratio of insulin levels in μU/mL to the concomitant glucose level in mg/dL. An insulin/glucose ratio of greater than 0.3 has been found in virtually all patients proven to have an insulinoma or other islet cell disease causing organic hyperinsulinism. The accuracy of the test can be increased by calculating the amended insulin/glucose ratio as follows:

amended ratio = insulin (μU/mL)/glucose (mg/dL) – 30

If the value is greater than 50, then organic hyperinsulinism is certain.238 Measurements of proinsulin and C peptide also have proven to be valuable in patients suspected of having organic hypoglycemia.181 Normally, the circulating proinsulin concentration accounts for less than 22% of the insulin immunoreactivity but is greater than 24% in over 90% of individuals with insulinomas. Furthermore, when the proinsulin level is greater than 40%, a malignant islet cell tumor should be strongly suspected.187,238,240 The C-peptide level is useful in ruling out factitious hypoglycemia from self-administration of insulin. Commercial insulin preparations contain no C peptide, and combined with high insulin levels, low C-peptide levels confirm the diagnosis of self-administration of insulin. High-performance liquid chromatography to characterize the insulin species found in the blood was useful before the advent of recombinant human insulin, which has provided the malingerer with a more powerful tool to test the resourcefulness of the physician. Patients who take sulfonylureas surreptitiously may have raised insulin and C-peptide values soon after ingestion, but chronic use will result in hypoglycemia without raised insulin or C-peptide levels. Only an index of suspicion and measurement of urine sulfonylureas will lead to the correct diagnosis. A variety of insulin stimulation and suppression tests were once used when precise and accurate insulin measurements were not available. Each had its limitations, and all are currently considered to be obsolete.88,238 The insulin response to secretin stimulation (2 μ/kg intravenously; peak response in 1–5 minutes) is a valuable measure to differentiate multiple adenomas from nesidioblastosis and single adenomas.241 The normal maximal increment is 74 μU/mL, whereas in single adenomas, the rise is only 17 μU/mL, in nesidioblastosis 10 μU/mL, and in two patients with multiple B-cell adenomas and hyperplasia, 214 and 497 μU/mL. Patients with single adenomas and nesidioblastosis do not respond to secretin, whereas those with multiple adenomas or hyperplasia have an excessive insulin response to the administration of secretin.


Once the diagnosis of suspected hyperinsulinism is confirmed, every effort should be made to localize the source of excessive insulin production. Preoperative localization is important because approximately 30% of insulinomas are less than 1 cm in diameter, 10% are multiple, 10 to 15% are malignant, and 10% will have either islet cell hyperplasia or nesidioblastosis and no tumor at all (Fig. 85.5).88,184,219,238,239,242–246 Because of their small size, the techniques most commonly used to demonstrate tumors in the upper abdomen, including ultrasound, CT, MRI, contrast studies of the upper GI tract, and endoscopic retrograde pancreatography, are of little value. Until the past decade, the only study considered to be of proven value in the localization of insulinomas was selective pancreatic angiography.239,242,245,247 Highly selective injections of contrast, subtraction procedures, and magnification increase the number of insulinomas identified by this technique (see Fig. 85.3). In one large series, 90% of insulinomas were reported to be localized by angiography alone239; however, most groups report less satisfactory results.247 A summary of all reports in the literature found that approximately 60% of insulinomas have been detected by this method.184 Selective intra-arterial injection of calcium with sampling of hepatic vein insulin appears to improve the ability to detect insulinomas,71,248 similar to the results seen with intra-arterial secretin in gastrinoma.

Figure 85.5. Nesidioblastosis showing islet hyperplasia, with immunoperoxidase evidence for insulin staining.

Figure 85.5

Nesidioblastosis showing islet hyperplasia, with immunoperoxidase evidence for insulin staining.

PTHVS of insulin from pancreatic veins has been used successfully in localizing occult sources of hyperinsulinism.242,249–252 We now believe that the combination of a secretin test to determine the nature of the hyperinsulinism (e.g., distinction of hyperplasia from adenoma or multiple adenomatosis) with PTHVS to localize provides the best means of establishing the specific cause of organic hyperinsulinism with near certainty. A skilled angiographer and careful analysis of the hormonal data in relationship to the venous anatomy in the individual case are required.

If PTHVS is not available and preoperative localization by angiography or other techniques has been negative, the surgeon may use intraoperative ultrasound if a careful exploration fails to detect a tumor. Some who have used this technique routinely have reported excellent results. Ultrasound does not identify hyperplasia or nesidioblastosis, however, and it appears to be operator dependent in its sensitivity.

Treatment of Islet β-cell Disease with Hyperinsulinism

The treatment of pancreatic islet β-cell disease usually is surgical; in the great majority of cases, it provides a complete cure. It should be performed only when the diagnosis is certain, however, and only by a surgeon who is skilled in pancreatic surgery. The surgical approach to insulinoma is straightforward when the tumor is localized. Precise localization obviates blind pancreatic resection.253 The results of PTHVS are very useful in helping to plan the surgical approach, even in the absence of finding a tumor during careful surgical exploration. In patients who have been unresponsive to medical therapy and in whom PTHVS suggests diffuse or multiple sources, such as adenomatosis, nesidioblastosis, or hyperplasia, a resection of at least 80% of the pancreas is indicated after a frozen-section specimen of the pancreatic tail confirms the diagnosis. When hypoglycemia can be controlled with diet alone or with small, well-tolerated doses of diazoxide, and/or when the medical condition of the patient may increase the hazard of surgery sufficiently, medical management alone may be considered. Patients with diffuse hyperinsulinism for whom an operation is planned first should have a trial of treatment with diazoxide and a natriuretic benzothiadiazine. Medical treatment is required for the great majority of malignant insulinomas because only occasionally are they cured by operation. Medical treatment for benign insulinomas is a change in meals to include “lente carbohydrate” or unrefined carbohydrate given as frequently as required to prevent hypoglycemia. Antihormonal therapy may be useful if diet is insufficient. The management of malignant insulinoma is antihormonal and antitumor therapy.

Medical Management of Benign Disease


The cornerstone of medical management of insulinoma and other forms of hyperinsulinism is the diet. Not uncommonly, patients may avoid symptoms of hypoglycemia for variable periods of time by shortening the number of hours between feedings. For some, the inclusion of a bedtime (11:00 pm) feeding is sufficient; for others, a midmorning, midafternoon, and/or a 3:00 snack are necessary. Although the tumor may be stimulated occasionally to secrete insulin by the ingestion of carbohydrates, it is inadvisable to restrict the intake of carbohydrate. More slowly absorbable forms of carbohydrates (e.g., starches, bread, potatoes, rice) generally are preferred. During hypoglycemic episodes, rapidly absorbable forms (e.g., fruit juices with added glucose or sucrose) are indicated. In patients with severe refractory hypoglycemia, use of a continuous intravenous infusion of glucose, coupled with increased dietary intake of carbohydrate, frequently alleviates hypoglycemia long enough to institute additional therapy.

Diazoxide and Natriuretic Benzothiadiazines

Diazoxide (Proglycem) owes its potent hyperglycemic properties to two effects254,255: it directly inhibits the release of insulin by B cells through stimu lation of α-adrenergic receptors, and it has an extrapancreatic hyperglycemic effect, probably by inhibiting cyclic adenosine monophosphate (AMP) phosphodiesterase, resulting in higher plasma levels of cyclic AMP and enhanced glycogenolysis. Because diazoxide induces the retention of sodium, edema is troublesome at higher dosages. The addition of a diuretic benzothiadiazine (e.g., trichlormethiazide) not only corrects or prevents edema but synergizes the hyperglycemic effect of diazoxide. At the doses needed to counteract the higher doses of diazoxide (e.g., 450–600 mg/d), natriuretic benzothiadiazines frequently induce hypokalemia. Nausea is an additional complication at higher dosages of diazoxide, and hypertrichosis may complicate long-term treatment. These compounds have been useful to elevate blood levels of glucose into the euglycemic range if operation must be delayed for weeks or months. Patients with benign insulinomas have been managed successfully for up to 16 years with diazoxide in doses of 150 to 450 mg/d in combination with trichlormethiazide in doses of 2 to 8 mg/d. If they can be tolerated, higher doses may be used in patients with malignant insulinomas.

Calcium Channel Blockers

Theoretically, calcium channel blockers are capable of inhibiting insulin secretion. Verapamil has been used successfully to alleviate the hypoglycemia caused by an insulin-secreting pancreatic tumor in a 94-year-old woman.256 Verapamil and diltiazem have been used with variable results in other patients with organic hyperinsulinism.


β-Adrenergic-receptor blocking drugs inhibit insulin secretion and therefore may be of value in treating organic hyperinsulin. Only a few reports of the use of propranolol have appeared.257–259 Its use has been associated with the reduction of plasma insulin levels and with the relief of hypoglycemic attacks in patients with benign or malignant insulinoma. In a patient with a benign insulinoma, 80 mg of propranolol a day was sufficient, whereas a patient with malignant insulinoma, in whom streptozotocin was no longer effective, required 640 mg of propranolol orally per day.259 Because these changes can mask the adrenergic symptoms of hyperglycemia and inhibit muscle glycogenolysis, however, there is a risk of aggravating the clinical syndrome. The drug should be used with extreme caution and careful monitoring.


The anticonvulsive diphenylhydantoin (Dilantin) has been shown to inhibit the in vitro release of insulin from both the labile and storage B-cell pools. It has been used successfully to control refractory hypoglycemia, as evidenced by normal overnight fasting glucose levels and absence of hypoglycemia during total fasting of up to 24 hours.260,261 In only one-third or less of patients with benign insulinoma, however, is the hyperglycemic effect of Dilantin of any clinical significance. Furthermore, with the dosage required, ataxia, nystagmus, hypertrophic gums, and megaloblastic anemia may be side effects. Maintenance doses range from 300 to 600 mg/d. The concurrent administration of diazoxide lowers measurable blood levels of dilantin, and their concurrent use is not recommended.

Long-acting Somatostatin Analogue

We initially reported the successful use of octreotide (Sandostatin) in prolonging the ability to fast in a patient with a benign insulinoma,262 and a similar experience was reported by Osei and O’Dorisio263 in a patient with a malignant tumor. Our more recent experience has shown a variety of responses not easily predictable by the clinical or biochemical profile. We have examined the effects of a long-acting octreotide analogue in seven patients with endogenous hyperinsulinism, five with proven single adenomas, one with multiple adenomas, and one with organic hyperinsulinism associated with MEN-1.245 In two patients, and possibly a third, octreotide prolonged the ability to fast without hypoglycemia, with variable decreases in plasma insulin concentrations. A trial of long-term administration of octreotide in one of these patients gave only short-term relief of hypoglycemia. Octreotide did not improve, or actually worsened, plasma glucose levels on fasting in the other four patients. In contrast, oral administration of diazoxide to four of these patients was effective in raising plasma glucose levels. A child treated for nesidioblastosis did well initially but subsequently required pancreatectomy and also grew at only the third percentile. It is unlikely that octreotide will be a useful addition to the therapeutic armamentarium for treatment of organic hyperinsulinism, except in familial forms of nesidioblastosis.


The use of glucocorticoids, which increase gluconeogenesis and cause insulin resistance, also can help to stabilize blood glucose at an acceptable level. Pharmacologic doses (prednisone, approximately 1 mg/kg) must be used.


Glucagon may help to raise blood glucose concentrations, but it may simultaneously directly stimulate the release of insulin.

Vasoactive Intestinal Peptide Tumor (VIPoma)

In 1958, Verner and Morrison264 first described refractory watery diarrhea and hypokalemia associated with noninsulin-secreting tumors of the pancreatic islets. The absence of gastric hypersecretion and even achlorhydria were documented in patients with this tumor syndrome,264–266 later termed pancreatic cholera because the observed severe diarrhea resembled Vibrio cholerae disease.267 The acronym WDHA (watery diarrhea [100%], hypokalemia [100%], achlorhydria)268 was proposed, although a more appropriate acronym might be WDHHA, for watery diarrhea hypokalemia, hypochlorhydria, and acidosis, because of bicarbonate wasting. Several reported series have confirmed the association between certain pancreatic tumors and watery diarrhea syndrome.257,269,270

In a review of 55 patients with the diarrhea and hypokalemia syndrome, other features were sometimes observed: alkalosis in mild cases but acidosis in severe diarrhea from bicarbonate wasting, flushing, hypercalcemia, tetany (perhaps from magnesium depletion), abnormal glucose tolerance, and dilation of the gallbladder.270 The most prominent symptom in most patients is profuse cholera-like diarrhea, which often is present for 3 or 4 years before diagnosis, with volumes usually exceeding 6 to 8 L of stool every 24 hours. Stool has the appearance of dilute tea and is rich in electrolytes, with an average secretion of 300 mmol of potassium per 24 hours. The diarrhea always is secretory in nature, will not disappear with fasting for 48 hours, and demonstrates an increased net secretion of electrolytes in the stool. This symptom may be confused with the diarrhea found in the Zollinger-Ellison syndrome; the distinguishing features are shown in Table 85.8.

Table 85.8. Differentiation of Gastrinoma and WDHHA Syndrome.

Table 85.8

Differentiation of Gastrinoma and WDHHA Syndrome.

Diarrhea that is not secretory always results from causes other than endocrine tumors. Laxative abuse may be very difficult to exclude, however, and the measurement of stool electrolytes and osmolarity may be required. Stool electrolytes should account for the osmolarity if the condition results from an endocrine tumor. An osmolarity exceeding that expected from the concentration of electrolytes invariably reflects laxative abuse, which must be carefully excluded.

The episodic and fulminating, secretory diarrhea associated with VIPomas results in profound hypokalemia, hypochlorhydria (rarely achlorhydria), bicarbonate wasting, and hyperchloremic metabolic acidosis. The more commonly observed hypochlorhydria results from the direct gastric acid inhibitory effect of VIP, a biologic property that is shared with other members of the secretin-glucagon family: secretin, glucagon, gastric inhibitory peptide (GIP), and polypeptide histidine and isoleucine.271 In the early stage of tumor growth, the predominant symptoms of diarrhea are episodic and intermittent. It generally is accepted that as the VIP tumor enlarges, the diarrhea becomes continuous and the ensuing electrolyte abnormalities life-threatening.257,269 Increased intestinal motility as well as secretion may contribute to the diarrhea.132

The clinical features of VIPomas are consistent with the known actions of VIP, which include stimulation of intestinal secretion, facial flushing, inhibition of gastric acid secretion, stimulation of glycogenolysis, and hypercalcemia.269,270,272–277 The structural homology between VIP and secretin, glucagon, GIP, and peptide histidine and isoleucine276 may account for enhanced secretion of pancreatic juice and inhibition of gastric acid secretion. VIP also has been reported to cause gallbladder relaxation; a large distended gallbladder often is found in patients with the VIPoma syndrome. Hypercalcemia has been noted in nearly 50% of patients with the syndrome. The cause is not clear, but it may relate to dehydration, electrolyte disturbances secondary to diarrhea, coincidental MEN accompanied by hyperparathyroidism, or secretion by the tumor of a calcitrophic peptide. Tetany has been reported in several patients and may result from hypomagnesemia secondary to the diarrhea. Nearly 8% of patients demonstrate facial flushing. The cause of this patchy erythematous and, sometimes, urticarial flushing is not clear, but it has been attributed to VIP or prostaglandins, which may be present in the tumor. The hyperglycemia often noted in patients with the watery diarrhea syndrome probably is secondary to the profound glycogenolytic effect of high portal vein VIP on the liver.275

Sites of Tumors Secreting VIP

Tumors secreting VIP usually originate in the pancreas or along the sympathetic chain. In a series of 62 patients, 52 (84%) had pancreatic tumors and 10 (16%) had ganglioneuroblastomas.278 Of the 10 patients with ganglioneuroblastomas, 7 were children.

There have been 18 other case reports of elevated plasma levels of VIP that have been associated with neurogenic tumors, including ganglioneuroblastoma, ganglioneuromas, neurofibroma, and pheochromocytoma.279–288 Primary VIPomas now have been reported in other sites as well, including colon, lung, esophagus, jejunum, and liver, and we have reported the eventual emergence of tumors masquerading as hypernephroma and cutaneous mastocytomas.289 Most neurogenic tumors associated with the VIPoma syndrome have been found in children, but priapism has occurred, presumably resulting from a VIP-induced increase in blood flow to the corpora cavernosa. Catecholamines frequently are elevated; in patients with excess catecholamine secretion, flushing, increased sweating, and hypertension may occur. Hyperglycemia and hypercalcemia have not been noted in children. Plasma levels of PP are normal and have not been detected in VIP-producing ganglioneuroblastomas. Plasma PP levels nearly always are elevated if the tumor is in the pancreas. Thus, it was hoped that PP levels would distinguish pancreatic and nonpancreatic sources of VIP; however, three adults with neurogenic tumors and a 64-year-old woman with a VIPoma of the lower left kidney had high serum levels of PP.290 Excessive quantities of immunoreactive VIP and PP were found in the renal tumor tissue.

Biochemical Diagnosis and Experience

VIP is synthesized as the 170 amino acid precursor pre-pro VIP, which post-translationally is modified to yield the 28 amino acid VIP itself as well as peptide histidine and methionine (PHM) and other fragments.291 By definition, VIP levels are elevated in all patients with the VIPoma syndrome. Some of the non-VIP products of the precursor are secreted at higher levels than VIP itself, but, unfortunately, assays for these products are not commercially available and their clinical usefulness not established. False-positive elevations of VIP can be observed in patients with small bowel ischemia or severe low-flow states caused by diarrhea and secondary dehydration not associated with VIP-producing tumors.274,292,293

However, VIP is not the only agent implicated in the diarrhea syndrome. Gastrin, secretin, glucagon, enteroglucagon, GIP, PP, VIP, thyrocalcitonin (TCT), prostaglandins, and peptide fragments of pre-pro VIP or any one of a number of combinations have been implicated as possible etiologic agents of the diarrhea syndrome.294 Bloom and colleagues reported 1,000 patients with various forms of diarrhea.292,295 Thirty-nine patients (3.9%) had greatly elevated levels of VIP, and, in each case, a tumor was found. In more than 50% of these patients, the tumor was successfully removed, the symptoms remitted, and the plasma levels of VIP returned to normal. Twelve patients had diarrhea secondary to TCT-producing tumors of the thyroid, 13 had carcinoma of the lung, 4 had a villous adenoma of the rectum, and 24 had carcinoid tumors. All 53 of these patients had normal plasma VIP levels. Eleven additional patients had classic clinical features of the VIPoma syndrome in whom VIP levels were normal and no tumor was found; they probably were secreting an unidentified humoral substance with the biologic properties of VIP.

Biochemical detection of VIP-secreting tumors necessitates a highly sensitive and specific VIP radioimmunoassay. The range of normal VIP concentration is 0 to 170 pg/mL, which is similar to that (0–190 pg/mL) found by others.273,281,296

Information gained from a single plasma VIP level may be misleading. The diagnosis of VIPoma in a patient with a good clinical history should not be excluded based on a single normal VIP because of vagaries in the assay. In addition, between periods of watery diarrhea, the VIPoma, unlike many endocrine tumors of the gut (e.g., insulinoma, gastrinoma), may not be actively secreting VIP; thus, a normal level creates a false sense of security and may delay a more vigorous search for the cause.


The first step in the treatment of these patients is prompt replacement of fluid and electrolyte losses. Symptoms of severe electrolyte imbalance include cardiac arrhythmias, neuromuscular deficits, profound shock, and cardiovascular collapse. The fluid of choice is an isotonic electrolyte solution containing adequate sodium, potassium, and base. In the series of 52 pancreatic cases reported by Long and colleagues,278 most of the solitary tumors were 8 cm or greater in diameter. Most of these tumors are demonstrable using ultrasound or CT, but, occasionally, angiography or PTHVS are required.136 Somatostatin-receptor scintigraphy may be useful in identifying extrapancreatic VIPomas, particularly those in the sympathetic chain, or metastases.69

If a tumor has been identified, complete surgical excision is the primary form of treatment. If the tumor cannot be removed completely, surgical debulking may have palliative benefit. In one series, surgical excision of the primary pancreatic tumor relieved all symptoms in 17 patients (27%).177 Surgical removal of a ganglioneuroblastoma was successful in 7 of 10 patients.

We do not advocate blind total pancreatectomy in patients who have diarrhea and in whom no tumor is demonstrable by angiography, CT, ultrasound, or PTHVS. Steroids have provided some symptomatic relief. A trial of prostaglandin synthesis inhibitors (e.g., indomethacin), phenothiazines, and lithium may be warranted.297 Octreotide has been used successfully in managing the diarrhea of VIPoma syndrome as well as that from the GEP tumors. Long-term octreotide treatment not only controls the diarrhea in these patients but also may cause arrest or regression of the tumor. Furthermore, we have seen spontaneous remission of watery diarrhea syndrome without establishing a cause, but we also have seen the eventual emergence of tumors in unusual sites, including the kidney and skin, only disclosed after careful follow-up for several years.

In summary, when confronted with severe chronic diarrhea, it must be established that the diarrhea is secretory in nature by fasting the patient for 48 hours and measuring stool volume. If diarrhea persists with fasting, VIP-producing tumors of the pancreas frequently are found, and plasma samples should be analyzed for VIP in these patients. If the VIP level is elevated, a VIP-secreting tumor (VIPoma) should be strongly suspected. In addition, a serum pancreatic polypeptide level should be determined simultaneously. If the tumor is located in the pancreas, this peptide almost invariably will be elevated. In children, catecholamine levels also should be obtained. If VIP levels are normal, screening for other causative agents, including gastrin, SP, somatostatin, PP, TCT, serotonin, glucagon, neuropeptide K, neurokinin A, peptide fragments of pre-pro VIP, and prostaglandins of the E series should be performed. Tumor localization should include CT, celiac, superior mesenteric, and renal angiography and, finally, PTHVS. Octreotide scanning may be useful, especially if metastases are being sought, but may not be quite as helpful in small primary lesions. If a tumor is found, it should be excised. In the absence of finding a tumor, symptomatic therapy, not empiric surgery, is warranted. With malignant tumors, treatment with Sandostatin or chemotherapy must be considered.

Glucagonoma Syndrome

Clinical Features

In 1966, McGavran and colleagues298 called attention to a syndrome that included acquired diabetes and glucagon-producing tumors. It became apparent only later that these tumors usually were accompanied by a very characteristic skin rash.299,300 The main features of the glucagonoma syndrome include a characteristic rash termed necrolytic migratory erythema (NME) (82% of patients) (Fig. 85.6), painful glossitis, angular stomatitis, normochromic normocytic anemia (61%), weight loss (90%), mild diabetes mellitus (80%), hypoaminoacidemia, deep vein thrombosis (50%), and depression (50%). The syndrome also goes by the acronym 4D syndrome, which stands for dermatosis, diarrhea, deep vein thromboses, and depression.

Figure 85.6. Migratory necrolytic erythema of glucagonoma syndrome.

Figure 85.6

Migratory necrolytic erythema of glucagonoma syndrome.

The frequency of islet cell tumors has been estimated in autopsy series to be between 0.0 and 1.4% of all cases studied. In a very thorough study of 1,366 consecutive adult autopsies, Grimelius and Wilander301 found a tumor frequency of 0.8%. All tumors were adenomas, and all contained histochemically defined glucagon cells. None of the tumors had been suspected during life. Although these adenomas contained glucagon, it is not known whether they were overproducing or even secreting glucagon. The incidence in vivo probably is 1% of all neuroendocrine tumors.

The NME rash of the glucagonoma syndrome has a characteristic distribution. It usually is widespread, but major sites of involvement are the perioral and perigenital regions along with the fingers, legs, and feet. It also may occur in areas of cutaneous trauma. The basic process in the skin seems to be one of superficial epidermal necrosis, fragile blister formation, crusting, and healing with hyperpigmentation. Skin biopsies usually show small bullae containing acantholytic epidermal cells as well as neutrophils and lymphocytes.299 The adjacent epidermis usually is intact, and the dermis contains a lymphocytic perivascular infiltrate. Different stages of the cutaneous lesions may be present simultaneously. Biopsy examination of a fresh skin lesion may be the most valuable aid in suggesting the diagnosis of glucagonoma syndrome, but repeated biopsy samples may be necessary to raise this possibility. A painful glossitis manifested by an erythematous, mildly atrophic tongue has been associated with the cutaneous lesions.

Two other features of the syndrome are noteworthy. First, an alarmingly high rate of thromboembolic complications occurs in patients with glucagonomas, and many patients succumb to pulmonary embolism. Unexplained thromboembolic disease should alert one to the possibility of glucagonoma. Second, depression and other psychiatric disturbances including depression are common, but these may relate in part to the chronic dermatosis.292,302

Several metabolic disorders are associated with cutaneous lesions closely resembling the NME of the glucagonoma syndrome. These include acrodermatitis enteropathica, zinc deficiency induced by hyperalimentation, essential fatty acid deficiency, the dermatosis of protein calorie malnutrition of kwashiorkor, and pellagra resulting from niacin deficiency.297,303–305 Cutaneous manifestations associated with malabsorptive states often are nonspecific, affecting approximately 20% of patients with steatorrhea. Improvement in the rash associated with the glucagonoma syndrome has been reported with amino acid repletion as well as administration of carbohydrate. The skin rash also has been shown to improve with the administration of zinc.306 Almost invariably, the dermatosis resolves after successful removal of a glucagon-producing tumor, even if the rash has been present for several years.307,308 In addition, in those patients who do not undergo curative resection but are treated with chemotherapeutic agents, dermatitis improves as the glucagon levels decrease.85,308,309

Glucose intolerance in the glucagonoma syndrome may relate to tumor size. Fasting plasma glucagon levels tend to be higher in patients with large hepatic metastases than in those without hepatic metastases,307 and all patients with large hepatic metastases had glucose intolerance. Massive hepatic metastases may decrease the ability of the liver to metabolize splanchnic glucagon, thus increasing peripheral plasma glucagon levels. Glucagon may not directly induce hyperglycemia, however, unless metabolism of glucose by the liver is directly compromised. Another factor may be variation in the molecular species of glucagon that is present in each case and its biologic potency.310

In previously reported cases of glucagonoma in which plasma glucagon concentrations were measured by radioimmunoassay, fasting plasma glucagon concentrations were 2,100 ± 334 pg/mL. These levels are markedly higher than those reported in normal, fasting subjects (i.e., 150 pg/mL) or in those with other disorders causing hyperglucagonemia, including diabetes mellitus, burn injury, acute trauma, bacteremia, cirrhosis, renal failure, or Cushing’s syndrome, where fasting plasma glucagon concentrations often are elevated but less than 500 pg/mL.

As with other islet cell neoplasms, glucagonomas may overproduce multiple hormones. Insulin is the most common second hormone secreted by these tumors. Others include ACTH, PP, parathyroid hormone or substances with parathyroid hormone-like activity, gastrin, serotonin, VIP, and melanocyte stimulating hormone in that order of frequency.


All reported glucagonomas with the cutaneous syndrome originated from single pancreatic tumors of considerable size (diameter 1.5–35 cm).303,311 All tumors occurred in the tail or body of the pancreas, where A cells normally are abundant, deriving from the dorsal anlage of the pancreas. At the time of diagnosis, 62% of the tumors had metastases. Glucagonomas not associated with the syndrome but characterized by morphologic and/or chemical criteria are diagnosed in various ways. First, the tumor may appear as a malignant pancreatic tumor, discovered because of local growth, with or without metastases. Second, the tumor may be associated with an insulinoma, gastrinoma, or as part of the MEN-1 syndrome. Glucagonoma also may occur as a single microadenoma found incidentally at autopsy in elderly patients.302

If the diagnosis is made while the tumor is still localized, surgical resection can be curative.305,312,313 As in other islet cell tumors, even when malignant, these tumors tend to be extremely slow growing. Like others, we have been impressed with the dramatic response in these patients to both curative and major palliative resections.307 Preoperative preparation may require a period of total parenteral nutrition because of the severe weight loss induced by the catabolic effects of glucagon. Antibiotics, steroids, and both amino acid and zinc supplementation may improve the skin rash when it is severe, but cure of the rash is achieved only with the return of glucagon levels to normal. Octreotide also is useful in helping to improve the perioperative condition of these patients. Prophylactic measures to prevent venous thrombosis, including low-dose subcutaneous heparin or intermittent pneumatic compression stockings, are mandatory for all patients during the perioperative period. In patients for whom surgery is not feasible, streptozotocin with or without 5-fluorouracil should be considered (as described later).


SRIF is a tetradecapeptide that inhibits numerous endocrine and exocrine secretory functions. Almost all gut hormones that have been studied are inhibited by SRIF, including insulin, PP, glucagon, gastrin, secretin, GIP, and motilin.314 In addition to inhibition of the endocrine secretions, SRIF has direct effects on a number of target organs.315 For example, it is a potent inhibitor of basal and PG-stimulated gastric acid secretion. It also has marked effects on GI transit time, intestinal motility, and absorption of nutrients from the small intestine. The major effect in the small intestine appears to be a delay in the absorption of fat and reduced absorption of calcium.

The salient features of the somatostatinoma syndrome are diabetes, diarrhea/steatorrhea, gallbladder disease, hypochlorhydria, and weight loss.316–318 The first cases of the somatostatinoma syndrome were reported in 1977 by Ganda and colleagues.316 We have examined the cases reported since 1977 and describe here the features now recognized to be a part of the syndrome. For convenience, we have divided the cases into those arising from the pancreas, the intestine, and extrapancreatic tumors. It appears that the syndrome differs among tumors arising from the pancreas and the intestine or extrapancreatic sites. Therefore, these will be considered separately.

Clinical Features

Most patients were between 40 and 60 years of age. There is a 2:1 ratio of female to male patients, which contrasts with the equal sex incidence for other islet cell tumors.319

Plasma Somatostatin-Like Immunoreactivity (SLI)

The mean SLI concentration in patients with pancreatic somatostatinoma was 50 times higher than normal (range, 1–250 times). Intestinal somatostatinomas, however, had only slightly elevated or normal SLI concentrations.

Diabetes Mellitus and Hypoglycemia

Seventy-five percent of patients with pancreatic tumors had diabetes mellitus. In contrast, diabetes occurred only in 11% of patients with intestinal tumors. In all instances, the diabetes was relatively mild and could be controlled with diet and/or oral hypoglycemic agents or with small doses of insulin. It is not clear, however, whether the differential inhibition of insulin and diabetogenic hormones can explain the usually mild degree of diabetes and the rarity of ketoacidosis in patients with somatostatinoma. Replacement of functional islet cell tissue by pancreatic tumor may be another reason for the development of diabetes in most patients with pancreatic somatostatinoma, contrasting with the low incidence in patients with intestinal tumors. These tumors usually are large and therefore destroy substantial portions of the pancreas.

Gallbladder Disease

Fifty-nine percent of patients with pancreatic tumors and 27% of patients with intestinal tumors had gallbladder disease. The high incidence of gallbladder disease in patients with somatostatinoma and the absence of such an association in any other islet cell tumor suggest a causal relationship between gallbladder disease and somatostatinoma. Infusion of somatostatin into normal human subjects has been shown to inhibit gallbladder emptying,315,320 suggesting that somatostatin-mediated inhibition of gallbladder emptying may cause the observed high rate of gallbladder disease in patients with somatostatinoma. This thesis is supported by the observation of massively dilated gallbladders without stones or other pathology321,322 in patients with somatostatin-secreting tumors.

Diarrhea and Steatorrhea

Diarrhea consisting of 3 to 10 frequently foul-smelling stools per day and/or steatorrhea from 20 to 76 g of fat per 24 hours is common in patients with pancreatic somatostatinoma. This could result from the effects of high levels of somatostatin within the pancreas, serving as a paracrine mediator to inhibit exocrine secretion or, alternatively, from the somatostatinoma’s causing duct obstruction. In some cases, the severity of diarrhea and steatorrhea parallels the course of the disease, worsening as the tumor advances and metastatic disease spreads, and improving after tumor resection. Somatostatin has been shown to inhibit the pancreatic secretion of proteolytic enzymes, water, bicarbonate,323 and gallbladder motility.324 In addition, it inhibits the absorption of lipids.325 All but one patient with diarrhea and steatorrhea have had high plasma somatostatin concentrations. The rarity of diarrhea and/or steatorrhea in patients with intestinal somatostatinomas may result from the lower SLI levels.


Infusion of somatostatin has been shown to inhibit gastric acid secretion in human subjects.326 Thus, hypochlorhydria in patients with somatostatinoma in the absence of gastric mucosal abnormalities likely results from elevated somatostatin concentrations. Basal and stimulated acid secretion was inhibited in 87% of patients with pancreatic tumors tested but in only 12% of patients with intestinal tumors.

Weight Loss

Weight loss ranging from 9 to 21 kg over several months occurred in one-third of patients with pancreatic tumors and one-fifth of patients with intestinal tumors. The weight loss may relate to malabsorption and diarrhea, but in small intestinal tumors, anorexia, abdominal pain, and yet unexplained reasons may be relevant.

Associated Endocrine Disorders

Of great interest is the presence of café-au-lait spots, neurofibromatosis, and paroxysmal hypertension in patients with intestinal tumors. Thus, approximately 50% of all patients have other endocrinopathies in addition to their somatostatinoma. Occurrence of MEN-1 has been recognized in patients with islet cell tumors, and MEN-2 or -3 syndromes are present in association with pheochromocytomas and neurofibromatosis, respectively. It seems that an additional dimension of the duct associated tumors is MEN-2. Secretion of different hormones by the same islet cell tumor, sometimes resulting in two distinct clinical disorders, is now being recognized with increasing frequency.327 These possibilities should be considered during endocrine work-ups of patients with islet cell tumors and their relatives.

Tumor Location

Of the reported primary tumors, 60% were found in the pancreas and 40% in the duodenum or jejunum. Of the pancreatic tumors, 50% were located in the head, and 25% in the tail, and the remaining tumors either infiltrated the whole pancreas or were found in the body. Regarding extrapancreatic locations, approximately 50% originate in the duodenum, approximately 50% originate in the ampulla, and, rarely, one is found in the jejunum. Thus, approximately 60% of somatostatinomas originate in the upper intestinal tract, which probably is a consequence of the relatively large number of D cells in this region.

Tumor Size

Somatostatinomas tend to be large, similar to glucagonomas,328 but unlike insulinomas and gastrinomas, which, as a rule, are small.329–331 Within the intestine, tumors have tended to be smaller. Symptoms associated with somatostatinomas and glucagonomas are less pronounced and probably do not develop until very high blood levels of the respective hormones have been attained. As a result, somatostatinomas and glucagonomas are likely to be diagnosed later.

Incidence of Malignancy

Eighty percent of patients with pancreatic somatostatinomas were metastatic at diagnosis, and 50% with intestinal tumors had evidence of metastatic disease. Metastasis to the liver is most frequent, and regional lymph node involvement and metastases to bone are less so. Thus, in approximately 70% of cases, metatastic disease is present at diagnosis. This is similar to the high incidence of malignancy in glucagonoma329 and in gastrinoma,330 but it is distinctly different from the low incidence of malignant insulinoma.331 The high prevalence of metastatic disease in somatostatinoma also may be a consequence of late diagnosis but apparently is not dependent on the tissue of origin.

Microscopic Appearance

On light microscopy, most tumors appear to be well-differentiated islet cell or carcinoid-type tumors. Some show a mixed picture, consisting of separate zones of differentiated and anaplastic cells. In the differentiated areas, cells are arranged in lobular or acinar patterns that are separated by fibrovascular stroma. Less well-differentiated areas consist of sheets of cells interrupted by fibrous septa.

Diffuse positive immunoreactivity for somatostatin usually is found, which contrasts with the rarity of somatostatin-positive cells in gastrinomas and other tumors. There is a unique occurrence of psammoma bodies in somatostatinomas localized within the duodenum. In addition, there is abundant immunologic evidence for the presence of cells containing insulin, calcitonin, gastrin and VIP, ACTH, prostaglandin E2, and SP. In tumors with multiple hormones, however, SLI-containing cells represent the large majority of all cells containing hormones detected by immunopathology.

Somatostatin-Containing Tumors Outside the GI Tract

Somatostatin has been found in many tissues outside the GI tract. Prominent among those are the hypothalamic and extrahypothalamic regions of the brain, the peripheral nervous system (including the sympathetic adrenergic ganglia), and the C cells of the thyroid gland. Not surprisingly, therefore, high concentrations of somatostatin have been found in tumors originating from these tissues. Sano and colleagues332 and Saito and colleagues333 reported seven patients with medullary carcinoma of the thyroid (MTC) who had high basal plasma SLI concentrations and high tumor SLI concentrations. Roos and colleagues334 reported elevated plasma SLI concentrations in three of seven patients with MTC and high tissue SLI concentrations in three of five MTC tumors. Some, but not all, of these patients exhibited the clinical somatostatinoma syndrome.

Elevated plasma SLI concentrations also have been reported in patients with small cell lung cancer.334 One case of metastatic bronchial oat cell carcinoma caused Cushing’s syndrome, diabetes, diarrhea, steatorrhea, anemia, and weight loss and had a plasma SLI concentration 20 times greater than normal.335 A patient with a bronchogenic carcinoma presenting with diabetic ketoacidosis and high levels of SLI (> 5,000 pg/mL) has been reported.336 Pheochromocytomas327,337 and catecholamine-producing extra-adrenal paragangliomas334 are other examples of endocrine tumors producing and secreting somatostatin in addition to other hormonally active substances. One-quarter of 37 patients with pheochromocytomas had elevated SLI levels.327


In the reported series cited, somatostatinomas often were found more or less accidentally. In most cases, the tumors were found either during exploratory laparotomy or upper GI radiographic studies, CT, or ultrasound, or endoscopy performed because of various symptoms, including unexplained abdominal pain, melena, hematemesis, persistent diarrhea, or in search of insulinomas or ACTH-secreting tumors. Once found, the tumors were identified as somatostatinoma by the demonstration of elevated tissue concentrations of SLI and/or prevalence of D cells by immunocytochemistry or demonstration of elevated plasma SLI concentrations. Thus, events leading to the diagnosis of somatostatinoma usually occur in reverse order. In other islet cell tumors, the clinical symptoms and signs usually suggest the diagnosis, which then is established by demonstration of diagnostically elevated blood hormone levels, following which efforts are undertaken to localize the tumors. It can be expected that the same sequence of diagnostic procedures will be followed in the future for the diagnosis of somatostatinoma, mainly for two reasons: (a) the increasing familiarity of physicians with the clinical somatostatinoma syndrome (this symptom complex, although not pathognomonic, is nevertheless sufficiently characteristic of somatostatinoma to suggest the correct diagnosis) and (b) the greater availability of reliable radioimmunoassays for the determination of SLI in blood has increased the yield. Presently, these assays are complicated by the need for cumbersome extraction procedures and are not readily available. It should be recognized, however, that the syndrome is rare. Of 1,199 cases screened for somatostatinoma at the University of Michigan between 1982 and 1986, only 8 cases had diagnostic serum levels.

The diagnosis of somatostatinoma at a time when blood SLI concentrations are normal or only marginally elevated, however, requires reliable provocative tests. Increased plasma SLI concentrations have been reported after intravenous infusion of tolbutamide and arginine, and decreased SLI concentrations have been observed after intravenous infusion of diazoxide. Arginine is a well-established stimulant for normal D cells and thus is unlikely to differentiate between normal and supranormal somatostatin secretion. The same may be true for diazoxide, which has been shown to decrease SLI secretion from normal dog pancreas as well as in patients with somatostatinoma.338 Tolbutamide stimulates SLI release from normal dog and rat pancreas,323,324,338 but no change was found in the circulating SLI concentrations of three normal human subjects after intravenous injection of 1 g of tolbutamide.339 Therefore, at present, tolbutamide appears to be a candidate for a provocative agent in the diagnosis of somatostatinoma, but its reliability must be established in a greater number of patients and controls. Until then, it may be necessary to measure plasma SLI concentrations during routine work-ups for postprandial dyspepsia and gallbladder disorders,317 for diabetes in patients without a family history, and for unexplained steatorrhea as these findings can be early signs of somatostatinomas.

Treatment of Somatostatinomas

Forty percent of patients with somatostatinomas died at intervals ranging from 1 week to 14 months after diagnosis, whereas 60% of patients were alive from 6 months to 5 years after diagnosis. Thus, the syndrome is associated with a high malignant potential, and it is important to be aggressive in management and to attempt to remove all tumor tissue in benign cases. For patients in whom metastases already have occurred at diagnosis, bulk reduction may be justified, if feasible. The optimal form of chemotherapy remains to be determined.

Pancreatic Polypeptide PPoma

PP was discovered by serendipity. In 1972, working in separate laboratories, Chance and Jones340 and Kimmel and colleagues341 independently purified a single major protein from a crude insulin preparation. The protein was named pancreatic polypeptide. In mammals, 93% of the cells producing PP are located in the pancreas.

There are very dramatic effects from meal ingestion, cerebral stimulation, and hormone administration on circulating levels of PP. A biologic role for PP has not been established, however.208,342–344 The only physiologic effects that are recognized in humans are the inhibition of gallbladder contraction and pancreatic enzyme secretion.344 Thus, a tumor deriving from PP cells is predicted to be clinically silent, although this is not always the case.

Tomita and colleagues345 reported two patients, one of whom had persistent watery diarrhea and the other high levels of circulating PP and PP-cell hyperplasia. A patient with chronic duodenal ulcer and a PP tumor also has been reported.346 A tumor that invaded the bile ducts, producing biliary obstruction, was a PPoma.347 It has been suggested that the watery diarrhea syndrome, which is seen in GEP endocrine tumors, may have its origin in PP overproduction.348 The picture is complicated by the fact that mixed tumors, PP-cell hyperplasia in association with other functioning islet cell tumors, ductal hyperplasia of PP cells, nesidioblastosis, and multiple islet tumors producing PP also have been described, either alone or as part of the MEN-1 syndrome.349,350 Basal concentrations of PP in plasma may be raised above 1,000 pg/mL in 22 to 77% of all endocrine-secreting tumors and in 29 to 50% of patients with carcinoid syndrome, even if the carcinoid is located outside the pancreas. Among 53 patients with adenocarcinomas of the pancreas, however, no instance of an elevated basal concentration of PP was found.129,178 The diagnostic accuracy of elevated basal PP concentrations as a marker for endocrine-secreting tumors can be marginally increased to around 50 to 60% by determining the response of PP to secretin administration.90,351 A response of greater than 5,000 pg/min/mL (i.e., integrated response) is more than two standard deviations above that observed in healthy subjects. It appears, however, that many cases of so-called nonfunctional GEP endocrine tumors are indeed PPomas, because it is our experience that 50 to 75% of these have raised basal PP levels and in 67% the response to secretin is exaggerated. Thus, in the absence of factors, such as chronic renal failure, that are known to cause marked elevation of PP levels, a markedly elevated PP level in an older, healthy patient occasionally may indicate a nonfunctioning pancreatic endocrine tumor. Differentiation of a high basal concentration in a healthy subject from that appearing in patients with tumor has been difficult. Schwartz325 suggested that administration of atropine would suppress concentrations in healthy subjects and would fail to do so in patients with tumors, but this has not been subjected to extensive examination.

Increased PP cells are found in 20 to 67% of functioning and nonfunctioning tumors of the pancreas.352 There does not appear to be a relationship between the number of cells and their function because islet tumors containing subnormal, normal, or supernormal concentrations of PP compared with that in the normal pancreas may be associated with normal or high levels of circulating PP. There are now at least 21 patients in the literature with PPomas. Their age ranges from 20 to 74 years, with a mean of 51 years and an equal sex incidence.

Diabetes was found in only two cases. Diarrhea, which formerly was thought to be a part of the syndrome,348 occurred in only one-third of cases. Steatorrhea was found in 100% of patients in whom it was sought. Decreased acid secretion was documented only in two of six people studied. Fifty-seven percent presented with weight loss. The PPoma syndrome is silent, and these tumors often are found unsuspectedly in the course of working up patients with hepatomegaly, abdominal pain, metastases to the liver, jaundice from obstruction of the common bile duct, or hematochezia. Upper GI bleeding may occur because of invasion of the wall of the duodenum or thrombosis of the splenic or portal vein, with consequent development of varices. Not infrequently, PPomas are recognized by the radiologist as highly vascular tumors with metastases to the liver. Six of the reported cases had PPomas as part of the MEN-1 syndrome.

Some authors contend that not every patient with raised PP levels has a tumor.88,90,184,352 If a tumor can be identified and localized, it should be removed. Raised PP levels occur as part of the MEN-1 syndrome and may reflect nesidioblastosis of PP cells or multiple adenomata not amenable to resection. The frequency of malignancy of these tumors is not established, and resection should be reserved for those patients with clearly identified solitary lesions.

It has been suggested that every patient with a markedly elevated level of PP should undergo exploratory laparotomy and careful inspection of the pancreas, even if the tumor cannot be diagnosed.353 This has not been our experience. Metastatic PPomas are best treated with streptozotocin plus doxorubicin. Although rare, PPomas may occur in the chest and elsewhere outside the pancreas so laparotomy should not be performed routinely. Somatostatin receptor scintigrapy should be performed in such cases to localize the source of PP overproduction. If such a locus is found, the abdominal or other exploration should be performed.


Neurotensin (NT) is a 13 amino acid polypeptide first extracted from bovine brain by Carraway and Leeman.354 It subsequently was isolated from the human GI tract and found to have the same amino acid sequence.355 Neurotensin has a number of interesting pharmacologic effects that include hypotension, tachycardia, and cyanosis58,356 and stimulation of secretion from the small intestine.357 It also has been reported to inhibit the interdigestive myoelectric complex and stimulate insulin release.358 NT also increases venous vascular permeability, raises blood glucose,152,359,360 and lowers blood pressure.354,356

High concentrations of NT-like immunoreactivity (NTLI) are present in the ileal mucosa, where it is localized to a specific “N” cell.361 Plasma concentrations rise after food ingestion,191 and high circulating levels362 have been found after surgery for duodenal ulcer and jejunoileal bypass for obesity.363 No clear physiologic role has been established for the peptide. High circulating levels also have been found in patients with VIPomas.39,364–369

In 1981, based on the pharmacologic actions of NT, it was predicted351 that a syndrome of excess would emerge, presenting with features that are consonant with the pharmacologic actions of the peptide: diabetes, hypotension, vasodilatation, cyanosis, and edema. In addition to these features, investigation would reveal net secretion of fluid and electrolytes, inhibition of gastric acid secretion, infrequent interdigestive myoelectric complexes, and prolonged biologic reaction of gastric emptying. The prediction that diabetes would occur was based on the predominant stimulation of adrenomedullary secretions despite stimulation of insulin secretion.370 The clinical features of reported cases include diarrhea, hypotension, hypokalemia, edema, weight loss, and, occasionally, diabetes.90,351

Apart from these reported cases, Blackburn and colleagues39 examined plasma NT levels in 326 fasting patients with tumors in a variety of sites. Of these patients, 180 had tumors of the pancreas, including glucagonomas,339 gastrinomas,334 insulinomas,317 nonsecretory tumors,319 and VIPomas.326 Plasma NTLI levels were raised in only six patients with VIPomas and none with the other tumors. Twenty-one of the tumors containing VIP were removed surgically, and six were found to contain NTLI. The clinical features of these six patients did not appear to differ from those of the remaining 15 patients.

With so few cases, it is difficult to generalize on the clinical picture. Fifty percent of the cases were cured by resection of tumors in the pancreas311 or lung,371 and the remainder have responded well to streptozotocin. The syndrome appears to comprise diarrhea, diabetes, and weight loss; as such, it may not be readily distinguishable from the VIPoma syndrome. Neurotensinomas probably are best characterized as yet another tumor that is capable of causing the WDHHA (watery diarrhea, hypokalemia, hypochlorhydria, and acidosis) syndrome. Edema, hypotension, and flushing should increase the suspicion of a neurotensinoma.

Octreotide in Treatment of Malignant Neuroendocrine Tumors

Somatostatin, a tetradecapeptide, inhibits the secretion and action of a number of peptide hormones, neurotransmitters, and exocrine secretions of the GEP axis. Its clinical use is limited because of its short half-life of 1 to 2 minutes. Development of its potent, long-acting octapeptide analogue (Sandostatin, octreotide acetate) with a half-life of over 100 minutes was a breakthrough for clinical application. Other analogues such as somatuline (BIM 23014 C) are being investigated.126 Thus far, their effectiveness and toxicity rates appear to be similar to those of octreotide. Several aspects of treatment of GEP neoplasms, including symptom reduction, hormone suppression, tumor growth, and survival, are discussed here.

System Control

Octreotide has a potent action in reducing symptoms in certain neuroendocrine tumors. Detection of somatostatin receptors by octreotide scintigraphy correlates well with the predicted response to treatment with octreotide.74 In carcinoid tumor, flushing is reduced in most patients.112,113,372 The acute effects on water and electrolyte transport are a reversal from a secretory to an absorptive state, thus normalizing transport across the proximal intestine.110 Long-term responses of diarrhea, however, differ in different reports: 9 of 14 patients with endocrine diarrhea responded to treatment in one report,118 in contrast to 19 of 25 in another.112 Diarrhea in VIPoma improves 95% of the time.372 This difference might result from the involvement of different peptides causing diarrhea and different mechanisms. In five of our patients with gastrinoma, the presenting symptom was diarrhea, which improved, as did 65% of 26 reported cases.372 Diarrhea in 16 patients with glucagonomas also improved uniformly.372,373 Diarrhea also improves in all patients with gastrinoma syndrome, and abdominal pain can be relieved in most patients.34 There is, however, the possibility of a rebound in symptoms and/or hormonal values during therapy. The mechanism of this is not clear, but it might involve accelerated enzymatic breakdown of octreotide and/or ligand-induced changes of somatostatin receptors on the target cell, preventing internalization of the hormone receptor complexes or a gradual adaptation of the target cell to the octreotide effect, as proposed by Koelz and colleagues.374

Wheezing, as one of the symptoms in carcinoid syndrome, can be reversed by octroetide, and spirometric improvement in lung function has been documented.118 In another patient who had severe proximal myopathic muscle weakness, clinical and electromyographic improvement occurred with octreotide treatment.118 The arthropathy of carcinoid, which may be SP mediated, also improves.370 Hypoglycemia with insulinoma responds erratically because of unpredictable effects on food absorption, suppression of glucagon, and insulin.110 Of 15 patients, 50% improved, and 30% got worse.372 The necrolytic migratory erythema of glucagonoma clears in only 50% of the cases.198

Hormone Suppression and Biochemical Features

Octreotide inhibits hormone secretion in some malignant GEP tumors. The most sensitive of these seems to be VIPoma, where lowering of VIP circulating levels parallels relief of symptoms.110,114 Gastrin levels, however, are not equivalently lowered with octreotide. One study of eight patients with gastrinoma showed that octreotide decreased gastrin levels in five patients by a mean of 76% of baseline.34 In worldwide pooled data (n = 26), 70% of patients are reported to respond. ACTH overproduction heralds unresponsiveness to the drug. Glucagon levels seldom decrease.372 Although the overall 5-HIAA level is significantly lower after octreotide treatment,112 blood serotonin level does not differ significantly.113,375 There is an overall reduction of 5-HIAA in 58% of patients.372

Perioperative Management

Carcinoid and other GEP tumors can be a major therapeutic problem perioperatively, when vast quantities of active peptides are released into the circulation from manipulation of the tumors. Octreotide is an effective suppressor of release and action of peptide hormones during surgery.262 Profound refractory hypotension in carcinoid syndrome can be rapidly reversed by octreotide,109 as can gastric acid secretion and fistula drainage.262

Tumor Growth

Because GEP tumors grow slowly, it is hard to assess the effect of treatment on tumor growth. Long-term CT monitoring, however, has shown shrinkage of liver metastasis in certain patients with carcinoid and other GEP tumors.112,124 In 85 carcinoid tumors, no change was found with doses under 50 mg/d, but Kvols and colleagues112 reported a decrease in size in 17% of patients using higher doses (1,500 mg/d). VIPoma, glucagonoma, and gastrinoma generally do not change in size,372 although a tumor infarction has occurred in VIPoma.262 Tumor metastases to bone may occur despite apparent control of the primary tumor or liver metastases.110,376


The role of octreotide in the treatment of GEP tumors is still well established. Because of the clear evidence of symptomatic relief (e.g., flushing, wheezing, diarrhea), it has established a place in treatment of such tumors both pre- and postoperatively. Perioperative use can prevent fatal episodes of rapid, extreme increases of hormones in the circulation. There is enough evidence for the control of tumor growth that primary treatment of select metastatic tumors, with proper monitoring of tumor growth, is recommended (Fig. 85.7).

Figure 85.7. Suggested management of suspect meuroendocrine tumors.

Figure 85.7

Suggested management of suspect meuroendocrine tumors.

Chemotherapy for Metastatic Islet Cell Carcinomas

Ajani and colleagues377 performed repetitive hepatic artery embolization with polyvinyl alcohol particles in 22 patients with metastatic pancreatic endocrine tumors and achieved partial remission of measurable hepatic tumor in 12 of 20 evaluable patients. From this experience, the authors suggested this modality for prolonged palliation in selected patients. Marlink and colleagues378 reported partial responses in all six patients with metastatic islet cell tumors following selective hepatic artery embolization; however, the duration of responses was not reported.

Because of the relative rarity of GEP neoplasms, chemotherapy trials frequently have combined several islet cell tumor subtypes within the same study. The experience from these studies suggests that whereas similar responses may be expected from chemotherapy for several tumor subtypes, there may be differences in the response of others. For example, streptozotocin alone or in combination with 5-fluorouracil is extremely effective against most VIPomas136 and is moderately effective against gastrinomas and most other islet cell tumors. In contrast, streptozotocin has little activity against glucagonomas, whereas dacarbazine appears to have significant activity.144

Streptozotocin is a drug that is selectively cytotoxic for pancreatic islet cells. Because of this property, the drug has been used to establish animal models for diabetes and islet cell hypofunction.379 This selective cytotoxicity also provided a rationale for using streptozotocin in neoplastic disorders of pancreatic endocrine cells. In several studies using intravenous and, less commonly, intra-arterial administration, streptozotocin was shown to be active against several pancreatic endocrine cancers, with nearly 40% tumor responses and over 50% hormonal responses reported.181,230,232,380,381 More frequent use of this agent is limited by its significant emetogenic and renal toxicities. In the case of symptomatic hepatic metastases from glucagonoma and somatostatinoma, Friesen183 claims that use of intra-arterial administration of streptozotocin is effective, with reduced incidence of nephrotoxicity, but this has not been confirmed.

Other drugs that have single-agent activity in islet cell carcinoma are chlorozotocin and doxorubicin. At a dose of 100 to 200 mg/m2, chlorozotocin resulted in a 53% objective response rate in 13 previously untreated patients.382 In 20 previously treated patients, doxorubicin, 60 mg/m2 every 3 to 4 weeks, resulted in four (20%) objective responses.233

Several authors have reported that dacarbazine is a highly effective agent for the treatment of pancreatic islet cell tumors, especially glucagon-secreting tumors. Using either 1,250 mg/m2 in divided doses over 5 days or a single dose of 650 mg/m2, Kessinger and colleagues reported two complete responses and two partial responses of elevated serum glucagon in four patients with glucagonomas.144 Three of four additional patients with malignant islet cell carcinoma associated with glucagonoma syndrome were cited in this report as having responded to dacarbazine alone. In a recently reported prospective study of 48 evaluable patients with advanced islet cell carcinoma, Hahn and colleagues383 reported 13 patients (27%) with objective responses (including three complete responses) following dacarbazine, 850 mg/m2 given every 4 weeks. The median survival in all patients was 19 months, and the authors concluded that dacarbazine clearly had beneficial activity in patients with advanced islet cell carcinoma.

None of six evaluable patients with islet cell carcinoma responded to etoposide in a phase II study.146 Only 2 of 41 patients with a variety of advanced apudomas responded to carboplatinum.384 No other conventional chemotherapy agents are reported to have activity in this disease.

In a multi-institutional study, streptozotocin combined with 5-fluorouracil was shown to be effective against malignant pancreatic endocrine tumors, with an objective response rate of 63% for a duration of 17.4 months.143,151,232 Furthermore, this combination produced a 37% complete response rate and a more prolonged median survival than streptozotocin alone; however, the combination was also associated with a high prevalence of moderately severe GI, hematopoietic, and renal toxicity.232 A smaller, nonrandomized series of patients receiving the same combination chemotherapy regimen produced similar results, and this study also suggested that the response rate in patients with nonfunctional tumors (50%) may be less than that in those with functional tumors (68%).151 Although the regimen of streptozotocin and fluorouracil is not considered to be the most active for malignant glucagonoma, responses to the combination have been reported.302

In a randomized three-arm trial by the Eastern Cooperative Oncology Group, streptozotocin plus 5-fluorouracil was compared to a combination of streptozotocin plus doxorubicin or to chlorozotocin.385 The streptozotocin plus doxorubicin arm was clearly superior to the other two arms with a 69% response rate and a median survival of 24 months. This study, which included 120 patients, has provided an important contribution toward further defining the optimal chemotherapeutic approach for malignant pancreatic endocrine tumors. Several other multicenter chemotherapeutic regimens have now been tried (Table 85.9), but, in general, their activity is no better than that with single-agent therapy. There has been no prospective investigation of adjuvant chemotherapy in patients with islet cell carcinoma.

Table 85.9. Systemic Anticancer therapy for Neoplasms of the Gastroenteropancreatic System.

Table 85.9

Systemic Anticancer therapy for Neoplasms of the Gastroenteropancreatic System.

Finally, the interferons have been reported to be active in GEP endocrine neoplasms as well. As reviewed by Oberg and colleagues,151 an objective hormonal response of 73% was observed in patients with malignant pancreatic endocrine tumors treated with human leukocyte interferon, 3 to 6 million units per day subcutaneously. Among their first 22 responders, 6 patients (27%) had a 50% reduction in tumor mass, and 2 patients (9%) had a complete response.386 The median duration of response was 9.5 months. Since 1986, this group has been using recombinant interferon-α-2b, 5 million units three times per week subcutaneously or intravenously. An update of their results in 57 patients showed objective responses in 29 patients (51%), with biochemical responses in 27 (47%) and radiologic responses in 7 (12%).387 The median duration of response was 20 months (range 2–96 months), and response rates were higher in patients with VIPomas (10 of 12 patients) than in those with other tumors. A review of 372 patients treated with interferon from various institutions showed an overall objective response rate of 44%.388 Interferon was well tolerated despite frequent occurrence of a flu-like syndrome, weight loss, and mild myelosuppression. A summary of these studies appears in Tables 85.9 and 85.10.


New approaches to the diagnosis and localization of GEP tumors have been stressed, including the importance of circulating hormone levels and sophisticated immunohistochemistry, tracer scanning, and the role of peptide therapy in the management of the symptom complex as well as the tumor. There is, however, much that remains unsolved, requiring diligent research and evaluation if we are ultimately to include neuroendocrine tumors among the curable cancers. An outline of the current approach to management of the patient suspected of harboring a GEP tumor is given in Figure 85.7.

Parathyroid Carcinomas, Pheochromocytomas, and Multiple Endocrine Neoplasia Syndromes


This section of the chapter focuses on three neoplasms of endocrine organs (parathyroid carcinoma, medullary thyroid carcinoma (MTC), and pheochromocytoma) and three endocrine neoplastic syndromes that are linked together by at least two major considerations. First, like the GEP tumors, each of these neoplasms has histologic and biochemical features that are common to all normal and neoplastic endocrine cells of the body. Histologically, these cells contain the cytoplasmic neurosecretory granules, which store either small polypeptide hormones and/or biogenic amines. These secretory products reflect the specific endocrine function of the normal cells from which the neoplasms derive (Table 85.11). In terms of biochemical features, these tumors also arise from the so-called APUD group of cells, which constitute the diffuse system of neuroendocrine cells distributed throughout the body.389,390 The APUD acronym denotes the capacity of these cells to synthesize and/or secrete biogenic amines formed through activity of the enzyme l-dopa decarboxylase.391

Table 85.11. Common Features of Amine Precursor, Uptake, and Decarboxylation (APUD) Cell.

Table 85.11

Common Features of Amine Precursor, Uptake, and Decarboxylation (APUD) Cell.

The second feature linking these particular neoplasms and syndromes is that they can occur in individual patients as a consequence of autosomally dominant genetically transmitted disorders. Inherited genetic defects affect different groups of APUD cells and lead to neoplastic development of related cell types in diverse anatomic regions.392 It is essential to consider these genetic disorders when approaching patients with these tumors or syndromes.

Historically, each of the three neoplasms was initially identified as independent pathologic entities. Parathyroid carcinoma was first described in 1935 by Hall and Chaffin,393 although parathyroid adenomas and hyperplasia had been recognized as early as 1903.394 Hazard and coworkers first recognized MTC as a distinct entity in 1959.395 In 1886, Frankel’s postmortem discovery of bilateral adrenal tumors in a young woman following sudden death was the first report of pheochromocytoma.396 Subsequently, complete descriptions of pheochromocytoma were made, and the surgical cure of the disease was demonstrated in the 1920s.397

Although the first description of multiple endocrine tumors in a single individual was reported in 1903,398 it was not until the 1950s that neoplasms of multiple endocrine glands in affected individuals and their families came to be recognized as three distinct syndromes, MEN types 1, 2a, and 2b. Wermer first described the autosomal dominant association of parathyroid adenoma or hyperplasia, pancreatic islet cell adenoma or carcinoma, and pituitary adenoma (MEN-1) in 1954399; Sipple first described the association of parathyroid adenoma or hyperplasia, MTC, and familial pheochromocytoma (MEN-2a) in 1961400; and Williams and Pollock first described the association of MTC, pheochromocytoma, and mucosal neuromas (MEN-2b) in 1966.401 From these early descriptions up to the present, a number of other investigators have contributed their observations to establish these three MEN syndromes.402–407 In addition, it is now recognized that MTC can occur as an inherited tumor in families without other associated endocrine lesions (non-MEN familial medullary thyroid carcinoma).408

Based on morphologic criteria, Pearse first proposed the APUD diffuse neuroendocrine system in 1968.389 Subsequent experimental evidence has challenged the notion of a common embryologic origin of APUD cells as originally proposed by Pearse.392,409–411 Thus, a neuroectodermal origin for the cells involved in the genetic MTC syndromes separate from the endodermal origin of those in the MEN-1 syndrome is now considered likely. Nonetheless, the APUD concept as proposed by Pearse has been pivotal to exploring how single genetic defects may cause simultaneous neoplasms in the same individual, and it still provides an extremely useful framework in which these closely linked neoplasms and their syndromes may be considered.

Parathyroid Carcinoma

The vast majority (>95%) of parathyroid tumors are benign and produce signs of primary hyperparathyroidism. The emphasis in this section will be on parathyroid carcinoma and its differential features with the more common benign tumors (adenomas and hyperplasia).

Embryology and Anatomy

Embryology is the key to understand the normal and ectopic locations of the parathyroid glands. The upper glands are derived from the fourth pharyngeal pouch together with the lateral thyroid, whereas the lower glands are derived from the third pharyngeal pouch together with the thymus.412,413 In the majority of cases, the upper parathyroid glands are found at the cricothyroid junction posteriorly (77%), less commonly behind the upper pole of the thyroid underneath its capsule (22%), and exceptionally in a retropharyngeal or retroesophageal location (1%).413 The lower parathyroid glands are located anywhere between the lower pole of the thyroid and the thymus, 42% being at the lower pole of the thyroid, 39% within the thymic tongue in the lower neck, and 2% being in the mediastinal thymus. Other ectopic locations are usually in the neck (15% juxtathyroidal, 2% in other locations).413 In addition, supernumerary glands have been found in 2 to 6% of individuals.414 Therefore, parathyroid tumors, including carcinomas, may arise in ectopic (often mediastinal) locations or even from a fifth gland.414,415


The normal parathyroid gland contains mainly chief cells, which are polyhedral, rich in glycogen (giving sometimes the appearance of clear cells) and fat, and secrete parathyroid hormone (PTH). Oxyphil cells appear later and increase in number with advancing age. They have a pyknotic nucleus and a granular eosinophilic cytoplasm packed with mitochondria.412 They are thought to represent senescent cells, whereas the water-clear cells are thought to represent transitional cells.416 In addition, fat cells and adipose tissue also increase with age.412

The distribution of parathyroid tumors in 1,200 cases of hyperparathyroidism seen at the Massachusetts General Hospital from 1932 to 1983 was as follows417: benign single adenoma = 83% (double adenomas <1%), hyperplasia of all four glands = 14% (chief cell hyperplasia = 2%, clear cell hyperplasia = 12%), and carcinoma = 2%. The majority of cases of hyperplasia occur in patients with MEN, either type 1 or type 2. It is often histologically difficult to differentiate these tumors, particularly to ascertain their benign or malignant nature. Parathyroid carcinoma appears as a grayish, hard, lobulated tumor, compared to the soft, reddish brown adenoma.412,417,418 It is surrounded by a dense fibrotic capsule. Its adherence to and invasion of surrounding structures reported in 50% of cases is an important sign of malignancy and should alert the surgeon.412,418 The average size of carcinomas is 3 cm, with a mean weight of 6 to 12 g.412,419 Microscopically, the carcinoma cells resemble “watermelon seeds”412 and are larger and better defined than adenomatous cells. The cells are bland and uniform, however, and cellular atypia is rare, surprisingly in contrast to adenomas. Criteria for malignancy as described by Castleman and Roth412 include a trabecular pattern with thick fibrous bands, nuclear palisading, mitotic figures, and capsular and blood vessel invasion. These features are not absolutely conclusive or constant, however, and even mitotic activity has been challenged as being “the single most valuable criterion”412 since it was also found in 12 of 17 benign adenomas and in 8 of 10 parathyroid hyperplasias.420 An important corollary is that when a carcinoma is suspected on clinical grounds and/or gross appearance, the surgeon should resect the tumor en bloc without relying on biopsy or frozen section.421

The use of flow cytometric DNA analysis to determine aneuploidy, S-phase fraction, and proliferation index values in an attempt to distinguish parathyroid carcinoma from adenoma or hyperplasia has yielded conflicting results.422,423 Tumor markers such as opioid peptides424 and chromogranin A425 have been described in benign parathyroid tumors. Production of human chorionic gonadotropin (hCG) subunits alpha and beta has been observed in parathyroid carcinoma and apparently not in benign tumors.426

Epidemiology and Etiology

In contrast to benign parathyroid tumors, which have been diagnosed increasingly since the introduction of automated multi-channel analyzers in the 1970s, with an annual age-adjusted incidence of 28 per 100,000,427 parathyroid carcinoma remains rare. Only about 200 cases have been reported.421 Its etiology is unknown. Usually, parathyroid carcinomas do not arise from adenoma or hyperplasia, and familial cases are exceptional.421,428 Prior exposure to radiation in the neck is a well-known risk factor for thyroid carcinoma and has also been reported in 9 to 30% of patients with hyperparathyroidism and benign parathyroid tumors, with an average latency period of 37 years.429 Up to 79% of these patients also have associated thyroid tumors, mainly nonmedullary carcinoma or adenoma. A history of prior radiation, however, has been reported in very few cases of parathyroid carcinoma.421 Chronic renal failure, which leads to secondary hyperparathyroidism, has been implicated in a patient with co-existing parathyroid carcinoma, adenoma, and hyperplasia.430 Another patient with parathyroid carcinoma had both chronic renal failure and a history of prior radiation to the neck.431

A plasma factor with a very high mitogenic activity for bovine parathyroid glands in vitro has recently been isolated from patients with MEN-1.432 Genetic studies have so far been largely limited to MEN syndromes. MEN type 1, where parathyroid hyperplasia is the rule, has been associated with loss of heterozygosity (LOH) (indicating loss of a possible suppressor gene) on chromosome 11q,433,434 as compared to chromosome 1p (together with a predisposing gene on chromosome 10) in MEN type 2.433,435 Despite earlier conflicting results, it appears that parathyroid adenomas, as well as hyperplasia in MEN type 1, are monoclonal neoplasms.436,437 The relevance of these findings for parathyroid carcinoma has not yet been evaluated. Abnormal genes regulating the cell cycle have been observed in some benign parathyroid adenomas (PRAD1 or cyclin D1), whereas the retinoblastoma tumor suppressor gene was completely inactivated in most specimens from nine patients with parathyroid carcinoma but not in those with parathyroid adenoma.438

Clinical Features

Parathyroid carcinomas are usually slow-growing tumors with a tendency to recur locally and metastasize late.412 The great majority of them (>95%) are functioning and produce a more severe picture of primary hyperparathyroidism as compared to parathyroid adenomas or hyperplasia (Table 85.12). The major distinguishing features of malignant hyperparathyroidism are equal incidence in men and women, younger mean age by more than a decade, presence of a palpable neck mass, and severe hypercalcemia, often >14 mg/dL. Hoarseness with recurrent nerve involvement is rare, occurring in less than 10% of patients.417,418 Metastases are seen in 36% of patients with parathyroid carcinoma, including involvement of cervical nodes in 21%, and distant metastases to lungs, bone, liver, and other organs in 16%.417–419,439 Almost all patients with malignant hyperparathyroidism are symptomatic at diagnosis, compared to only half of those with benign tumors. Symptoms are usually severe and include a range of classic manifestations427,440–447: (1) renal involvement with polyuria, polydipsia, urolithiasis (calcium oxalate or calcium phosphate stones), nephrocalcinosis, and decreased function; (2) bone involvement with classic osteitis fibrosa cystica (subperiostal resorption of distal phalanges, salt and pepper appearance of the skull, disappearance of the lamina dura of the teeth, and bone cysts, and “brown” tumors) and/or osteopenia, pathologic fractures, and bone pain; concomitant renal and bone involvement, exceptional in benign hyperparathyroidism, which is seen in up to 39% of patients with parathyroid carcinoma417,448; (3) neuromuscular symptoms with proximal muscle weakness, easy fatigability, muscle aches, paresthesias, mental disturbances (decreased recent memory, irritability, depression, somnolence), headaches, and pruritus; (4) rheumatologic symptoms with joint pains, gout, pseudogout (deposition of calcium pyrophosphate crystals), chondrocalcinosis, and calcific tendinitis; (5) gastrointestinal symptoms with anorexia, nausea, vomiting, constipation, peptic ulcer, and pancreatitis; (6) cardiovascular manifestations with decreased Q-T interval, arrhythmias, and possibly hypertension; and (7) calcifications of the cornea (classic band keratopathy) and other soft tissues (skin, lungs).

Table 85.12. Clinical Features of Primary Hyperparathyroidism due to Parathyroid Carcinoma and Benign Tumors.

Table 85.12

Clinical Features of Primary Hyperparathyroidism due to Parathyroid Carcinoma and Benign Tumors.

About 73 cases of hyperparathyroidism have been reported during pregnancy,449 including two cases of parathyroid carcinoma.450 Hypercalcemia can have serious consequences on the fetus, and both maternal and fetal complication rates are high, including abortion, perinatal death, or neonatal tetany. Surgical treatment prior to delivery has been recommended, usually during the second and third trimesters of pregnancy.451

Laboratory Tests

Hypercalcemia, the hallmark of hyperparathyroidism, is usually severe in patients with parathyroid carcinoma. The serum calcium level is above 14 mg/dL in about two-thirds of the patients, compared to less than 10% of patients with benign hyperparathyroidism (see Table 85.12). The total serum calcium, however, may be affected by several factors. Hypoalbuminemia lowers bound calcium and an emprical correction formula can be used short of measuring the physiologically important portion, that is, the ionized calcium level (add 0.8 mg/dL of calcium for every g/dL of reduction of serum albumin).452 Renal insufficiency lowers ionized calcium and can also mask the degree of hypercalcemia. Ionized calcium may also be lowered by the tumor lysis syndrome, severe hypomagnesemia, acute pancreatitis, vitamin D deficiency, and hypothyroidism.443 Drugs such as thiazide diuretics and lithium carbonate can increase serum calcium and should be avoided. Other laboratory features include hypophosphatemia, hypercalciuria (>250 mg/d in about one-quarter of patients), hyperphosphaturia, and, in some cases, hypomagnesemia, hypokalemia, and hyperuricemia.441,452,453 Increased serum chloride and decreased bicarbonate can lead to metabolic acidosis, which aggravates hypercalcemia by decreasing the binding of calcium to albumin and increasing the dissolution of bone mineral.440

Urinary cyclic AMP is elevated as a result of PTH binding to renal receptors. Excessive PTH and hypophosphatemia also increase the renal production of 1,25-dihydroxyvitamin D, which is usually elevated in the serum. In cases of metabolic bone disease (without metastases), the serum alkaline phosphatase level is increased as well as the urinary excretion of hydroxyproline, an amino acid unique to collagen. Recently, elevated serum levels of osteocalcin, a major noncollagenous protein of bone, have been reported in hyperparathyroidism.454

Two features may be useful in differentiating parathyroid carcinoma versus benign tumors. Anemia is more common in carcinoma (up to 80% vs. less than 10%, respectively)439,445 and serum levels of subunits of hCG as mentioned above.

By far the most important test to diagnose primary hyperparathyroidism is the serum level of immunoreactive PTH (iPTH).440,452 Different radioimmunoassays are now available directed either at the intact molecule or the active fragments (amino- or N-terminal) or at inactive fragments (mid-region, carboxyl- or C-terminal region). Elevated levels of iPTH are virtually diagnostic and can be very high in cases of functioning parathyroid carcinoma. Ectopic production of PTH is exceptional and has been documented in very few cases of nonparathyroid carcinomas (see below).

Imaging Techniques

In benign hyperparathyroidism, first-time exploration of the neck by an experienced surgeon will successfully detect the tumor(s) in more than 90% of cases.455 Imaging techniques are most useful in cases of recurrent or persistent hyperparathyroidism after initial surgery. They are also useful before initial surgery whenever a carcinoma is suspected on clinical grounds, allowing evaluation of the local extent of the tumor particularly with regard to the thyroid, trachea, and esophagus, as well as possible metastases to cervical nodes and other organs.

Noninvasive Techniques

Esophagograms with careful evaluation of the cervical esophagus can indirectly visualize parathyroid tumors.456 Ultrasonography with high-resolution, real-time technology is an excellent noninvasive technique, although its overall results are operator dependent.455 Also, the retroesophageal, retrotracheal, and mediastinal areas cannot usually be well assessed.455 CT scanning can readily visualize these areas and also evaluate the extent of disease in patients with parathyroid carcinoma. Scintigraphy, formerly using radionuclides as selenomethionine-75 or gallium-67 citrate, has been improved by computer subtraction techniques. The sequential use of thallium-201, which concentrates both in parathyroid and thyroid, and of technetium 99m, which concentrates in the thyroid, followed by subtraction allows imaging of the parathyroid tumors.455 It has good sensitivity, but its specificity can be affected by concomitant thyroid diseases, including adenomas and carcinomas (sometimes associated with parathyroid carcinoma). Thallium-201 can also accumulate in metastatic cancer to lymph nodes. MRI is improving but at this time does not appear superior to CT. In a prospective comparison based on 100 patients with benign parathyroid tumors before surgery,457 overall sensitivities were as follows: scintigraphy = 73%, CT = 68%, MRI = 57%, sonography = 55%, with respective specificities of 94, 92, 87, and 95%. None of these imaging techniques had a sensitivity of more than 50% for small (< 250 mg) tumors, and sensitivity also decreases in patients who had previous surgery to the neck.

For patients with parathyroid carcinoma, CT scanning appears most useful at this time since it has good sensitivity in detecting the primary tumor and allows evaluation of its local extent and metastases. Technetium Tc99m sestamibi scanning, previously used for myocardial perfusion studies, has been recently introduced for parathyroid imaging.458 A high sensitivity of up to 80 to 90% has been observed in detecting abnormal glands. Its evaluation in parathyroid carcinoma is in progress.

Invasive Techniques

These techniques require highly skilled personnel and are currently indicated for difficult cases only. Venography with venous samplings for iPTH remains one of the most sensitive techniques.455 It measures PTH from the venous effluents (thyroid veins) before the hormone is degraded in the peripheral blood. A unilateral gradient is in favor of a single adenoma or carcinoma, whereas a bilateral gradient usually indicates diffuse hyperplasia. Multiple venous samples are usually taken, including the vertebral, thymic, and internal mammary veins in addition to the thyroid veins. It is a time consuming but safe procedure.

Angiographic studies have been obtained with a number of techniques and are rarely indicated today. Selective or superselective angiography necessitates experienced personnel. Nonectopic parathyroid glands are supplied by branches of the inferior thyroid artery, which originates from the thyrocervical trunk. Instances of severe neurologic complications, quadriplegia, and even death can occur by inadvertent injection of contrast material into spinal branches of the thyrocervical trunk or the costocervical trunk.459 Safer but less sensitive techniques include nonselective intra-arterial or intravenous digital subtraction angiography.455 Angiography has also been used to ablate functioning parathyroid tumors by direct injection of contrast material.459

Sonography or CT can also guide percutaneous fine-needle biopsy for diagnostic purposes, and some authors have even ablated functional tissue by direct injection of ethanol. The possible risk of these biopsies is spillage of cells, which, in the case of carcinoma, can lead to recurrent tumors.421 Even in cases of benign parathyroid adenomas, recurrent adenomas (parathyromatosis) have been described following spillage. The diagnosis of primary hyperparathyroidism is clinical and biochemical. Biopsy is not necessary in the majority of cases before definitive surgery for either benign or malignant parathyroid tumors and is, in fact, generally contraindicated.

Nonfunctioning Parathyroid Carcinoma

The existence of nonfunctioning parathyroid carcinoma has long been controversial because of the difficulties in differentiating them from thyroid carcinomas. Nonfunctioning tumors, however, do occur throughout the endocrine system. We have reported a case in a 69-year-old woman with multiple recurrences in the neck, a large anterior mediastinal mass, and a malignant left pleural effusion.460 A total of 11 such cases, including one of their own, has been collected in the English literature by Murphy et al.,461 indicating that they represent about 5% of parathyroid carcinomas. There were six women and five men, with a median age of 50 years (range, 27–71 years) and a median survival of 2 years (range, 9 months to 5 years), a pattern similar to functioning carcinomas. These patients had no hypercalcemia, and serum iPTH levels were within normal limits.460,462

Electron microscopy is important to confirm the diagnosis by showing lipid, glycogen, and neurosecretory granules in the cytoplasm, thus distinguishing these tumors from thyroid carcinoma or metastatic renal cell carcinoma.460,463 Three possible hypotheses may explain the absence of hyperparathyroidism: lack of hormone synthesis, impairment or decrease of hormone secretion, and synthesis of an abnormal hormone. The second hypothesis seems most likely in view of the presence of secretory granules by electron microscopy, the demonstration of immunoreactivity for PTH in the tumor tissue in one case,461 and the demonstration of mRNA coding for pre-pro PTH, the cellular precursor of PTH, in the tumor tissue of another case.462 These investigations further support the parathyroid origin of these nonfunctioning carcinomas. These tumors should be distinguished from other nonfunctional parathyroid neoplasms, including oxyphil adenomas, parathyroid cysts, and metastatic carcinomas (most often from breast, lung, and renal carcinomas).412

Differential Diagnosis of Hypercalcemia

The major differential diagnosis of parathyroid carcinoma, besides benign parathyroid adenoma, is to rule out other causes of cancer-related hypercalcemia. In addition to the presence of lytic bone metastasis, hypercalcemia can result from humoral factors secreted by the tumor itself (humoral hypercalcemia of malignancy or HHM). This was hypothesized in 1941 by Fuller Albright, who said “I suspect that the tumor might be producing parathyroid hormone,” while discussing a patient with renal cell carcinoma and a lytic metastasis to the ilium.464 In addition to hypercalcemia, the patient also had hypophosphatemia, whereas most patients with hypercalcemia from bone metastasis have a normal serum phosphate level. Urinary cyclic AMP, an important marker, is increased in patients with HHM or primary hyperparathyroidism, whereas it is low in hypercalcemia related to lytic bone metastases.465,466 Ectopic production of PTH by nonparathyroid tumors, however, is exceptional and was demonstrated only in a few cases, such as ovarian or small cell lung carcinomas.467 Most often, serum levels of iPTH are low in HHM, and PTH mRNA is not expressed by these tumors.468,469

Great progress has recently been accomplished in elucidating this syndrome. In 1987, isolation of a novel PTH-related protein (PTHrP) and cloning of its gene were reported.466,469 That protein contains 141 amino acids, compared to 84 for PTH (Table 85.13), and 8 of the 13 amino acids of the biologically active N-terminal fragment are identical to PTH. Thereafter, the two molecules are totally different. The corresponding gene has been mapped to the short arm of human chromosome 12, compared to the short arm of chromosome 11 for PTH.465,470 This similarity and proximity suggested that both genes derived from a common ancestral gene, which duplicated and separated during evolution.469,470 There are now at least three forms of PTHrP mRNAs known. Homology at the N-terminal region may explain similarities in biologic activities of the two proteins and the binding of PTHrP to PTH receptors. PTHrP increases bone resorption (but not bone formation), increases tubular calcium reabsorption (although less than PTH), and inhibits tubular phosphate reabsorption. Distinguishing features with primary hyperparathyroidism, however, include decreased production of 1,25-dihydroxyvitamin D, due to the limited capacity of PTHrP to stimulate 1-hydroxylase in the proximal tubule, and alkalosis rather than hyperchloremic acidosis (see Table 85.13). In HHM, serum chloride levels are usually low or normal, and bicarbonate levels are normal or high.453 In contrast, bicarbonaturia is increased in primary hyperparathyroidism.440,453 Hypokalemia is common in HHM (50%) and rare in primary hyperparathyroidism (17%).453 Increased plasma levels of PTHrP have been found in about half of the patients with HHM by assays using an antiserum against synthetic human PTHrP [1-34].471 More sensitive radioimmunoassays directed at other fragments have been described.472 The primary tumors producing PTHrP are mainly squamous carcinomas (lung, esophagus, head, and neck), although a wide range of other tumors can also cause HMM, including renal, bladder, breast, and ovarian carcinomas. This syndrome can also occur in patients with bone metastasis as well.473 Of interest is that at the difference of PTH, which is restricted to the parathyroid cells, PTHrP has also been found in a wide range of normal tissues, such as keratinocytes, breast tissue, milk, placenta, central nervous system, adrenals, mesothelium, and even parathyroid glands, suggesting a widespread physiologic role.473,474 Since PTHrP is not elevated in some patients with HHM and since some tumors producing PTHrP do not cause hypercalcemia, other factors that could act independently or synergistically with PTHrP may be implicated in HHM.473 These may include other bone resorbing factors such as transforming growth factor alpha, interleukin-1, and tumor necrosis factor (TNF).470

Table 85.13. Biologic Characteristics and Effects of Parathyroid Hormone (PTH) and Related Peptide (PTHrP)*.

Table 85.13

Biologic Characteristics and Effects of Parathyroid Hormone (PTH) and Related Peptide (PTHrP)*.

In patients with multiple myeloma, the osteoclast-activating factors produced by the malignant plasma cells are thought to be cytokines, particularly lymphotoxin or TNF-β.470 In patients with lymphomas, production of 1,25-dihydroxyvitamin D by the neoplastic cells themselves has been implicated.465,470 The urinary cyclic AMP (cAMP) is depressed.465 A similar mechanism was proposed to account for the hypercalcemia of adult T-cell leukemias caused by human T-cell lymphoma virus (HTLV)-1, but it appears that these patients have classic HHM as described above, with increased urinary cAMP and decreased 1,25-dihydroxyvitamin D.465

Prostaglandins, particularly of the E series, have been also implicated based on in vitro experiments in cases of metastatic breast cancer, particularly after administration of antiestrogens.470 Indomethacin and other prostaglandin inhibitors, however, have been rarely effective in treating hypercalcemia of malignancy.

Other causes of hypercalcemia are usually easy to rule out.452 Endocrine disorders include hyperthyroidism, adrenal insufficiency, pheochromocytoma, and VIPomas. The last two might co-exist with hyperparathyroidism as part of MEN syndromes.452 It has been recently suggested that pheochromocytoma may also produce HHM, as described above.475 Vitamin D excess can be seen in granulomatous disorders (sarcoidosis, tuberculosis, histoplasmosis, etc.) or some lymphomas, as mentioned above. Medications inducing hypercalcemia include thiazide diuretics and lithium carbonate. Estrogen and antiestrogen therapy (tamoxifen) can induce hypercalcemia in patients with breast cancer and bone metastasis. Vitamin A toxicity, milk-alkali syndrome, and immobilization are well-known causes of hypercalcemia. Familial hypocalciuric hypercalcemia can mimic primary hyperparathyroidism.452,476 This autosomal dominant disease starts in childhood and follows a benign course with mild symptoms. Its etiology is unknown. PTH levels are normal or slightly elevated, and the parathyroid glands are normal or mildly hyperplastic.

A normal serum calcium with hypophosphatemia and hyperphosphaturia could raise the possibility of oncogenic osteomalacia, a rare paraneoplastic syndrome seen in benign mesenchymal tumors and sometimes in carcinomas (prostate, small cell lung) and characterized by low serum levels of 1,25-dihydroxyvitamin D.477 It may be caused by ectopic secretion of a factor that inhibits renal tubular reabsorption of phosphate.478



Surgery is the major and only curative treatment of parathyroid carcinoma. It requires an impeccable technique, and the initial operation is the most important one.421 Removal of the tumor en bloc, with all involved surrounding structures and without violating its capsule, is mandatory. For Wang and Gaz,417 all cases where the tumor capsule was violated had local tumor recurrence. Often, the surgeon will rely on the gross appearance to suspect a carcinoma: presence of a thick fibrous capsule with local adherences, gray-white color, and hard consistency, as opposed to the soft reddish brown appearance of adenomas. Simple biopsy with frozen sections should not be attempted in view of its unreliability in distinguishing benign from malignant lesions and its risk of tumor seeding.421,479 The surgical specimen should include all areas of local adherence such as the ipsilateral thyroid lobe and isthmus, involved strap muscles, and blood vessels. If the recurrent laryngeal nerve is involved, it should be sacrificed as well, since attempts to dissect it from the tumor carry the risk of local recurrence.418 Occasionally, the trachea and/or esophagus may be involved as well. Biopsy of the lymph nodes of the tracheoesophageal groove should be performed. Lymph node metastasis is uncommon during initial surgery,417 and, if not present, most authors do not recommend a prophylactic radical neck dissection.421 When the gross distinction with a benign enlargement is in doubt, the other ipsilateral parathyroid should be removed as well to rule out the possibility of diffuse hyperplasia.

Close monitoring after surgery is essential to detect hypocalcemia (“hungry bone” syndrome), which is usually temporary but may require supplements of calcium and vitamin D.480

The 5-year survival is about 50% (including 30% without recurrence), and the 10-year survival varies from 13 to 35%.418,419,439 Parathyroid carcinomas tend to grow slowly and metastasize late. The presence of mitosis or vascular invasion has not been useful in predicting prognosis.419 Early recurrence, however, seems to be an unfavorable factor. Most recurrences occur within 2 to 3 years following initial surgery. Since the disease grows slowly, and most patients die from metabolic complications of hyperparathyroidism rather than tumor burden, an aggressive surgical approach for recurrent or metastic disease is advisable.418,419 Patients may survive many years despite repeated recurrences and metastasis.439 Local recurrences are common (30%), as well as metastases to cervical lymph nodes (30–40%). Distant metastases involve most commonly lungs (20–40%) but also other sites, including mediastinum, bone, pleura, pericardium, and pancreas.417,418,439

Systemic Therapy

Parathyroid carcinomas are resistant to radiotherapy, although it can occasionally be useful for palliation of pain from bone metastasis.481 There is little experience with systemic therapy.460 Partial and temporary remissions were observed with hormonal therapy, including estrogens and testosterone. A partial remission of 10 months duration was reported with hexestrol, a synthetic estrogen compound [phenol, 4,4’-(1,2-diethylethylene].482 Glucocorticoids do not appear active.482 One patient was treated with autoimmunotherapy (portion of resected parathyroid carcinoma emulsified with Freund’s adjuvant and reinjected) without response.482

Experience with chemotherapy is anecdotal. Nitrogen mustard was given to two patients without response.460 We described in 1981 the first successful combination chemotherapy in a patient with metastatic nonfunctioning parathyroid carcinoma.460 The MACC combination (methotrexate, doxorubicin, cyclophosphamide, and lomustine [CCNU]) produced a dramatic regression of a large metastatic mediastinal mass and malignant pleural effusion lasting 18 months. Cisplatin given once (50 mg/m2) at relapse produced no response. A combination of cyclophosphamide, 5-fluorouracil, and dacarbazine (DTIC) produced complete regression of pulmonary metastases and a partial biochemical response of 13 months duration in a patient with a functioning carcinoma.483 DTIC alone has produced a partial response with marked decrease of serum calcium and iPTH but of short duration (<2 months) in a patient with functioning carcinoma.484 Another case of nonfunctioning carcinoma was treated with a modification of the MACC protocol (mitoxantrone substituted for doxorubicin) and had a partial response for 101 months.461

Treatment of Hypercalcemia

The treatment of hypercalcemia in patients with parathyroid carcinoma follows the same general methods used in other forms of hypercalcemia except that the calcium levels may be persistently elevated and more difficult to control by medical treatment, justifying attempts at palliative surgery as mentioned before. Whereas mild hypercalcemia (between 11 and 13 mg/dL) produces variable symptoms, levels higher than 13 mg/dL are usually poorly tolerated.485 Severe hypercalcemia (≥ 15 mg/dL) is life-threatening and constitutes a medical emergency. Serum calcium levels as high as 24 mg/dL have been reported in parathyroid carcinoma.439 Hydration with normal saline, the fluid of choice, is the first step,486 since dehydration secondary to polyuria, anorexia, and nausea is often present. It also promotes renal calcium excretion by increasing the glomerular filtration rate and by reducing reabsorption of calcium and sodium, which are linked in the proximal tubule.452,485 The volume of fluid should be carefully adjusted to avoid fluid overload. Loop diuretics (furosemide, ethacrynic acid) should be added to further increase urinary excretion of calcium and decrease the risk of fluid overload, but only after adequate hydration first. Thiazide diuretics are contraindicated since they may aggravate hypercalcemia. Care should also be given to correct other electrolyte disturbances (potassium, magnesium). It is unlikely that hydration and diuretics alone will normalize serum calcium or even decrease it to safe levels. The role of a calcium-poor diet is minimal in this setting. Mobilization may help but to a small extent.

Mithramycin is one of the most effective agents available.452,485 It inhibits osteoclast function. The starting dose is usually 25 mg/kg as a single intravenous dose given by slow infusion of 4 hours or by IV bolus (the drug is a vesicant). This corresponds to one-tenth the antineoplastic dose. Serum calcium usually starts to decrease within 12 to 24 hours. The peak effect is seen in 48 to 72 hours, and serum calcium may remain low for variable periods of time, usually 3 to 9 days. Doses can be repeated either daily for 3 to 4 days (up to 7 days) or intermittently, depending on the effects on calcium levels. Repeated doses of mithramycin carry the risk of toxic effects, which may limit the usefulness of this agent in the chronic long-term treatment of hypercalcemia and may necessitate dose reductions. Side effects include nausea and vomiting, bone-marrow depression (particularly thrombocytopenia), and bleeding diathesis, as well as hepatic, renal, and dermatologic (flushing, skin rash) toxicity.

Calcitonin inhibits osteoclastic bone resorption and also increases urinary excretion of calcium with relatively few side effects. It appears, therefore, to be an ideal agent, but unfortunately its effect is very limited, lasting less than 24 hours, and it loses its efficacy after repeated administration.452 This “escape” effect may be somewhat corrected by the addition of glucocorticoids as observed in a patient with parathyroid carcinoma.487

Bisphosphonates (formerly diphosphonates) are analogs of the natural substance pyrophosphate. They bind to hydroxyapatite and inhibit bone crystal dissolution and also osteoclastic resorption.485,488,489 Clodronate has shown effectiveness in parathyroid carcinoma490 but is no longer available in the United States because of potential leukemogenicity.488,489 Etidronate is available in the United States. It is given intravenously at a dose of 7.5 mg/kg/day in 250 mL of normal saline infused over 2 hours during 1 to 4 consecutive days. Maintenance with oral etidronate may prolong the therapeutic effect, although oral bisphosphonates are poorly absorbed. Newer compounds in this class, such as pamidronate, hold promise because of increased effectiveness by both the intravenous and oral routes. The recommended dose of pamidronate is 60 to 90 mg as a single dose by 24-hour intravenous infusion or 60 mg as a single dose by 4-hour intravenous infusion. The effect on serum calcium is gradual, with a nadir occurring within 1 week. Addition of calcitonin may hasten its effect.491 Bisphosphonates also have less acute toxic effects than mithramycin and may even be useful in patients with various metastatic bone disease to limit the invasion and destruction of bone and alleviate pain in addition to controlling hypercalcemia.485 Alendronate, newly available, is orally active in osteoporosis and Paget’s disease and will likely find a role in the treatment of hypercalcemia.

Neutral phosphates are modestly effective orally in mild to moderate hypercalcemia and indicated particularly when hypophosphatemia is present. The most common side effect is diarrhea, which is rare at doses below 3 g per day. The potential risk of ectopic calcifications by precipitation of calcium phosphates in soft tissues, however, limits its usefulness, particularly if intravenous phosphate is given. The latter is reserved for extreme, life-threatening hypercalcemia refractory to all other modalities.452

Other agents such as glucocorticoids are of little value here, except occasionally in combination with calcitonin. They are effective in hypercalcemia secondary to abnormal production of 1,25-dihydroxyvitamin D such as lymphomas (see above). Prostaglandin synthesis inhibitors (indomethacin) have been disappointing in treating hypercalcemia of malignancy. Other less established drugs include β-adrenergic inhibitors (propranolol), cimetidine, and estrogens.486 Cisplatin may have antihypercalcemic activity, distinct or not from its antineoplastic activity.488

Gallium nitrate is an antineoplastic drug, which was found to produce hypocalcemia during phase I trials. It inhibits bone resorption and can control hypercalcemia mediated by PTH or related peptide.492,493 At a dose of 200 mg/m2 day for 5 to 7 days by continuous infusion, it has been effective and shown to be superior to calcitonin in treating hypercalcemia from various cancers492 and from parathyroid carcinoma as well.493 Nephrotoxicity is a potential serious side effect. WR 2721 (amifostine) is an organic thiophosphate compound that is concentrated in normal tissues (except the central nervous system) and much less in most neoplastic tissues.488,494 It has been used as a protective agent against the toxicity of radiation and chemotherapy. Phase I trials revealed that WR 2721 can cause hypocalcemia, which appears related not only to inhibition of bone resorption but also to inhibition of PTH secretion and increased urinary calcium excretion.452,488 It has shown activity in parathyroid carcinoma.495

Although mithramycin remains currently the most effective agent for hypercalcemia in patients with parathyroid carcinoma, the development of new drugs (bisphosphonates, gallium nitrate, WR 2721 [amfostine]) and perhaps in the future of peptide hormone antagonists448 will significantly add to the therapeutic armamentarium to treat this most ominous metabolic complication.

Medullary Thyroid Carcinoma


MTC is an uncommon tumor representing 5 to 10% of all thyroid cancers.496 The only known etiologic factors for occurrence of this neoplasm are the autosomal dominant genetic disorders MEN-2a, MEN-2b, and familial non-MEN syndromes, which account for 20% of patients with MTC. Otherwise, MTC arises as a sporadic tumor with an equal frequency between men and women and among different ethnic groups. The peak onset of the sporadic form of MTC is in the fifth or sixth decade of life, whereas this tumor appears much earlier in the MEN syndromes discussed below.497

Natural History

Pathologic Considerations

MTC is a neoplasm of the calcitonin-secreting C cells, which are sparsely distributed in the thyroid gland.498 In approximately 80% of patients, MTC occurs as a sporadic tumor with a unilateral origin in the thyroid. In 20% of patients, however, the neoplasm occurs in an autosomal dominant genetic syndome, of which there are three or more that may involve other endocrine and neural lesions. In these inherited forms, MTC arises as multifocal, bilateral tumors in the thyroid.

Patients with the sporadic form of MTC present with palpable thyroid nodules and almost always have cervical lymph node involvement. MTCs are well-demarcated, whitish, firm nodules that, microscopically, consist of sheets or nests of polygonal cells separated by variable amounts of fibrous stroma (Fig. 85.8). Often the tumors stain positive for amyloid. The hallmark histologic feature of MTC, however, is positive immunostaining for the peptide hormone, calcitonin, which is the major biochemical product of normal thyroid C cells. The presence of calcitonin can help make the diagnosis of MTC when patients present with one of the several variant histologic forms that have been described.499 Immunostaining for calcitonin is also necessary for the diagnosis of the precursor lesions for MTC, which occur bilaterally in the genetic forms of this tumor discussed in more detail below.

Figure 85.8. Histologic features of medullary thyroid cancer.

Figure 85.8

Histologic features of medullary thyroid cancer. A. Nests of polygonal cells. B. Spindle-shaped cells. C. Amyloid deposits (arrows). D. Large amount of fibrous stroma with sparse cells and amyloid nodules (arrows) (reproduced with permission from Mendelsohn (more...)

Biologic Characteristics

By far the most striking biologic characteristic of MTC is the occurrence of this neoplasm in a multifocal pattern in autosomal dominant genetic syndromes.500 The molecular basis for these genetic forms of MTC is not yet understood, but the known chromosomal changes and stages for development of the tumors are discussed below in the section on inherited MTC.

The molecular basis for the loss of differentiation in the aggressive forms of MTC is not yet fully established. In contrast to many solid tumors, chromosomal changes in MTC, such as frequent allelic deletions, are not common.501,502 Although several investigators have implicated chromosome 10,503–507 the only consistent abnormalities appear to be deletions on the short arm of chromosome 1,508 and these could be involved with tumor progression rather than initiation.

Studies of cultured MTC cells from a patient with virulent MTC indicate that whatever chromosome regions are involved, a deficient activation of one or more cellular signal transduction pathways may be a key step in progression of MTC. Activation of either the protein kinase C or protein kinase A pathways can partially differentiate cultured MTC cells as manifested by an increase in transcription of the calcitonin gene and slowing of cell growth.509 A virtually complete differentiation response can be elicited in these same cells by insertion of a mutated Harvey ras oncogene.509 In this situation, not only is there an increase in calcitonin gene expression, but the mRNA splicing for the resultant transcripts resembles the pattern of mRNA splicing in the normal thyroid C cell. In addition, the cells acquire the typical mature neurosecretory granules of APUD cells, which are lacking in the control cultured cells. The final mediators of this response to an inserted ras gene are being investigated, but a coordinated increase in the protein kinase A and C pathways, plus other signal transduction input, is probably involved. A marked increase in expression of the c-jun oncogene,509 which is known to participate in multiple protein kinase C mediated events, accompanies the ras gene-induced differentiation of the MTC cells. Presumably, the increase in this transcription factor activates a series of other transcription factors that mediate maturation of the cells.

Clinical Features

The most common clinical features are a local neck mass and, less commonly, morbid signs or symptoms from distant metastases. In general, the production of secretory peptides is of no clinical significance, although, occasionally, apparent manifestations of MTC endocrine activity may be observed. For example, patients with MTC can develop Cushing’s syndrome due to ACTH production.510 More often, serotonin, prostaglandins, and perhaps other hormones produced by the tumor may be implicated in the secretory diarrhea seen in up to 30% of patients with advanced MTC.511 Although a physiologic role for calcitonin gene-related peptide (CGRP) has not been established, it is possible that, as a powerful peripheral vasodilator, CGRP, together with substance P, may play a role in the flushing observed in certain patients with advanced MTC.

Another important feature of MTC is the variable clinical behavior of this cancer. Although MTC metastasizes early, especially to cervical lymph nodes and mediastinal structures, it behaves in a relatively indolent manner in approximately 70 to 80% of patients.496,497,512 Some patients, even with well-documented hepatic and pulmonary metastases, also take an indolent course. In another group of patients, however, MTC can behave aggressively, and patients die from widespread bony and visceral metastases to lung, liver, and adrenals.513 The overall survival rates for individuals with MTC are 80% for 5 years and 60% for 10 years (Fig. 85.9, A and B).497

Figure 85.9. Survival of patients with medullary thyroid carcinoma (MTC).

Figure 85.9

Survival of patients with medullary thyroid carcinoma (MTC). A. Adjusted survival of all patients with MTC. B. Survival of patients with sporadic MTC compared to patients with MEN 2a. C. Relative survival of patients according to amyloid positive (+) (more...)

The complete basis for the variable clinical behavior of MTC is not known. Inability of neoplastic C cells to attain a fully differentiated phenotype appears to be important.509 This deficiency in maturation is manifest as a marked decrease in the immunoreactive calcitonin and amyloid content of the tumor cells in patients with aggressive MTC.509,514 Immunostaining of such tumors reveals large areas of calcitonin positive cells that can co-exist with areas of negative staining.509,515 This heterogeneous calcitonin staining pattern or lack of amyloid, when found in primary MTC lesions, is associated with a virulent course and poor survival at 5 years (Figure 85.9, C and D).514–516

Biochemical Features

The distinguishing biochemical features of MTC relate primarily to the origin of this cancer in the calcitonin-producing C-cells of the thyroid498 and from the general characteristics of the group of neuroendocrine cells to which these C cells belong.

The main secretory product of the C cells and the biochemical marker of most clinical utility in patients with MTC is the 32-amino acid peptide calcitonin. Calcitonin is encoded by a multi-exonic gene, which, by alternative processing of a primary RNA transcript, generates two mRNAs. One codes for calcitonin itself and another for a 37-amino acid peptide called CGRP.517 The calcitonin mRNA predominates in normal thyroid C cells but, in MTC, both CGRP and calcitonin mRAs are often found in high quantities. Both peptides may circulate at high levels in the blood of patients with MTC, but CGRP levels are much more variable and are usually lower than calcitonin levels.518,519 During provocative diagnostic testing, as discussed below, calcitonin levels increase briskly in response to calcium and/or pentagastrin stimulation, whereas CGRP responses have been variable.518,519

MTC cells also express several biochemical markers that relate to the APUD features of these neuroendocrine cells, including small polypeptide hormones such as somatostatin,520 ACTH,510 and GRP.521 Like other neuroendocrine cells, MTC contains the enzyme l-dopa decarboxylase,522 prostaglandins,523 chromogranin A,524 and NSE.525,526 High levels of the histamine-metabolizing enzyme, histaminase or diamine oxidase, are also characteristic of MTC.522 Furthermore, these biochemical markers may occasionally be of diagnostic utility. Immunostaining of chromogranin A is positive in a very high percentage of MTC tumors and thus may help make the diagnosis of MTC in tumors that stain poorly for calcitonin.524–526

Another biochemical marker frequently expressed by MTC is carcinoembryonic antigen (CEA). This protein is synthesized by the tumor cells at all stages of disease.527,528 Even in the aggressive forms of MTC, where the tumor tissue becomes heterogeneous for calcitonin staining, CEA remains present. In fact, a rising blood CEA level in the face of a stable or declining calcitonin level indicates a poor prognosis in patients with MTC.528

Diagnostic Tests

The majority of patients with sporadic MTC present with palpable thyroid nodules, which are manifested as cold nodules on 131I radionuclide imaging and as solid masses on echography. Occasionally, plain x-rays of the neck reveal a dense pattern of calcifications that is characteristic of MTC, different from the fine calcification pattern observed with papillary carcinoma. In most patients, the diagnosis of MTC is made unexpectedly from examination of frozen or permanent sections of a thyroid mass removed at the time of initial surgery.

Even though virtually all patients with palpable MTC have elevated basal serum levels of calcitonin, the relative rarity of MTC makes it impractical to use this test to screen all patients who have thyroid nodules. Stimulated calcitonin secretion, as described in the section on MEN-2 below, should be reserved for testing patients suspected of having MEN-2 or familial non-MEN MTC and for screening their immediate family members.529,530 A more practical approach involves use of fine-needle aspiration (FNA) biopsy to assess any patient with a suspicious thyroid nodule (Fig. 85.10). The cytologic evaluation of such specimens, especially when combined with immunostaining for calcitonin, may suggest MTC and serum calcitonin immunoassays can be employed to confirm the diagnosis.

Figure 85.10. Algorithm for the diagnosis and management of medullary thyroid carcinoma.

Figure 85.10

Algorithm for the diagnosis and management of medullary thyroid carcinoma.

In all patients documented to have MTC, a prime consideration is the possibility that the patient may represent the index case for one of the familial forms of the disease. In the rare genetic syndrome, MEN-2b, an associated Marfan-like habitus, and the presence of neuromas over the eyelids, lips, and tongue should make the diagnosis obvious. For the other forms of genetic MTC, however, there are no particular physical stigmata. The possibility of familial disease then must be ruled out in virtually every patient with MTC. One extremely helpful criterion for the diagnosis of familial MTC is the presence of bilateral tumors and/or C-cell hyperplasia. Occurrence of MTC in patients younger than 40 years of age also suggests familial disease. Screening of first-degree relatives with calcitonin determinations is, however, the only definitive way to exclude genetic disease. Recent studies suggest that the genetic form of MTC is found in 10 to 15% of cases when evaluating relatives of patients with apparently sporadic MTC.529 The most effective approach, if possible, is first to screen the parents of a newly diagnosed MTC patient. A single negative test in the parents dramatically reduces the probability of familial disease. If the parents are not available, screening of as many siblings and offspring as possible is mandatory.

Therapeutic Considerations

Surgical Management

Sporadic MCT usually presents as a solitary nodule in the upper half of the lateral lobe on either side, although, in some cases, a metastatic lymph node may be detected first while the primary tumor remains occult to clinical examination. Currently, the diagnosis is frequently established before operation by FNA cytology, after which a basal serum calcitonin can be obtained to confirm the diagnosis (see Fig. 85.10). The calcitonin level may be of value in predicting the amount of tumor present and whether lymph nodes are likely to be involved. Urinary catecholamine levels must be obtained to rule out pheochromocytoma, even when the history is negative for MEN-2a and there are no physical findings to suggest MEN-2b before a thyroidectomy is undertaken (see Fig. 85.10). If present, the pheochromocytoma should always be removed prior to the thyroidectomy.

The minimal treatment of MTC is total thyroidectomy.531 In sporadic disease, this allows for excision of any intraglandular lymphatic spread and careful immunohistopathologic study of the contralateral lobe for possible C-cell hyperplasia. Even in some patients with metastases, given the fact that MTC is often slow growing, minimal treatment is a total thyroidectomy. Although not curative, this may prevent tumor growth that can impinge on major structures such as the trachea and esophagus. Most patients with sporadic disease have lymph node metastases when first diagnosed. A central lymph node compartment dissection, preserving the parathyroid glands and recurrent laryngeal nerves, is indicated. Dissection of the nodes includes the Delphian group, those around the upper pole of the thyroid lobe, those in the tracheoesophageal groove along the recurrent laryngeal nerve, and the anterior mediastinal lymph nodes to the level of the innominate artery. Some nodes contain metastases in nearly all patients with a palpable primary tumor within the thyroid gland at operation. If lateral lymph nodes are involved, a modified radical neck dissection should be done.532 Occasionally, because of invasion through the lymph node capsule and involvement of contiguous structures, a formal radical dissection may be required.

In patients with MTC, discovered by calcitonin screening and no palpable tumor, central compartment lymph nodes may be tumor-free. Nevertheless, even normal-sized nodes should be sampled for frozen section examination to determine whether a complete and thorough central compartment dissection is required (see Figure 85.10). Lateral lymph node involvement is treated by modified neck dissection, which may be bilateral, performed in one or two stages. When the lateral lymph nodes are involved with MCT, a biochemical cure, as determined by calcitonin testing, is unlikely (<20%). As a result, a formal (modified) radical neck dissection has been considered by many to be futile.532 Occasionally, this is still indicated if the procedure is required to excise all areas of gross disease because of lymph node invasion of local tissues. For this reason, when possible prior to initial surgery or following surgery, CT or MRI image scans of the cervical, mediastinum, and abdominal regions should be done to document areas of discernible metastases. When calcitonin levels remain elevated despite lack of clinically evident disease after a total thyroidectomy and central compartment dissection, controversy continues as to whether a neck dissection on one, or both sides should be done. Tisell et al.533 favors a meticulous radical neck dissection and have achieved a biochemical cure in about half of a relatively small group of patients treated this way. Alternatively, others have favored regional excision of any palpable nodes or those suspected on the basis of a positive thallium scan or cervical ultrasound when the disease has been limited to the lateral neck or anterior mediastinum. One of the causes of failure after performing a radical neck dissection based entirely on an elevated calcitonin level is that clinically occult MTC already may have spread hematogenously to involve the liver, lungs, or bone. Therefore, it is reasonable to perform selective venous sampling for calcitonin to rule out disseminated disease before considering any extensive additional neck procedures.

Treatment of Recurrent or Metastatic Disease

When persistent, recurrent, or disseminated disease is present, MTC usually progresses slowly. Since effective radiation therapy or chemotherapy is not well established, it is important to consider several prognostic factors when deciding if chemotherapy is indicated. As discussed previously, tumors that have poor immunocytochemical staining for calcitonin tend to have a more aggressive course.514–516 Although the serum calcitonin level correlates with the extent of disease, it does not help in identifying patients with a poorer prognosis. Rapidly rising, high serum CEA is more predictive of a rapid disease course.528

Recurrent tumors may be amenable to repeated surgical resection, especially for palliation of symptoms to local tissue invasion or to a syndrome of hormonal excess. Radiation therapy does not have an established role in the treatment of locally advanced MTC.512 In selected cases of patients with symptomatic bone metastases, a trial of radiation may offer transient palliative benefit.

Although most reports of chemotherapy for MTC are anecdotal, the experience provides some guidelines for therapeutic approaches. Since MTC belongs to the APUD family of neoplasms, a number of single-agent and combination chemotherapy treatments that show activity in other APUDomas have been used in advanced MTC.

Gottlieb and colleagues534 reported three partial remissions and resolution of disease-related diarrhea in six patients with advanced MTC following treatment with doxorubicin. Additional reports by others suggest an overall partial reponse rate of 30% in 46 patients with MTC treated with doxorubicin as a single agent.535–538 The combination of streptozocin and doxorubicin was not active in a small trial of patients.539,540 Reports of the combination of 5-fluorouracil and DTIC (including a complete response),541 doxorubicin, and cisplatin,542 or DTIC,543 5-fluorouracil,544 or etoposide,544,545 used as single agents suggest limited activity for these drugs.537,546 The combination of cyclophosphamide, vincristine, and DTIC, found to be effective in malignant pheochromocytoma,547 has been studied in three patients (Averbuch et al.548 and A. de Bustros and S Baylin, personal observation, 1992). Two of these patients had a partial response demonstrated by reduced serum calcitonin and/or CEA and objective regression of radiologically demonstrated masses. The other patient had stable disease for more than 17 months. Until prospective multi-institutional studies of combination chemotherapy regimens for patients with metastatic MTC are undertaken, DTIC or cisplatin and doxorubicin containing regimens should be considered for individual patients with progressive, symptomatic disease.

Since biologic response modifiers, such as the somatostatin analog octreotide acetate, have been shown to reduce circulating hormones, halt progression, and occasionally reduce tumor size in various neuroendocrine tumors,549 this agent may have a role in patients with MTC.549,550 Long-term subcutaneous injection of octreotide acetate to 21 patients with MTC reduced serum calcitonin in 11, but CEA did not change.550,551 Flushing and diarrhea improved in some, and several patients reportedly had objective tumor response. Additional clinical studies are required to determine the activity of somatostatin analogs in patients with metastatic MTC.


Pheochromocytoma and paraganglioma are terms describing a neoplasm of chromaffin cells found in the adrenal medulla or elsewhere within the sympathetic paraganglionic axis. The adrenal tumors are usually referred to as pheochromocytomas, whereas an extra-adrenal tumor is often termed either extra-adrenal pheochromocytoma or paraganglioma, the latter usually reserved for a nonfunctional (i.e., noncatecholamine secreting) neoplasm. This terminology is based on historical histopathologic techniques, and since these neoplasms are otherwise indistinguishable, the terminology may be confusing. Therefore, all of these neoplasms considered here will be referred to as pheochromocytomas. Additional descriptions (e.g., nonfunctional, extra-adrenal, or malignant) should be included in the terminology as appropriate. Rare chromaffin neoplasms arising from special structures in the neck may be referred to as chemodectomas, glomus jugulare, or carotid body tumors.390,552


Pheochromocytomas occur infrequently and are found in approximately 0.1 to 0.5% of hypertensive patients.553–555 Autopsy series suggest that up to one-third of pheochromocytomas may not be diagnosed premortem.556–558 From the Mayo Clinic data, it is estimated that approximately 800 cases of pheochromocytoma are diagnosed in the U.S. each year.553 The average annual incidence of pheochromocytoma in Sweden and Denmark is 2.1 and 1.9 cases per million population, respectively.559,560

Ninety percent of pheochromocytomas are sporadic neoplasms. Thus, when considering the diagnosis and management of this disease, it is important also to consider the “rough rule of 10s.” That is, 10% of neoplasms occur in children, 10% are associated with familial syndromes, 10% of sporadic cases are bilateral, 10% are extra-adrenal, and 10% are malignant. There is a higher chance of extra-adrenal disease in children.555,558,561,562 This mnemonic provides only an estimate of these presentations, and there is overlap within the pediatric, familial, and bilateral groups.563,564 The most common familial syndromes that include pheochromocytoma as an element are the autosomal dominant MEN syndrome types 2a and 2b and von Hippel-Lindau (VHL) disease.555,565–567 MEN-2a is characterized by parathyroid adenoma and MEN-2b by ganglioneuromatosis and Marfanoid-like body habitus. MTC and pheochromocytoma are common to both syndromes. VHL can have associated retinal angioma, hemangioblastoma of the central nervous system, renal cysts and carcinoma, and pancreatic cysts.

Carriers of these familial syndromes can have pheochromocytoma as the only or the first manifestation of their inheritance. Hartmut et al.567 reported that 23% of unselected patients with pheochromocytoma are carriers of either MEN-2 or VHL disease. Therefore, all patients with pheochromocytoma should have screening tests for these familial disorders. Conversely, all carriers of these familial syndromes should be screened for pheochromocytoma because of high prevalence (up to 80%). Many such patients discovered by screening are normotensive and asymptomatic. Pheochromocytomas have also been seen in neurofibromatosis as a component of Carney’s triad and in families unassociated with other tumors or syndromes.563,568–571 Familial pheochromocytomas occur at a younger age and very often involve both adrenal glands, either synchronously or metachronously. It typically follows a benign course, but because of their potential for causing significant morbidity or mortality, this tumor must be diagnosed and removed prior to any surgical management of thyroid or parathyroid disease.

Malignant pheochromocytoma is a rare entity among malignant diseases, and its exact incidence is not known. Multiple series have estimated the frequency of malignancy among pheochromocytomas from 5 to 46%,557,572–577 although the latter figure is probably inflated since it comes from a very selective referral patient population.572 Overall, a figure of 13% of all pheochromocytomas probably represents a reliable incidence for malignant pheochromocytoma.547 A review of SEER data for 1973 to 1985 suggests that the yearly age-adjusted rate of malignant pheochromocytoma is 0.04 per 100,000 population or approximately 100 cases per year in the U.S. (SD Averbuch, unpublished observation). Extra-adrenal pheochromocytoma has been associated with a higher frequency of malignancy (30%),552,555,574,576,578 although this has been challenged recently.579

Natural History

Embryology and Anatomy

Chromaffin tissue constitutes one component of the diffuse neuroendocrine (APUD) system, thought to be derived from the embryonic neuroectodermal crest.390,580 Although this embryologic origin of APUD tumors is now disputed,392,409–411 the common genetic and clinicopathologic characteristics of pheochromocytoma and APUD tumors justify their consideration as entities of a common neuroendocrine system. In the fetus and in infancy, diffuse paraganglionic chromaffin tissue is prominent but later regresses, aside from that found within the adrenal medulla.581 Because of this, pheochromocytomas may arise from chromaffin remnants virtually anywhere, but the vast majority (90%) are found in the adrenal medulla.569,576 The most common extra-adrenal sites are the region where the left renal vein crosses the aorta, renal hilus, and the origin of the inferior mesenteric artery (organ of Zuckerkandl).

Pathologic Characteristics

The typical adrenal pheochromocytoma is a sporadically occurring neoplasm, arising from either gland. When detected, it is approximately 5 cm in diameter and weighs 50 to 100 g.569 The adrenal mass is often pseudoencapsulated, and it is highly vascularized with a beefy appearance and consistency. Larger tumors frequently contain areas of hemorrhage or empty or fluid-filled cysts surrounded by connective tissue and calcifications (Fig. 85.11A). The microscopic appearance of a pheochromocytoma is similar to the architecture and morphology of normal chromaffin tissue. The cells are usually round or polygonal with abundant eosinophilic or basophilic fine granular cytoplasm and are frequently arranged in cords or clusters (Fig. 85.11B).569 Nuclear pleomorphism and hyperchromasia are common. Mitotic figures are often seen in adrenal hyperplasia and in pheochromocytoma, but they are not necessarily prominent histologic features. Chromaffin cells and pheochromocytomas show a characteristic brown staining following application of chromium salts (hence, chromaffin), although this method has largely been replaced by the Grimelius argyrophil stain.582 The demonstration of a wide array of neuroendocrine products by immunocytochemical analysis reflects the content of dense intracytoplasmic neurosecretory granules, which are apparent by electron microscopic examination (Fig. 85.11C).569 Commonly identified products include biogenic amines, neuron-specific enzymes, and neuropeptides (Table 85.14).562,565,569,583–596

Figure 85.11. Pheochromocytoma.

Figure 85.11

Pheochromocytoma. A. Gross appearance of a surgically removed hemisected extra-adrenal pheochromocytoma. B. Histopathologic appearance of a pheochromocytoma showing typical cords of glandular cells separated by bands of stroma (hematoxylin and eosin, (more...)

Table 85.14. Biologic Markers in Pheochromocytoma.

Table 85.14

Biologic Markers in Pheochromocytoma.

There are no pathognomonic criteria for malignancy of a pheochromocytoma other than the natural history of an individual’s tumor that manifests chromaffin cell invasion or dissemination at sites where chromaffin tissue is normally not present. Malignant tumors have a predilection for spreading to bone (predominantly to spine, ribs, and skull),597 lung, liver, and retroperitoneal and mediastinal lymph nodes.547,552,598 A number of studies have attempted to identify characteristics that can discriminate malignant from benign tumors.569,599 Among these, nuclear pleomorphism, mitotic figures, vascular invasion, cortical extension, necrosis, and immunocytochemical characteristics are not particularly useful. Some authors have shown that increased tumor size and extra-adrenal location are associated with a malignant phenotype.555,576,599 Investigations of tumor DNA ploidy by flow cytometry have demonstrated the potential utility of this technique for defining a malignant subset.600–602 Of 62 tumors studied, approximately one-third of tumors containing aneuploid, polyploid, or tetraploid DNA were malignant, whereas all 18 that were diploid followed a benign course, a statistically significant difference.600 However, DNA ploidy is not discriminant for malignancy since this study and others demonstrated a high prevalence of aneuploidy in benign pheochromocytomas as well.603–605 Sustentacular cells are dendritic cells stained positive for S-100. These cells are found in normal paraganglionic tissue and benign pheochromocytomas. Absence of these cells suggests malignancy in several studies.606

Biologic Characteristics

Germline mutations of theret oncogene have been found in lymphocytes, medullary thyroid carcinoma, and pheochromocytoma in carriers of MEN-2a and -2b.607–610 The ret oncogene encodes a transmembrane tyrosine kinase, but this mutation was rarely found in sporadic pheochromocytomas. LOH, which suggests loss of a tumor suppressor gene at chromosomes 1p, 3p, 17p, and 22q, is common in both familial and sporadic pheochromocytomas.611–613 These molecular and cytogenetic findings suggest that the development of pheochromocytoma follows the model of multi-stage carcinogenesis exemplified in colon cancer.

Clinical Features

There is no correlation between the amount of catecholamines produced and the severity of blood pressure changes.561,614 Thus, patients may present anywhere in the spectrum from normotensive and asymptomatic to a severe, life-threatening hypertensive crisis causing cerebral hemorrhage, myocardial infarction, or cardiac failure.556,615 In fact, many patients can be quite asymptomatic during their lifetime, specifically the elderly, so that up to one-third of patients in autopsy series were not diagnosed before death.616 In clinically diagnosed patients, hypertension can be either sustained or episodic, and each occurs in approximately one half of patients with pheochromocytoma. Five percent are normotensive. In rare cases, episodic hypotension is the main symptom due to secretion of predominantly epinephrine or dopamine. Hypertensive episodes may be precipitated by physical stress, an increase in intra-abdominal pressure, or by certain drugs including phenothiazine, a tricyclic antidepressant, metoclopramide, naloxone, and droperodol.565,617 Characteristically, symptoms occur paroxysmally even in patients with sustained hypertension. The most common symptoms are headache, sweating, and palpitation; each occurs in about 60% of patients. Almost all patients have at least one or two of these three symptoms. But the positive predictive value of this triad is low because only 5.9% of hypertensive patients with this entire triad have pheochromocytoma. Other common symptoms, in decreasing frequency, are pallor, nausea, anxiety, weakness, dyspnea, visual disturbance, abdominal pain, tremor, and weight loss.618 Tachycardia, tremor, and anxiety are prominent in pheochromocytomas secreting a lot of epinephrine. Attacks of symptoms happen abruptly and usually do not last more than 15 minutes. An important feature that distinguishes hypertension of pheochromocytoma from essential hypertension (in the absence of pharmacologic therapy) is the presence of postural hypotension, manifested as a significant drop in systolic pressure in the upright position, but it happens in less than 50% of patients.556,561,619,620 Because of chronic vasoconstriction, the down-regulation of peripheral alpha receptors and the presence of vasodilatory biogenic amines or peptides, such as VIP and enkephalins, patients with pheochromocytoma are commonly hypovolemic, accounting for postural blood pressure changes.565,566,619 Cardiomyopathy and congestive heart failure due to persistently high circulating catecholamines have been reported. Pheochromocytomas in MEN patients are frequently asymptomatic, but these patients can go into hypertensive crises during surgery for hyperparathyroidism or MTC. Therefore, all patients with MEN-2 should be carefully screened for the presence of pheochromocytoma before any surgery or invasive procedure.

Biochemical Features

Along with other neoplasms of the diffuse neuroendocrine (APUD) system, pheochromocytomas are specialized neoplasms that can synthesize, store, and secrete biologic amines and peptides. A large number of these substances have been associated with pheochromocytoma and are often capable of producing specific clinical syndromes (see Table 85.14).561,565,583–585,591–596 Chromogranin A is a soluble binding protein found in the neurosecretory granule; it is the most prevalent biologic marker for pheochromocytoma.588 This marker is not specific, however, since it is also expressed in other neuroendocrine and nonendocrine neoplasms as well.589,621,622

Neuropeptide Y is a peptide with potent vasoconstrictor activity. High neuropeptide Y immunoreactivity has been found in both benign and malignant pheochromocytomas623–627; by far, the most important secretory products of pheochromocytomas are the biogenic amines (Fig. 85.15; see Table 85.14). The majority of these neoplasms secrete excess norepinephrine that results in sporadic or sustained hypertension.554 Epinephrine is the major catecholamine secreted by normal adrenal medulla, and it is frequently elevated in pheochromocytoma, especially in familial cases, but norepinephrine predominates in most tumors.628 Dopamine and the catecholamine precursor, dihydroxyphenylalanine (dopa), are also secreted by pheochromocytomas, and there is some evidence that high circulating levels of these norepinephrine precursors are more commonly associated with a malignant phenotype.629,630

Figure 85.15. Actuarial survival of 22 patients with malignant pheochromocytoma from the time of surgical diagnosis.

Figure 85.15

Actuarial survival of 22 patients with malignant pheochromocytoma from the time of surgical diagnosis.

Diagnostic Tests

The fundamental basis for the diagnosis of pheochromocytoma is a high index of clinical suspicion with confirmation by biochemical determinations for catecholamines or catecholamine metabolites in blood or urine.619 The most common and reliable tests are the measurements of 24-hour urinary excretion for catecholamines, metanephrines, or vanillylmandelic acid (Fig. 85.12).628,631 Urinary free catecholamine and metanephrines have higher sensitivity, but many medications can interfere with the measurements. More than 80% of patients with pheochromocytoma have urinary excretion of free catecholamines or metanephrines higher than twice the upper limit of normal. From 2 to 12% of all hypertensive patients have elevated urinary excretion, but patients without pheochromocytoma almost always have values less than twice the upper limit of normal.632 Spot (2-hour) urine specimens for metanephrines or plasma anorepinephrine are preferred by some authors, although these tests may be associated with a higher number of false-positive and false-negative outcomes.618,628,632,633 Physiologic and pathologic fluctuations, such as anxiety and alcohol withdraw, can cause transient elevation of catecholamines. Conversely, blood taken during a normotensive period in a patient with episodic hypertension may show normal or borderline levels of catecholamines. More sophisticated catecholamine metabolite assays have been proposed to increase the specificity of urinary determinations.554,634–637

Figure 85.12. Synthetic and metabolic pathways for the catecholamines, norepinephrine and epinephrine, which are stored and secreted by chromaffin cells and pheochromocytomas.

Figure 85.12

Synthetic and metabolic pathways for the catecholamines, norepinephrine and epinephrine, which are stored and secreted by chromaffin cells and pheochromocytomas. Curved arrows, physiologic agonist—receptor interaction. Boxed arrows, competitive (more...)

Bravo620 has suggested that when the biochemical tests are diagnostically high, such as urinary metanephrines >3.0 mg/24 hours or plasma catecholamines >2,000 pg/mL in hypertensive patients with typical symptoms, anatomic localization of the tumor should be carried out. In patients with borderline results, such as urinary metanephrines between 1.4 and 3.0 mg/24 hours or plasma catecholamines between 400 and 2,000 pg/mL, pharmacologic tests can be used to confirm the diagnosis. If patients are hypertensive and plasma catecholamines are more than 1,000 pg/mL, a clonidine suppression test is preferred. Plasma catecholamines are sampled before and 3 hours after an oral dose of 0.3 mg of clonidine. Plasma catecholamines will fall below 500 pg/mL in patients with essential hypertension, but they do not fall in pheochromocytoma. Overnight urinary catecholamine determination after clonidine has also been used.638 Blood pressure needs to be monitored during the testing and will drop in both groups. For patients with mild hypertension or normotension and plasma catecholamines between 400 and 1,000 pg/mL, a glucagon provocative test is preferred. Plasma catecholamines are sampled before and 1 to 3 minutes after injection of 1.0 to 2.0 mg of glucagon. A three-fold increase in plasma catecholamines or values over 2,000 pg/mL is diagnostic for pheochromocytoma. The rise of blood pressure can be prevented by prazocin or nifedipine given 1 hour before the glucagon injection.618

For anatomic localization, angiography, selective venography, and intravenous pyelography now rarely have a role in the localization of pheochromocytoma because 90% of pheochromocytoma are located in the adrenal gland. CT scanning can visualize nearly all adrenal pheochromocytomas. Therefore, a CT scan should be conducted in all patients with a biochemical diagnosis of pheochromocytoma.617 MIBG is a structural analogue of guanethidine and, as such, is readily taken up by the chromaffin cell and stored in neurosecretory granules.639 Experience reported in over 1,000 patients uniformly shows a sensitivity of approximately 90% and a specificity of nearly 100% (Fig. 85.13A).631,640–642 As compared to CT and MRI, MIBG is at least as good as the other two modalities.643,644 All patients should have an MIBG scan to confirm that the tumor seen in CT scan is a pheochromocytoma. In addition, extra-adrenal tumors, which are not well visualized in CT scans, can be picked up in an MIBG scan. The sensitivity of MIBG scanning may be considerably less in malignant pheochromocytoma, and its specificity is limited by the fact that MIBG is readily accumulated by other neuroendocrine tumors.640,641,645 Certain drugs (e.g., labetalol) may reduce the uptake of MIBG into the tumor’s catecholamine storage vesicles, causing a false-negative test.641,646 Occasionally, the CT characteristics of size, contrast enhancement, and consistency may provide clues regarding the probability of malignancy.647 Because of the risk of catastrophic hemorrhage or hypertensive complications, FNA should not be attempted for cytologic diagnosis.

Figure 85.13. Diagnostic imaging in metastatic pheochromocytoma.

Figure 85.13

Diagnostic imaging in metastatic pheochromocytoma. A. Gamma camera image of the upper body of a patient 48 hours following injection of l-metaiodobenzylguanidine. Areas of abnormal isotope uptake are noted at the base of the brain, the cervical region, (more...)

Although not possessing the resolution of CT, MRI may have a special role in the localization of pheochromocytomas. These tumors have a particularly intense detectable signal on T2-weighted MRIs, appearing as very bright spots compared to normal tissue (Fig. 85.13B).648,649 In addition, MRI reconstruction to demonstrate coronal or sagittal views of the tumor provide important preoperative anatomic information.643,650 The MRI is probably not necessary for routine pheochromocytomas, but it should be used for localization in the case of malignant or extra-adrenal tumors, especially in the neck, mediastinum, liver, and retroperitoneum.651 Because of the high prevalence of bone metastases, a bone scan should be performed in patients thought to have metastatic disease, since this test has a higher sensitivity than MIBG for bone metastases.597 If the bone scan detects lesions in the axial skeleton, a spinal MRI may be considered to rule out early spinal cord compression.

Most pheochromocytomas express somatostatin receptors on the cell surface; therefore, these tumors can be shown in a 123I-labeled octreotide scan. Like MIBG scan,652 many other neuroendocrine tumors also show positive uptake in an octreotide scan and thus limit its specificity. [11C]Hydroxyepinephrine is a newly developed radiotracer that concentrates in adrenergic nerve terminals. Ninety percent of pheochromocytomas can be localized by a PET scan using this agent.653 Malignant pheochromocytoma has also been reported to show up in thallium and gallium scans. The role of these new scans in clinical practice is undetermined. In summary, each of the methods for localization of pheochromocytoma described above are complementary; they should be employed in selective combination depending on individual circumstances.643

Differential Diagnosis

There are many clinical situations and drugs that can alter catecholamine secretion and catabolism. Hypertension and elevated levels of catecholamines and their metabolites can be seen in anxiety, panic state, intracranial lesions, autonomic hyperreflexia, diencephalic seizure, eclampsia, use of monoamine oxidase inhibitors, decongestants, caffeine, diazoxide, vasodilators, theophylline, appetite suppressants, carcinoid, hypoglycemia, neuroblastoma, acute abdomen, alcohol or colonidine withdrawal, and acute coronary ischemia.617,618

Therapeutic Considerations

Medical Management

The mainstay of preoperative pharmacologic management is an α-adrenergic blockade with phenoxybenzamine in doses ranging from 10 mg twice daily up to tolerable doses that will control blood pressure, allow for restitution of normal blood volume, and block catecholamine-induced gut hypomotility (Fig. 85.14).555,556,560,565,628,631 The major side effect is orthostatic hypotension, and reflex supraventricular tachycardias or arrhythmias may occur. The latter may be controlled with the addition of β-blocking agents such as propranolol, atenolol, or esmolol only after adequate α-blockade is established, since unopposed β-blockade may worsen vasoconstriction and hypertension. Additional agents may need to be added or substituted for optimal management.619 These include α-blockers prazosin or terazosin,654 the combined α- and β-blocker labetolol,655 calcium channel antagonists (nifedipine or verapamil),656 and the angiotensin-converting enzyme inhibitors (captopril or enalapril).657 None of these agents has any particular advantages, and some have disadvantages, so their use depends on individual circumstances and the experience of the clinician. In severe hypertension, α-adrenergic blockade with intravenous phentolamine or vasodilation with nitroprusside may be used.658

Figure 85.14

Figure 85.14

Algorithm for the diagnosis and management of pheochromocytoma

Metyrosine (α-methyl-paratyrosine) is a competitive inhibitor of the rate-limiting hydroxylation step of catecholamine synthesis and is used in addition to α- and β-adrenergic active agents to deplete tumor catecholamines and further reduce blood pressure before surgery or in patients who have failed standard treatment or whose tumor cannot be resected (see Fig. 85.12).619,659 The starting dose is 250 mg four times daily, and it may be titrated up to 4 g per day. The central nervous system side effects of sedation, irritability, nightmares, sleep disturbance, and hallucinations are, however, often dose limiting.

Surgical Management of Benign or Recurrent Resectable Disease

Nearly all benign pheochromocytomas can be cured by surgical resection. Because of its slow growth rate and accompanying significant morbidity, complete resection of local recurrence or limited metastases of malignant pheochromocytoma should be attempted. But the value of debulking surgery for patients whose tumor cannot be completely resected is not established.552,566,660,661 Most soft-tissue spread including some liver metastases is amenable to resection; the majority of patients with malignant pheochromocytoma also have bone metastases as well.547,597

Traditionally, all patients, regardless of blood pressure readings, would be prepared with an α-blocking agent or calcium channel blocker656 as described above to control blood pressure preoperatively. Induction of general anesthesia and manipulation of the tumor may provoke a release of massive amounts of catecholamines, making prior receptor blockade important. In addition, most patients have significant reduction of intravascular fluid volume, and an α-blockade permits volume reexpansion. The administration of a β-blocker may not always be necessary but clearly should be given if the patient has tachycardia, arrhythmia, or a catecholamine profile showing a preponderance of epinephrine secretion. One approach is to give propranolol to most patients for 48 hours preoperatively, beginning with a dose of 10 mg four times a day. Propranolol and phenoxybenzamine may be given with a sip of water early on the morning of operation. The caveat of this approach is that it will be more difficult for surgeons to find other occult pheochromocytomas because the clues of residual tumor (i.e., persistent hypertension after resection and hypertensive response during exploration of the abdomen after tumor removal) are abolished by preoperative preparation. With advancement in anesthesiology and intraoperative monitoring, some surgeons prefer not to prepare patients for operation with an α-adrenergic blocker. The morbidity and mortality seem to be comparable in a major center.662

The operative approach is determined by the location of the tumor(s) as determined by preoperative imaging investigations. For intra-abdominal pheochromocytomas, an anterior approach through a bucket handle or chevron upper abdominal approach is used to permit exploration of both adrenal glands and a thorough examination of the retroperitoneum for possible occult extra-adrenal pheochromocytomas with the least amount of manipulation.555,556,565,628,661,663,664 For MEN-2 patients, bilateral disease is common. Bilateral total adrenalectomy is associated with a lifelong requirement to manage adrenal insufficiency. In addition, malignant pheochromocytoma is very rare in MEN-2. Therefore, unilateral or bilateral subtotal resection with preservation of adrenocortical function can be considered in this population. For the control of hypertension intraoperatively, the rapidly acting direct vasodilating agent, sodium nitroprusside, nitroglycerin, phentolamine, nicardipine, or labetalol may be used intravenously as a drip when the systolic blood pressure exceeds 160 mm of Hg. The rate of infusion can be readily titrated to maintain the pressure at this level or lower. For cardiac arrhythmia or tachycardia, short-acting esmolol or lidocaine is preferred. After the removal of the tumor, there may be an increase in the intravascular capacity and an acute fall in blood pressure that is best managed by intravenous fluid replacement rather than vasopressor drugs.566,663,665 Rarely, if the patient has been well prepared, an intravenous infusion of norepinephrine may be required while volume is being restored. Transient hypoglycemia can occur after surgery because of increased insulin secretion secondary to high circulating catecholamines. Blood sugar should be monitored postoperatively.

During operative manipulation of a pheochromocytoma, great care and gentleness are required not only to avoid episodes of severe hypertension but to avoid disruption of the tumor capsule. Malignancy cannot be determined either by the gross appearance or by histopathologic studies of the primary tumor in most cases. Some patients with proven malignant pheochromoctyoma as determined by bone, liver, or lung metastases have had well-encapsulated tumors without evidence of invasion or lymph node involvement. Capsular disruption by application of instruments or rough handling can result in implantation of tumor cells even when the neoplasm is considered benign.

Most patients become normotensive after resection of pheochromocytoma but some remain hypertensive. Urinary or plasma catecholamines or metabolites should be checked 2 weeks after surgery. If test results are normal, these patients may have concurrent essential hypertension. Otherwise, residual tumors are likely to be present.618 The median time for recurrence following primary resection of malignant pheochromocytoma is approximately 6 years and may be as long as 20 years.557,562,572,597 The lack of discriminating features of malignancy makes lifetime follow-up necessary for all patients.577 The follow-up consists of clinical and biochemical assessment several times during the first year and then a yearly test of urine catecholamines.556,557,567,572,577,628,660,666 Patients with extra-adrenal primaries or non-diploid tumors may require more frequent follow-up with urine catecholamines and perhaps an MIBG scan.552

Pheochromocytoma during pregnancy requires special considerations.667,668 In general, if diagnosed in the first or second trimester, surgical removal of the tumor is indicated following medical preoperative preparation. If diagnosed in the third trimester, medical management is indicated, combined with cesarean delivery of the mature fetus.

Medical Treatment of Recurrent or Metastatic Disease

The diagnosis of malignant pheochromocytoma can be made only when the tumor is locally invasive and unresectable, recurs after primary extirpation, or is found to be metastatic. Although the natural history of the disease in each of these situations may be variable and somewhat unpredictable, advanced malignant pheochromocytoma is associated with a high morbidity and mortality.547,555,562,573,578,661,669 These cancers also secrete catecholamines and often produce biogenic amines at a level much higher than benign neoplasms. Thus, the blood pressure elevations, cardiac effects, decreased bowel motility, and other clinical complications of catecholamine excess may be severe and unrelenting. The management of these problems uses the same principles of pharmacologic adrenergic blockade and inhibition of catecholamine synthesis described previously.

The rarity and highly variable natural history of malignant pheochromocytoma preclude determining accurate survival estimates. Analysis of SEER data demonstrated a 5-year relative survival rate of 52% with a median survival time of 4 years (SD Averbuch, unpublished observation).579 Three retrospective analyses with a long duration of patient follow-up reported a 5-year survival rate of 60, 32, and 44%, respectively.562,573,574 A recent series of 22 patients treated at the National Institutes of Health and the Mount Sinai Medical Center had a 5-year survival rate of 66% with a median survival time of 74 months from the time of initial diagnosis of pheochromocytoma (Fig. 85.15) (SD Averbuch, unpublished observation). All of these studies demonstrate that a significant number of patients with disseminated disease may live for long periods without specific antineoplastic therapy.552,670 Overall, it appears that there are two distinct subsets within the population of patients with malignant pheochromocytoma: a group with aggressive disease that leads to early death (within 3 or 4 years) and a group with indolent disease that is compatible with long-term survival (up to 20 or more years) (see Fig. 85.15).555,562

From the Mayo Clinic series, it appears that survival has not changed over the past several decades despite advances in diagnosis, localization, and pharmacotherapy of catecholamine excess).555,562 Surgical debulking of malignant pheochromocytomas that cannot be completely extirpated is controversial and carries a certain operative risk without clear benefit.552,566,660,661 The results of standard external-beam radiation therapy for malignant pheochromocytoma have been limited to reports from a small series of selected patients treated with a variety of techniques (Table 85.15).598,661,671 In general, these data do not support the use of this modality except for palliation of painful bony metastases or spinal cord compression.

Table 85.15. Treatment of Malignant Pheochromocytoma.

Table 85.15

Treatment of Malignant Pheochromocytoma.

Targeted radiotherapy using high specific activity MIBG has been extensively investigated at the University of Michigan.566 Because of the specificity of MIBG uptake by chromaffin tumors, this novel therapeutic approach initially generated much interest; in practice, it was found that the majority of patients with malignant pheochromocytoma do not take up and retain sufficient MIBG to deliver an effective radiation dose to the tumor.552,672,673 In their initial 63 patients screened with a tracer dose of MIBG, only 18 had sufficient uptake to permit therapeutic dosing, that is, where between 100 and 250 mCi of MIBG will deliver 20 Gy to the tumor.642 Of a total of 28 patients treated by the Michigan group, 8 patients had tumor and biochemical responses, with most responses requiring several months and repeated dosing to become manifest. The duration of benefit has been short.566,641 Other investigators have reported similar results in highly selected patients (see Table 85.15).640,674–678 The cause of the insufficient uptake of MIBG for therapy by malignant chromaffin neoplasms is not fully understood, but it may be due to the fact that these neoplasms may have a less differentiated amine uptake and storage phenotype compared to benign and normal chromaffin cells.629 Methods for accurate calculation of absorbed radiation dose are under development,679 and experimental models may provide new approaches to modulating tumor cell uptake of MIBG;680 but until such time as this and other difficulties are overcome, high-dose MIBG for the treatment of pheochromocytoma has little clinical utility.

Until 1985, the data regarding standard systemic chemotherapy were limited to reports of empirically chosen single agents or combinations in small retrospective series and in anecdotal cases.598,661 Because of its activity against gastroenteropancreatic tumors, streptozotocin was given to patients with metastatic pheochromocytoma with documented responses in some681 but not others (see Table 85.15).682 Based on the premise that malignant pheochromocytoma and neuroblastoma are two APUD neoplasms that have many clinicopathologic features in common,629,683 a regimen highly effective in children with advanced neuroblastoma,672,684 was adapted for use in malignant pheochromocytoma. This regimen, a combination of cyclophosphamide, vincristine, and dacarbazine (CVD), was used in treatment of 23 patients with advanced, progressive, and symptomatic pheochromocytoma at the National Cancer Institute and Mount Sinai Medical Center.547,548 There were 2 (9%) complete and 12 (52%) partial tumor remissions for a median duration of more than 22 months. Improvement in hypertension, reduction in requirement for antihypertensive medication, and improvement in overall performance status correlated well with complete and partial biochemical responses in 17 (74%) of the patients. Toxicity included moderate nausea and vomiting, myelosuppression, and mild neurotoxicity. Some moderate degree of postural hypotension developed that responded promptly to volume replacement therapy.547 Major hemodynamic side effects from chemotherapy were observed in two patients with paroxysmal hypertension. The lack of hypertensive events in most patients is probably due to the fact that patients were prepared with adequate volume repletion and pharmacologic adrenergic blockade prior to initiating chemotherapy. Since hypertensive episodes with release of stored catecholamine have been observed following chemotherapy (SD Averbuch, unpublished observation; de Asis et al.,685; Taub et al.686), patients need to be prepared as if for surgery and require close monitoring during their initial chemotherapy treatment. Patients with paroxysmal hypertension often present with unique problems because they cannot tolerate a full dose of antihypertensives. These antihypertensives lower their baseline blood pressure and worsen their orthostatic hypotension. Two patients in our series developed hypertensive crises and severe ileus after CVD treatment. This problem resolved after optimizing the antihypertensive regimens and adding metyrosine to deplete catecholamine storage.687

The CVD study is the largest prospectively studied chemotherapy series in malignant pheochromocytoma. The results have been confirmed by additional clinical experience.548,671,689 Thus, CVD should be the treatment of choice for symptomatic, disseminated pheochromocytoma. With the introduction of colony-stimulating factors and newer antiemetics, dose escalation of CVD can be explored. Recent experience in neuroblastoma, where CVD has been replaced by the use of new agents and more intensive regimens,689 provides a basis for possible extrapolation to pheochromocytoma in future clinical trials.

There is no information regarding the activity of interferon in malignant pheochromocytoma despite its reported activity in other neuroendocrine tumors.690 The somatostatin analogue octreotide acetate has been reported to produce symptomatic response in patients with endocrine syndromes caused by peptide-secreting pheochromocytomas.585

Multiple Endocrine Neoplasia Syndromes

There are three distinct MEN syndromes and non-MEN familial medullary thyroid carcinoma (Table 85.16) that share two characteristics common to neuroendocrine neoplasms: (1) the tumors comprising MEN syndromes arise from APUD neuroendocrine cells and (2) the syndromes are each inherited as an autosomal dominant trait. This second feature provides for a molecular diagnosis of affected individuals and has led to the recent recognition of specific genetic defects that will enable a fundamental understanding of the pathogenesis of these tumors.

Table 85.16. Multiple Endocrine Neoplasia Syndromes.

Table 85.16

Multiple Endocrine Neoplasia Syndromes.

Multiple Endocrine Neoplasia Type 1


MEN-1 syndrome is quite rare, with an estimated prevalence of between 0.02 and 0.2 per thousand and an incidence of 0.25% as determined from randomly chosen postmortem studies.691–693 However, the importance of this syndrome is related to its autosomal dominant hereditary pattern with high penetrance (Fig. 85.16). Approximately one-third of patients with gastrinomas are associated with MEN-1.694–697 In contrast, insulinomas are usually sporadic, and fewer than 5% are found in MEN-1 patients.698

Figure 85.16. Pedigree of a typical kindred with MEN type 1 (reproduced with permission from Samaan et al.

Figure 85.16

Pedigree of a typical kindred with MEN type 1 (reproduced with permission from Samaan et al.)

Pathologic Characteristics

MEN-1 is characterized by hyperplasia and/or neoplasms of the pituitary, parathyroid, and pancreatic islets. Hyperparathyroidism occurs in 90% of patients, pituitary adenomas in 40% of patients, and endocrine pancreatic tumors in 60% of patients.692,699,700

Although the parathyroid glands are the most frequently involved organs (90%)693 and hyperparathyroidism is usually the first manifestation of the syndrome, its presence may not be detected until clinical disease of the pituitary or pancreas has brought the patient to medical attention. Hyperparathyroidism is often found during the second decade of life when screening immediate family members of those with proven MEN-1. In adults first suspected of the MEN-1 syndrome because of manifestations of gastrinoma, hyperparathyroidism is often diagnosed after obtaining serum calcium and parathyroid hormone levels, even though such patients may have had a decade-long history of renal stones.

MEN-1 patients characteristically have multiglandular nodular hyperplasia as the cause of their hyperparathyroidism. Often, the individual gland involvement is variable and is best described as asymmetric hyperplasia, resulting in enlargement of only one or two glands, particularly in younger patients. This disease usually takes a slow but progressive course, and eventually all glands are involved.

The most frequent manifestation of MEN-1 pancreatic involvement is gastrinoma, usually developing during the third or fourth decade of life. With biochemical screening of MEN-1 kindreds, pancreatic abnormalities have been found at a much earlier age and often become the first manifestation of the syndrome.701,702 Gastrinomas in the MEN-1 syndrome are typically small, multiple adenomas of the endocrine pancreas or duodenum703 that produce excess gastrin, causing gastric hyperacidity and multiple peptic ulcerations, classically known as the Zollinger-Ellison syndrome.704 The malignant potential of MEN-1–associated gastrinomas is probably less than sporadic tumors. Additional tumors found are VIPomas, glucagonomas, somatostatinomas, and PPomas.705 In some MEN-1 patients, tumors may develop and even metastasize to lymph nodes or liver with no clinical manifestations whatsoever. In others, more than one clinical functional syndrome may develop in the same patient either synchronously or more often metachronously.

Immunohistochemical studies of the pancreas from MEN-1 patients have shown that most tumors that stain positively for gastrin are in the head, uncinate process, or duodenum.697 Many of the larger tumors in the body or tail of the pancreas in gastrinoma patients stain positively only for hormones such as PP and somatostatin. Furthermore, even though islet-cell dysplasia (nesidioblastosis, hyperplasia, microadenomas) was found in all cases, these cells failed to stain positively for either gastrin or insulin. Therefore, when serum gastrin is elevated, the disease is in a more advanced stage, and at least 50% of patients have metastases already.702 Discrete tumors rather than diffuse islet-cell disease are usually present in patients with clinical syndromes.706,707 The subsequent use of selective venous sampling for gastrin, insulin, or other hormones in MEN-1 patients has supported this thesis.708 It has also become apparent that gastrinomas are most likely to develop in the duodenum in MEN-1 patients.703 These tumors may be multiple and, in some cases, may be associated with pancreatic gastrinomas.

Micro- or macroadenomas of the pituitary gland are commonly detected in MEN-1 patients when biochemical and imaging studies have been performed.691,692 Most tumors are functionally active and secrete prolactin.709 Less frequently, MEN-1 patients may develop tumor-secreting ACTH or growth hormone and present with Cushing’s syndrome or acromegaly. In the MEN-1 patient, it is especially important to establish that the Cushing’s syndrome is pituitary dependent (Cushing’s disease) rather than caused by an adrenal adenoma or the ectopic secretion of ACTH or corticotropin-releasing factor from islet-cell tumors or a bronchial carcinoid tumor.

Patients with MEN-1 syndrome have an increased frequency of both functional and nonfunctional adrenal cortical hyperplasia or adenomas.406,698,710,711 Furthermore, there may be an increased frequency of adrenal cortical carcinoma in MEN-1 patients, although only five cases have been well documented.

Carcinoid tumors have been reported more frequently in MEN-1 patients than would be expected.712 Male patients appear to have a predilection for developing carcinoid tumors within the thymus, whereas bronchial carcinoids occur almost exclusively in women. Gastric carcinoids can develop in MEN-1 patients with Zollinger-Ellison syndrome who are on long-term H2 blocker or omeprazole.713

Biologic Characteristics

The MEN-1 gene locus has been mapped to the long arm of chromosome 11 (11q13).714 By using restriction fragment length polymorphism (RFLPs) and microsatellite polymorphisms from affected kindreds, MEN-1 gene carriers in the family can be identified with a predictive accuracy of 99.5%. When compared with leukocyte DNA, endocrine tumors from MEN-1 patients have LOH at the region of chromosome 11q13.691,713,715–719 The allele lost is always from the normal chromosome belonging to the unaffected parent. This is analogous to the second hit in retinoblastoma. The gene involved in MEN-1, although not identified yet, is most likely a tumor suppressor gene. Adrenal adenomas are exceptions because they do not have LOH at chromosome 11q13. Furthermore, they occur only in patients with pancreatic endocrine tumors. This suggests that adrenal hyperplasia and adenoma are secondary to other endocrine abnormalities.702 Deletion at chromosome 11q13 has also been found in a significant portion of sporadic adenomas of parathyroid gland, pancreas, and pituitary gland.719,720 The gene or genes in this region certainly play an important role in endocrine tumorigenesis, either familial or sporadic. In addition to chromosome 11, other chromosomes and genetic changes may also be involved, such as PRAD 1 in parathyroid adenoma and Gs α- chain gene in pituitary adenoma.719,720

Clinical Features

The clinical features of patients with MEN-1 depend entirely on expression of the natural history of the individual tumor and endocrine hyperfunction. Most patients with MEN-1 pancreatic disease requiring surgical intervention present with a syndrome caused by hypersecretion of a specific hormone such as gastrin, insulin, VIP, or glucagon.699,700 However, in some patients, a tumor may be detected by imaging studies obtained after serum laboratory studies have shown an elevation of one or more hormones such as pancreatic polypeptide or somatostatin. Overall, patients with familial MEN-1 neoplasms have long survival that is significantly better than that for patients with sporadic endocrine pancreatic tumors.699,700

Diagnostic and Screening Tests

A patient presenting with hyperparathyroidism or with hypergastrinemia should be questioned carefully regarding a family history of MEN-1 syndrome.721 In patients without family history, the diagnosis of MEN-1 can be made only by repeated biochemical testing to screen for other endocrine abnormalities. DNA analysis cannot be applied because it requires DNA from at least two affected family members to conclude which allele of the marker is inherited with the MEN-1 gene. But this limitation will no longer exist when the gene is cloned in the future. Once MEN-1 is diagnosed in a proband, all family members should undergo biochemical screening. Because endocrine abnormalities occur at different time points in different carriers, biochemical screening needs to be repeated for many years. Depending on the extensiveness of the screening program, the yield can be quite different. In one program, only 44% of gene carriers are identified at age 20.722 With more extensive screening, 100% of gene carriers can be identified at age 25,723 whereas in known MEN-1 kindreds, genetic screening with RFLPs detects 99.5% of gene carriers at birth.702,722 Only those who carry the mutated allele need to undergo yearly biochemical screening from childhood and continue for life. Peptic ulcer, renal complications, and malignant tumors are the common causes of death in MEN-1 patients.724 Early detection and early treatment of endocrine abnormalities as the result of screening will reduce morbidity and possibly mortality from endocrinopathy.

The biochemical screening program that gives the highest yield includes PTH, albumin-corrected total serum calcium, prolactin, somatomedin C, blood glucose, insulin, proinsulin, gastrin, PP, glucagon, and a meal test with PP and gastrin analysis. Radiologic examination of pituitary gland and upper abdomen can be done once every 3 to 5 years.702 The diagnostic approach to MEN-1 patients is determined by a clinical syndrome or clearly elevated hormone level. Hyperparathyroidism is diagnosed by hypercalcemia with elevated or nonsuppressible PTH value. Pituitary adenomas usually have elevated serum prolactin or somatomedin C. The tumors are best visualized by MRI. Gastrinoma can be confirmed by measurements of basal and stimulated gastric acid output and provocative test with calcium or secretin. Insulinoma can be diagnosed by increased insulin and proinsulin level in the presence of hypoglycemia.

Localization procedures (discussed earlier in this chapter) for pancreatic endocrine tumors in MEN-1 syndrome present a special challenge due to their small size, multiplicity, and tendency to be malignant. However, these procedures are particularly important since complete excision of all tumors and cure are achievable.557,707,725 Sonography, CT scan, and arteriography are successful in less than 50% of patients.726 Endoscopic ultrasound has been shown to be much more sensitive and specific. Tumors as small as 0.5 cm can be identified.727 Calcium and secretin angiography and transhepatic venous sampling can be used for occult tumors not imaged with other modalities.728 123I-Octreotide scan may be helpful.729 Intraoperative ultrasound of the pancreas should be used to locate nonpalpable tumors. Gastrinomas commonly occur in the duodenum, which can elude all imaging studies.730 Intraoperative transduodenal endoscopic illumination may help to identify the tumor during exploration.

Therapeutic Considerations

Generally, the management of patients with MEN-1 is the same as for each sporadic tumor comprising the syndrome. Even when distant metastases are present, systemic chemotherapy is rarely indicated in this syndrome. The elements of the management of patients with MEN-1 may include surgical removal of all four parathyroid glands (transplanting a portion of one of the glands to the forearm), subtotal pancreatectomy (removing as many multifocal tumors as possible in patients with endocrine pancreatic tumors), and medical management of pituitary adenomas with bromocriptine for prolactinomas and octreotide for acromegaly.

The surgical treatment of the MEN-1 syndrome is dependent on the genetic expression in the individual patient. Because components of the syndrome may be metachronous, surgical procedures involving different endocrine organs may be required over a period of many years. Regardless of initial findings, MEN-1 patients must be followed for life for involvement of the pituitary gland, the parathryoid glands, the endocrine pancreas or duodenum, the adrenal glands, the thymus, and the lungs (bronchial carcinoids). Hypercalcemia in MEN-1 is usually subtle and nonaggressive; early intervention is not necessary except in patients with gastrinoma because calcium increases gastrin secretion and worsens peptic ulcer disease. A source of persistent or recurrent disease is an overlooked supernumerary parathyroid gland, which is found most commonly in the upper thymus in 6 to 15%. Because of this, cervical thymectomy is considered an essential component of an adequate neck exploration in the MEN-1 patient.445 A common approach is subtotal parathyroidectomy, which leaves only a small remnant gland in place. Transient hypocalcemia is the desired result of these procedures, and if it does not occur, it usually means that a supernumerary gland has been overlooked and recurrence is likely. If properly performed, oral calcium and vitamin D therapy can usually be tapered and discontinued within weeks. If performed correctly, permanent hypocalcemia should not develop. Although recurrent hypercalcemia may occur in patients after 10 years, successful surgical management is accomplished by trimming the hypertrophied remnant back to 50 mg.731

An alternative treatment, strongly advocated by some authors because of a recurrence rate as high as 40% after subtotal parathyroidectomy, is total parathyroidectomy, cervical thymectomy, forearm muscle autografting, and cryopreservation of parathyroid tissue for possible future need.732,733 This operation requires just as thorough a cervical-mediastinal exploration as in subtotal parathyroidectomy to prevent cervical recurrence. Its advantage is that should recurrence develop from arm graft overgrowth, trimming back the implanted tissue can be performed under a local anesthesia. Its disadvantage is that all patients will require complete replacement therapy (vitamin D and oral calcium) for 3 months or longer, and some may be rendered permanently hypoparathyroid unless a subsequent thawed, cryopreserved transplant is successful. Both of these procedures are currently widely used in managing MEN-1 patients with hyperparathyroidism.

The surgical treatment of MEN-1 pancreatic disease is controversial.706,707,734 One of the major issues centers on the fact that virtually all patients with pancreatic disease have a diffuse islet-cell dysplasia expressed as nesidioblastosis, islet-cell hyperplasia, microadenomatosis, and/or benign or malignant islet-cell tumors. As a result, it can be concluded that a cure of the pancreatic disease can only be achieved by a total pancreatectomy. However, the malignant potential of MEN-1 islet-cell neoplasm is relatively low, and, with current medical therapy, there is little justification for total pancreatectomy either because of hormone hypersecretion or potential malignancy. In contrast, there is accumulating evidence that the majority of duodenal gastrinomas are malignant and lymph node and/or hepatic metastases from them develop in most patients if followed for a long enough period.730,735

By a combination of preoperative localization and thorough exploration of both the pancreas and the duodenum, selected MEN-1 patients with hypergastrinemia can be rendered eugastrinemic, avoiding the necessity for either long-term drug therapy or total gastrectomy.706,707,725 In patients with either insulinomas or gastrinomas, a distal pancreatectomy is performed, in most cases preserving the spleen, followed by a complete exploration of the remaining pancreatic head, uncinate process, and peripancreatic lymph nodes.725 Any tumor found in the head or uncinate process by palpation or intraoperative ultrasound is enucleated. In all patients with gastrinoma, a longitudinal duodenotomy is made, and the mucosa from the pylorus to the third portion is evaginated into the incision and carefully palpated for submucosal tumors, which may be as small as 1 to 2 mm. When present, they are locally excised, as are any lymph nodes in their drainage area.736 Using this approach, we have been able to achieve eugastrinemia in 12 patients with gastrinoma since 1978.725 Of significance is the fact that more than one half have had at least one peripancreatic lymph node involved with metastases, although primary tumors were as small as 2 mm in diameter. Even though some of these patients have subsequently shown a positive response to secretin stimulation, they have not required drug therapy or gastric operations. For patients with persistent, symptomatic hypergastrinemia from unresectable or metastatic gastrinoma, medical therapy with histamine-2 blockers or proton-pump inhibitors is indicated.737

MEN-1 patients with hyperinsulinism usually have had more than one insulin-secreting tumor. However, they are confined to the pancreas, and when all are enucleated or excised (distal pancreatectomy), the syndrome is cured and recurrences appear to be rare. Octreotide may be useful to palliate symptoms resulting from VIPoma, gastrinoma, glucagonoma, and carcinoid.738 Streptozocin plus doxorubicin achieved the best response in patients with unresectable, progressive malignant tumors.739 Symptomatic hepatic-dominant metastases can be palliated with surgical debulking or chemoembolization.740

Prolactinoma should be treated with bromocriptine or other dopamine analogues first. Both prolactin level and tumor size will decrease in most patients. Transphenoidal hypophysectomy is reserved for patients who fail to respond to medical therapy, but surgery is the treatment of choice for GH-secreting adenoma. Octreotide reduces tumor size and circulating GH and somatomedin C levels in a significant portion of patients.741 Cushing’s disease is best treated by transphenoidal hypophysectomy. Radiation, either limited sellar field or stereotaxic, can be used in patients who failed other modalities, but hormone level decreases very slowly, and hypopituitarism is common after conventional radiation.709

Surgical resection is indicated for carcinoid tumors. Unfortunately, the thymic carcinoids have usually been too far advanced when detected to allow for total excision and have been the cause of death in those with this tumor. Periodic mediastinal and chest CT scans should be used routinely in the follow-up of MEN-1 patients.

Multiple Endocrine Neoplasia 2A, 2B, and Non-Men Familial Medullary Thyroid Carcinoma


All three syndromes have autosomal transmission patterns (Fig. 85.17). Children of affected individuals have a 50% chance of inheriting the genetic abnormality with virtually 100% penetrance by biochemical screening, although only 60 to 70% manifest apparent clinical symptoms.693,742 From the German MTC (Medullary Thyroid Cancer) registry, nearly 25% of patients have one of these familial syndromes. Two-thirds have MEN-2a, and the rest have non-MEN familial FMTC or MEN 2b.743 Five to 23% of all pheochromocytoma patients also have a familial disorder,567,743 mostly either VHL disease or MEN-2. The syndromes have been described in virtually all ethnic groups throughout the world, and an appreciation of the genetic inheritance patterns has provided effective screening methods to direct early treatment to reduce morbidity and mortality in affected individuals (see Fig. 85.10).

Figure 85.17. Pedigree of a typical kindred with MEN type 2a.

Figure 85.17

Pedigree of a typical kindred with MEN type 2a. Solid circles, number of pheochromocytomas found at surgery (courtesy of d. Pertsemlidis, Mount Sinai School of Medicine).

Pathologic Characteristics

MEN-2a involves patients with virtually a 100% incidence of C-cell hyperplasia or MTC, a 50% incidence of clinically significant, usually bilateral pheochromocytomas and a 20 to 30% incidence of parathyroid adenomas with associated hyperparathyroidism. This syndrome always involves autosomal dominant transmission. A second syndrome, MEN-2b, as for MEN-2a, has 100% incidence of MTC and frequent pheochromocytomas. In addition, however, they have a characteristic physical appearance at birth or shortly after due to multiple neural defects including mucosal neuromas of the eyelids, lips, and tongue.401,403 These patients also have a marfanoid habitus with hyperflexible joints but no lens or aortic abnormalities. The neural abnormalities also include widespread ganglioneuromatosis of the gastrointestinal tract leading to abnormal gut motility. Thus, even as infants or young children, patients with MEN-2b may have diarrhea or constipation or may present with the clinical picture of megacolon. Patients with MEN-2b seldom have hyperparathyroidism.

The third and most recently defined form of genetic MTC is non-MEN MTC.408 Patients have MTC but no other associated endocrine or neural tissue involvement.

The major differences in the clinical pathology of MTC and pheochromocytomas in the MEN and familial syndromes, as compared to the sporadic forms of these tumors, involve the multifocality of the lesions, the presence of hyperplastic states as precursors to frank tumors, and the different clinical behavior of the tumors in each genetic disease.

Patients diagnosed as having genetic forms of MTC may manifest bilateral C-cell hyperplasia in the thyroid as the sole lesion or in association with frank MTC. Immunostaining of calcitonin is essential in making this diagnosis (see Fig. 85.10) since the hyperplasia may not be apparent on routine histologic examination. Patients diagnosed early may also have multifocal microscopic MTC diagnosed with such immunostaining. C-cell hyperplasia and microscopic MTC are the only stages of this cancer consistently curable by total thyroidectomy.522,744 Similarly, patients with MEN-2a or -2b have a stage of adrenal hyperplasia that precedes development of pheochromocytomas. The clinical significance and management of this early condition is controversial.

Biologic Characteristics

The biologic properties of MTC, pheochromocytoma, and parathyroid neoplasms in the MEN syndromes are similar to those for each of the sporadic forms of these lesions described earlier. The gene for all three diseases has been identified to be RET proto-oncogene at the centromeric region of chromosome 10.607–610 The RET proto-oncogene is a transmembrane tyrosine kinase. Its ligand and substrate have not been identified yet. MEN-2a and non-MEN FMTC have point mutations at one of the five cysteine residues in the extracellular domain. Eighty percent of MEN-2a and 50% of non-MEN FMTC have the mutation at codon 634.745 MEN-2b has point mutation in the intracellular kinase catalytic domain, and most instances involve substitution of threonine for a methionine at codon 918.608 All MEN-2a families studied so far have mutations at the RET proto-oncogene, but a few families with MEN-2b or non-MEN FMTC do not have such mutations.610,746 Some sporadic MTC and, rarely, sporadic pheochromocytoma also have mutations at RET proto-oncogene.608,610 Interestingly, mutations in the extracellular domain of this gene are found in Hirschsprung’s disease. Therefore, RET proto-oncogene may be tightly associated with the growth regulation of neuroendocrine cells. Studies with transgenic mice do suggest that RET proto-oncogene is involved in the embryologic development of the enteric nervous system. Both germline (leukocyte) and tumors from patients with these syndromes contain a normal allele of RET gene. This suggests that the mutations at RET proto-oncogene act in a dominant fashion, which is contrary to the tumor-suppressive genes involved in MEN-1 and retinoblastoma. This is the first example of mutations at an oncogene causing a familial cancer syndrome.747 Besides RET proto-oncogene, LOH at chromosome 1p, 22q, 17p, or 3p is commonly found in MTC and pheochromocytomas associated with MEN-2 and non-MEN FMTC.611,612 Therefore, tumorigenesis in MEN-2 may also follow the model of multi-stage carcinogenesis established in colon cancer.613 It is unknown why different families with the same point mutations can have different clinical manifestation. It may be possible that other genetic changes such as the deletions at chromosomes 1p, 22q, 17p, or 3p contribute to the difference.

Biochemical and Clinical Features

The biochemical features of MTC, pheochromocytomas, and parathyroid neoplasms in the genetic syndromes under discussion are similar to those for the sporadic forms of each of these disorders. There are no distinguishing markers that allow the genetic forms of each neoplasm to be separated from the noninherited types.

Pheochromocytomas develop in 40 to 50% of MEN-2 patients and may arise bilaterally from medullary hyperplasia. Although the adrenal component usually develops at a later age than the thyroid disease, occasionally, it may appear in childhood. The clinical course of pheochromocytomas in MEN-2a and 2b is typically that of benign tumors with peak incidence in the fourth and fifth decades. Malignant pheochromocytomas have been reported only rarely.565,566,577 The ratio of norepinephrine to epinephrine is generally lower in the genetic forms of pheochromocytoma than the sporadic form. In fact, epinephrine can actually be the dominant form in MEN-2a and 2b.628,743 Most commonly, these patients complain of palpitations, anxiety spells, or headache early in their disease. But many patients whose tumors were found by family screening have no symptoms. Hypertension may not be noted until a crisis is induced by an operation or delivery.

Familial MTC occurs at a younger age than sporadic MTC. The peak incidence is in the second and third decades for MEN-2a and non-MEN FMTC, whereas it is in the first and second decades for MEN-2b. But all ages can be affected. The clinical behavior of MTC differs for each of the genetic syndromes under discussion. In MEN-2a, the cancer, although it metastasizes early, often behaves in a relatively indolent fashion. Thus, the survival rates for patients with this syndrome are a bit longer than that for patients with the sporadic form of MTC (Fig. 85.9). Aggressive malignant behavior of MTC occurs in a small subset of patients with MEN-2a. This fact emphasizes the need to excise all tumors at the very early stages of this disease to prevent the consequences of widely metastatic tumor. Cutaneous lichen amyloidosis, a pruritic lichenoid skin lesion of the upper back, often appears before MTC in MEN-2a patients.743

MTC in MEN-2b may be a more aggressive and lethal cancer.406,513 Death from metastatic disease has been reported in young children with this disorder.748 When the physical stigmata of MEN-2b are recognized (e.g., mucosal neuromas), even in infants, surgical intervention for MTC should be undertaken as early as is feasible.

In non-MEN familial MTC, the thyroid neoplasm behaves in its least aggressive manner.408 The cancer generally appears in the fourth to fifth decade rather than in the second decade, as in MEN-2a. Although local metastases may occur frequently, the disease usually follows an indolent course and virtually never results in death of the patient.

Diagnostic and Screening Tests

Patients with clinical MTC have elevated serum calcitonin. Pheochromocytoma can be diagnosed by urinary epinephrine or epinephrine/norepinephrine ratio and various imaging studies. Any patient with either MTC or pheochromocytoma should undergo investigation of the possibility of MEN-2. Their family members should be screened for both tumors. A negative family history is not reliable because 40% of MEN-2a gene carriers never develop apparent clinical disease. This has been demonstrated in a recently published study that 174 patients with MTC were screened for pheochromocytoma; in addition to five cases from known MEN-2 families, another five index cases were found, which led to discovery of five new MEN-2 families.749 Before the era of genetic screening, members of MEN-2a and non-MEN FMTC families began a yearly pentagastrin/calcium stimulation tests before age 5 and continued until age 40 if all tests were normal. The possibility of conversion to positive result after age 35 is less than 5%.743,750 Urinary catecholamine measurement is done for MEN-2a and 2b families.

Patients with the earliest subclinical stages of MTC (premalignant C-cell hyperplasia and/or microscopic carcinoma) usually do not have elevated basal serum levels of calcitonin. However, even patients with C-cell hyperplasia increase calcitonin levels abnormally in response to the secretagogues calcium and/or pentagastrin. Although several regimens for stimulating calcitonin secretion are available, the combination test devised by Wells and colleagues consisting of a 50-second infusion of calcium gluconate (2 mg of elemental calcium/kg) followed by a 10-second bolus of pentagastrin (Peptavalon, Ayerst, 0.5 mg/kg) seems most reliable.530 This procedure results in less false negatives than tests performed with either of the two agents alone, is rapid, and has minimal side effects consisting of only transient warmth, flushing, and nausea. Calcitonin levels, measured at 0, 2, 3.5, and 5 minutes of the test, generally peak at the 2- or 3.5-minute points. Several commercial diagnostic laboratories have standardized calcitonin results for this test in normal individuals. Although normal ranges vary somewhat for different calcitonin assays, in general, normal females do not have a provoked level higher than 29 pg/mL, and the limit for males is 106 pg/mL. It is critical that the physician screening patients for MTC be thoroughly familiar with the performance of a given calcitonin assay in detecting patients with early MTC. The provocative test becomes clearly abnormal at an average age of 8 to 9 in the gene carriers of MEN-2a, and total thyroidectomy should be done. Patients operated at this stage typically have C-cell hyperplasia with/without microscopic MTC. Over 90% are cured. False-positive results do occur in a small number of subjects with normal thyroid glands and in 5% of normal people who have C-cell hyperplasia.744,750,751

Genetic screening with molecular linkage techniques can identify gene carriers with 95 to 99% accuracy. The identification of mutations at RET proto-oncogene has made the clinical calcium pentagastrin challenge technique almost obsolete. Four studies have confirmed that direct analysis of germline leukocyte DNA by polymerase chain reaction amplification, single-strand conformation polymorphism, restriction enzyme digestion or direct DNA sequencing can identify the index case of a new family and every gene carrier in any known family of MEN-2a with 100% accuracy.745,752–754 Furthermore, all thyroid glands removed from gene carriers who have normal pentagastrin stimulation tests contain C-cell hyperplasia. Some even contain microscopic MTC.752,754 The accuracy for MEN-2b and non-MEN FMTC might not be so good because a small number of families do not have the common mutations at the RET proto-oncogene. Because MTC, which is always malignant, has been the major cause of morbidity and mortality, preventive total thyroidectomy is usually done in MEN-2a as soon as gene carrier status is established by biochemical screening in the past. Morbidity from surgery is low, and hormone replacement is easy. The optimal timing for surgery is less certain now because gene carriers can be identified at birth by genetic screening. Probably surgery should not be later than age 6 because a metastatic MTC was reported to develop at this age. Family members of MEN-2a who are not gene carriers by genetic screening do not need to undergo biochemical testing. MTC in MEN-2b occurs in early age and can be more aggressive than in MEN-2a. Total thyroidectomy should be performed as soon as the typical phenotype is recognized, preferably before age 2, even before a calcitonin test is available. The accuracy of screening by direct analysis of RET proto-oncogene for non-MEN FMTC still needs to be confirmed.

Surgical Management

The primary management for the genetic forms of MTC is, as for sporadic disease, total thyroidectomy (see Fig. 85.10).532 The effectiveness of surgical treatment is dependent on the stage at which the disease is first detected and treated. The object is to do surgery before there are any clinical signs of disease. C-cell hyperplasia and microscopic MTC are the only stages consistently curable by thyroidectomy.530,755

Patients with MEN-2 syndromes must be evaluated for possible pheochromocytomas before undergoing thyroidectomy for MCT. Operations for the adrenal disease component, if present, should always take precedence over any neck procedures to avoid a potential catastrophic hypertensive crisis following anesthesia induction.

Once the diagnosis of pheochromocytomas has been established by biochemical testing, noninvasive localization and surgical approaches are conducted as described previously for sporadic pheochromocytomas. MIBG scans are sensitive in detecting both medullary hyperplasia and small pheochromocytomas even when CT scans and biochemical screening have been considered normal. Conversely, an imaging study always reveals an abnormality when biochemical testing is abnormal,752 but CT and MIBG scans are not suitable screening modalities because of the radiation exposure. Although pheochromocytomas in a MEN-2 patient almost always occurs bilaterally (see Fig. 85.17), they often do not occur synchronously. In fact, the contralateral adrenal lesion can develop many years later. Pheochromocytoma is almost always benign in this situation. In addition, hormone replacement after bilateral adrenalectomy is more complicated than that after thyroidectomy. Addisonian crises do occur in these patients. Therefore, the treatment goal for pheochromocytoma should be different from MTC. Even though microscopic hyperplasia is common, surgery probably only needs to be done for patients who have demonstrated excess catecholamine secretion, tumors, or symptoms. Bilateral adrenalectomy should be performed for patients presenting with bilateral disease. But unilateral adrenalectomy can be considered for patients who present with unilateral disease. With yearly biochemical monitoring, the remaining adrenal gland can be removed if necessary before excess catecholamine causes symptoms. Actually, only one-third to one half of the patients who had unilateral adrenalectomy for unilateral disease need second surgery for recurrent pheochromocytoma in the remaining adrenal gland. Another option instead of bilateral adrenalectomy is to perform a cortical sparing subtotal adrenalectomy.754

Total thyroidectomy is essential in patients with the genetic forms of MTC because of the multifocal origins of the tumor in this setting. The operation must be extracapsular, leaving no thyroid tissue or rim of capsule. Embryologically, the C cells are concentrated in the posterior portion of the upper two-thirds of the thyroid lobes. This is the area most frequently left by some surgeons in performing near total thyroidectomy. Any procedure less than a total thyroidectomy is an inadequate operation for this disease, since failure to remove all thyroid tissue inevitably leads to recurrent disease.531,532 This point cannot be overemphasized and is particularly important in children where the disease has an excellent chance of being cured. Some have even recommended 131I scintiscanning following total thyroidectomy and 131I ablation of any detected thyroid remnants. In addition to thyroidectomy, central compartment lymph nodes should be excised as described previously for sporadic MTC. In MEN-2 patients diagnosed by calcitonin testing, there are usually no palpable thyroid abnormalities, and perithyroidal lymph nodes are frequently free of disease. In performing both total thyroidectomy and central compartment lymph node dissection, it is imperative to identify and preserve all parathyroid glands until a decision has been made about which glands should be excised. For patients with involved central compartment lymph nodes, an ipsilateral or bilateral modified neck dissection should be considered. When a modified neck dissection has not been done and the postoperative calcitonin level remains elevated, we perform selective venous sampling for calcitonin. When elevated levels are detected from one or both sides of the neck, a modified neck dissection is then recommended.

Not infrequently, however, young adult patients have liver or bone metastases when initially diagnosed, preventing any curative operative attempts.513 The screening of first-degree family members of those with newly discovered MTC, particularly when bilateral tumors and associated C-cell hyperplasia have been found, has led to earlier diagnosis and treatment of patients at risk during the past 15 years since calcitonin assays have been widely available (see Fig. 85.10). Calcitonin testing has been particularly valuable in MEN-2a family members who lack any of the characteristic features found in MEN-2b individuals. Genetic testing, when available, allows for recognition of MEN-2a family members with the trait in early infancy and eliminates the need for periodic childhood testing as currently done.

Clinical evidence of hyperparathyroidism is present in 20 to 30% of MEN-2a patients, whereas hypercalcemia rarely occurs in MEN-2b patients. Nevertheless, one or two parathyroid glands may be abnormal in MEN-2a patients even when they are normocalcemic preoperatively. The surgical treatment of MEN-2a parathyroid disease usually took place during total thyroidectomy for MTC in the past and does not differ from that of MEN-1 disease. Subtotal parathyroidectomy or total parathyroidectomy and arm muscle autotransplant can be performed for patients who are hypercalcemic.751,753 Recurrence, despite long-term follow-up, rarely, if ever, occurs. Surgical treatment for normocalcemic patients has been controversial. More conservative surgery with removal of enlarged glands can be considered for patients whose family history reveals little hyperparathyroidism. Hyperparathyroidism is very rare after total thyroidectomy for C-cell hyperplasia discovered by screening, even though the parathyroid glands are left in place.750,753

Treatment of Recurrent or Metastatic Disease

The treatment of advanced MTC in a patient with a genetic syndrome is not distinguished from the approach used in sporadic disease. Locally recurrent disease in the neck may be amenable to further surgical management.533 There is little evidence supporting a role for radiation therapy,512 and in patients with progressive, symptomatic advanced disease, only anecdotal reports of combination chemotherapy have appeared.537,541,548 We have treated a patient from the MEN-2a kindred shown in Figure 85.17. This 26-year-old male with advanced MTC metastatic to lung and bones had little palliative benefit from radiation therapy to symptomatic lesions in the thoracic spine and pelvis. Following combination chemotherapy with CVD, the patient had a partial response with complete resolution of pulmonary metastases, improvement of bone pain, and markedly reduced serum calcitonin and CEA for 14 months.548 Subsequently, six sporadic MTC patients were treated with this regimen. Two had partial response and another had stable disease. Response duration ranged from 9 to 29 months.756 Further improvement on this regimen and adjuvant treatment after total thyroidectomy for patients with gross MTC need to be explored.


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© 2000, BC Decker Inc.
Bookshelf ID: NBK20776


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