Chapter 51: Endocrine Tumors of the Gastrointestinal Tract and Pancreas

Gastrointestinal (GI) neuroendocrine tumors (NETs) are tumors derived from the diffuse neuroendocrine system of the GI tract; that system is composed of amine- and acid-producing cells with different hormonal profiles, depending on the site of origin. The tumors historically are divided into GI-NETs (in the GI tract) (also frequently called carcinoid tumors) and pancreatic neuroendocrine tumors (pNETs), although newer pathologic classifications have proposed that they all be classified as GI-NETs. The term GI-NET has been proposed to replace the term carcinoid; however, the term carcinoid is widely used, and many are not familiar with this change. Accordingly, this chapter will use the term GI-NETs (carcinoids). These tumors originally were classified as APUDomas (for amine precursor uptake and decarboxylation), as were pheochromocytomas, melanomas, and medullary thyroid carcinomas, because they share certain cytochemical features as well as various pathologic, biologic, and molecular features (Table 51-1). It was originally proposed that APUDomas had a similar embryonic origin from neural crest cells, but it is now known the peptide-secreting cells are not of neuroectodermal origin. Nevertheless, the concept of APUDomas is useful because these tumors have important similarities as well as some differences (Table 51-1). In this section, the areas of similarity between pNETs and GI-NETs (carcinoids) will be discussed together, and areas in which there are important differences will be discussed separately.

NETs generally are composed of monotonous sheets of small round cells with uniform nuclei, and mitoses are uncommon. They can be identified tentatively on routine histology; however, these tumors are now recognized principally by their histologic staining patterns due to shared cellular proteins. Historically, silver staining was used, and tumors were classified as showing an argentaffin reaction if they took up and reduced silver or as being argyrophilic if they did not reduce it. Currently, immunocytochemical localization of chromogranins (A, B, C), neuron-specific enolase, and synaptophysin, which are all neuroendocrine cell markers, is used (Table 51-1). Chromogranin A is the most widely used.

Ultrastructurally, these tumors possess electron-dense neurosecretory granules and frequently contain small clear vesicles that correspond to synaptic vesicles of neurons. NETs synthesize numerous peptides, growth factors, and bioactive amines that may be ectopically secreted, giving rise to a specific clinical syndrome (Table 51-2). The diagnosis of the specific syndrome requires the clinical features of the disease (Table 51-2) and cannot be made from the immunocytochemistry results alone. The presence or absence of a specific clinical syndrome also cannot be predicted from the immunocytochemistry alone (Table 51-1). Furthermore, pathologists cannot distinguish between benign and malignant NETs unless metastasis or invasion is present.

GI-NETs (carcinoids) frequently are classified according to their anatomic area of origin (i.e., foregut, midgut, hindgut) because tumors with similar areas of origin share functional manifestations, histochemistry, and secretory products (Table 51-3). Foregut tumors generally have a low serotonin (5-HT) content; are argentaffin-negative but argyrophilic; occasionally secrete adrenocorticotropic hormone (ACTH) or 5-hydroxytryptophan (5-HTP), causing an atypical carcinoid syndrome (Fig. 51-1); are often multihormonal; and may metastasize to bone. They uncommonly produce a clinical syndrome due to the secreted products. Midgut carcinoids are argentaffin-positive, have a high serotonin content, most frequently cause the typical carcinoid syndrome when they metastasize (Table 51-3, Fig. 51-1), release serotonin and tachykinins (substance P, neuropeptide K, substance K), rarely secrete 5-HTP or ACTH, and less commonly metastasize to bone. Hindgut carcinoids (rectum, transverse and descending colon) are argentaffin-negative, are often argyrophilic, rarely contain serotonin or cause the carcinoid syndrome (Fig. 51-1, Table 51-3), rarely secrete 5-HTP or ACTH, contain numerous peptides, and may metastasize to bone.

pNETs can be classified into nine well-established specific functional syndromes (Table 51-2), six additional very rare specific functional syndromes (less than five cases described), five possible specific functional syndromes (pNETs secreting calcitonin, neurotensin, pancreatic polypeptide, ghrelin) (Table 51-2), and nonfunctional pNETs. Other functional hormonal syndromes due to nonpancreatic tumors (usually intraabdominal in location) have been described only rarely and are not included in (Table 51-2). These include secretion by intestinal and ovarian tumors of peptide tyrosine tyrosine (PYY), which results in altered motility and constipation, and ovarian tumors secreting renin or aldosterone causing alterations in blood pressure or somatostatin causing diabetes or reactive hypoglycemia. Each of the functional syndromes listed in Table 51-2 is associated with symptoms due to the specific hormone released. In contrast, nonfunctional pNETs release no products that cause a specific clinical syndrome. “Nonfunctional” is a misnomer in the strict sense because those tumors frequently ectopically secrete a number of peptides (pancreatic polypeptide [PP], chromogranin A, ghrelin, neurotensin, α subunits of human chorionic gonadotropin, and neuron-specific enolase); however, they cause no specific clinical syndrome. The symptoms caused by nonfunctional pNETs are entirely due to the tumor per se. pNETs frequently ectopically secrete PP (60–85%), neurotensin (30–67%), calcitonin (30–42%), and to a lesser degree, ghrelin (5–65%). Whereas a few studies have proposed their secretion can cause a specific functional syndrome, most studies support the conclusion that their ectopic secretion is not associated with a specific clinical syndrome, and thus they are listed in Table 51-2 as possible clinical syndromes. Because a large proportion of nonfunctional pNETs (60–90%) secrete PP, these tumors are often referred to as PPomas (Table 51-2).

GI-NETs (carcinoids) can occur in almost any GI tissue (Table 51-3); however, at present, most (70%) have their origin in one of three sites: bronchus, jejunoileum, or colon/rectum. In the past, GI-NET (carcinoids) most frequently were reported in the appendix (i.e., 40%); however, the bronchus/lung, rectum, and small intestine are now the most common sites. Overall, the GI tract is the most common site for these tumors, accounting for 64%, with the respiratory tract a distant second at 28%. Both race and sex can affect the frequency as well as the distribution of GI-NETs (carcinoids). African Americans have a higher incidence of carcinoids. Race is particularly important for rectal carcinoids, which are found in 41% of Asians/Pacific Islanders with NETs compared to 32% of American Indians/Alaskan natives, 26% of African Americans, and 12% of white Americans. Females have a lower incidence of small intestinal and pancreatic carcinoids.

The term pancreatic neuroendocrine or endocrine tumor, although widely used and therefore retained here, is also a misnomer, strictly speaking, because these tumors can occur either almost entirely in the pancreas (insulinomas, glucagonomas, nonfunctional pNETs, pNETs causing hypercalcemia) or at both pancreatic and extrapancreatic sites (gastrinomas, VIPomas [vasoactive intestinal peptide], somatostatinomas, GRFomas [growth hormone–releasing factor]). pNETs are also called islet cell tumors; however, the use of this term is discouraged because it is not established that they originate from the islets, and many can occur at extrapancreatic sites.

Whereas the classification of GI neuroendocrine tumors into foregut, midgut, or hindgut is widely used and generally useful because the NETs within these areas have many similarities, they also have marked differences, particularly in biologic behavior, and it has not proved useful for prognostic purposes. More general classifications have been developed that allow NETs with similar features in different locations to be compared, have proven prognostic value, and are widely used. New classification systems have been developed for both GI-NETs (carcinoids) and pNETs by the World Health Organization (WHO), European Neuroendocrine Tumor Society (ENETS), and the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC). Although there are some differences between these different classification systems, each uses similar information, and it is now recommended that the basic data underlying the classification be included in all standard pathology reports. These classification systems divide NETs from all sites into those that are well differentiated (low grade [G1] or intermediate grade [G2]) and those that are poorly differentiated (high grade [G3] divided into either small-cell carcinoma or large-cell neuroendocrine carcinoma). In these classification systems, both pNETs and GI-NETs (carcinoids) are classified as neuroendocrine tumors, and the old term of carcinoid is equivalent to well-differentiated neuroendocrine tumors of the GI tract. These classification systems are based on not only the differentiation of the NET, but also a grading system assessing proliferative indices (Ki-67 and the mitotic count). NETs are considered low grade (ENETS G1) if the Ki-67 is <3% and the mitotic count is <2 mitoses/high-power field (HPF), intermediate grade (ENETS G2) if the Ki-67 is 3–20% and the mitotic count is 2–20 mitoses/HPF, and high grade (ENETS G3) if the Ki-67 is >20% and the mitotic count is >20 mitoses/HPF. In addition to the grading system, a TNM classification has been proposed that is based on the level of tumor invasion, tumor size, and tumor extent (see Table 51-4 for an example with pNETs and appendiceal GI-NETs [carcinoids]). Because of the proven prognostic value of these classification and grading systems, as well as the fact that NETs with different classifications/grades respond differently to treatments, the systems are now essential for the management of all NETs.

In addition to these classification/grading systems, a number of other factors have been identified that provide important prognostic information that can guide treatment (Table 51-5).

The exact incidence of GI-NETs (carcinoids) or pNETs varies according to whether only symptomatic tumors or all tumors are considered. The incidence of clinically significant carcinoids is 7–13 cases/million population per year, whereas any malignant carcinoids at autopsy are reported in 21–84 cases/million population per year. The incidence of GI-NETs (carcinoids) is approximately 25–50 cases per million in the United States, which makes them less common than adenocarcinomas of the GI tract. However, their incidence has increased sixfold in the last 30 years. In an analysis of 35,825 GI-NETs (carcinoids) (2004) from the U.S. Surveillance, Epidemiology, and End Results (SEER) database, their incidence was 5.25/100,000 per year, and the 29-year prevalence was 35/100,000. Clinically significant pNETs have a prevalence of 10 cases/million population, with insulinomas, gastrinomas, and nonfunctional pNETs having an incidence of 0.5–2 cases/million population per year (Table  51-2). pNETs account for 1–10% of all tumors arising in the pancreas and 1.3% of tumors in the SEER database, which consists primarily of malignant tumors. VIPomas are 2–8 times less common, glucagonomas are 17–30 times less common, and somatostatinomas are the least common. In autopsy studies, 0.5–1.5% of all cases have a pNET; however, in less than 1 in 1000 cases was a functional tumor thought to occur.

Both GI-NETs (carcinoids) and pNETs commonly show malignant behavior (Tables 51-2 and 51-3). With pNETs, except for insulinomas in which <10% are malignant, 50–100% in different series are malignant. With GI-NETs (carcinoids), the percentage showing malignant behavior varies in different locations (Table 51-3). For the three most common sites of occurrence, the incidence of metastases varies greatly from the jejunoileum (58%), lung/bronchus (6%), and rectum (4%) (Table 51-3). With both GI-NETs (carcinoids) and pNETs, a number of factors (Table 51-5) are important prognostic factors in determining survival and the aggressiveness of the tumor. Patients with pNETs (excluding insulinomas) generally have a poorer prognosis than do patients with GI-NETs (carcinoids). The presence of liver metastases is the single most important prognostic factor in single and multivariate analyses for both GI-NETs (carcinoids) and pNETs. Particularly important in the development of liver metastases is the size of the primary tumor. For example, with small intestinal carcinoids, which are the most common cause of the carcinoid syndrome due to metastatic disease in the liver (Table 51-2), metastases occur in 15–25% if the tumor is <1 cm in diameter, 58–80% if it is 1–2 cm in diameter, and >75% if it is >2 cm in diameter. Similar data exist for gastrinomas and other pNETs; the size of the primary tumor is an independent predictor of the development of liver metastases. The presence of lymph node metastases or extrahepatic metastases; the depth of invasion; the rapid rate of growth; various histologic features (differentiation, mitotic rates, growth indices, vessel density, vascular endothelial growth factor [VEGF], and CD10 metalloproteinase expression); necrosis; presence of cytokeratin; elevated serum alkaline phosphatase levels; older age; presence of circulating tumor cells; and flow cytometric results, such as the presence of aneuploidy, are all important prognostic factors for the development of metastatic disease (Table 51-5). For patients with GI-NETs (carcinoids), additional associations with a worse prognosis include the development of the carcinoid syndrome (especially the development of carcinoid heart disease), male sex, the presence of a symptomatic tumor or greater increases in a number of tumor markers (5-hydroxyindolacetic acid [5-HIAA], neuropeptide K, chromogranin A), and the presence of various molecular features. With pNETs or gastrinomas, a worse prognosis is associated with female sex, overexpression of the Ha-ras oncogene or p53, the absence of multiple endocrine neoplasia type 1 (MEN 1), higher levels of various tumor markers (i.e., chromogranin A, gastrin), and presence of various histologic features (immunohistochemistry for c-KIT, low cyclin B1, loss of PTEN/TSC-2, expression of fibroblast growth factor-13) and various molecular features (Table 51-5). The TNM classification systems and the grading systems (G1–G3) have important prognostic value.

A number of diseases due to various genetic disorders are associated with an increased incidence of NETs (Table 51-6). Each one is caused by a loss of a possible tumor-suppressor gene. The most important is MEN 1, which is an autosomal dominant disorder due to a defect in a 10-exon gene on 11q13, which encodes for a 610-amino-acid nuclear protein, menin (Chap. 52). Patients with MEN 1 develop hyperparathyroidism due to parathyroid hyperplasia in 95–100% of cases, pNETs in 80–100%, pituitary adenomas in 54–80%, adrenal adenomas in 27–36%, bronchial carcinoids in 8%, thymic carcinoids in 8%, gastric carcinoids in 13–30% of patients with Zollinger-Ellison syndrome, skin tumors (angiofibromas [88%], collagenomas [72%]), central nervous system (CNS) tumors (meningiomas [<8%]), and smooth-muscle tumors (leiomyomas, leiomyosarcomas [1–7%]). Among patients with MEN 1, 80–100% develop nonfunctional pNETs (most are microscopic with 0–13% large/symptomatic), and functional pNETs occur in 20–80% in different series, with a mean of 54% developing Zollinger-Ellison syndrome, 18% insulinomas, 3% glucagonomas, 3% VIPomas, and <1% GRFomas or somatostatinomas. MEN 1 is present in 20–25% of all patients with Zollinger-Ellison syndrome, 4% of patients with insulinomas, and a low percentage (<5%) of patients with other pNETs.

Three phacomatoses associated with NETs are von Hippel–Lindau disease (VHL), von Recklinghausen’s disease (neurofibromatosis type 1 [NF-1]), and tuberous sclerosis (Bourneville’s disease) (Table 51-6). VHL is an autosomal dominant disorder due to defects on chromosome 3p25, which encodes for a 213-amino-acid protein that interacts with the elongin family of proteins as a transcriptional regulator (Chaps. 48, 52, and 53). In addition to cerebellar hemangioblastomas, renal cancer, and pheochromocytomas, 10–17% develop a pNET. Most are nonfunctional, although insulinomas and VIPomas have been reported. Patients with NF-1 (von Recklinghausen’s disease) have defects in a gene on chromosome 17q11.2 that encodes for a 2845-amino-acid protein, neurofibromin, which functions in normal cells as a suppressor of the ras signaling cascade (Chap. 48). Up to 10% of these patients develop an upper GI-NET (carcinoid), characteristically in the periampullary region (54%). Many are classified as somatostatinomas because they contain somatostatin immunocytochemically; however, they uncommonly secrete somatostatin and rarely produce a clinical somatostatinoma syndrome. NF-1 has rarely been associated with insulinomas and Zollinger-Ellison syndrome. NF-1 accounts for 48% of all duodenal somatostastinomas and 23% of all ampullary GI-NETs (carcinoids). Tuberous sclerosis is caused by mutations that alter either the 1164-amino-acid protein hamartin (TSC1) or the 1807-amino-acid protein tuberin (TSC2) (Chap. 48). Both hamartin and tuberin interact in a pathway related to phosphatidylinositol 3-kinases and mammalian target of rapamycin (mTOR) signaling cascades. A few cases including nonfunctional and functional pNETs (insulinomas and gastrinomas) have been reported in these patients (Table 51-6). Mahvash disease is associated with the development of α-cell hyperplasia, hyperglucagonemia, and the development of NF pNETs and is due to a homozygous P86S mutation of the human glucagon receptor.

Mutations in common oncogenes (ras, myc, fos, src, jun) or common tumor-suppressor genes (p53, retinoblastoma susceptibility gene) are not commonly found in either pNETs or GI-NETs (carcinoids) (Table 51-1). However, frequent (70%) gene amplifications in MDM2, MDM4, and WIPI inactivating the p53 pathway are noted in well-differentiated pNETs, and the retinoblastoma pathway is altered in the majority of pNETs. In addition to these genes, additional alterations that may be important in their pathogenesis include changes in the MEN1 gene, p16/MTS1 tumor-suppressor gene, and DPC4/Smad4 gene; amplification of the HER-2/neu protooncogene; alterations in transcription factors (Hoxc6 [GI carcinoids]), growth factors, and their receptors; methylation of a number of genes that probably results in their inactivation; and deletions of unknown tumor-suppressor genes as well as gains in other unknown genes (Table 51-1). The clinical antitumor activity of everolimus, an mTOR inhibitor, and sunitinib, a tyrosine kinase inhibitor (PDGFR, VEGFR1, VEGFR2, c-KIT, FLT-3), support the importance of the mTOR-AKT pathway and tyrosine kinase receptors in mediating growth of malignant NETs (especially pNETs). The importance of the mTOR pathway in pNET growth is further supported by the finding that a single-nucleotide polymorphism (FGFR4-G388R, in fibroblast growth factor receptor 4) affects selectivity to the mTOR inhibitor and can result in significantly higher risk of advanced pNET stage and liver metastases (Table 51-5). Comparative genomic hybridization, genome-wide allelotyping studies, and genome-wide single-nucleotide polymorphism analyses have shown that chromosomal losses and gains are common in pNETs and GI-NETs (carcinoids), but they differ between these two NETs, and some have prognostic significance (Table 51-5). Mutations in the MEN1 gene are probably particularly important. Loss of heterozygosity at the MEN 1 locus on chromosome 11q13 is noted in 93% of sporadic pNETs (i.e., in patients without MEN 1) and in 26–75% of sporadic GI-NETs (carcinoids). Mutations in the MEN1 gene are reported in 31–34% of sporadic gastrinomas. Exomic sequencing of sporadic pNETs found that the most frequently altered gene was MEN1, occurring in 44% of patients, followed by mutations in 43% of patients in genes encoding for two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain-associated protein) and ATRX (α-thalassemia/mental retardation syndrome X-linked) and in 15% of patients in the mTOR pathway. The presence of a number of these molecular alterations in pNETs or GI-NETs (carcinoids) correlates with tumor growth, tumor size, and disease extent or invasiveness and may have prognostic significance (Table 51-5).

CHARACTERISTICS OF THE MOST COMMON GI-NETs (CARCINOIDS)

Appendiceal NETs (carcinoids)

Appendiceal NETs (carcinoids) occur in 1 in every 200–300 appendectomies, usually in the appendiceal tip, have an incidence of 0.15/100,000 per year, comprise 2–5% of all GI-NETs (carcinoids), and comprise 32–80% of all appendiceal tumors. Most (i.e., >90%) are <1 cm in diameter without metastases in older studies, but more recently, 2–35% have had metastases (Table 51-3). In the SEER data of 1570 appendiceal carcinoids, 62% were localized, 27% had regional metastases, and 8% had distant metastases. The risk of metastases increases with size, with those <1 cm having a 0 to <10% risk of metastases and those >2 cm having a 25–44% risk. Besides tumor size, other important prognostic factors for metastases include basal location, invasion of mesoappendix, poor differentiation, advanced stage or WHO/ENETS classification, older age, and positive resection margins. The 5-year survival is 88–100% for patients with localized disease, 78–100% for patients with regional involvement, and 12–28% for patients with distal metastases. In patients with tumors <1 cm in diameter, the 5-year survival is 95–100%, whereas it is 29% if tumors are >2 cm in diameter. Most tumors are well-differentiated G1 tumors (87%) (Table 51-4), with the remainder primarily well-differentiated G2 tumors (13%); poorly differentiated G3 tumors are uncommon (<1%). Their percentage of the total number of carcinoids decreased from 43.9% (1950–1969) to 2.4% (1992–1999). Appendiceal goblet cell (GC) NETs (carcinoids)/carcinomas are a rare subtype (<5%) that are mixed adeno-neuroendocrine carcinomas. They are malignant and are thought to comprise a distinct entity; they frequently present with advanced disease and are recommended to be treated as adenocarcinomas, not carcinoid tumors.

Small Intestinal NETs (carcinoids)

Small intestinal (SI) NETs (carcinoids) have a reported incidence of 0.67/100,000 in the United States, 0.32/100,000 in England, and 1.12/100,000 in Sweden and comprise >50% of all SI tumors. There is a male predominance (1.5:1), and race affects frequency, with a lower frequency in Asians and greater frequency in African Americans. The mean age of presentation is 52–63 years, with a wide range (1–93 years). Familial SI carcinoid families exist but are very uncommon. These are frequently multiple; 9–18% occur in the jeunum, 70–80% are present in the ileum, and 70% occur within 6 cm (2.4 in.) of the ileocecal valve. Forty percent are <1 cm in diameter, 32% are 1–2 cm, and 29% are >2 cm. They are characteristically well differentiated; however, they are generally invasive, with 1.2% being intramucosal in location, 27% penetrating the submucosa, and 20% invading the muscularis propria. Metastases occur in a mean of 47–58% (range 20–100%). Liver metastases occur in 38%, to lymph nodes in 37% and more distant in 20–25%. They characteristically cause a marked fibrotic reaction, which can lead to intestinal obstruction. Tumor size is an important variable in the frequency of metastases. However, even small NETs (carcinoids) of the small intestine (<1 cm) have metastases in 15–25% of cases, whereas the proportion increases to 58–100% for tumors 1–2 cm in diameter. Carcinoids also occur in the duodenum, with 31% having metastases. Duodenal tumors <1 cm virtually never metastasize, whereas 33% of those >2 cm had metastases. SI NETs (carcinoids) are the most common cause (60–87%) of the carcinoid syndrome and are discussed in a later section (Table 51-7). Important prognostic factors are listed in (Table 51-5), and particularly important are the tumor extent, proliferative index by grading, and stage (Table 51-4). The overall survival at 5 years is 55–75%; however, it varies markedly with disease extent, being 65–90% with localized disease, 66–72% with regional involvement, and 36–43% with distant disease.

Rectal NETs (carcinoids)

Rectal NETs (carcinoids) comprise 27% of all GI-NETs (carcinoids) and 16% of all NETs and are increasing in frequency. In the U.S. SEER data, they currently have an incidence of 0.86/100,000 per year (up from 0.2/100,000 per year in 1973) and represent 1–2% of all rectal tumors. They are found in approximately 1 in every 1500/2500 proctoscopies/colonoscopies or 0.05–0.07% of individuals undergoing these procedures. Nearly all occur between 4 and 13 cm above the dentate line. Most are small, with 66–80% being <1 cm in diameter, and rarely metastasize (5%). Tumors between 1 and 2 cm can metastasize in 5–30%, and those >2 cm, which are uncommon, in >70%. Most invade only to the submucosa (75%), with 2.1% confined to the mucosa, 10% to the muscular layer, and 5% to adjacent structures. Histologically, most are well differentiated (98%) with 72% ENETS/WHO grade G1 and 28% grade G2 (Table 51-4). Overall survival is 88%; however, it is very much dependent of the stage, with 5-year survival of 91% for localized disease, 36–49% for regional disease, and 20–32% for distant disease. Risk factors are listed in Table 51-5 and particularly include tumor size, depth of invasion, presence of metastases, differentiation, and recent TNM classification and grade.

Bronchial NETs (carcinoids)

Bronchial NETs (carcinoids) comprise 25–33% of all well-differentiated NETs and 90% of all the poorly differentiated NETs found, likely due to a strong association with smoking. Their incidence ranges from 0.2 to 2/100,000 per year in the United States and European countries and is increasing at a rate of 6% per year. They are slightly more frequent in females and in whites compared with those of Hispanic/Asian/African descent, and are most commonly seen in the sixth decade of life, with a younger age of presentation for typical carcinoids (45 years) compared to atypical carcinoids (55 years).

A number of different classifications of bronchial GI-NETs (carcinoids) have been proposed. In some studies, they are classified into four categories: typical carcinoid (also called bronchial carcinoid tumor, Kulchitsky cell carcinoma I [KCC-I]), atypical carcinoid (also called well-differentiated neuroendocrine carcinoma [KC-II]), intermediate small-cell neuroendocrine carcinoma, and small-cell neuroendocarcinoma (KC-III). Another proposed classification includes three categories of lung NETs: benign or low-grade malignant (typical carcinoid), low-grade malignant (atypical carcinoid), and high-grade malignant (poorly differentiated carcinoma of the large-cell or small-cell type). The WHO classification includes four general categories: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma, and small-cell carcinoma. The ratio of typical to atypical carcinoids is 8–10:1, with the typical carcinoids comprising 1–2% of lung tumors, atypical 0.1–0.2%, large-cell neuroendocrine tumors 0.3%, and small-cell lung cancer 9.8% of all lung tumors. These different categories of lung NETs have different prognoses, varying from excellent for typical carcinoid to poor for small-cell neuroendocrine carcinomas. The occurrence of large-cell and small-cell lung carcinoids, but not typical or atypical lung carcinoids, is related to tobacco use. The 5-year survival is very much influenced by the classification of the tumor, with survival of 92–100% for patients with a typical carcinoid, 61–88% with an atypical carcinoid, 13–57% with a large-cell neuroendocrine tumor, and 5% with a small-cell lung cancer.

Gastric NET (carcinoids)

Gastric NETs (carcinoids) account for 3 of every 1000 gastric neoplasms and 1.3–2% of all carcinoids, and their relative frequency has increased three- to fourfold over the last five decades (2.2% in 1950 to 9.6% in 2000–2007, SEER data). At present, it is unclear whether this increase is due to better detection with the increased use of upper GI endoscopy or to a true increase in incidence. Gastric NETs (carcinoids) are classified into three different categories, and this has important implications for pathogenesis, prognosis, and treatment. Each originates from gastric enterochromaffin-like (ECL) cells, one of the six types of gastric neuroendocrine cells, in the gastric mucosa. Two subtypes are associated with hypergastrinemic states, either chronic atrophic gastritis (type I) (80% of all gastric NETs [carcinoids]) or Zollinger-Ellison syndrome, which is almost always a part of the MEN 1 syndrome (type II) (6% of all cases). These tumors generally pursue a benign course, with type I uncommonly (<10%) associated with metastases, whereas type II tumors are slightly more aggressive, with 10–30% associated with metastases. They are usually multiple, small, and infiltrate only to the submucosa. The third subtype of gastric NETs (carcinoids) (type III) (sporadic) occurs without hypergastrinemia (14–25% of all gastric carcinoids) and has an aggressive course, with 54–66% developing metastases. Sporadic carcinoids are usually single, large tumors; 50% have atypical histology, and they can be a cause of the carcinoid syndrome. Five-year survival is 99–100% in patients with type I, 60–90% in patients with type II, and 50% in patients with type III gastric NETs (carcinoids).

CLINICAL PRESENTATION OF NETs (CARCINOIDS)

GI/Lung NET (carcinoid) without the carcinoid syndrome

The age of patients at diagnosis ranges from 10 to 93 years, with a mean age of 63 years for the small intestine and 66 years for the rectum. The presentation is diverse and is related to the site of origin and the extent of malignant spread. In the appendix, NETs (carcinoids) usually are found incidentally during surgery for suspected appendicitis. SI NETs (carcinoids) in the jejunoileum present with periodic abdominal pain (51%), intestinal obstruction with ileus/invagination (31%), an abdominal tumor (17%), or GI bleeding (11%). Because of the vagueness of the symptoms, the diagnosis usually is delayed approximately 2 years from onset of the symptoms, with a range up to 20 years. Duodenal, gastric, and rectal NETs (carcinoids) are most frequently found by chance at endoscopy. The most common symptoms of rectal carcinoids are melena/bleeding (39%), constipation (17%), and diarrhea (12%). Bronchial NETs (carcinoids) frequently are discovered as a lesion on a chest radiograph, and 31% of the patients are asymptomatic. Thymic NETs (carcinoids) present as anterior mediastinal masses, usually on chest radiograph or computed tomography (CT) scan. Ovarian and testicular NETs (carcinoids) usually present as masses discovered on physical examination or ultrasound. Metastatic NETs (carcinoids) in the liver frequently presents as hepatomegaly in a patient who may have minimal symptoms and nearly normal liver function test results.

GI-NETs (CARCINOIDS) WITH SYSTEMIC SYMPTOMS DUE TO SECRETED PRODUCTS

GI/lung NETs (carcinoids) immunocytochemically can contain numerous GI peptides: gastrin, insulin, somatostatin, motilin, neurotensin, tachykinins (substance K, substance P, neuropeptide K), glucagon, gastrin-releasing peptide, vasoactive intestinal peptide (VIP), PP, ghrelin, other biologically active peptides (ACTH, calcitonin, growth hormone), prostaglandins, and bioactive amines (serotonin). These substances may or may not be released in sufficient amounts to cause symptoms. In various studies of patients with GI-NETs (carcinoids), elevated serum levels of PP were found in 43%, motilin in 14%, gastrin in 15%, and VIP in 6%. Foregut NETs (carcinoids) are more likely to produce various GI peptides than are midgut NETs (carcinoids). Ectopic ACTH production causing Cushing’s syndrome is seen increasingly with foregut carcinoids (respiratory tract primarily) and, in some series, has been the most common cause of the ectopic ACTH syndrome, accounting for 64% of all cases. Acromegaly due to growth hormone–releasing factor release occurs with foregut NETs (carcinoids), as does the somatostatinoma syndrome, but rarely occurs with duodenal NETs (carcinoids). The most common systemic syndrome with GI-NETs (carcinoids) is the carcinoid syndrome, which is discussed in detail in the next section.

CARCINOID SYNDROME

Clinical features

The cardinal features from a number of series at presentation as well as during the disease course are shown in Table 51-7. Flushing and diarrhea are the two most common symptoms, occurring in a mean of 69–70% of patients initially and in up to 78% of patients during the course of the disease. The characteristic flush is of sudden onset; it is a deep red or violaceous erythema of the upper body, especially the neck and face, often associated with a feeling of warmth and occasionally associated with pruritus, lacrimation, diarrhea, or facial edema. Flushes may be precipitated by stress; alcohol; exercise; certain foods, such as cheese; or certain agents, such as catecholamines, pentagastrin, and serotonin reuptake inhibitors. Flushing episodes may be brief, lasting 2–5 min, especially initially, or may last hours, especially later in the disease course. Flushing usually is associated with metastatic midgut NETs (carcinoids) but can also occur with foregut NETs (carcinoids). With bronchial NETs (carcinoids), the flushes frequently are prolonged for hours to days, reddish in color, and associated with salivation, lacrimation, diaphoresis, diarrhea, and hypotension. The flush associated with gastric NETs (carcinoids) can also be reddish in color, but with a patchy distribution over the face and neck, although the classic flush seen with midgut NETs (carcinoids) can also be seen with gastric NETs (carcinoids). It may be provoked by food and have accompanying pruritus.

Diarrhea usually occurs with flushing (85% of cases). The diarrhea usually is described as watery, with 60% of patients having <1 L/d of diarrhea. Steatorrhea is present in 67%, and in 46%, it is >15 g/d (normal <7 g). Abdominal pain may be present with the diarrhea or independently in 10–34% of cases.

Cardiac manifestations occur initially in 11–40% (mean 26%) of patients with carcinoid syndrome and in 14–41% (mean 30%) at some time in the disease course. The cardiac disease is due to the formation of fibrotic plaques (composed of smooth-muscle cells, myofibroblasts, and elastic tissue) involving the endocardium, primarily on the right side, although lesions on the left side also occur occasionally, especially if a patent foramen ovale exists. The dense fibrous deposits are most commonly on the ventricular aspect of the tricuspid valve and less commonly on the pulmonary valve cusps. They can result in constriction of the valves, and pulmonic stenosis is usually predominant, whereas the tricuspid valve is often fixed open, resulting in regurgitation predominating. Overall, in patients with carcinoid heart disease, 90–100% have tricuspid insufficiency, 43–59% have tricuspid stenosis, 50–81% have pulmonary insufficiency, 25–59% have pulmonary stenosis, and 11% (0–25%) left-side lesions. Up to 80% of patients with cardiac lesions develop heart failure. Lesions on the left side are much less extensive, occur in 30% at autopsy, and most frequently affect the mitral valve. Up to 80% of patients with cardiac lesions have evidence of heart failure. At diagnosis in various series, 27–43% of patients are in New York Heart Association class I, 30–40% are in class II, 13–31% are in class III, and 3–12% are in class IV. At present, carcinoid heart disease is reported to be decreasing in frequency and severity, with mean occurrence in 20% of patients and occurrence in as few as 3–4% in some reports. Whether this decrease is due to the widespread use of somatostatin analogues, which control the release of bioactive agents thought involved in mediating the heart disease, is unclear.

Other clinical manifestations include wheezing or asthma-like symptoms (8–18%), pellagra-like skin lesions (2–25%), and impaired cognitive function. A variety of noncardiac problems due to increased fibrous tissue have been reported, including retroperitoneal fibrosis causing urethral obstruction, Peyronie’s disease of the penis, intraabdominal fibrosis, and occlusion of the mesenteric arteries or veins.

Pathobiology

Carcinoid syndrome occurred in 8% of 8876 patients with GI-NETs (carcinoids), with a rate of 1.7–18.4% in different studies. It occurs only when sufficient concentrations of products secreted by the tumor reach the systemic circulation. In 91–100% of cases, this occurs after distant metastases to the liver. Rarely, primary GI-NETs (carcinoids) with nodal metastases with extensive retroperitoneal invasion, pNETs (carcinoids) with retroperitoneal lymph nodes, or NETs (carcinoids) of the lung or ovary with direct access to the systemic circulation can cause the carcinoid syndrome without hepatic metastases. All GI-NETs (carcinoids) do not have the same propensity to metastasize and cause the carcinoid syndrome (Table 51-3). Midgut NETs (carcinoids) account for 57–67% of cases of carcinoid syndrome, foregut NETs (carcinoids) for 0–33%, hindgut for 0–8%, and an unknown primary location for 2–26% (Tables 51-3 and 51-7).

One of the main secretory products of GI-NETs (carcinoids) involved in the carcinoid syndrome is serotonin (5-HT) (Fig.  51-1), which is synthesized from tryptophan. Up to 50% of dietary tryptophan can be used in this synthetic pathway by tumor cells, and this can result in inadequate supplies for conversion to niacin; hence, some patients (2.5%) develop pellagra-like lesions. Serotonin has numerous biologic effects, including stimulating intestinal secretion with inhibition of absorption, stimulating increases in intestinal motility, and stimulating fibrogenesis. In various studies, 56–88% of all GI-NETs (carcinoids) were associated with serotonin overproduction; however, 12–26% of the patients did not have the carcinoid syndrome. In one study, platelet serotonin was elevated in 96% of patients with midgut NETs (carcinoids), 43% with foregut tumors, and 0% with hindgut tumors. In 90–100% of patients with the carcinoid syndrome, there is evidence of serotonin overproduction. Serotonin is thought to be predominantly responsible for the diarrhea. Patients with the carcinoid syndrome have increased colonic motility with a shortened transit time and possibly a secretory/absorptive alteration that is compatible with the known actions of serotonin in the gut mediated primarily through 5-HT₃ and, to a lesser degree, 5-HT₄ receptors. Serotonin receptor antagonists (especially 5-HT₃ antagonists) relieve the diarrhea in many, but not all, patients. A tryptophan 5-hydroxylase inhibitor, LX-1031, which inhibits serotonin synthesis in peripheral tissues, is reported to cause a 44% decrease in bowel movement frequency and a 20% improvement in stool form in patients with the carcinoid syndrome. Additional studies suggest that tachykinins may be important mediators of diarrhea in some patients. In one study, plasma tachykinin levels correlated with symptoms of diarrhea. Serotonin does not appear to be involved in the flushing because serotonin receptor antagonists do not relieve flushing. In patients with gastric carcinoids, the characteristic red, patchy pruritic flush is thought due to histamine release because H₁ and H₂ receptor antagonists can prevent it. Numerous studies have shown that tachykinins (substance P, neuropeptide K) are stored in GI-NETs (carcinoids) and released during flushing. However, some studies have demonstrated that octreotide can relieve the flushing induced by pentagastrin in these patients without altering the stimulated increase in plasma substance P, suggesting that other mediators must be involved in the flushing. A correlation between plasma tachykinin levels (but not substance P levels) and flushing has been reported. Prostaglandin release could be involved in mediating either the diarrhea or flush, but conflicting data exist. Both histamine and serotonin may be responsible for the wheezing as well as the fibrotic reactions involving the heart, causing Peyronie’s disease and intraabdominal fibrosis.

The exact mechanism of the heart disease remains unclear, although increasing evidence supports a central role for serotonin. Patients with heart disease have higher plasma levels of neurokinin A, substance P, plasma atrial natriuretic peptide (ANP), pro-brain natriuretic peptide, chromogranin A, and activin A as well as higher urinary 5-HIAA excretion.

The valvular heart disease caused by the appetite-suppressant drug dexfenfluramine is histologically indistinguishable from that observed in carcinoid disease. Furthermore, ergot-containing dopamine receptor agonists used for Parkinson’s disease (pergolide, cabergoline) cause valvular heart disease that closely resembles that seen in the carcinoid syndrome. Furthermore, in animal studies, the formation of valvular plaques/fibrosis occurs after prolonged treatment with serotonin as well as in animals with a deficiency of the 5-HIAA transporter gene, which results in an inability to inactivate serotonin. Metabolites of fenfluramine, as well as the dopamine receptor agonists, have high affinity for serotonin receptor subtype 5-HT_2B receptors, whose activation is known to cause fibroblast mitogenesis. Serotonin receptor subtypes 5-HT_1B,1D,2A,2B normally are expressed in human heart valve interstitial cells. High levels of 5-HT_2B receptors are known to occur in heart valves and occur in cardiac fibroblasts and cardiomyocytes. Studies of cultured interstitial cells from human cardiac valves have demonstrated that these valvulopathic drugs induce mitogenesis by activating 5-HT_2B receptors and stimulating upregulation of transforming growth factor β and collagen biosynthesis. These observations support the conclusion that serotonin overproduction by GI-NETs (carcinoids) is important in mediating the valvular changes, possibly by activating 5-HT_2B receptors in the endocardium. Both the magnitude of serotonin overproduction and prior chemotherapy are important predictors of progression of the heart disease, whereas patients with high plasma levels of ANP have a worse prognosis. Plasma connective tissue growth factor levels are elevated in many fibrotic conditions; elevated levels occur in patients with carcinoid heart disease and correlate with the presence of right ventricular dysfunction and the extent of valvular regurgitation in patients with GI-NETs (carcinoids).

Patients may develop either a typical or, rarely, an atypical carcinoid syndrome (Fig. 51-1). In patients with the typical form, which characteristically is caused by midgut NETs (carcinoids), the conversion of tryptophan to 5-HTP is the rate-limiting step (Fig. 51-1). Once 5-HTP is formed, it is rapidly converted to 5-HT and stored in secretory granules of the tumor or in platelets. A small amount remains in plasma and is converted to 5-HIAA, which appears in large amounts in the urine. These patients have an expanded serotonin pool size, increased blood and platelet serotonin, and increased urinary 5-HIAA. Some GI-NETs (carcinoids) cause an atypical carcinoid syndrome that is thought to be due to a deficiency in the enzyme dopa decarboxylase; thus, 5-HTP cannot be converted to 5-HT (serotonin), and 5-HTP is secreted into the bloodstream (Fig. 51-1). In these patients, plasma serotonin levels are normal but urinary levels may be increased because some 5-HTP is converted to 5-HT in the kidney. Characteristically, urinary 5-HTP and 5-HT are increased, but urinary 5-HIAA levels are only slightly elevated. Foregut carcinoids are the most likely to cause an atypical carcinoid syndrome; however, they also can cause a typical carcinoid syndrome.

One of the most immediate life-threatening complications of the carcinoid syndrome is the development of a carcinoid crisis. This is more common in patients who have intense symptoms or have greatly increased urinary 5-HIAA levels (i.e., >200 mg/d). The crisis may occur spontaneously; however, it is usually provoked by procedures such as anesthesia, chemotherapy, surgery, biopsy, endoscopy, or radiologic examinations such as during biopsies, hepatic artery embolization, and vessel catheterization. It can be provoked by stress or procedures as mild as repeated palpation of the tumor during physical examination. Patients develop intense flushing, diarrhea, abdominal pain, cardiac abnormalities including tachycardia, hypertension, or hypotension, and confusion or stupor. If not adequately treated, this can be a terminal event.

DIAGNOSIS OF THE CARCINOID SYNDROME AND GI-NETs (CARCINOIDS)

The diagnosis of carcinoid syndrome relies on measurement of urinary or plasma serotonin or its metabolites in the urine. The measurement of 5-HIAA is used most frequently. False-positive elevations may occur if the patient is eating serotonin-rich foods such as bananas, pineapples, walnuts, pecans, avocados, or hickory nuts or is taking certain medications (cough syrup containing guaifenesin, acetaminophen, salicylates, serotonin reuptake inhibitors, or l-dopa). The normal range for daily urinary 5-HIAA excretion is 2–8 mg/d. Serotonin overproduction was noted in 92% of patients with carcinoid syndrome in one study, and in another study, 5-HIAA had 73% sensitivity and 100% specificity for carcinoid syndrome. Serotonin overproduction is not synonymous with the presence of clinical carcinoid syndrome because 12–26% of patients with serotonin overproduction do not have clinical evidence of the carcinoid syndrome.

Most physicians use only the urinary 5-HIAA excretion rate; however, plasma and platelet serotonin levels, if available, may provide additional information. Platelet serotonin levels are more sensitive than urinary 5-HIAA but are not generally available. A single plasma 5-HIAA determination was found to correlate with the 24-h urinary values, raising the possibility that this could replace the standard urinary collection because of its greater convenience and avoidance of incomplete or improper collections. Because patients with foregut NETs (carcinoids) may produce an atypical carcinoid syndrome, if this syndrome is suspected and the urinary 5-HIAA is minimally elevated or normal, other urinary metabolites of tryptophan, such as 5-HTP and 5-HT, should be measured (Fig. 51-1).

Flushing occurs in a number of other diseases, including systemic mastocytosis, chronic myeloid leukemia with increased histamine release, menopause, reactions to alcohol or glutamate, and side effects of chlorpropamide, calcium channel blockers, and nicotinic acid. None of these conditions cause increased urinary 5-HIAA.

The diagnosis of carcinoid tumor can be suggested by the carcinoid syndrome, recurrent abdominal symptoms in a healthy-appearing individual, or the discovery of hepatomegaly or hepatic metastases associated with minimal symptoms. Ileal NETs (carcinoids), which make up 25% of all clinically detected carcinoids, should be suspected in patients with bowel obstruction, abdominal pain, flushing, or diarrhea.

Serum chromogranin A levels are elevated in 56–100% of patients with GI-NETs (carcinoids), and the level correlates with tumor bulk. Serum chromogranin A levels are not specific for GI-NETs (carcinoids) because they are also elevated in patients with pNETs and other NETs. Furthermore, a major problem is caused by potent acid antisecretory drugs such as proton pump inhibitors (omeprazole and related drugs) because they almost invariably cause elevation of plasma chromogranin A levels; the elevation occurs rapidly (3–5 days) with continued use, and the elevated levels overlap with the levels seen in many patients with NETs. Plasma neuron-specific enolase levels are also used as a marker of GI-NETs (carcinoids) but are less sensitive than chromogranin A, being increased in only 17–47% of patients. Newer markers have been proposed including pancreastatin (a chromogranin A breakdown product) and activin A. The former is not affected by proton pump inhibitors; however, its sensitivity and specificity are not established. Plasma activin elevations are reported to correlate with the presence of cardiac disease with a sensitivity of 87% and specificity of 57%.

TREATMENT

Functional pNETs usually present clinically with symptoms due to the hormone-excess state (Table 51-2). Only late in the course of the disease does the tumor per se cause prominent symptoms such as abdominal pain. In contrast, all the symptoms due to nonfunctional pNETs are due to the tumor per se. The overall result of this is that some functional pNETs may present with severe symptoms with a small or undetectable primary tumor, whereas nonfunctional tumors usually present late in the disease course with large tumors, which are frequently metastatic. The mean delay between onset of continuous symptoms and diagnosis of a functional pNET syndrome is 4–7 years. Therefore, the diagnoses frequently are missed for extended periods.

TREATMENT

GASTRINOMA (ZOLLINGER-ELLISON SYNDROME)

A gastrinoma is an NET that secretes gastrin; the resultant hypergastrinemia causes gastric acid hypersecretion (Zollinger-Ellison syndrome [ZES]). The chronic hypergastrinemia results in marked gastric acid hypersecretion and growth of the gastric mucosa with increased numbers of parietal cells and proliferation of gastric ECL cells. The gastric acid hypersecretion characteristically causes peptic ulcer disease (PUD), often refractory and severe, as well as diarrhea. The most common presenting symptoms are abdominal pain (70-100%), diarrhea (37-73%), and gastroesophageal reflux disease (GERD) (30-35%); 10-20% of patients have diarrhea only. Although peptic ulcers may occur in unusual locations, most patients have a typical duodenal ulcer. Important observations that should suggest this diagnosis include PUD with diarrhea; PUD in an unusual location or with multiple ulcers; PUD refractory to treatment or persistent; PUD associated with prominent gastric folds; PUD associated with findings suggestive of MEN 1 (endocrinopathy, family history of ulcer or endocrinopathy, nephrolithiases); and PUD without Helicobacter pylori present. H. pylori is present in >90% of idiopathic peptic ulcers but is present in <50% of patients with gastrinomas. Chronic unexplained diarrhea also should suggest ZES.

Approximately 20-25% of patients with ZES have MEN 1 (MEN1/ZES), and in most cases, hyperparathyroidism is present before the ZES develops. These patients are treated differently from those without MEN 1 (sporadic ZES); therefore, MEN 1 should be sought in all patients with ZES by family history and by measuring plasma ionized calcium and prolactin levels and plasma hormone levels (parathormone, growth hormone).

Most gastrinomas (50–90%) in sporadic ZES are present in the duodenum, followed by the pancreas (10–40%) and other intraabdominal sites (mesentery, lymph nodes, biliary tract, liver, stomach, ovary). Rarely, the tumor may involve extraabdominal sites (heart, lung cancer). In MEN 1/ZES the gastrinomas are also usually in the duodenum (70–90%), followed by the pancreas (10–30%), and are almost always multiple. About 60–90% of gastrinomas are malignant (Table 51-2) with metastatic spread to lymph nodes and liver. Distant metastases to bone occur in 12–30% of patients with liver metastases.

Diagnosis

The diagnosis of ZES requires the demonstration of inappropriate fasting hypergastrinemia, usually by demonstrating hypergastrinemia occurring with an increased basal gastric acid output (BAO) (hyperchlorhydria). More than 98% of patients with ZES have fasting hypergastrinemia, although in 40–60% the level may be elevated less than tenfold. Therefore, when the diagnosis is suspected, a fasting gastrin is usually the initial test performed. It is important to remember that potent gastric acid suppressant drugs such as proton pump inhibitors (PPIs) (omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole) can suppress acid secretion sufficiently to cause hypergastrinemia; because of their prolonged duration of action, these drugs have to be tapered or frequently discontinued for a week before the gastrin determination. Withdrawal of PPIs should be performed carefully because PUD complications can rapidly develop in some patients and is best done in consultation with GI units with experience in this area. The widespread use of PPIs can confound the diagnosis of ZES by raising a false-positive diagnosis by causing hypergastrinemia in a patient being treated with idiopathic PUD (without ZES) and lead to a false-negative diagnosis because at routine doses used to treat patients with idiopathic PUD, PPIs control symptoms in most ZES patients and thus mask the diagnosis. If ZES is suspected and the gastrin level is elevated, it is important to show that it is increased when gastric pH is ≤2.0 because physiologically hypergastrinemia secondary to achlorhydria (atrophic gastritis, pernicious anemia) is one of the most common causes of hypergastrinemia. Nearly all ZES patients have a fasting pH ≤2 when off antisecretory drugs. If the fasting gastrin is >1000 pg/mL (increased tenfold) and the pH is ≤2.0, which occurs in 40–60% of patients with ZES, the diagnosis of ZES is established after the possibility of retained antrum syndrome has been ruled out by history. In patients with hypergastrinemia with fasting gastrins <1000 pg/mL (<10-fold increased) and gastric pH ≤2.0, other conditions, such as H. pylori infections, antral G-cell hyperplasia/hyperfunction, gastric outlet obstruction, and, rarely, renal failure, can masquerade as ZES. To establish the diagnosis in this group, a determination of BAO and a secretin provocative test should be done. In patients with ZES without previous gastric acid–reducing surgery, the BAO is usually (>90%) elevated (i.e., >15 mEq/h). The secretin provocative test is usually positive, with the criterion of a >120-pg/mL increase over the basal level having the highest sensitivity (94%) and specificity (100%). Unfortunately the diagnosis of ZES is becoming increasing more difficult. This is due not only to the widespread use of PPIs (leading to false-positive results as well as masking ZES presentation), but also recent studies demonstrate than many of the commercial gastrin kits that are used by most laboratories to measure fasting serum gastrin levels are not reliable. In one study, 7 of the 12 tested commercial gastrin kits inaccurately assessed the true serum concentration of gastrin primarily because the antibodies used had inappropriate specificity for the different circulating forms of gastrin and were not adequately validated. Both underestimation and overestimation of fasting serum gastrin levels occurred using these commercial kits. To circumvent this problem, it is either necessary to use one of the five reliable kits identified or, alternatively, to refer the patient to a center with expertise in making the diagnosis in your area, or if this is not possible, to contact such a center and use the gastrin assay they recommend. An accurate gastrin assay is essential for accurate measurement of fasting serum gastrin level as well as for assessing gastrin levels during the secretin provocative test, and thus, the diagnosis of ZES cannot reliably be made without one.

TREATMENT

INSULINOMAS

An insulinoma is an NET of the pancreas that is thought to be derived from beta cells that ectopically secrete insulin, which results in hypoglycemia. The average age of occurrence is 40–50 years old. The most common clinical symptoms are due to the effect of the hypoglycemia on the CNS (neuroglycemic symptoms) and include confusion, headache, disorientation, visual difficulties, irrational behavior, and even coma. Also, most patients have symptoms due to excess catecholamine release secondary to the hypoglycemia, including sweating, tremor, and palpitations. Characteristically, these attacks are associated with fasting.

Insulinomas are generally small (>90% are <2 cm) and usually not multiple (90%); only 5–15% are malignant, and they almost invariably occur only in the pancreas, distributed equally in the pancreatic head, body, and tail.

Insulinomas should be suspected in all patients with hypoglycemia, especially when there is a history suggesting that attacks are provoked by fasting, or with a family history of MEN 1. Insulin is synthesized as proinsulin, which consists of a 21-amino-acid α chain and a 30-amino-acid β chain connected by a 33-amino-acid connecting peptide (C peptide). In insulinomas, in addition to elevated plasma insulin levels, elevated plasma proinsulin levels are found, and C-peptide levels are elevated.

Diagnosis

The diagnosis of insulinoma requires the demonstration of an elevated plasma insulin level at the time of hypoglycemia. A number of other conditions may cause fasting hypoglycemia, such as the inadvertent or surreptitious use of insulin or oral hypoglycemic agents, severe liver disease, alcoholism, poor nutrition, and other extrapancreatic tumors. Furthermore, postprandial hypoglycemia can be caused by a number of conditions that confuse the diagnosis of insulinoma. Particularly important here is the increased occurrence of hypoglycemia after gastric bypass surgery for obesity, which is now widely performed. A new entity, insulinomatosis, was described that can cause hypoglycemia and mimic insulinomas. It occurs in 10% of patients with persistent hyperinsulinemic hypoglycemia and is characterized by the occurrence of multiple macro-/microadenomas expressing insulin, and it is not clear how to distinguish this entity from insulinoma preoperatively. The most reliable test to diagnose insulinoma is a fast up to 72 h with serum glucose, C-peptide, proinsulin, and insulin measurements every 4–8 h. If at any point the patient becomes symptomatic or glucose levels are persistently below <2.2 mmol/L (40 mg/dL), the test should be terminated, and repeat samples for the above studies should be obtained before glucose is given. Some 70–80% of patients will develop hypoglycemia during the first 24 h, and 98% by 48 h. In nonobese normal subjects, serum insulin levels should decrease to <43 pmol/L (<6 µU/mL) when blood glucose decreases to <2.2 mmol/L (<40 mg/dL) and the ratio of insulin to glucose is <0.3 (in mg/dL). In addition to having an insulin level >6 µU/mL when blood glucose is <40 mg/dL, some investigators also require an elevated C-peptide and serum proinsulin level, an insulin/glucose ratio >0.3, and a decreased plasma β-hydroxybutyrate level for the diagnosis of insulinomas. Surreptitious use of insulin or hypoglycemic agents may be difficult to distinguish from insulinomas. The combination of proinsulin levels (normal in exogenous insulin/hypoglycemic agent users), C-peptide levels (low in exogenous insulin users), antibodies to insulin (positive in exogenous insulin users), and measurement of sulfonylurea levels in serum or plasma will allow the correct diagnosis to be made. The diagnosis of insulinoma has been complicated by the introduction of specific insulin assays that do not also interact with proinsulin, as do many of the older radioimmunoassays (RIAs), and therefore give lower plasma insulin levels. The increased use of these specific insulin assays has resulted in increased numbers of patients with insulinomas having lower plasma insulin values (<6 µU/mL) than levels proposed to be characteristic of insulinomas by RIA. In these patients, the assessment of proinsulin and C-peptide levels at the time of hypoglycemia is particularly helpful for establishing the correct diagnosis. An elevated proinsulin level when the fasting glucose level is <45 mg/dL is sensitive and specific.

TREATMENT

GLUCAGONOMAS

A glucagonoma is NET of the pancreas that secretes excessive amounts of glucagon, which causes a distinct syndrome characterized by dermatitis, glucose intolerance or diabetes, and weight loss. Glucagonomas principally occur between 45 and 70 years of age. The tumor is clinically heralded by a characteristic dermatitis (migratory necrolytic erythema) (67–90%), accompanied by glucose intolerance (40–90%), weight loss (66–96%), anemia (33–85%), diarrhea (15–29%), and thromboembolism (11–24%). The characteristic rash usually starts as an annular erythema at intertriginous and periorificial sites, especially in the groin or buttock. It subsequently becomes raised, and bullae form; when the bullae rupture, eroded areas form. The lesions can wax and wane. The development of a similar rash in patients receiving glucagon therapy suggests that the rash is a direct effect of the hyperglucagonemia. A characteristic laboratory finding is hypoaminoacidemia, which occurs in 26–100% of patients.

Glucagonomas are generally large tumors at diagnosis (5–10 cm). Some 50–80% occur in the pancreatic tail. From 50 to 82% have evidence of metastatic spread at presentation, usually to the liver. Glucagonomas are rarely extrapancreatic and usually occur singly.

Two new entities have been described that can also cause hyperglucagonemia and may mimic glucagonomas. Mahvah disease is due to a homozygous P86S mutation of the human glucagon receptor. It is associated with the development of α-cell hyperplasia, hyperglucagonemia, and the development of nonfunctioning pNETs. A second disease called glucagon cell adenomatosis can mimic glucagonoma ­syndrome clinically and is characterized by the presence of hyperplastic islets staining positive for glucagon instead of a single glucagonoma.

Diagnosis

The diagnosis is confirmed by demonstrating an increased plasma glucagon level. Characteristically, plasma glucagon levels exceed 1000 pg/mL (normal is <150 pg/mL) in 90%; 7% are between 500 and 1000 pg/mL, and 3% are <500 pg/mL. A trend toward lower levels at diagnosis has been noted in the last decade. A plasma glucagon level >1000 pg/mL is considered diagnostic of glucagonoma. Other diseases causing increased plasma glucagon levels include cirrhosis, diabetic ketoacidosis, celiac disease, renal insufficiency, acute pancreatitis, hypercorticism, hepatic insufficiency, severe stress, and prolonged fasting or familial hyperglucagonemia, as well as danazol treatment. With the exception of cirrhosis, these disorders do not increase plasma glucagon >500 pg/mL.

Necrolytic migratory erythema is not pathognomonic for glucagonoma and occurs in myeloproliferative disorders, hepatitis B infection, malnutrition, short-bowel syndrome, inflammatory bowel disease, zinc deficiency, and malabsorption disorders.

TREATMENT

SOMATOSTATINOMA SYNDROME

The somatostatinoma syndrome is due to an NET that secretes excessive amounts of somatostatin, which causes a distinct syndrome characterized by diabetes mellitus, gallbladder disease, diarrhea, and steatorrhea. There is no general distinction in the literature between a tumor that contains somatostatin-like immunoreactivity (somatostatinoma) and does (11–45%) or does not (55–90%) produce a clinical syndrome (somatostatinoma syndrome) by secreting somatostatin. In a review of 173 cases of somatostatinomas, only 11% were associated with the somatostatinoma syndrome. The mean age is 51 years. Somatostatinomas occur primarily in the pancreas and small intestine, and the frequency of the symptoms and occurrence of the somatostatinoma syndrome differ in each. Each of the usual symptoms is more common in pancreatic than in intestinal somatostatinomas: diabetes mellitus (95% vs 21%), gallbladder disease (94% vs 43%), diarrhea (92% vs 38%), steatorrhea (83% vs 12%), hypochlorhydria (86% vs 12%), and weight loss (90% vs 69%). The somatostatinoma syndrome occurs in 30–90% of pancreatic and 0–5% of SI somatostatinomas. In various series, 43% of all duodenal NETs contain somatostatin; however, the somatostatinoma syndrome is rarely present (<2%). Somatostatinomas occur in the pancreas in 56–74% of cases, with the primary location being the pancreatic head. The tumors are usually solitary (90%) and large (mean size 4.5 cm). Liver metastases are common, being present in 69–84% of patients. Somatostatinomas are rare in patients with MEN 1, occurring in only 0.65%.

Somatostatin is a tetradecapeptide that is widely distributed in the CNS and GI tract, where it functions as a neurotransmitter or has paracrine and autocrine actions. It is a potent inhibitor of many processes, including release of almost all hormones, acid secretion, intestinal and pancreatic secretion, and intestinal absorption. Most of the clinical manifestations are directly related to these inhibitory actions.

Diagnosis

In most cases, somatostatinomas have been found by accident either at the time of cholecystectomy or during endoscopy. The presence of psammoma bodies in a duodenal tumor should particularly raise suspicion. Duodenal somatostatin-containing tumors are increasingly associated with von Recklinghausen’s disease (NF-1) (Table 51-6). Most of these tumors (>98%) do not cause the somatostatinoma syndrome. The diagnosis of the somatostatinoma syndrome requires the demonstration of elevated plasma somatostatin levels.

TREATMENT

VIPOMAS

VIPomas are NETs that secrete excessive amounts of vasoactive intestinal peptide (VIP), which causes a distinct syndrome characterized by large-volume diarrhea, hypokalemia, and dehydration. This syndrome also is called Verner-Morrison syndrome, pancreatic cholera, and WDHA syndrome for watery diarrhea, hypokalemia, and achlorhydria, which some patients develop. The mean age of patients with this syndrome is 49 years; however, it can occur in children, and when it does, it is usually caused by a ganglioneuroma or ganglioneuroblastoma.

The principal symptoms are large-volume diarrhea (100%) severe enough to cause hypokalemia (80–100%), dehydration (83%), hypochlorhydria (54–76%), and flushing (20%). The diarrhea is secretory in nature, persisting during fasting, and is almost always >1 L/d and in 70% is >3 L/d. In a number of studies, the diarrhea was intermittent initially in up to half the patients. Most patients do not have accompanying steatorrhea (16%), and the increased stool volume is due to increased excretion of sodium and potassium, which, with the anions, accounts for the osmolality of the stool. Patients frequently have hyperglycemia (25–50%) and hypercalcemia (25–50%).

VIP is a 28-amino-acid peptide that is an important neurotransmitter, ubiquitously present in the CNS and GI tract. Its known actions include stimulation of SI chloride secretion as well as effects on smooth-muscle contractility, inhibition of acid secretion, and vasodilatory effects, which explain most features of the clinical syndrome.

In adults, 80–90% of VIPomas are pancreatic in location, with the rest due to VIP-secreting pheochromocytomas, intestinal carcinoids, and rarely ganglioneuromas. These tumors are usually solitary, 50–75% are in the pancreatic tail, and 37–68% have hepatic metastases at diagnosis. In children <10 years old, the syndrome is usually due to ganglioneuromas or ganglioblastomas and is less often malignant (10%).

Diagnosis

The diagnosis requires the demonstration of an elevated plasma VIP level and the presence of large-volume diarrhea. A stool volume <700 mL/d is proposed to exclude the diagnosis of VIPoma. When the patient fasts, a number of diseases can be excluded that can cause marked diarrhea because the high volume of diarrhea is not sustained during the fast. Other diseases that can produce a secretory large-volume diarrhea include gastrinomas, chronic laxative abuse, carcinoid syndrome, systemic mastocytosis, rarely medullary thyroid cancer, diabetic diarrhea, sprue, and AIDS. Among these conditions, only VIPomas caused a marked increase in plasma VIP. Chronic surreptitious use of laxatives/diuretics can be particularly difficult to detect clinically. Hence, in a patient with unexplained chronic diarrhea, screens for laxatives should be performed; they will detect many, but not all, laxative abusers. Elevated plasma levels of VIP should not be the only basis of the diagnosis of VIPomas because they can occur with some diarrheal states including inflammatory bowel disease, post small bowel resection, and radiation enteritis. Furthermore, nesidioblastosis can mimic VIPomas by causing elevated plasma VIP levels, diarrhea, and even false-positive location in the pancreatic region on somatostatin receptor scintigraphy.

TREATMENT

NONFUNCTIONAL PANCREATIC NEUROENDOCRINE TUMORS (NF-pNETs)

NF-pNETs are NETs that originate in the pancreas and either secrete no products or their products do not cause a specific clinical syndrome. Their symptoms are due entirely to the tumor per se. NF-pNETs secrete chromogranin A (90–100%), chromogranin B (90–100%), α-HCG (human chorionic gonadotropin) (40%), neuron-specific enolase (31%), and β-HCG (20%), and because 40–90% secrete PP, they are also often called PPomas. Because the symptoms are due to the tumor mass, patients with NF-pNETs usually present late in the disease course with invasive tumors and hepatic metastases (64–92%), and the tumors are usually large (72% >5 cm). NF-pNETs are usually solitary except in patients with MEN 1, in which case they are multiple. They occur primarily in the pancreatic head. Even though these tumors do not cause a functional syndrome, immunocytochemical studies show that they synthesize numerous peptides and cannot be distinguished from functional pNETs by immunocytochemistry. In MEN 1, 80–100% of patients have microscopic NF-pNETs, but they become large or symptomatic in a minority (0–13%) of cases. In VHL, 12–17% develop NF-pNETs, and in 4%, they are ≥3 cm in diameter.

The most common symptoms are abdominal pain (30–80%), jaundice (20–35%), and weight loss, fatigue, or bleeding; 10–35% are found incidentally. The average time from the beginning of symptoms to diagnosis is 5 years.

Diagnosis

The diagnosis is established by histologic confirmation in a patient without either the clinical symptoms or the elevated plasma hormone levels of one of the established syndromes. The principal difficulty in diagnosis is to distinguish an NF-pNET from a nonendocrine pancreatic tumor, which is more common, as well as from a functional pNET. Even though chromogranin A levels are elevated in almost every patient, this is not specific for this disease as it can be found in functional pNETs, GI-NETs (carcinoids), and other neuroendocrine disorders. Plasma PP elevations should strongly suggest the diagnosis in a patient with a pancreatic mass because it is usually normal in patients with pancreatic adenocarcinomas. Elevated plasma PP is not diagnostic of this tumor because it is elevated in a number of other conditions, such as chronic renal failure, old age, inflammatory conditions, alcohol abuse, pancreatitis, hypoglycemia, postprandially, and diabetes. A positive somatostatin receptor scan in a patient with a pancreatic mass should suggest the presence of pNET/NF-pNET rather than a nonendocrine tumor.

TREATMENT

GRFOMAS

GRFomas are NETs that secrete excessive amounts of growth hormone–releasing factor (GRF) that cause acromegaly. GRF is a 44-amino-acid peptide, and 25–44% of pNETs have GRF immunoreactivity, although it is uncommonly secreted. GRFomas are lung tumors in 47–54% of cases, pNETs in 29–30%, and SI carcinoids in 8–10%; up to 12% occur at other sites. Patients have a mean age of 38 years, and the symptoms usually are due to either acromegaly or the tumor per se. The acromegaly caused by GRFomas is indistinguishable from classic acromegaly. The pancreatic tumors are usually large (>6 cm), and liver metastases are present in 39%. They should be suspected in any patient with acromegaly and an abdominal tumor, a patient with MEN 1 with acromegaly, or a patient without a pituitary adenoma with acromegaly or associated with hyperprolactinemia, which occurs in 70% of GRFomas. GRFomas are an uncommon cause of acromegaly. GRFomas occur in <1% of MEN 1 patients. The diagnosis is established by performing plasma assays for GRF and growth hormone. Most GRFomas have a plasma GRF level >300 pg/mL (normal <5 pg/mL men, <10 pg/mL women). Patients with GRFomas also have increased plasma levels of insulin-like growth factor type I (IGF-I) similar to those in classic acromegaly. Surgery is the treatment of choice if diffuse metastases are not present. Long-acting somatostatin analogues such as octreotide and lanreotide are the agents of choice, with 75–100% of patients responding.

OTHER RARE PANCREATIC NEUROENDOCRINE TUMOR SYNDROMES

Cushing’s syndrome (ACTHoma) due to a pNET occurs in 4–16% of all ectopic Cushing’s syndrome cases. It occurs in 5% of cases of sporadic gastrinomas, almost invariably in patients with hepatic metastases, and is an independent poor prognostic factor. Paraneoplastic hypercalcemia due to pNETs releasing parathyroid hormone–related peptide (PTHrP), a PTH-like material, or unknown factor, is rarely reported. The tumors are usually large, and liver metastases are usually present. Most (88%) appear to be due to release of PTHrP. pNETs occasionally can cause the carcinoid syndrome. A number of very rare pNET syndromes involving a few cases (less than five) have been described; these include a renin-producing pNET in a patient presenting with hypertension; pNETs secreting luteinizing hormone, resulting in masculinization or decreased libido; a pNET secreting erythropoietin, resulting in polycythemia; pNETs secreting IGF-II, causing hypoglycemia; and pNETs secreting enteroglucagon, causing small intestinal hypertrophy, colonic/SI stasis, and malabsorption (Table 51-2). A number of other possible functional pNETs have been proposed, but most authorities classify these as unclear or as a nonfunctional pNET because in each case numerous patients have been described with similar plasma hormone elevations that do not cause any symptoms. These include pNETs secreting calcitonin, neurotensin (neurotensinoma), PP (PPoma), and ghrelin (Table 51-2).

Localization of the primary tumor and knowledge of the extent of the disease are essential to the proper management of all GI-NETs (carcinoids) and pNETs. Without proper localization studies, it is not possible to determine whether the patient is a candidate for surgical resection (curative or cytoreductive) or requires antitumor treatment, to determine whether the patient is responding to antitumor therapies, or to appropriately classify/stage the patient’s disease to assess prognosis.

Numerous tumor localization methods are used in both types of NETs, including cross-sectional imaging studies (CT, magnetic resonance imaging [MRI], transabdominal ultrasound), selective angiography, somatostatin receptor scintigraphy (SRS), and positron emission tomography. In pNETs, endoscopic ultrasound (EUS) and functional localization by measuring venous hormonal gradients are also reported to be useful. Bronchial carcinoids are usually detected by standard chest radiography and assessed by CT. Rectal, duodenal, colonic, and gastric carcinoids are usually detected by GI endoscopy. Because of their wide availability, CT and MRI are generally initially used to determine the location of the primary NETs and the extent of disease. NETs are hypervascular tumors, and with both MRI and CT, contrast enhancement is essential for maximal sensitivity, and it is recommended that generally triple-phase scanning be used. The ability of cross-sectional imaging and, to a lesser extent, SRS to detect NETs is a function of NET size. With CT and MRI, <10% of tumors <1 cm in diameter are detected, 30–40% of tumors 1–3 cm are detected, and >50% of tumors >3 cm are detected. Many primary GI-NETs (carcinoids) are small, as are insulinomas and duodenal gastrinomas, and are frequently not detected by cross-sectional imaging, whereas most other pNETs present late in the course of their disease and are large (>4 cm). Selective angiography is more sensitive, localizing 60–90% of all NETs; however, it is now used infrequently. For detecting liver metastases, CT and MRI are more sensitive than ultrasound, and with recent improvements, 5–25% of patients with liver metastases will be missed by CT and/or MRI.

pNETs, as well as GI-NETs (carcinoids), frequently (>80%) overexpress high-affinity somatostatin receptors in both the primary tumors and the metastases. Of the five types of somatostatin receptors (sst_1–5), radiolabeled octreotide binds with high affinity to sst₂ and sst₅, has a lower affinity for sst₃, and has a very low affinity for sst₁ and sst₄. Between 80 and 100% of GI-NETs (carcinoids) and pNETs possess sst₂, and many also have the other four sst subtypes. Interaction with these receptors can be used to treat these tumors as well as to localize NETs by using radiolabeled somatostatin analogues (SRS). In the United States, [¹¹¹In-DTPA-d-Phe¹]octreotide (octreoscan) is generally used with gamma camera detection using single-photon emission computed tomography (SPECT) imaging. Numerous studies, primarily in Europe, using gallium-68-labeled somatostatin analogues and positron emission tomography (PET) detection, demonstrate even greater sensitivity than with SRS with ¹¹¹In-labeled somatostatin analogues. Although not yet approved in the United States, there are a number of centers starting to use this approach. Because of its sensitivity and ability to localize tumor throughout the body, SRS is the initial imaging modality of choice for localizing both the primary tumor and metastatic NETs. SRS localizes tumor in 73–95% of patients with GI-NETs (carcinoids) and in 56–100% of patients with pNETs, except insulinomas. Insulinomas are usually small and have low densities of sst receptors, resulting in SRS being positive in only 12–50% of patients with insulinomas. SRS identifies >90–95% of patients with liver metastases due to NETs. Figure 51-3 shows an example of the increased sensitivity of SRS in a patient with a GI-NET (carcinoid) tumor. The CT scan showed a single liver metastasis, whereas the SRS demonstrated three metastases in the liver in multiple locations. Occasional false-positive responses with SRS can occur (12% in one study) because numerous other normal tissues as well as diseases can have high densities of sst receptors, including granulomas (sarcoid, tuberculosis, etc.), thyroid diseases (goiter, thyroiditis), and activated lymphocytes (lymphomas, wound infections). If liver metastases are identified by SRS, to plan the proper treatment, either a CT or an MRI (with contrast enhancement) is recommended to assess the size and exact location of the metastases because SRS does not provide information on tumor size. For pNETs in the pancreas, EUS is highly sensitive, localizing 77–100% of insulinomas, which occur almost exclusively within the pancreas. Endoscopic ultrasound is less sensitive for extrapancreatic tumors. It is increasingly used in patients with MEN 1, and to a lesser extent VHL, to detect small pNETs not seen with other modalities or for serial pNET assessments to determine size changes or rapid growth in patients in whom surgery is deferred. EUS with cytologic evaluation also is used frequently to distinguish an NF-pNET from a pancreatic adenocarcinoma or another nonendocrine pancreatic tumor. Not infrequently patients present with liver metastases due to an NET and the primary site is unclear. Occult small intestinal NETs (carcinoids) are increasingly detected by double-balloon enteroscopy or capsule endoscopy.

Insulinomas frequently overexpress receptors for glucagon-like peptide-1 (GLP-1), and radiolabeled GLP-1 analogues have been developed that can detect occult insulinomas not localized by other imaging modalities. Functional localization by measuring hormonal gradients is now uncommonly used with gastrinomas (after intra-arterial secretin injections) but is still frequently used in insulinoma patients in whom other imaging studies are negative (assessing hepatic vein insulin concentrations post-intra-arterial calcium injections). Functional localization measuring hormone gradients in insulinomas or gastrin gradients in gastrinoma is a sensitive method, being positive in 80–100% of patients. The intra-arterial calcium test may also allow differentiation of the cause of the hypoglycemia and indicate whether it is due to an insulinoma or a nesidioblastosis. The latter entity is becoming increasingly important because hypoglycemia after gastric bypass surgery for obesity is increasing in frequency, and it is primarily due to nesidioblastosis, although it can occasionally be due to an insulinoma.

PET and use of hybrid scanners such as CT and SRS may have increased sensitivity. PET scanning with ¹⁸F-fluoro-DOPA in patients with carcinoids or with ¹¹C-5-HTP in patients with pNETs or GI-NETs (carcinoids) has greater sensitivity than cross-sectional imaging studies and may be used increasingly in the future. PET scanning for GI-NETs is not currently approved in the United States.

TREATMENT