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InternalMed_Harrison. 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 113-4). Overall survival is 88%; however, it is very much dependent of the


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InternalMed_Harrison. adjacent structures. Histologically, most are well differentiated (98%) with 72% ENETS/WHO grade G1 and 28% grade G2 (Table 113-4). 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 113-5 and particularly include tumor size, depth of invasion, presence of metastases, differentiation, and recent TNM classification and grade.


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InternalMed_Harrison. 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).


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InternalMed_Harrison. 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


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InternalMed_Harrison. Endocrine Tumors of the Gastrointestinal Tract and Pancreas 564 (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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 threeto 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


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InternalMed_Harrison. 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).


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InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 113-7. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 113-3). Midgut NETs (carcinoids) account for 57–67% of cases of carcinoid syndrome, fore-gut NETs (carcinoids) for 0–33%, hindgut for 0–8%, and an unknown primary location for 2–26% (Tables 113-3 and 113-7).


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InternalMed_Harrison. One of the main secretory products of GI-NETs (carcinoids) involved in the carcinoid syndrome is serotonin (5-HT) (Fig. 113-1), 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


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InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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


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InternalMed_Harrison. 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.


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InternalMed_Harrison. Both histamine and serotonin may be responsible for the wheezing as 565 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.


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InternalMed_Harrison. 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-HT2B receptors, whose activation is known to cause fibroblast mitogenesis. Serotonin receptor subtypes normally are expressed in human heart valve intersti- 5-HT1B,1D,2A,2B tial cells. High levels of 5-HT2B receptors are known to occur in heart valves and occur in


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InternalMed_Harrison. Serotonin receptor subtypes normally are expressed in human heart valve intersti- 5-HT1B,1D,2A,2B tial cells. High levels of 5-HT2B 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-HT2B receptors and stimulating upregulation of transforming growth factor β and collagen biosynthesis. These observations support the conclu sion that serotonin overproduction by GI-NETs (carcinoids) is important in mediating the valvular changes, possibly by activating 5-HT2B 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


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InternalMed_Harrison. 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).


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InternalMed_Harrison. Patients may develop either a typical or, rarely, an atypical carcinoid syndrome (Fig. 113-1). 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. 113-1). 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. 113-1). In these patients, plasma serotonin levels are normal but urinary levels may be increased because some 5-HTP is converted to 5-HT in


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InternalMed_Harrison. and 5-HTP is secreted into the bloodstream (Fig. 113-1). 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.


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InternalMed_Harrison. 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.


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InternalMed_Harrison. Endocrine Tumors of the Gastrointestinal Tract and Pancreas 566 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


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InternalMed_Harrison. 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


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InternalMed_Harrison. 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. 113-1). 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


InternalMed_Harrison

InternalMed_Harrison. 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


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InternalMed_Harrison. 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%.


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InternalMed_Harrison. Treatment includes avoiding conditions that precipitate flushing, dietary supplementation with nicotinamide, treatment of heart failure with diuretics, treatment of wheezing with oral bronchodilators, and control of the diarrhea with antidiarrheal agents such as loperamide and diphenoxylate. If patients still have symptoms, serotonin receptor antagonists or somatostatin analogues (Fig. 113-2) are the drugs of choice.


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InternalMed_Harrison. There are 14 subclasses of serotonin receptors, and antagonists for many are not available. The 5-HT1 and 5-HT2 receptor antagonists methysergide, cyproheptadine, and ketanserin have all been used to control the diarrhea but usually do not decrease flushing. The use of methysergide is limited because it can cause or enhance retroperitoneal fibrosis. Ketanserin diminishes diarrhea in 30–100% of patients. 5-HT3 receptor antagonists (ondansetron, tropisetron, alosetron) can control diarrhea and nausea in up to 100% of patients and occasionally ameliorate the flushing. A combination of histamine H1 and H2 receptor antagonists (i.e., diphenhydramine and cimetidine or ranitidine) may control flushing in patients with foregut carcinoids. The tryptophan 5-hydoxylase inhibitor telotristat etiprate decreased bowel frequency in 44% and improved stool consistency in 20%.


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InternalMed_Harrison. 111In-[DTPA-D-Phe1, Tyr3]-octreotide = 111In-pentetreotide; Octreoscan-111 90Y-[DOTA0-D-Phe1 , Tyr3]-octreotide177Lu-[DOTA0-D-Phe1,Tyr3]-octreotateTHRCYSCYSSSCYSCYSSSCYSCYSSSD-PHELYSTYRTHRD-TRPLYSTYRTHRD-TRPLYSTYRTHRD-TRPHOOC-CH2CH2-COCH2-COOHCOOHHOOCNHHOOCN–(CH2)2–N–(CH2)2–ND-PHED-PHETHR-olTHR-olNNONN90Y111InCOOHHOOCNHHOOCNNONN177Lu FIGURE 113-2 Structure of somatostatin and synthetic analogues used for diagnostic or therapeutic indications.


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InternalMed_Harrison. Synthetic analogues of somatostatin (octreotide, lanreotide) are now the most widely used agents to control the symptoms of patients with carcinoid syndrome (Fig. 113-2). These drugs are effective at relieving symptoms and decreasing urinary 5-HIAA levels in patients with this syndrome. Octreotide-LAR and lanreotideSR/autogel (Somatuline) (sustained-release formulations allowing monthly injections) control symptoms in 74% and 68% of patients, respectively, with carcinoid syndrome and show a biochemical response in 51% and 64%, respectively. Patients with mild to moderate symptoms usually are treated initially with octreotide 100 µg SC every 8 h and then begun on the long-acting monthly depot forms (octreotide-LAR or lanreotide-autogel). Forty percent of patients escape control after a median time of 4 months, and the depot dosage may have to be increased as well as supplemented with the shorter-acting formulation, SC octreotide. Pasireotide (SOM230) is a somatostatin analogue with


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InternalMed_Harrison. median time of 4 months, and the depot dosage may have to be increased as well as supplemented with the shorter-acting formulation, SC octreotide. Pasireotide (SOM230) is a somatostatin analogue with broader selectivity (high-affinity somatostatin receptors [sst1, sst2, sst3, sst5]) than octreotide/lanreotide (sst2, sst5). In a phase II study of patients with refractory carcinoid syndrome, pasireotide controlled symptoms in 27%.


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InternalMed_Harrison. Carcinoid heart disease is associated with a decreased mean survival (3.8 years), and therefore, it should be sought for and carefully assessed in all patients with carcinoid syndrome. Transthoracic echocardiography remains a key element in establishing the diagnosis of carcinoid heart disease and determining the extent and type of cardiac abnormalities. Treatment with diuretics and somatostatin analogues can reduce the negative hemodynamic effects and secondary heart failure. It remains unclear whether long-term treatment with these drugs will decrease the progression of carcinoid heart disease. Balloon valvuloplasty for stenotic valves or cardiac valve surgery may be required.


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InternalMed_Harrison. In patients with carcinoid crises, somatostatin analogues are effective at both treating the condition and preventing their development during known precipitating events such as surgery, anesthesia, chemotherapy, and stress. It is recommended that octreotide 150–250 µg SC every 6 to 8 h be used 24–48 h before anesthesia and then continued throughout the procedure. Currently, sustained-release preparations of both octreotide (octreotide-LAR [long-acting release], 10, 20, 30 mg) and lanreotide (lanreotide-PR [prolonged release, lanreotide-autogel], 60, 90, 120 mg) are available and widely used because their use greatly facilitates long-term treatment. Octreotide-LAR (30 mg/month) gives a plasma level ≥1 ng/mL for 25 days, whereas this requires three to six injections a day of the non-sustained-release form. Lanreotideautogel (Somatuline) is given every 4–6 weeks.


InternalMed_Harrison

InternalMed_Harrison. Short-term side effects occur in up to one-half of patients. Pain at the injection site and side effects related to the GI tract (59% discomfort, 15% nausea, diarrhea) are the most common. They are usually short-lived and do not interrupt treatment. Important long-term side effects include gallstone formation, steatorrhea, and deterioration in glucose tolerance. The overall incidence of gallstones/biliary sludge in one study was 52%, with 7% having symptomatic disease that required surgical treatment.


InternalMed_Harrison

InternalMed_Harrison. Interferon α is reported to be effective in controlling symptoms of the carcinoid syndrome either alone or combined with hepatic artery embolization. With interferon α alone, the clinical response rate is 30–70%, and with interferon α with hepatic artery embolization, diarrhea was controlled for 1 year in 43% and flushing was controlled in 86%. Side effects develop in almost all patients, with the most frequent being a flu-like syndrome (80–100%), followed by anorexia and fatigue, even though these frequently improve with continued treatment. Other more severe side effects include bone marrow toxicity, hepatotoxicity, autoimmune disorders, and rarely CNS side effects (depression, mental disorders, visual problems).


InternalMed_Harrison

InternalMed_Harrison. Hepatic artery embolization alone or with chemotherapy (chemoembolization) has been used to control the symptoms of carcinoid syndrome. Embolization alone is reported to control symptoms in up to 76% of patients, and chemoembolization (5-fluorouracil, doxorubicin, cisplatin, mitomycin) controls symptoms in 60–75% of patients. Hepatic artery embolization can have major side effects, 567 including nausea, vomiting, pain, and fever. In two studies, 5–7% of patients died from complications of hepatic artery occlusion. Other drugs have been used successfully in small numbers of patients to control the symptoms of carcinoid syndrome. Parachlorophenylanine can inhibit tryptophan hydroxylase and therefore the conversion of tryptophan to 5-HTP. However, its severe side effects, including psychiatric disturbances, make it intolerable for long-term use. α-Methyldopa inhibits the conversion of 5-HTP to 5-HT, but its effects are only partial.


InternalMed_Harrison

InternalMed_Harrison. Peptide radioreceptor therapy (using radiotherapy with radio-labeled somatostatin analogues), the use of radiolabeled micro-spheres, and other methods for treatment of advanced metastatic disease may facilitate control of the carcinoid syndrome and are discussed in a later section dealing with treatment of advanced disease. Surgery is the only potentially curative therapy. Because with most


InternalMed_Harrison

InternalMed_Harrison. GI-NETs (carcinoids), the probability of metastatic disease increases with increasing size, the extent of surgical resection is determined accordingly. With appendiceal NETs (carcinoids) <1 cm, simple appendectomy was curative in 103 patients followed for up to 35 years. With rectal NETs (carcinoids) <1 cm, local resection is curative. With SI NETs (carcinoids) <1 cm, there is not complete agreement. Because 15–69% of SI NETs (carcinoids) this size have metastases in different studies, some recommend a wide resection with en bloc resection of the adjacent lymph-bearing mesentery. If the tumor is >2 cm for rectal, appendiceal, or SI NETs (carcinoids), a full cancer operation should be done. This includes a right hemicolectomy for appendiceal NETs (carcinoids), an abdominoperineal resection or low anterior resection for rectal NETs (carcinoids), and an en bloc resection of adjacent lymph nodes for SI NETs (carcinoids). For appendiceal NETs (carcinoids) 1–2 cm in diameter, a simple


InternalMed_Harrison

InternalMed_Harrison. or low anterior resection for rectal NETs (carcinoids), and an en bloc resection of adjacent lymph nodes for SI NETs (carcinoids). For appendiceal NETs (carcinoids) 1–2 cm in diameter, a simple appendectomy is proposed by some, whereas others favor a formal right hemicolectomy. For 1–2 cm rectal NETs (carcinoids), it is recommended that a wide, local, full-thickness excision be performed.


InternalMed_Harrison

InternalMed_Harrison. With type I or II gastric NETs (carcinoids), which are usually <1 cm, endoscopic removal is recommended. In type I or II gastric carcinoids, if the tumor is >2 cm or if there is local invasion, some recommend total gastrectomy, whereas others recommend antrectomy in type I to reduce the hypergastrinemia, which has led to regression of the carcinoids in a number of studies. For types I and II gastric NETs (carcinoids) of 1–2 cm, there is no agreement, with some recommending endoscopic treatment followed by chronic somatostatin treatment and careful follow-up and others recommending surgical treatment. With type III gastric NETs (carcinoids) >2 cm, excision and regional lymph node clearance are recommended. Most tumors <1 cm are treated endoscopically. Resection of isolated or limited hepatic metastases may be beneficial and will be discussed in a later section on treatment of advanced disease.


InternalMed_Harrison

InternalMed_Harrison. Resection of isolated or limited hepatic metastases may be beneficial and will be discussed in a later section on treatment of advanced disease. Functional pNETs usually present clinically with symptoms due to the hormone-excess state (Table 113-2). 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. Endocrine Tumors of the Gastrointestinal Tract and Pancreas


InternalMed_Harrison

InternalMed_Harrison. Endocrine Tumors of the Gastrointestinal Tract and Pancreas Treatment of pNETs requires two different strategies. First, treatment must be directed at the hormone-excess state such as the gastric acid hypersecretion in gastrinomas or the hypoglycemia in insulinomas. Ectopic hormone secretion usually causes the presenting symptoms and can cause life-threatening complications. Second, with all the tumors except insulinomas, >50% are malignant (Table 113-2); therefore, treatment must also be directed against the tumor per se. Because in many patients these tumors are not surgically curable due to the presence of advanced disease at diagnosis, surgical resection for cure, which addresses both treatment aspects, is often not possible.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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).


InternalMed_Harrison

InternalMed_Harrison. 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 113-2) with metastatic spread to lymph nodes and liver. Distant metastases to bone occur in 12–30% of patients with liver metastases.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Gastric acid hypersecretion in patients with ZES can be controlled in almost every case by oral gastric antisecretory drugs. Because of their long duration of action and potency, which allows dosing once or twice a day, the PPIs (H+, K+-ATPase inhibitors) are the drugs of choice. Histamine H2-receptor antagonists are also effective, although more frequent dosing (q 4–8 h) and high doses are required. In patients with MEN 1/ZES with hyperparathyroidism, correction of the hyperparathyroidism increases the sensitivity to gastric antisecretory drugs and decreases the basal acid output. Long-term treatment with PPIs (>15 years) has proved to be safe and effective, without development of tachyphylaxis. Although patients with ZES, especially those with MEN 1/ZES, more frequently develop gastric NETs (carcinoids), no data suggest that the long-term use of PPIs increases this risk in these patients. With long-term PPI use in ZES patients, vitamin B12 deficiency can develop; thus, vitamin B12


InternalMed_Harrison

InternalMed_Harrison. NETs (carcinoids), no data suggest that the long-term use of PPIs increases this risk in these patients. With long-term PPI use in ZES patients, vitamin B12 deficiency can develop; thus, vitamin B12 levels should be assessed during follow-up. Epidemiologic studies suggest that long-term PPI use may be associated with an increased incidence of bone fractures; however, at present, there is no such report in ZES patients.


InternalMed_Harrison

InternalMed_Harrison. With the increased ability to control acid hypersecretion, more than 50% of patients who are not cured (>60% of patients) will die from tumor-related causes. At presentation, careful imaging studies are essential to localize the extent of the tumor to determine the appropriate treatment. A third of patients present with hepatic metastases, and in <15% of those patients, the disease is limited, so that surgical resection may be possible. Surgical short-term cure is possible in 60% of all patients without MEN 1/ZES or liver metastases (40% of all patients) and in 30% of patients long term. In patients with MEN 1/ZES, long-term surgical cure is rare because the tumors are multiple, frequently with lymph node metastases. Surgical studies demonstrate that successful resection of the gastrinoma not only decreases the chances of developing liver metastases but also increases the disease-related survival rate. Therefore, all patients with gastrinomas without MEN 1/ZES or a medical condition


InternalMed_Harrison

InternalMed_Harrison. not only decreases the chances of developing liver metastases but also increases the disease-related survival rate. Therefore, all patients with gastrinomas without MEN 1/ZES or a medical condition that limits life expectancy should undergo surgery by a surgeon experienced in the treatment of these disorders.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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 pro-insulin, 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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 569 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


InternalMed_Harrison

InternalMed_Harrison. of specific insulin 569 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.


InternalMed_Harrison

InternalMed_Harrison. Only 5–15% of insulinomas are malignant; therefore, after appropriate imaging (see below), surgery should be performed. In different studies, 75–100% of patients are cured by surgery. Before surgery, the hypoglycemia can be controlled by frequent small meals and the use of diazoxide (150–800 mg/d). Diazoxide is a benzothiadiazide whose hyperglycemic effect is attributed to inhibition of insulin release. Its side effects are sodium retention and GI symptoms such as nausea. Approximately 50–60% of patients respond to diazoxide. Other agents effective in some patients to control the hypoglycemia include verapamil and diphenylhydantoin. Long-acting somatostatin analogues such as octreotide and lanreotide are acutely effective in 40% of patients. However, octreotide must be used with care because it inhibits growth hormone secretion and can alter plasma glucagon levels; therefore, in some patients, it can worsen the hypoglycemia.


InternalMed_Harrison

InternalMed_Harrison. For the 5–15% of patients with malignant insulinomas, these drugs or somatostatin analogues are used initially. In a small number of patients with insulinomas, some with malignant tumors, mammalian target of rapamycin (mTOR) inhibitors (everolimus, rapamycin) are reported to control the hypoglycemia. If they are not effective, various antitumor treatments such as hepatic arterial embolization, chemoembolization, chemotherapy, and peptide receptor radiotherapy have been used (see below). Insulinomas, which are usually benign (>90%) and intrapancreatic in location, are increasingly resected using a laparoscopic approach, which has lower morbidity rates. This approach requires that the insulinoma be localized on preoperative imaging studies.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. Endocrine Tumors of the Gastrointestinal Tract and Pancreas 570 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,


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. In 50–80% of patients, hepatic metastases are present, and so curative surgical resection is not possible. Surgical debulking in patients with advanced disease or other antitumor treatments may be beneficial (see below). Long-acting somatostatin analogues such as octreotide and lanreotide improve the skin rash in 75% of patients and may improve the weight loss, pain, and diarrhea, but usually do not improve the glucose intolerance.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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%.


InternalMed_Harrison

InternalMed_Harrison. 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 113-6). 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.


InternalMed_Harrison

InternalMed_Harrison. Pancreatic tumors are frequently (70–92%) metastatic at presentation, whereas 30–69% of SI somatostatinomas have metastases. Surgery is the treatment of choice for those without widespread hepatic metastases. Symptoms in patients with the somatostatinoma syndrome are also improved by octreotide treatment. 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.


InternalMed_Harrison

InternalMed_Harrison. 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%).


InternalMed_Harrison

InternalMed_Harrison. 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%).


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. The most important initial treatment in these patients is to correct their dehydration, hypokalemia, and electrolyte losses with fluid and electrolyte replacement. These patients may require 5 L/d of fluid and >350 mEq/d of potassium. Because 37–68% of adults with VIPomas have metastatic disease in the liver at presentation, a significant number of patients cannot be cured surgically. In these patients, long-acting somatostatin analogues such as octreotide and lanreotide are the drugs of choice.


InternalMed_Harrison

InternalMed_Harrison. Octreotide/lanreotide will control the diarrhea shortand longterm in 75–100% of patients. In nonresponsive patients, the combination of glucocorticoids and octreotide/lanreotide has proved helpful in a small number of patients. Other drugs reported to be helpful in small numbers of patients include prednisone (60– 100 mg/d), clonidine, indomethacin, phenothiazines, loperamide, lidamidine, lithium, propranolol, and metoclopramide. Treatment of advanced disease with cytoreductive surgery, embolization, chemoembolization, chemotherapy, radiotherapy, radiofrequency ablation, and peptide receptor radiotherapy may be helpful (see below).


InternalMed_Harrison

InternalMed_Harrison. 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%


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. Overall survival in patients with sporadic NF-pNET is 30–63% at 5 years, with a median survival of 6 years. Unfortunately, surgical curative resection can be considered only in a minority of these patients because 64–92% present with diffuse metastatic disease. Treatment needs to be directed against the tumor per se using the various modalities discussed below for advanced disease. The treatment of NF-pNETs in either MEN 1 patients or patients with VHL is controversial. Most recommend surgical resection for any tumor >2–3 cm in diameter; however, there is no consensus on smaller 571 NF-pNETs in these inherited disorders, with most recommending careful surveillance of these patients. The treatment of small sporadic, asymptomatic NF-pNETs (≤2 cm) is also controversial. Most of these are low-or intermediate-grade lesions, and <7% are malignant. Some advocate a nonoperative approach with careful, regular follow-up, whereas other recommend an operative approach with specially consideration


InternalMed_Harrison

InternalMed_Harrison. intermediate-grade lesions, and <7% are malignant. Some advocate a nonoperative approach with careful, regular follow-up, whereas other recommend an operative approach with specially consideration for a laparoscopic surgical approach.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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 reninproducing 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


InternalMed_Harrison

InternalMed_Harrison. 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 113-2). 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 113-2).


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InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. Endocrine Tumors of the Gastrointestinal Tract and Pancreas 572 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 hyper-vascular 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


InternalMed_Harrison

InternalMed_Harrison. 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 (sst1–5), radiolabeled octreotide binds with high affinity to sst2 and sst5, has a lower


InternalMed_Harrison

InternalMed_Harrison. receptors in both the primary tumors and the metastases. Of the five types of somatostatin receptors (sst1–5), 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


InternalMed_Harrison

InternalMed_Harrison. 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 113-3 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.


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InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. FIGURE 113-3 Ability of computed tomography (CT) scanning (top) or somatostatin receptor scintigraphy (SRS) (bottom) to localize metastatic carcinoid in the liver.


InternalMed_Harrison

InternalMed_Harrison. 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


InternalMed_Harrison

InternalMed_Harrison. 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.


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InternalMed_Harrison. 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. The single most important prognostic factor for survival is the presence of liver metastases (Fig. 113-4). For patients with foregut carcinoids without hepatic metastases, the 5-year survival in one A.ENETS Stage D. Appendiceal NETs (Carcinoids) ---Stage 3–4 ENETS pT classification pT1–2 vs pT3–4: p = 0.0004 Probability of survival .75 .5 .25 B.UICC/AJCC/WHO2010 Stage E. Appendiceal NETs (Carcinoids) Endocrine Tumors of the Gastrointestinal Tract and Pancreas WHO/AJCC pT classification pT1–2 vs pT3–4: p <0.0001 C.ENETS/WHO Grade F.Midgut NETs (Carcinoids)


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InternalMed_Harrison. Endocrine Tumors of the Gastrointestinal Tract and Pancreas WHO/AJCC pT classification pT1–2 vs pT3–4: p <0.0001 C.ENETS/WHO Grade F.Midgut NETs (Carcinoids) Probability of survival .75 .5 .25 .75 .5 .25


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InternalMed_Harrison. FIGURE 113-4 Survival (Kaplan-Meier plots) of patients with pancreatic neuroendocrine tumors (pNETs; n = 1072) (A–C) or gastrointestinal neuroendocrine tumors (GI-NETs; carcinoids) (appendix, n = 138; midgut, n = 238) (D–F) stratified according to recent proposed classification and grading systems. (Panels A–C are drawn from data in G Rindi et al: J Natl Cancer Inst 104:764, 2012; panels D and E are drawn from data in M Volante et al: Am J Surg Pathol 37:606, 2013; and panel F is drawn from data in MS Khan: Br J Cancer 108:1838, 2013.) study was 95%, and with distant metastases, it was 20% (Fig. 113-4). With gastrinomas, the 5-year survival without liver metastases is 98%; with limited metastases in one hepatic lobe, it is 78%; and with diffuse metastases, 16% (Fig. 113-4). In a large study of 156 patients (67 pNETs, rest carcinoids), the overall 5-year survival rate was 77%; it was 96% without liver metastases, 73% with liver metastases, and 50% with distant disease. Another very


InternalMed_Harrison

InternalMed_Harrison. study of 156 patients (67 pNETs, rest carcinoids), the overall 5-year survival rate was 77%; it was 96% without liver metastases, 73% with liver metastases, and 50% with distant disease. Another very important prognostic factor is whether the NET is well-differentiated (G1/G2) or poorly differentiated (<1% of all NETs) (G3). Well-differentiated NETs have a 5-year survival of 50–80%, whereas poorly differentiated NETs have a 5-year survival of only 0–15%.


InternalMed_Harrison

InternalMed_Harrison. Therefore, treatment for advanced metastatic disease is an important challenge. A number of different modalities are reported to be effective, including cytoreductive surgery (surgically or by radiofrequency ablation [RFA]), treatment with chemotherapy, somatostatin analogues, interferon α, hepatic embolization alone or with chemotherapy (chemoembolization), molecular targeted therapy, radiotherapy with radiolabeled beads/microspheres, peptide radioreceptor therapy (PRRT), and liver transplantation.


InternalMed_Harrison

InternalMed_Harrison. Cytoreductive surgery is considered if either all of the visible metastatic disease or at last 90% is thought resectable; however, unfortunately, this is possible in only the 9–22% of patients who present with limited hepatic metastases. Although no randomized studies have proven that it extends life, results from a number of studies suggest that it may increase survival; therefore, it is recommended, if possible. RFA can be applied to NET liver metastases if they are 574 limited in number (usually less than five) and size (usually <3.5 cm in diameter). It can be used at the time of surgery (either general or laparoscopic) or using radiologic guidance. Response rates are >80%, the responses can last up to 3 years, the morbidity rate is low, and this procedure may be particularly helpful in patients with functional pNETs that are difficult to control medically. Although RFA has not been established in a controlled trial, both the European and North American Neuroendocrine Tumor Society


InternalMed_Harrison

InternalMed_Harrison. patients with functional pNETs that are difficult to control medically. Although RFA has not been established in a controlled trial, both the European and North American Neuroendocrine Tumor Society guidelines (ENETS, NANETS) state it can be an effective antitumor treatment for both refractory functional syndromes and for palliative treatment. Chemotherapy plays a different role in the treatment of patients with pNETs and GI-NETs (carcinoids). Chemotherapy continues to be widely used in the treatment of patients with advanced pNETs with moderate success (response rates 20–70%); however, in general, its results in patients with metastatic GI-NETs (carcinoids) has been disappointing, with response rates of 0–30% with various twoand three-drug combinations, and thus, it is infrequently used in these patients. An important distinction in patients with pNETs is whether the tumor is well differentiated (G1/G2) or poorly differentiated (G3). The chemotherapeutic approach is different for


InternalMed_Harrison

InternalMed_Harrison. in these patients. An important distinction in patients with pNETs is whether the tumor is well differentiated (G1/G2) or poorly differentiated (G3). The chemotherapeutic approach is different for these two groups. The current regimen of choice for patients with well-differentiated pNETs is the combination of streptozotocin and doxorubicin with or without 5-fluorouracil. Streptozotocin is a glucosamine nitrourea compound originally found to have cytotoxic effects on pancreatic islets, and later in studies with doxorubicin with or without 5-fluorouracil, it produced response rates of 20–45% in advanced pNETs. Streptozotocin causes considerable morbidity, with 70–100% of patients developing side effects (most prominent being nausea/vomiting in 60–100% or leukopenia/thrombocytopenia) and 15–40% of patients developing some degree of renal dysfunction (proteinuria in 40–50%, decreased creatine clearance). The combination of temozolomide (TMZ) with capecitabine produces partial response


InternalMed_Harrison

InternalMed_Harrison. 15–40% of patients developing some degree of renal dysfunction (proteinuria in 40–50%, decreased creatine clearance). The combination of temozolomide (TMZ) with capecitabine produces partial response rates as high as 70% in patients with advance pNETs and a 2-year survival of 92%. The use of TMZ or another alkylating agent in advanced pNETs is supported by studies that show low levels of the DNA repair enzyme O6-methylguanine DNA methyltransferase in pNETs, but not in GI-NETs (carcinoids), which increases the sensitivity of pNETs to TMZ. In poorly differentiated NETs (G3), chemotherapy with a cisplatin-based regimen with etoposide or other agents (vincristine, paclitaxel) is the recommended treatment, with response rates of 40–70%; however, responses are generally short-lived (<12 months). This chemotherapy regimen can be associated with significant toxicity including GI toxicities (nausea, vomiting), myelosuppression, and renal toxicity. In addition to the effectiveness in


InternalMed_Harrison

InternalMed_Harrison. months). This chemotherapy regimen can be associated with significant toxicity including GI toxicities (nausea, vomiting), myelosuppression, and renal toxicity. In addition to the effectiveness in controlling the functional hormonal state, long-acting somatostatin analogues such as octreotide and lanreotide are increasingly used for their antiproliferative effects. Whereas somatostatin analogues rarely decrease tumor size (i.e., 0–17%), these drugs have tumoristatic effects, stopping additional growth in 26–95% of patients with NETs. In a randomized, double-blind study in patients with metastatic midgut carcinoids (PROMID study) octreotide-LAR demonstrated a marked lengthening of time to progression (14.3 vs 6 months, p = .000072). This improvement was seen in patients with limited liver involvement. This study did not assess whether such treatment will extend survival. A double-blind, randomized, placebo-controlled, phase III study in patients with well-differentiated, metastatic,


InternalMed_Harrison

InternalMed_Harrison. involvement. This study did not assess whether such treatment will extend survival. A double-blind, randomized, placebo-controlled, phase III study in patients with well-differentiated, metastatic, inoperable pNETs (45%) or GI-NETs (carcinoids) (55%) (CLARINET study) showed that monthly treatment with lanreotide-autogel reduced tumor progression or death by 53%. Somatostatin analogues can induce apoptosis in GI-NETs (carcinoids), which probably contributes to their tumoristatic effects. Treatment with somatostatin analogues is generally well-tolerated, with most side effects being mild and uncommonly leading to stopping the drug. Potential longterm side effects include diabetes/glucose intolerance, steatorrhea, and the development of gallbladder sludge/gallstones (10–80%), although only 1% of patients develop symptomatic gallbladder disease. Because of these phase III studies, somatostatin analogues are generally recommended as first-line treatment for patients with


InternalMed_Harrison

InternalMed_Harrison. although only 1% of patients develop symptomatic gallbladder disease. Because of these phase III studies, somatostatin analogues are generally recommended as first-line treatment for patients with well-differentiated metastatic NETs.


InternalMed_Harrison

InternalMed_Harrison. Interferon α, similar to somatostatin analogues, is effective at controlling the hormonal excess symptoms of NETs and has antiproliferative effects in NETs, which primarily result in disease stabilization (30–80%), with a decrease in tumor size in <15% of patients. Interferon can inhibit DNA synthesis, block cell cycle progression in the G1 phase, inhibit protein synthesis, inhibit angiogenesis, and induce apoptosis. Interferon α treatment results in side effects in the majority of patients, with the most frequent being a flu-like syndrome (80–100%), anorexia with weight loss, and fatigue. These side effects frequently decrease in severity with continued treatment. In addition, patients become accommodated to the symptoms. More serious side effects include hepatotoxicity (31%), hyperlipidemia (31%), bone marrow toxicity, thyroid disease (19%), and rarely CNS side effects (depression, mental/visual disorders). ENETS 2012 guidelines conclude that in patients with well-differentiated


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InternalMed_Harrison. (31%), bone marrow toxicity, thyroid disease (19%), and rarely CNS side effects (depression, mental/visual disorders). ENETS 2012 guidelines conclude that in patients with well-differentiated NETs that are slowly progressive, interferon α treatment should be considered if the tumor is somatostatin receptor negative or if somatostatin treatment fails.


InternalMed_Harrison

InternalMed_Harrison. Selective internal radiation therapy (SIRT) using yttrium-90 (90Y) glass or resin microspheres is a relatively newer approach being evaluated in patients with unresectable NET liver metastases, with approximately 500 NET patients treated. The treatment requires careful evaluation for vascular shunting before treatment and a pretreatment angiogram to evaluate placement of the catheter and is generally is reserved for patients without extrahepatic metastatic disease and with adequate hepatic reserve. One of two types of 90Y microspheres are used: either microspheres with a 20to 60-µm diameter and 50 Bq/sphere (SIR-Spheres) or glass microspheres (TheraSpheres) with a 20to 30-µm diameter and 2500 Bq/sphere. The 90Y-microspheres are delivered to the liver by intra-arterial injection from percutaneously placed catheters. In four studies involving metastatic NETs, the response rate varied from 50–61% (partial or complete), tumor stabilization occurred in 22–41%, 60–100% had symptomatic