CHARACTERISTICS OF THE MOST COMMON GI-NETs (CARCINOIDS)
Appendiceal NETs (Carcinoids)
Appendiceal NETs (carcinoids) occur in 1 in every 200–300 appendectomies, usually in the appendiceal tip, have an incidence of 0.15/100,000 per year, comprise 2–5% of all GI-NETs (carcinoids), and comprise 32–80% of all appendiceal tumors. Most (i.e., >90%) are <1 cm in diameter without metastases in older studies, but more recently, 2–35% have had metastases (Table 113-3). In the SEER data of 1570 appendiceal carcinoids, 62% were localized, 27% had regional metastases, and 8% had distant metastases. The risk of metastases increases with size, with those <1 cm having a 0 to <10% risk of metastases and those >2 cm having a 25–44% risk. Besides tumor size, other important prognostic factors for metastases include basal location, invasion of mesoappendix, poor differentiation, advanced stage or WHO/ENETS classification, older age, and positive resection margins. The 5-year survival is 88–100% for patients with localized disease, 78–100% for patients with regional involvement, and 12–28% for patients with distal metastases. In patients with tumors <1 cm in diameter, the 5-year survival is 95–100%, whereas it is 29% if tumors are >2 cm in diameter. Most tumors are well-differentiated G1 tumors (87%) (Table 113-4), with the remainder primarily well-differentiated G2 tumors (13%); poorly differentiated G3 tumors are uncommon (<1%). Their percentage of the total number of carcinoids decreased from 43.9% (1950–1969) to 2.4% (1992–1999). Appendiceal goblet cell (GC) NETs (carcinoids)/carcinomas are a rare subtype (<5%) that are mixed adeno-neuroendocrine carcinomas. They are malignant and are thought to comprise a distinct entity; they frequently present with advanced disease and are recommended to be treated as adenocarcinomas, not carcinoid tumors.
Small Intestinal NETs (carcinoids)
Small intestinal (SI) NETs (carcinoids) have a reported incidence of 0.67/100,000 in the United States, 0.32/100,000 in England, and 1.12/100,000 in Sweden and comprise >50% of all SI tumors. There is a male predominance (1.5:1), and race affects frequency, with a lower frequency in Asians and greater frequency in African Americans. The mean age of presentation is 52–63 years, with a wide range (1–93 years). Familial SI carcinoid families exist but are very uncommon. These are frequently multiple; 9–18% occur in the jeunum, 70–80% are present in the ileum, and 70% occur within 6 cm (2.4 in.) of the ileocecal valve. Forty percent are <1 cm in diameter, 32% are 1–2 cm, and 29% are >2 cm. They are characteristically well differentiated; however, they are generally invasive, with 1.2% being intramucosal in location, 27% penetrating the submucosa, and 20% invading the muscularis propria. Metastases occur in a mean of 47–58% (range 20–100%). Liver metastases occur in 38%, to lymph nodes in 37% and more distant in 20–25%. They characteristically cause a marked fibrotic reaction, which can lead to intestinal obstruction. Tumor size is an important variable in the frequency of metastases. However, even small NETs (carcinoids) of the small intestine (<1 cm) have metastases in 15–25% of cases, whereas the proportion increases to 58–100% for tumors 1–2 cm in diameter. Carcinoids also occur in the duodenum, with 31% having metastases. Duodenal tumors <1 cm virtually never metastasize, whereas 33% of those >2 cm had metastases. SI NETs (carcinoids) are the most common cause (60–87%) of the carcinoid syndrome and are discussed in a later section (Table 113-7). Important prognostic factors are listed in (Table 113-5), and particularly important are the tumor extent, proliferative index by grading, and stage (Table 113-4). The overall survival at 5 years is 55–75%; however, it varies markedly with disease extent, being 65–90% with localized disease, 66–72% with regional involvement, and 36–43% with distant disease.
TABLE 113-7Clinical Characteristics in Patients with Carcinoid Syndrome |Favorite Table|Download (.pdf) TABLE 113-7Clinical Characteristics in Patients with Carcinoid Syndrome
| ||Percentage (Range) |
| ||At Presentation ||During Course of Disease |
| Diarrhea ||32–93% ||68–100% |
| Flushing ||23–100% ||45–96% |
| Pain ||10% ||34% |
| Asthma/wheezing ||4–14% ||3–18% |
| Pellagra ||0–7% ||0–5% |
| None ||12% ||22% |
| Carcinoid heart disease present ||11–40% ||14–41% |
| Male ||46–59% ||46–61% |
| Mean ||57 yrs ||59.2 yrs |
| Range ||25–79 yrs ||18–91 yrs |
|Tumor location |
| Foregut ||5–14% ||0–33% |
| Midgut ||57–87% ||60–100% |
| Hindgut ||1–7% ||0–8% |
| Unknown ||2–21% ||0–26% |
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 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.
Bronchial NETs (Carcinoids)
Bronchial NETs (carcinoids) comprise 25–33% of all well-differentiated NETs and 90% of all the poorly differentiated NETs found, likely due to a strong association with smoking. Their incidence ranges from 0.2 to 2/100,000 per year in the United States and European countries and is increasing at a rate of 6% per year. They are slightly more frequent in females and in whites compared with those of Hispanic/Asian/African descent, and are most commonly seen in the sixth decade of life, with a younger age of presentation for typical carcinoids (45 years) compared to atypical carcinoids (55 years).
A number of different classifications of bronchial GI-NETs (carcinoids) have been proposed. In some studies, they are classified into four categories: typical carcinoid (also called bronchial carcinoid tumor, Kulchitsky cell carcinoma I [KCC-I]), atypical carcinoid (also called well-differentiated neuroendocrine carcinoma [KC-II]), intermediate small-cell neuroendocrine carcinoma, and small-cell neuroendocarcinoma (KC-III). Another proposed classification includes three categories of lung NETs: benign or low-grade malignant (typical carcinoid), low-grade malignant (atypical carcinoid), and high-grade malignant (poorly differentiated carcinoma of the large-cell or small-cell type). The WHO classification includes four general categories: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma, and small-cell carcinoma. The ratio of typical to atypical carcinoids is 8–10:1, with the typical carcinoids comprising 1–2% of lung tumors, atypical 0.1–0.2%, large-cell neuroendocrine tumors 0.3%, and small-cell lung cancer 9.8% of all lung tumors. These different categories of lung NETs have different prognoses, varying from excellent for typical carcinoid to poor for small-cell neuroendocrine carcinomas. The occurrence of large-cell and small-cell lung carcinoids, but not typical or atypical lung carcinoids, is related to tobacco use. The 5-year survival is very much influenced by the classification of the tumor, with survival of 92–100% for patients with a typical carcinoid, 61–88% with an atypical carcinoid, 13–57% with a large-cell neuroendocrine tumor, and 5% with a small-cell lung cancer.
Gastric NETs (carcinoids) account for 3 of every 1000 gastric neoplasms and 1.3–2% of all carcinoids, and their relative frequency has increased three- to fourfold over the last five decades (2.2% in 1950 to 9.6% in 2000–2007, SEER data). At present, it is unclear whether this increase is due to better detection with the increased use of upper GI endoscopy or to a true increase in incidence. Gastric NETs (carcinoids) are classified into three different categories, and this has important implications for pathogenesis, prognosis, and treatment. Each originates from gastric enterochromaffin-like (ECL) cells, one of the six types of gastric neuroendocrine cells, in the gastric mucosa. Two subtypes are associated with hypergastrinemic states, either chronic atrophic gastritis (type I) (80% of all gastric NETs [carcinoids]) or Zollinger-Ellison syndrome, which is almost always a part of the MEN 1 syndrome (type II) (6% of all cases). These tumors generally pursue a benign course, with type I uncommonly (<10%) associated with metastases, whereas type II tumors are slightly more aggressive, with 10–30% associated with metastases. They are usually multiple, small, and infiltrate only to the submucosa. The third subtype of gastric NETs (carcinoids) (type III) (sporadic) occurs without hypergastrinemia (14–25% of all gastric carcinoids) and has an aggressive course, with 54–66% developing metastases. Sporadic carcinoids are usually single, large tumors; 50% have atypical histology, and they can be a cause of the carcinoid syndrome. Five-year survival is 99–100% in patients with type I, 60–90% in patients with type II, and 50% in patients with type III gastric NETs (carcinoids).
CLINICAL PRESENTATION OF NETs (CARCINOIDS)
GI/Lung NET (Carcinoid) Without the Carcinoid Syndrome
The age of patients at diagnosis ranges from 10 to 93 years, with a mean age of 63 years for the small intestine and 66 years for the rectum. The presentation is diverse and is related to the site of origin and the extent of malignant spread. In the appendix, NETs (carcinoids) usually are found incidentally during surgery for suspected appendicitis. SI NETs (carcinoids) in the jejunoileum present with periodic abdominal pain (51%), intestinal obstruction with ileus/invagination (31%), an abdominal tumor (17%), or GI bleeding (11%). Because of the vagueness of the symptoms, the diagnosis usually is delayed approximately 2 years from onset of the symptoms, with a range up to 20 years. Duodenal, gastric, and rectal NETs (carcinoids) are most frequently found by chance at endoscopy. The most common symptoms of rectal carcinoids are melena/bleeding (39%), constipation (17%), and diarrhea (12%). Bronchial NETs (carcinoids) frequently are discovered as a lesion on a chest radiograph, and 31% of the patients are asymptomatic. Thymic NETs (carcinoids) present as anterior mediastinal masses, usually on chest radiograph or computed tomography (CT) scan. Ovarian and testicular NETs (carcinoids) usually present as masses discovered on physical examination or ultrasound. Metastatic NETs (carcinoids) in the liver frequently presents as hepatomegaly in a patient who may have minimal symptoms and nearly normal liver function test results.
GI-NETs (CARCINOIDS) WITH SYSTEMIC SYMPTOMS DUE TO SECRETED PRODUCTS
GI/lung NETs (carcinoids) immunocytochemically can contain numerous GI peptides: gastrin, insulin, somatostatin, motilin, neurotensin, tachykinins (substance K, substance P, neuropeptide K), glucagon, gastrin-releasing peptide, vasoactive intestinal peptide (VIP), PP, ghrelin, other biologically active peptides (ACTH, calcitonin, growth hormone), prostaglandins, and bioactive amines (serotonin). These substances may or may not be released in sufficient amounts to cause symptoms. In various studies of patients with GI-NETs (carcinoids), elevated serum levels of PP were found in 43%, motilin in 14%, gastrin in 15%, and VIP in 6%. Foregut NETs (carcinoids) are more likely to produce various GI peptides than are midgut NETs (carcinoids). Ectopic ACTH production causing Cushing’s syndrome is seen increasingly with foregut carcinoids (respiratory tract primarily) and, in some series, has been the most common cause of the ectopic ACTH syndrome, accounting for 64% of all cases. Acromegaly due to growth hormone–releasing factor release occurs with foregut NETs (carcinoids), as does the somatostatinoma syndrome, but rarely occurs with duodenal NETs (carcinoids). The most common systemic syndrome with GI-NETs (carcinoids) is the carcinoid syndrome, which is discussed in detail in the next section.
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 foregut NETs (carcinoids). With bronchial NETs (carcinoids), the flushes frequently are prolonged for hours to days, reddish in color, and associated with salivation, lacrimation, diaphoresis, diarrhea, and hypotension. The flush associated with gastric NETs (carcinoids) can also be reddish in color, but with a patchy distribution over the face and neck, although the classic flush seen with midgut NETs (carcinoids) can also be seen with gastric NETs (carcinoids). It may be provoked by food and have accompanying pruritus.
Diarrhea usually occurs with flushing (85% of cases). The diarrhea usually is described as watery, with 60% of patients having <1 L/d of diarrhea. Steatorrhea is present in 67%, and in 46%, it is >15 g/d (normal <7 g). Abdominal pain may be present with the diarrhea or independently in 10–34% of cases.
Cardiac manifestations occur initially in 11–40% (mean 26%) of patients with carcinoid syndrome and in 14–41% (mean 30%) at some time in the disease course. The cardiac disease is due to the formation of fibrotic plaques (composed of smooth-muscle cells, myofibroblasts, and elastic tissue) involving the endocardium, primarily on the right side, although lesions on the left side also occur occasionally, especially if a patent foramen ovale exists. The dense fibrous deposits are most commonly on the ventricular aspect of the tricuspid valve and less commonly on the pulmonary valve cusps. They can result in constriction of the valves, and pulmonic stenosis is usually predominant, whereas the tricuspid valve is often fixed open, resulting in regurgitation predominating. Overall, in patients with carcinoid heart disease, 90–100% have tricuspid insufficiency, 43–59% have tricuspid stenosis, 50–81% have pulmonary insufficiency, 25–59% have pulmonary stenosis, and 11% (0–25%) left-side lesions. Up to 80% of patients with cardiac lesions develop heart failure. Lesions on the left side are much less extensive, occur in 30% at autopsy, and most frequently affect the mitral valve. Up to 80% of patients with cardiac lesions have evidence of heart failure. At diagnosis in various series, 27–43% of patients are in New York Heart Association class I, 30–40% are in class II, 13–31% are in class III, and 3–12% are in class IV. At present, carcinoid heart disease is reported to be decreasing in frequency and severity, with mean occurrence in 20% of patients and occurrence in as few as 3–4% in some reports. Whether this decrease is due to the widespread use of somatostatin analogues, which control the release of bioactive agents thought involved in mediating the heart disease, is unclear.
Other clinical manifestations include wheezing or asthma-like symptoms (8–18%), pellagra-like skin lesions (2–25%), and impaired cognitive function. A variety of noncardiac problems due to increased fibrous tissue have been reported, including retroperitoneal fibrosis causing urethral obstruction, Peyronie’s disease of the penis, intraabdominal fibrosis, and occlusion of the mesenteric arteries or veins.
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, foregut NETs (carcinoids) for 0–33%, hindgut for 0–8%, and an unknown primary location for 2–26% (Tables 113-3 and 113-7).
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 is thought to be predominantly responsible for the diarrhea. Patients with the carcinoid syndrome have increased colonic motility with a shortened transit time and possibly a secretory/absorptive alteration that is compatible with the known actions of serotonin in the gut mediated primarily through 5-HT3 and, to a lesser degree, 5-HT4 receptors. Serotonin receptor antagonists (especially 5-HT3 antagonists) relieve the diarrhea in many, but not all, patients. A tryptophan 5-hydroxylase inhibitor, LX-1031, which inhibits serotonin synthesis in peripheral tissues, is reported to cause a 44% decrease in bowel movement frequency and a 20% improvement in stool form in patients with the carcinoid syndrome. Additional studies suggest that tachykinins may be important mediators of diarrhea in some patients. In one study, plasma tachykinin levels correlated with symptoms of diarrhea. Serotonin does not appear to be involved in the flushing because serotonin receptor antagonists do not relieve flushing. In patients with gastric carcinoids, the characteristic red, patchy pruritic flush is thought due to histamine release because H1 and H2 receptor antagonists can prevent it. Numerous studies have shown that tachykinins (substance P, neuropeptide K) are stored in GI-NETs (carcinoids) and released during flushing. However, some studies have demonstrated that octreotide can relieve the flushing induced by pentagastrin in these patients without altering the stimulated increase in plasma substance P, suggesting that other mediators must be involved in the flushing. A correlation between plasma tachykinin levels (but not substance P levels) and flushing has been reported. Prostaglandin release could be involved in mediating either the diarrhea or flush, but conflicting data exist. Both histamine and serotonin may be responsible for the wheezing as well as the fibrotic reactions involving the heart, causing Peyronie’s disease and intraabdominal fibrosis.
The exact mechanism of the heart disease remains unclear, although increasing evidence supports a central role for serotonin. Patients with heart disease have higher plasma levels of neurokinin A, substance P, plasma atrial natriuretic peptide (ANP), pro-brain natriuretic peptide, chromogranin A, and activin A as well as higher urinary 5-HIAA excretion.
The valvular heart disease caused by the appetite-suppressant drug dexfenfluramine is histologically indistinguishable from that observed in carcinoid disease. Furthermore, ergot-containing dopamine receptor agonists used for Parkinson’s disease (pergolide, cabergoline) cause valvular heart disease that closely resembles that seen in the carcinoid syndrome. Furthermore, in animal studies, the formation of valvular plaques/fibrosis occurs after prolonged treatment with serotonin as well as in animals with a deficiency of the 5-HIAA transporter gene, which results in an inability to inactivate serotonin. Metabolites of fenfluramine, as well as the dopamine receptor agonists, have high affinity for serotonin receptor subtype 5-HT2B receptors, whose activation is known to cause fibroblast mitogenesis. Serotonin receptor subtypes 5-HT1B,1D,2A,2B normally are expressed in human heart valve interstitial 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 conclusion 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 occur in patients with carcinoid heart disease and correlate with the presence of right ventricular dysfunction and the extent of valvular regurgitation in patients with GI-NETs (carcinoids).
Patients may develop either a typical or, rarely, an atypical carcinoid syndrome (Fig. 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 the kidney. Characteristically, urinary 5-HTP and 5-HT are increased, but urinary 5-HIAA levels are only slightly elevated. Foregut carcinoids are the most likely to cause an atypical carcinoid syndrome; however, they also can cause a typical carcinoid syndrome.
One of the most immediate life-threatening complications of the carcinoid syndrome is the development of a carcinoid crisis. This is more common in patients who have intense symptoms or have greatly increased urinary 5-HIAA levels (i.e., >200 mg/d). The crisis may occur spontaneously; however, it is usually provoked by procedures such as anesthesia, chemotherapy, surgery, biopsy, endoscopy, or radiologic examinations such as during biopsies, hepatic artery embolization, and vessel catheterization. It can be provoked by stress or procedures as mild as repeated palpation of the tumor during physical examination. Patients develop intense flushing, diarrhea, abdominal pain, cardiac abnormalities including tachycardia, hypertension, or hypotension, and confusion or stupor. If not adequately treated, this can be a terminal event.
DIAGNOSIS OF THE CARCINOID SYNDROME AND GI-NETs (CARCINOIDS)
The diagnosis of carcinoid syndrome relies on measurement of urinary or plasma serotonin or its metabolites in the urine. The measurement of 5-HIAA is used most frequently. False-positive elevations may occur if the patient is eating serotonin-rich foods such as bananas, pineapples, walnuts, pecans, avocados, or hickory nuts or is taking certain medications (cough syrup containing guaifenesin, acetaminophen, salicylates, serotonin reuptake inhibitors, or l-dopa). The normal range for daily urinary 5-HIAA excretion is 2–8 mg/d. Serotonin overproduction was noted in 92% of patients with carcinoid syndrome in one study, and in another study, 5-HIAA had 73% sensitivity and 100% specificity for carcinoid syndrome. Serotonin overproduction is not synonymous with the presence of clinical carcinoid syndrome because 12–26% of patients with serotonin overproduction do not have clinical evidence of the carcinoid syndrome.
Most physicians use only the urinary 5-HIAA excretion rate; however, plasma and platelet serotonin levels, if available, may provide additional information. Platelet serotonin levels are more sensitive than urinary 5-HIAA but are not generally available. A single plasma 5-HIAA determination was found to correlate with the 24-h urinary values, raising the possibility that this could replace the standard urinary collection because of its greater convenience and avoidance of incomplete or improper collections. Because patients with foregut NETs (carcinoids) may produce an atypical carcinoid syndrome, if this syndrome is suspected and the urinary 5-HIAA is minimally elevated or normal, other urinary metabolites of tryptophan, such as 5-HTP and 5-HT, should be measured (Fig. 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 in 56–100% of patients with GI-NETs (carcinoids), and the level correlates with tumor bulk. Serum chromogranin A levels are not specific for GI-NETs (carcinoids) because they are also elevated in patients with pNETs and other NETs. Furthermore, a major problem is caused by potent acid antisecretory drugs such as proton pump inhibitors (omeprazole and related drugs) because they almost invariably cause elevation of plasma chromogranin A levels; the elevation occurs rapidly (3–5 days) with continued use, and the elevated levels overlap with the levels seen in many patients with NETs. Plasma neuron-specific enolase levels are also used as a marker of GI-NETs (carcinoids) but are less sensitive than chromogranin A, being increased in only 17–47% of patients. Newer markers have been proposed including pancreastatin (a chromogranin A breakdown product) and activin A. The former is not affected by proton pump inhibitors; however, its sensitivity and specificity are not established. Plasma activin elevations are reported to correlate with the presence of cardiac disease with a sensitivity of 87% and specificity of 57%.
TREATMENT Carcinoid Syndrome and Nonmetastatic Gastrointestinal Neuroendocrine Tumors (Carcinoids) CARCINOID SYNDROME
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.
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%.
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 lanreotide-SR/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 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%.
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.
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. Lanreotide-autogel (Somatuline) is given every 4–6 weeks.
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.
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).
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, 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.
Peptide radioreceptor therapy (using radiotherapy with radiolabeled somatostatin analogues), the use of radiolabeled microspheres, 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. GI-NETs (CARCINOIDS) (NONMETASTATIC)
Surgery is the only potentially curative therapy. Because with most 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 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.
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.
Structure of somatostatin and synthetic analogues used for diagnostic or therapeutic indications.