Symptom
Frequency (%)
Flushing
85
Telangiectasia
25
Cyanosis
18
Pellagra
2–25
Diarrhea
75–80
Abdominal cramp
75
Bronchospasm
20
Valvular lesions
50
Right heart
40
Left heart
13
Asthenia
<5
Neuropsychiatric symptoms
<5
Musculoskeletal
<5
The two most common symptoms of carcinoid tumors are flushing and diarrhea. Both of them associate with releasing serotonin and its metabolites into the bloodstream. Flushing occurs in about 85 % of patients with carcinoid syndrome and usually is of sudden onset. It is observed on the skin of the face, neck, upper chest, and the nipple line, and the skin color varies from pink to red. Although the flush may be provoked by stress, exercise, some foods such as chocolate and cheese, drinking alcohol, certain drugs such as serotonin reuptake inhibitors, and catecholamines, sometimes it may happen spontaneously [6–8].
Foods that triggered the flush usually contain tyramines. Flushing episodes are usually brief and last a few minutes. The flushes observed with gastric and bronchopulmonary tumors tend to be more intense, and they may continue several hours or days but are not permanent. In these cases, the involvement of the upper trunk is uncommon.
Diarrhea occurs in 75–80 % of cases with carcinoid syndrome, and in 85 %, it is accompanied by flushing. The diarrhea observed in patients with carcinoid syndrome is a secretory diarrhea, and the episodes are up to 20 per day. The diarrhea is described as watery. Thus, it may cause fluid and electrolyte depletion. Abdominal cramps may be accompanied by a watery diarrhea. The diarrhea is unrelated to nutrition and may continue during fasting.
Other manifestations of carcinoid syndrome include cardiac and pulmonary symptoms and skin lesions. Cardiac disease in patients with carcinoid syndrome occurs in about 50 % of the cases and is usually characterized by valvular lesions [9, 10]. The lesions develop due to the formation of fibrotic plaques on the cardiac valves, especially on the right side. Retraction of the valves results in regurgitation and right-sided congestive heart failure [11]. The right-sided involvement in patients with carcinoid syndrome is predominant. Of these patients, 97 % have tricuspid insufficiency, 59 % tricuspid stenosis, 50 % pulmonary insufficiency, 25 % pulmonary stenosis, and 11 % (0–25 %) left-side lesions [12]. These patients may be present with tachycardia, palpitation, low blood pressure, and heart failure symptoms such as dyspnea, edema, and effusion.
The most common pulmonary symptoms in patients with carcinoid syndrome are wheezing, shortness of breath, and asthma-like symptoms developing due to bronchospasm [13]. They occur about 20 % of these patients. These symptoms occur due to hormone and peptide release such as serotonin and its metabolites or pulmonary fibrosis.
Carcinoid syndrome-related skin lesions include facial telangiectasis, pellagra-like skin lesions, and purplish areas. They occur about 2–25 % of the patients and appear on the face and upper lip. Other uncommon symptoms in patients with carcinoid syndrome include asthenia, irritability, agitation, aggression, arthritis, arthralgia, myopathy, fatigue, abdominal pain, and tenderness [14].
29.3 Causes
The etiology of carcinoid tumor is unclear. It occurs usually as sporadically but rarely to be hereditary. In small bowel carcinoid tumors, loss of arms 9p and 16q on chromosome 18 has been thought to be associated with these tumors [15]. Also, these tumors may be present as a part of multiple endocrine neoplasia.
Although most of carcinoid tumors are asymptomatic and silent tumor, they become symptomatic disease when carcinoid tumors metastasized to the liver. In this stage, serotonin and other vasoactive substances secreted by the tumor cells escape hepatic metabolization and reach to the systemic circulation. Thus, they are called as carcinoid syndrome. The principal chemical substrates which are responsible for these symptoms and signs are presented in Table 1.2. Some carcinoid tumors secrete certain and specific vasoactive amines and peptides. For example, gastric carcinoids produce usually histamine, but serotonin and adrenocorticotropic hormone (ACTH) are released by carcinoid tumors arising from the lung. Primary tumor location, peptides secreted from the tumor cells, and frequency of carcinoid syndrome were illustrated in Table 1.3.
Table 1.2
Substrates causing carcinoid tumors
Amines |
Serotonin |
5-Hydroxytryptophan |
Norepinephrine |
Dopamine |
Histamine |
Polypeptides |
Gastrin |
Corticotropin (ACTH) |
Bradykinin |
Pancreatic polypeptide (PP) |
Somatostatin |
Vasoactive intestinal peptide (VIP) |
Substance P |
Peptide YY |
Neurokinin A and B |
Motilin |
Kallikrein |
Growth hormone |
Neuropeptide K |
Glucagon |
Beta-endorphin |
Neurotensin |
Chromogranin A |
Table 1.3
Primary tumor location, peptides secreted from the tumor cells, and frequency of carcinoid syndrome
Location | Secretory products | Carcinoid syndrome |
|---|---|---|
Foregut | 5-Hydroxytryptophan histamine, multiple polypeptides | Rare |
Midgut | Serotonin prostaglandins, polypeptides | Often |
Hindgut | Variable | Rare |
29.4 Diagnosis
The first step for the diagnosis is medical history and physical examination. Patients should be questioned for symptoms and signs of carcinoid syndrome, when they have symptoms including unexplained recurrent flushing and severe diarrhea episodes. Secondly, to determine the levels of substances released by tumor cells, laboratory tests including blood and urine analyses are done. These laboratory tests include the following.
29.4.1 5-HIAA
5-Hydroxyindoleacetic acid (HIAA), a metabolite of serotonin, is extensively used for the diagnosis of the carcinoid syndrome. To measure 24-h urinary excretion of 5-HIAA is the most sensitive test and should be used as an initial diagnostic test. Its sensitivity and specificity is over 90 % for the carcinoid syndrome [16]. To avoid false-positive elevation of urinary excretion of 5-HIAA, patients should prohibit intake of tryptophan- and serotonin-rich foods such as bananas, walnuts, pecans, avocados, and pineapples for 3 days prior to urine collection and discontinue certain drugs containing serotonin reuptake inhibitors, acetaminophen, salicylates, and L-dopa [17]. Reasons of false-positive and false-negative 5-HIAA urinary excretion are shown in Table 1.4. Urinary excretion of HIAA is more sensitive in patients with primary midgut than those with hindgut and foregut which rarely secreted serotonin.
Table 1.4
Reasons of false-positive and false-negative 5-HIAA urinary excretion
False positive | False negative |
|---|---|
Drugs | Drugs |
Phenobarbital | Corticotrophin |
Phentolamine | Levodopa |
Nicotine | MAO inhibitors |
Acetaminophen | Phenothiazines |
Fluorouracil | Aspirin |
Melphalan | Isoniazid |
Guaifenesin | Ethanol |
Ephedrine | Streptozotocin |
Phenacetin | Methyldopa |
Methamphetamine | Heparin |
Foods and drinks | |
Pineapples | |
Bananas | |
Walnuts | |
Avocados | |
Tomatoes | |
Pecans | |
Hickory nuts | |
Kiwi fruit | |
Caffeine |
29.4.2 Serotonin
Measurement of serum levels and urinary excretion of serotonin may be beneficial for the diagnosis. The benefit is higher in patients with midgut carcinoid tumor secreting serotonin, but its benefit is limited for the other carcinoids. Blood serotonin concentration may be measured by using different methods, but there is no described standard method to measure serum serotonin level.
29.4.3 Chromogranin A
Chromogranin A, a group of acidic glycoprotein, is stored and released from chromaffin granules of neuroendocrine cells. The measurement of serum chromogranin A is often used to diagnose well-differentiated neuroendocrine tumors. The serum level of chromogranin A is associated with tumor burden [18, 19]. As a tumor marker, chromogranin A is moderately sensitive and nonspecific [17]. Foods and drugs such as proton pump inhibitors may affect serum chromogranin concentration [20]. Due to a nonspecific marker, plasma chromogranin A is useful with urinary excretion of 5-HIAA. For patients who have elevated plasma chromogranin A at the baseline, it is an appropriate marker for detection of recurrence and monitoring of response to different treatments.
29.5 Imaging
Imaging studies including computed tomography, magnetic resonance imaging, and scintigraphy are available for carcinoid tumors. For diagnosis of carcinoid tumors and related syndromes, the first step for imaging tests is computed tomography of the abdomen. Computed tomography is usually recommended to localize the site of primary tumor and to assess the extension of tumor metastases. Carcinoid tumor and its metastasis may appear as a hypervascular lesion. Carcinoid tumor is isodense with liver on a noncontrasted imaging, whereas it appears as a hyperdense lesion at the early arterial phase after the injection of intravenous contrast. Carcinoid tumors originating in the small bowel may not be seen on computed tomography because of their small size.
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