Carcinoid syndrome is a collective of symptoms that occurs in patients with Carcinoid tumor. It is caused by excessive endogenous secretion of hormones mainly serotonin and kallikrein. The syndrome includes flushing and diarrhea, and, less frequently, heart failure and bronchoconstriction. Carcinoid tumors arise from neuroendocrine cells, which are widespread in the human body, especially in the organs derived from the primitive intestine.In 1980, the World Health Organization (WHO) applied the term carcinoid to all tumors of the diffuse endocrine system (synonymous with amine precursor uptake and decarboxylation [APUD] and neuroendocrine cell system). The carcinoid syndrome is seen in approximately 10% of carcinoid tumors and the symptoms appear when the vasoactive substances from the tumors enter the systemic circulation escaping hepatic degradation. Typically, 90% of carcinoid tumors originate from the distal ileum or appendix (the embryologic midgut); carcinoid tumors represent 90% of appendiceal tumor
Four key symptoms of carcinoid syndrome
Chronic diarrhea and carcinoid syndrome
Chronic diarrhea is seen up to 80% of patients with carcinoid syndrome. There are many causes of chronic diarrhea; however, certain characteristics may help identify this symptom with carcinoid syndrome.The stools in carcinoid syndrome are watery and result from intestinal hypermotility and hypersecretion. The increase in gut motility in patients with carcinoid syndrome is likely to be caused by serotonin, which is released as part of carcinoid syndrome(10) and stimulates small bowel and colonic secretions and motility."A clue to carcinoid syndrome is that fasting does not reduce the diarrhea, because the increased motility and increased secretion are independent of intake." -Dr David C Metz. Another clue is that diarrhea may be nocturnal.Nocturnal diarrhea may be observed in other conditions (eg, IBD), but it is typically not seen in IBS. If IBD is suspected clinically, the patient can be evaluated endoscopically and/or radiologically.
Abdominal pain and carcinoid syndrome
Abdominal pain is a nonspecific symptom with many different potential causes. Diagnosing abdominal pain associated with carcinoid syndrome is difficult, as there are no real distinguishing factors. In carcinoid syndrome, abdominal pain or discomfort may be due to gut hypermotility, obstructive-type symptoms or, rarely, tumor intussusception. Pain may also be due to serosal involvement of the tumor or stretching of the liver capsule because of large hepatic metastases. Abdominal pain in carcinoid syndrome is intermittent and crampy, and occurs in approximately 40%-51% of patients. Pain associated with diarrhea in carcinoid syndrome may be colicky and may not be relieved with defecation.
Flushing and carcinoid syndrome
Flushing is the most common symptom of carcinoid syndrome and occurs in more than 90% of patients. Usually pink to red in color, flushing typically affects the face, neck, and upper trunk. Flushing in carcinoid syndrome is characteristically dry—in women, this helps distinguish it from menopausal hot flashes, which are often associated with perspiration. The specific cause of flushing in carcinoid syndrome is unknown, although it has been shown to be preceded by a rise in substance P. Transient hypotension, headache, and bronchoconstriction may coincide with flushing in patients with carcinoid syndrome, particularly in those with foregut NETs. Physicians should consider that menopausal hot flashes are not associated with a fall in blood pressure.
Cardiac disease and carcinoid syndrome
Cardiac disease is one of the most serious aspects of this disease, occurring in approximately two-thirds of patients with carcinoid syndrome. Carcinoid heart disease can be detected with 2-dimensional echocardiographic and Doppler examinations. A combination of tricuspid and pulmonary lesions is characteristic of carcinoid heart disease.
Epidemiologic studies have reported incidences of carcinoid tumors ranging from 0.79 to 1.88 per 100,000 population; a study from the Netherlands found an incidence of 1.95 per 100,000 population. These numbers are probably underestimates, because a large number of affected individuals do not develop the related syndrome. A Swedish autopsy study reported an incidence of 8.4 cases per 100,000 population. Carcinoid tumors are discovered in approximately 1-2 appendectomy cases per 200-300 per year.
Tumors that are smaller than 1 cm in diameter rarely metastasize, while lesions larger than 2 cm often metastasize. The presence of a few small metastases to the liver is associated with a longer life expectancy. Morbidity is related to vasoactive amine production. The survival rate usually correlates inversely with the levels of daily urinary 5-HIAA excretion. Death is usually caused by cardiac or hepatic failure and by complications associated with tumor growth. Factors associated with higher mortality are high plasma levels of neuropeptide K and chromogranin A, location of the tumor in the large bowel, advanced disease, and a concomitant second malignancy. Mucus-producing tumors developing in the appendix also have some malignant characteristics.
Race: No racial prevalence is known. Sex: This syndrome affects men and women equally.
Age: Carcinoids occur most frequently in patients aged 50-70 years. Age at diagnosis ranges from 10- 93 years (mean age 55 y).
Similar to many other cancers, the exact cause is unknown. Malignant carcinoid syndrome does not generally appear to be hereditary. A study of genetic alterations in small bowel carcinoid tumors found that loss of all or most of chromosome 18 was the most common finding. Heterozygosity was also lost on chromosome arms 9p and 16q. Although the amplitude of observed gains was modest in comparison with those reported in some other tumor types, one focal region of recurrent gain on 14q mapped to the locus of the gene encoding the antiapoptotic protein DAD1.
Diagnosing Carcinoid tumors can be a challenge. The appropriate use of biomarker testing may be helpful in diagnosing Carcinoid tumors, even in the absence of a secretory syndrome. Initial indications should then be confirmed by additional imaging and/or endoscopic techniques, biochemical evaluation, and biopsy, as appropriate.
Biomarkers Chromogranin A (CgA): Up to 90% of patients with NETs have elevated CgA levels. 5-Hydroxyindoleacetic acid (5-HIAA): Has diagnostic and prognostic value in NETs associated with carcinoid syndrome.(23) Plasma neuronal specific enolase (NSE): A useful circulating marker for poorly differentiated NETs, where NSE sensitivity exceeds 70% and specificity can reach 85%.Imaging
Computed tomography (CT): A widely available tool for the localization and staging of solid tumors, including Carcinoid tumors. Magnetic resonance imaging (MRI): A well-recognized imaging technique, useful in the localization of NETs and their metastases.
Octreoscan™: A unique, whole-body imaging technique that identifies primary NETs and metastases that express somatostatin receptors.
NETs are complex cancers with the potential to involve multiple co morbidities. Management of a NET may depend on factors such as tumor size, grade, stage, location, secretory status, and potential associated symptoms, if any. Gathering input from a multidisciplinary team gives physicians an opportunity to improve outcomes. Among the treatment options that may be considered on a patient-by-patient basis are:
1. Surgery with curative intent for localized NETs. Surgery can also play a palliative role in certain metastatic patients
2. Chemotherapy and other systemic agents
3. Targeted radionuclide therapy
4. Radiofrequency ablation and chemoembolization to address hepatic metastases
5. Clinical trial participation.
Because of the rarity of carcinoid syndrome and complexity of the symptoms, many patients remainundiagnosed until well into the late stages of the illness, at the time when their carcinoid syndrome becomes apparent. With the increase in clinical awareness, carcinoid will become increasingly identified, often at an earlier stage in the course of the disease. This review provides brief information in detecting and assessing advanced carcinoid disease, and then continues to discuss strategies (both potentially curative and palliative) to control symptoms, at earlier stages and improve quality of life for these patients.