Carcinoid syndrome refers to a group of symptoms caused by the systemic release of different kinds of humoral factors like polypeptides, biogenic amines, and prostaglandins mostly from well-differentiated neuroendocrine tumors. Previously well-differentiated neuroendocrine tumors were known as carcinoid tumors. Neuroendocrine tumors are derived from enterochromaffin cells that are ubiquitous in our body. It is reported that only about 8% to 10% of neuroendocrine tumors result into carcinoid syndrome.
Carcinoid syndrome is most commonly caused by neuroendocrine tumors of midgut that metastasize to the liver. Neuroendocrine tumors of foregut and hindgut can also rarely cause carcinoid syndrome. The most common neuroendocrine tumors occur in the gastrointestinal (GI) tract (68%) followed by respiratory tract (28%). Neuroendocrine tumors can rarely arise from other areas like ovaries, testicles, and kidneys.
Neuroendocrine tumors are relatively rare tumors. As mentioned above, only 8% to 10% of neuroendocrine tumors result into carcinoid syndrome. According to Surveillance, Epidemiology, and End Results (SEER), the age-adjusted incidence of nonpancreatic neuroendocrine tumors is 4.7 per 100,000. The incidence of neuroendocrine tumors has been rising. The incidence of neuroendocrine tumors, including non-pancreatic and pancreatic neuroendocrine tumors, increased from 1.09 to 5.25/100,000 between 1973 through 2004 (per data from SEER). This increase in incidence in the past decades is likely due to an increased number of endoscopic and radio-imaging studies. Incidence varies by gender and race. Recent data suggest the incidence of neuroendocrine tumors is higher in black males compared to Caucasians (6.46 versus 4.6/100,000). The ratio of tumor incidence among male and female is almost equal with slightly higher in a male. The median age of diagnosis of neuroendocrine tumors is between 55 and 60.
Carcinoid syndrome occurs when biologically active amines and peptides enter the systemic circulation escaping the first pass metabolism of the liver. Normally, these bioactive products are inactivated by the liver. However, in cases of neuroendocrine tumors with liver metastasis, either these bioactive products are directly released into the systemic circulation, or they escape inactivation due to deranged liver function.
Less commonly, carcinoid syndrome can occur without liver metastasis in conditions like a primary gut tumor with extensive retroperitoneal nodal metastases, bronchial carcinoid, or ovarian tumor, which releases bioactive amines directly into the systemic circulation.
It is reported that neuroendocrine tumors release about 40 different types of biologically active amines and peptides. The most common are serotonin, histamine, tachykinins, kallikrein, and prostaglandins. The majority of symptoms are due to serotonin which is a product of tryptophan metabolism.
Usually, only 1% of dietary tryptophan is converted into serotonin. However, in a patient with neuroendocrine tumors, up to 70% of tryptophan is converted into serotonin. Serotonin undergoes oxidative reaction and leads to the formation of 5-hydroxy indoleacetic acid (5-HIAA) by aldehyde dehydrogenase, which subsequently is eliminated into the urine.
Serotonin causes increased motility and secretion of gastrointestinal tract resulting in diarrhea. As most of the body's tryptophan is diverted to serotonin formation pathway by neuroendocrine tumors, it leads to a deficiency of tryptophan which is needed for synthesis of niacin. Subsequently, deficiency of niacin occurs causing Pellagra which manifests as dermatitis, dementia, and diarrhea. Prostaglandins also mediate increased intestinal motility and fluid secretion in GI tract causing diarrhea.
Neuroendocrine tumors of foregut and lungs do not contain the enzyme aromatic L-amino acid decarboxylase which converts 5-hydroxytryptophan to serotonin. Thus lungs and foregut neuroendocrine tumors do not produce serotonin. Hindgut neuroendocrine tumors usually do not produce any bioactive hormone.
Histamine is released mostly by gastric neuroendocrine tumors which can cause atypical flushing and pruritus. Flushing is also secondary to the vasodilatory effect of tachykinins (substance p, neurokinin A, neuropeptide k). In some gastric neuroendocrine tumors, flushing is secondary to overproduction of histamine.
Common clinical presentations of carcinoid syndrome include vasodilatory effects of biologically active amines, peptides and prostaglandins (flushing, wheezing), gastrointestinal symptoms (diarrhea, malabsorption), Pellagra (secondary to niacin deficiency), cardiac symptoms (right sided valvular disease, mostly tricuspid regurgitation), fatigue, and sometimes cognitive impairment.
Flushing is the most common presentation and occurs in about 85% of patience with carcinoid syndrome. It is paroxysmal and is described as salmon pink to dark red discoloration of the skin of upper body such as the face, neck, and upper trunk, lasting anywhere from 30 seconds to 30 minutes. It occurs spontaneously, but it can also be precipitated by eating, drinking alcohol, stress, liver palpation, and anesthesia. It is mostly associated with midgut neuroendocrine tumors. The patient can also have tachycardia, peri-orbital swelling and increased lacrimation.
Diarrhea occurs in about 80% of cases. Patients usually describe diarrhea as explosive, non-bloody, and watery. It can occur up to 30 times a day. Diarrhea is usually chronic in carcinoid syndrome. Abdominal cramping may occur. Diarrhea is not always associated with flushing.
Cardiac involvement occurs in up to 60% to 70% of patients. It can cause plaque like deposits of fibrous tissue on the endometrium, valves, chambers, pulmonary and aortic arteries. Patients may present with signs and symptoms of heart failure or valvular heart disease. It usually affects the right side of the heart, unless it is right to left shunt or the neuroendocrine tumors are in the lungs.
Bronchospasm is not very common and occurs in about 10% to 20% of patients with carcinoid syndrome. It presents as wheezing and dyspnea associated with flushing episodes. It may get worse with beta agonists.
Due to prolonged vasodilation, purplish rash (usually on the nose, upper lip, and malar area) tend to appear at the late stage of carcinoid syndrome.
Other less common manifestations include Pellagra, muscle wasting, ureteral obstruction due to retroperitoneal fibrosis.
There are some atypical symptoms which are caused by gastric and lung neuroendocrine tumors. Gastric neuroendocrine tumors can cause patchy, well demarcated, serpiginous, cherry red flushing with intense pruritus due to secretion of histamine. Lung neuroendocrine tumors can cause severe and prolonged flushing, lasting hours to days, associated with anxiety, altered mental status, and tremors. It may be related to histamine release, but the exact cause is unknown.
The diagnostic workup of carcinoid syndrome includes initial testing for biochemical markers followed by localization of tumor with radiographic and endoscopic studies.
Testing for Biochemical Markers
Twenty-four-hour urine for 5-HIAA is the initial diagnostic test. The 5-HIAA is the end product of serotonin metabolism. This urine test has 90% sensitivity and specificity. A false positive can be due to tryptophan-rich food like banana, pineapple, plum, kiwi, avocado, eggplant, pecan, and walnut. Various medicines including acetaminophen, guaifenesin, caffeine, nicotine, methamphetamine, and phenobarbital can increase the 5-HIAA level. On the other hand, medications like aspirin, ethanol, heparin, imipramine, levodopa, methyldopa, monoamine oxidase (MAOI), INH, and corticotropin can decrease 5-HIAA level. Patients should avoid these foods and medicines for at least 24 hours before and during urine collection. The 5-HIAA correlates with tumor burden and can be used to follow treatment response.
Chromogranin A is a glycoprotein secreted by neuroendocrine tumors. It is useful for detection of the non-secreting tumor. It has very good sensitivity but poor specificity. It is an excellent marker for follow up. Certain conditions like the use of proton pump inhibitors, atrophic gastritis, renal failure, hyperthyroidism, heart failure, HTN, prostate cancer can also cause marked elevation of CgA.
Twenty-four-hour Urine for serotonin is not available in the United States but can be useful in foregut neuroendocrine tumors with rare carcinoid syndrome due to 5-HT.
Blood serotonin is usually not recommended as the specificity of this test is not reliable.
Plasma 5-HIAA level is convenient but yet to be validated.
Localizing and Staging Studies
If positive for biomarkers, various radiographic imaging and or endoscopic procedures can be obtained for tumor localization.
Radiographic imaging includes cross-sectional imaging with triple phase Computerized tomography scan, Magnetic Resonance Imaging, and somatostatin receptor scintigraphy. Abdominal CT (with triphasic CT of the liver) is the diagnostic test of choice. Some prefer MRI over CT due to greater sensitivity for liver metastases.
Indium-111 pentetreotide (Octreoscan) has more than 90% sensitivity in symptomatic patients and 80% to 90% sensitivity in asymptomatic patients. It cannot detect poorly differentiated neuroendocrine tumors, and its specificity is low. Functional PET imaging with 68-Ga Dotatate is preferred, and it is a newer modality with improved sensitivity and better resolution for a small tumor.
Bronchoscopy with biopsy can be performed for bronchial neuroendocrine tumors. If positive for radiographic findings, based on the location of the disease, upper or lower endoscopy or ultrasound-guided biopsy could be performed for histopathology. Neuron-specific enolase, Chromogranin A, Ki-67 mitotic index, saprophytic, and serotonin markers could be checked in tissue obtained.
There are different treatment modalities for carcinoid syndrome which include somatostatin analogs, liver-directed treatment therapy, surgical debulking for early-stage low-grade neuroendocrine tumors, and chemotherapy for treatment of poorly differentiated neuroendocrine tumors or refractory carcinoid syndrome.
Surgery plays a vital role in the treatment of carcinoid syndrome with or without metastases. If possible, always consider surgical resection of the primary tumor as well as nodal and liver metastases to reduce the tumor burden.
For medical management, there are two somatostatin analogs available, Octreotide and Lanreotide. Somatostatin is an amino acid peptide which is an inhibitory hormone, which is synthesized by paracrine cells located ubiquitously throughout the gastrointestinal tract. It inhibits the release of most of the gastrointestinal, endocrine hormones. About 80% of neuroendocrine tumors have somatostatin receptors. Using somatostatin analog inhibits the release of biogenic amines which leads to control of symptoms such as flushing and diarrhea.
Octreotide is available as short-acting subcutaneous injection as well as depot form intramuscular injection (Sandostatin LAR) which can be administered monthly. Patients should start with 20 mg to 30 mg IM every four weeks, and a gradual dose increase may be necessary. Short-acting Octreotide can be started for a patient with severe or refractory symptoms.
Lanreotide is a long-acting formulation (Somatuline Depot) which is administered at dose 60 mg to 120 mg every four weeks. It has similar efficacy as Octreotide.
Both somatostatin analogs provide symptoms relief in 50% to 70% of patients and biochemical response in 40% to 60% patients. Many studies have shown that Octreotide and Lanreotide also inhibit the proliferation of tumor cells.
The most common side effects associated with somatostatin analogs are nausea, abdominal bloating, and steatorrhea, which is due to pancreatic malabsorption. Supplementing pancreatic enzymes usually helps to alleviate the adverse symptoms. Due to decreased motility and contraction of the gallbladder from somatostatin’s inhibitory effect, patients are at risk for developing biliary sludge and gallstones, which has to be discussed with patients before starting therapy.
In patients with bronchial neuroendocrine tumors with carcinoid syndrome diagnosed at early stage, surgical resection of the tumor leads to complete cure of carcinoid syndrome. Patients who have surgically resectable hepatic metastases, surgical resection or partial hepatectomy leads to symptomatic improvement. In patients with heavy tumor burden and widely metastatic disease, palliative cytoreductive or tumor debulking surgery has been reported to improve symptoms, morbidity, and mortality. Elective cholecystectomy can also be offered during surgery to prevent biliary sludging and gallstones which can occur with somatostatin analog therapy. Endoscopic resection of early gastric and rectal neuroendocrine tumors (smaller than 1 cm) may lead to a complete cure of carcinoid syndrome.
In patients with cardiac neuroendocrine tumor with severe tricuspid regurgitation, tricuspid valve replacement may improve the mortality.
A patient who is not a surgical candidate but has higher tumor burden, especially hepatic metastases, can undergo percutaneous hepatic transarterial embolization. A radiolabeled Yittrium 90 (Y) resin or glass microsphere has also been used for embolization; however, its long-term risk has not been identified.
For a patient with refractory symptoms the following options are available:
1. Additional doses of short-acting Octreotide or more frequent doses of depot Octreotide or Lanreotide (every three weeks in place of every four weeks).
2. Telotristat: An oral tryptophan hydroxylase inhibitor, recently approved for carcinoid syndrome to be used in combination with somatostatin analogs to control diarrhea. It is given at the dose of 250 mg three times a day with meals.
3. Interferon: Interferon-alpha can be used in a patient who does not respond to somatostatin analog. Interferon works by leading to cell cycle arrest in tumors cells, stimulation of T-cells and inhibition of angiogenesis of tumor cells leading to tumor necrosis.
4. Antidiarrheal agents like loperamide, Lomotil, cholestyramine (especially for those who had bowel surgery).
5. Systemic therapy: Most common cytotoxic chemotherapy used in carcinoid syndrome is Everolimus, which is an mTOR inhibitor. Everolimus has shown to improve symptoms by increasing excretion of 5-HIAA, but studies have failed to show improvement in disease-free survival.
6. Peptide receptor radioligand therapy to deliver targeted radiation to somatostatin receptor-expressing tumors.
Prevention and Management of Carcinoid Crisis
Carcinoid crisis: Patients with carcinoid syndrome can present with severe hemodynamic instability due to severe acute attacks of sustained flushing with bronchoconstriction and hypotension. The factors that can precipitate carcinoid crisis are sedatives, anesthetics, catecholamines, surgery and necrosis of tumor itself. It is caused by the acute release of an overwhelming number of vasoactive compounds.
A 24-hour urine 5-HIAA level should be performed in all patients with metastases. If elevated, prophylactic octreotide should be administered. In patients with functioning tumor or with hepatic metastasis, pre-operative Octreotide 300 mcg to 500 mcg IM/SQ is mandatory to prevent carcinoid crisis. Additional dosing may be required intraoperatively. We must avoid adrenergic agent for blood pressure control which can have a paradoxical effect.
If carcinoid crisis occurs, Octreotide 500 mcg to 1000 mcg IV bolus should be given followed by continuous infusion at 50mcg to 200 mcg/hour. In the case of intraoperative hypotension, calcium products and Catecholamine should be avoided as they worsen release of mediators from the tumor.
An echocardiogram should be performed in patients with significant elevation (greater than five times the upper limit of normal) of serum serotonin/urine 5-HIAA, signs and symptoms of carcinoid heart disease, or if major surgery is planned.