Carcinoid Syndrome

Etiology

Carcinoid syndrome is most commonly caused by neuroendocrine tumors of the midgut that metastasize to the liver. Neuroendocrine tumors of the foregut and hindgut can also rarely cause carcinoid syndrome. Neuroendocrine tumors mostly arise in the gastrointestinal (GI) tract (about 70%), followed by the respiratory tract (about 25%).[2] Neuroendocrine tumors can rarely arise from other areas like ovaries, testicles, and kidneys.

Epidemiology

Neuroendocrine tumors are relatively rare tumors. As mentioned above, only about 10% of neuroendocrine tumors result in 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 nonpancreatic 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 males and females is almost equal, with slightly higher in males. The median age of diagnosis of neuroendocrine tumors is between 55 and 60.[2]

Pathophysiology

The pathophysiology of carcinoid syndrome is based on biologically active amines and peptides entering the systemic circulation and escaping the first-pass metabolism of the liver. Usually, these bioactive products are inactivated in the liver. However, in the cases of neuroendocrine tumors with liver metastasis, either these bioactive products directly enter into the systemic circulation or are not inactivated due to deranged liver function.

Less frequently, carcinoid syndrome can occur without liver metastasis in conditions such as primary gut tumors with widespread retroperitoneal nodal metastases, ovarian tumors, or bronchial carcinoids, which release bioactive amines directly into the systemic circulation.[1]

Neuroendocrine tumors release approximately 40 types of biologically active amines and peptides. The most common ones are serotonin, histamine, tachykinins, kallikrein, and prostaglandins.[3] Most of the clinical features are due to serotonin, which is an end product of tryptophan metabolism.

Usually, only 1% of dietary tryptophan is metabolized into serotonin. However, in the cases of neuroendocrine tumors, up to 70% of tryptophan is metabolized into serotonin. Serotonin undergoes oxidative reactions that lead to the formation of 5-hydroxy indoleacetic acid (5-HIAA) with the help of aldehyde dehydrogenase, which is then eliminated in the urine.

Serotonin causes increased motility and excessive secretion of the gastrointestinal tract, leading to diarrhea. As most of the tryptophan is diverted to the serotonin formation pathway by neuroendocrine tumors, it results in a deficiency of tryptophan, which is needed for the synthesis of niacin. Consequently, deficiency of niacin leads to Pellagra, which manifests as a triad of dermatitis, dementia, and diarrhea. Prostaglandins also play their part in increased intestinal motility and fluid secretion in the gastrointestinal tract, causing diarrhea.

Neuroendocrine tumors of the foregut and lungs lack the enzyme aromatic L-amino acid decarboxylase, which metabolizes 5-hydroxytryptophan to serotonin. Thus, the neuroendocrine tumors of the lungs and foregut do not produce serotonin. On the other hand, hindgut neuroendocrine tumors usually do not produce any bioactive hormone.

Pulmonary neuroendocrine tumors mainly produce histamine, which can cause atypical flushing and pruritus. Tachykinins (substance p, neurokinin A, neuropeptide k) are also responsible for causing flushing due to their vasodilatory effect.

History and Physical

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.[4]

Flushing is the most common presentation and occurs in about 85% of patients with carcinoid syndrome. It is paroxysmal and is described as salmon pink to dark red discoloration of the skin of the 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, a purplish rash (usually on the nose, upper lip, and malar area) tends to appear at the late stage of carcinoid syndrome.

Other less common manifestations include pellagra, muscle wasting, and ureteral obstruction due to retroperitoneal fibrosis.

There are some atypical symptoms that 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 the 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.

Evaluation

The diagnostic workup of carcinoid syndrome includes initial testing for biochemical markers followed by localization of tumors with radiographic and endoscopic studies.

Testing for Biochemical Markers [1]

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 levels. 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 the 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, and 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.

The plasma 5-HIAA level is convenient but has 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 the tissue obtained.

Treatment / Management

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 the treatment of poorly differentiated neuroendocrine tumors or refractory carcinoid syndrome.[5][6][7](B3)

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.

Medical Management                                                                                       

For medical management, two somatostatin analogs are available: octreotide and lanreotide. Somatostatin is an amino acid peptide, an inhibitory hormone synthesized by paracrine cells located ubiquitously throughout the gastrointestinal tract. It inhibits the release of most of the gastrointestinal and endocrine hormones. About 80% of neuroendocrine tumors have somatostatin receptors. Using somatostatin analog inhibits the release of biogenic amines, which leads to the 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 administered at 60 mg to 120 mg every four weeks. It has similar efficacy as octreotide.

Both somatostatin analogs provide symptomatic relief in 50% to 70% of patients and biochemical responses in 40% to 60% of 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 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.

Surgical Treatment

In patients with bronchial neuroendocrine tumors with carcinoid syndrome diagnosed at an early stage, surgical resection of the tumor leads to a complete cure of carcinoid syndrome. Patients who have surgically resectable hepatic metastases, surgical resection, or partial hepatectomy lead 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 tumors with severe tricuspid regurgitation, tricuspid valve replacement may improve mortality.

A patient who is not a surgical candidate but has a higher tumor burden, especially hepatic metastases, can undergo percutaneous hepatic transarterial embolization. A radiolabeled yttrium 90 (Y) resin or glass microsphere has also been used for embolization; however, its long-term risk has not been identified.

Refractory Symptoms

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 instead 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 250 mg three times a day with meals.

3. Interferon: Interferon-alpha can be used in patients who do not respond to a somatostatin analog. Interferon works by leading to cell cycle arrest in tumor cells, stimulation of T-cells, and inhibition of angiogenesis of tumor cells, leading to tumor necrosis.

4. Antidiarrheal agents like loperamide, diphenoxylate/atropine, and cholestyramine (especially for those who had bowel surgery).

5. Systemic therapy: The most common cytotoxic chemotherapy used in carcinoid syndrome is everolimus, which is an mTOR inhibitor. Everolimus has been shown to improve symptoms by increasing the 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 crises are sedatives, anesthetics, catecholamines, surgery, and necrosis of the 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 tumors or with hepatic metastasis, preoperative octreotide 300 mcg to 500 mcg IM/SQ is mandatory to prevent a carcinoid crisis. Additional dosing may be required intraoperatively. We must avoid adrenergic agents for blood pressure control, which can have a paradoxical effect. 

If a carcinoid crisis occurs, octreotide 500 mcg to 1000 mcg IV bolus should be given, followed by continuous infusion at 50 mcg to 200 mcg/hour. In the case of intraoperative hypotension, calcium products, and catecholamine should be avoided as they worsen the release of mediators from the tumor.

Echocardiogram Recommendation

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.[8](B3)

Differential Diagnosis

Carcinoid syndrome tends to present with varying clinical features which accounts for the wide range of its differential diagnoses. Following are some important differential diagnoses that should be considered while establishing a diagnosis of carcinoid syndrome:

• Irritable bowel syndrome
• Gastrointestinal motility disorders
• Celiac disease
• Anaphylaxis
• Acute urticaria
• Angioedema
• Ogilvie syndrome