Carcinoid Syndrome

Etiology

Carcinoid syndrome is caused by neuroendocrine tumors that metastasize to the liver, with the majority of these tumors originating from the midgut, particularly the appendix and small intestine. Neuroendocrine tumors without liver metastases typically do not produce carcinoid syndrome, as the liver metabolizes the biogenic amines produced by the primary tumor. Less commonly, tumors arising from the foregut or thorax can also result in carcinoid syndrome.[3][5]

Epidemiology

Neuroendocrine tumors are relatively rare, but their incidence and prevalence have increased, likely due to improved diagnostic techniques and greater clinical awareness. The annual incidence of neuroendocrine tumors is estimated to be approximately 6.98 cases per 100,000 individuals, with a prevalence of approximately 35 cases per 100,000 individuals in the United States. These tumors can affect individuals of all racial and ethnic backgrounds, although some studies suggest a slightly higher prevalence among Caucasians.[5] Neuroendocrine tumors are generally more common in females than males, depending on the primary tumor site. For instance, a female predominance is observed in pancreatic and gastrointestinal neuroendocrine tumors. However, the gender distribution can vary across anatomical sites and tumor types. The peak age for diagnosis typically falls between the fifth and seventh decades of life.[6][7]

Pathophysiology

Carcinoid syndrome arises from the release of biologically active amines and peptides into the systemic circulation, bypassing the liver’s first-pass metabolism. The liver normally inactivates these substances, but liver metastases from neuroendocrine tumors can allow these products to enter the circulation and exert systemic effects.[8][9] Rarely, carcinoid syndrome can occur without liver metastases in certain primary gastrointestinal tumors, ovarian neuroendocrine tumors, or bronchial carcinoids.

Neuroendocrine tumors secrete about 40 types of biologically active amines and peptides, with serotonin being the most significant in carcinoid syndrome. While only 1% of dietary tryptophan is normally converted to serotonin, up to 70% may be diverted in these tumors. As niacin is synthesized from dietary tryptophan, this excessive utilization of tryptophan to synthesize serotonin can result in niacin deficiency and its associated symptoms. Serotonin is metabolized to 5-HIAA and excreted in urine. 

Excess serotonin causes increased gastrointestinal motility and hypersecretion, leading to diarrhea, one of the hallmarks of carcinoid syndrome.[10] Foregut and pulmonary neuroendocrine tumors do not produce serotonin due to a lack of the necessary enzyme, while hindgut tumors typically do not secrete significant hormones. Pulmonary neuroendocrine tumors mainly produce histamine, causing atypical flushing and pruritus, while tachykinins contribute to flushing through vasodilatory effects, further complicating the clinical presentation of carcinoid syndrome.[9][11]

History and Physical

Carcinoid syndrome presents a range of symptoms due to the vasodilatory effects of biologically active amines, peptides, and prostaglandins. Common clinical features include flushing, wheezing, gastrointestinal disturbances (eg, diarrhea and malabsorption), niacin deficiency leading to pellagra, cardiac complications including right-sided valvular disease, most often tricuspid regurgitation, fatigue, and in some cases, cognitive impairment.[3]

Flushing is the most prevalent symptom, reported in approximately 85% of patients. Sudden episodes of salmon-pink characterize it to dark-red discoloration of the upper body, particularly the face, neck, and upper trunk. These episodes can last anywhere from 30 seconds to 30 minutes and may occur spontaneously or be triggered by certain factors, eg, eating, alcohol consumption, emotional stress, liver palpation, or anesthesia. Flushing is predominantly associated with midgut neuroendocrine tumors and is often accompanied by tachycardia, swelling around the eyes, and increased tearing.[2][3][12]

Diarrhea, affecting about 80% of patients, is another hallmark symptom. It tends to be chronic, explosive, nonbloody, and watery, with patients reporting up to 30 bowel movements per day. Abdominal cramping is also common, although diarrhea does not always coincide with flushing episodes. This chronic condition can significantly impair a patient’s quality of life.[2][3][12]

Cardiac involvement occurs in 60% to 70% of patients and is caused by fibrotic plaque-like deposits on the endocardium, valves, and other cardiac structures, eg, the pulmonary and aortic arteries. The right side of the heart is predominantly affected, often leading to valvular dysfunction like tricuspid regurgitation or pulmonic stenosis. In rare cases, left-sided heart involvement can occur, typically in the presence of a right-to-left shunt or pulmonary neuroendocrine tumors. Cardiac manifestations may include symptoms of heart failure or valvular heart disease, which can significantly impact prognosis.[13]

Although less common, bronchospasm affects 10% to 20% of patients and typically manifests as wheezing and difficulty breathing, often during flushing episodes. These respiratory symptoms may worsen with the use of beta-agonists. Prolonged vasodilation in advanced carcinoid syndrome can also result in a purplish rash localized to the nose, upper lip, and malar regions.[2][3][12]

Additional, less common manifestations of carcinoid syndrome include pellagra, which is caused by niacin deficiency due to excessive tryptophan being used for serotonin synthesis. Other complications may involve muscle wasting and ureteral obstruction due to retroperitoneal fibrosis.[2][3][12] Certain atypical symptoms are associated with neuroendocrine tumors arising from the stomach and lungs. Gastric neuroendocrine tumors may cause well-defined, serpiginous, cherry-red flushing accompanied by intense itching, often linked to histamine secretion. Lung neuroendocrine tumors can lead to severe and prolonged flushing lasting hours to days, often associated with anxiety, altered mental status, and tremors. While these symptoms are thought to be related to histamine release, the exact mechanisms remain unclear.[2][3][11][12]

Evaluation

The diagnostic evaluation of carcinoid syndrome involves initial testing for biochemical markers to confirm the presence of the syndrome, followed by tumor localization and staging through radiographic and endoscopic studies.

Biochemical Marker Testing

The 24-hour urinary 5-HIAA test is the initial diagnostic test for carcinoid syndrome. 5-HIAA is the primary end product of serotonin metabolism, and this test demonstrates approximately 90% sensitivity and specificity. False-positive results can occur due to dietary intake of tryptophan-rich foods eg, bananas, pineapples, plums, kiwis, avocados, eggplants, pecans, and walnuts. Additionally, medications, including acetaminophen, guaifenesin, caffeine, nicotine, methamphetamine, and phenobarbital, can elevate 5-HIAA levels. Conversely, medications, eg, aspirin, ethanol, heparin, imipramine, levodopa, methyldopa, monoamine oxidase inhibitors (MAOIs), isoniazid, and corticotropin can suppress 5-HIAA levels. Patients should avoid these substances for at least 24 hours before and during urine collection to ensure accurate results. Urinary 5-HIAA levels correlate with tumor burden and can also be used to monitor treatment response over time.[2][4][2][14]

Chromogranin A, a glycoprotein secreted by neuroendocrine tumors, is another essential biochemical marker. While chromogranin A is beneficial for detecting nonsecretory tumors, it demonstrates high sensitivity but poor specificity. This biochemical marker is also an excellent marker for monitoring disease progression and treatment response. However, elevated levels can also occur in various conditions, including the use of proton pump inhibitors, atrophic gastritis, renal failure, hyperthyroidism, heart failure, hypertension, and prostate cancer, which must be considered during interpretation.[2][4][2][14]

In the United States, 24-hour urinary serotonin testing is not widely available but may be helpful in rare cases of foregut neuroendocrine tumors with serotonin production. Blood serotonin testing is generally not recommended due to low specificity, and while plasma 5-HIAA testing is more convenient, its diagnostic utility is not yet fully validated.[2][4][2][14]

Tumor Localization and Staging Studies

When biochemical markers confirm the diagnosis of carcinoid syndrome, imaging studies are essential for tumor localization and staging. Cross-sectional imaging techniques such as triple-phase computed tomography (CT) scans, magnetic resonance imaging (MRI), and somatostatin receptor scintigraphy are commonly employed. Due to its high sensitivity, abdominal CT with triphasic imaging of the liver is often the diagnostic modality of choice. MRI is sometimes preferred for its superior sensitivity in detecting liver metastases.[2][4][2][14]

Functional imaging, particularly 68-gallium dotatate positron emission tomography (PET), has emerged as the preferred modality for identifying neuroendocrine tumors due to its improved sensitivity and resolution, particularly for small tumors. Indium-111 pentetreotide scintigraphy (Octreoscan) has a sensitivity of >90% in symptomatic patients and 80% to 90% in asymptomatic patients. However, it has limited ability to detect poorly differentiated neuroendocrine tumors and exhibits lower specificity than newer imaging modalities.[2][4][2][14]

Bronchoscopy with biopsy can be performed for direct visualization and histological confirmation of bronchial neuroendocrine tumors. For tumors identified through imaging, site-specific procedures such as upper or lower endoscopy or endoscopic ultrasound-guided biopsy may be indicated to obtain tissue samples. Histopathological evaluation typically includes testing for markers such as neuron-specific enolase, chromogranin A, serotonin, Ki-67 mitotic index, and synaptophysin, which aid in confirming the diagnosis and determining tumor differentiation and proliferation rate.[15]

Echocardiogram

Patients with significant elevation of serum serotonin or urinary 5-HIAA (≥5 times the upper limit of normal), symptoms of carcinoid heart disease, or those undergoing major surgery should undergo echocardiographic evaluation to assess for cardiac involvement.[13]

Treatment / Management

The management of carcinoid syndrome centers on suppressing biogenic amine release and reducing tumor burden using multiple modalities.[3]

Medical Management

Somatostatin analogs (SSA) are the cornerstone of medical management. Two commonly used analogs, octreotide and lanreotide, mimic the action of somatostatin, an inhibitory peptide hormone that regulates the release of gastrointestinal and endocrine hormones. These drugs inhibit the secretion of biogenic amines, thereby controlling symptoms such as flushing and diarrhea.[16] Octreotide is available as a short-acting subcutaneous injection or a long-acting intramuscular depot formulation, while lanreotide is a long-acting formulation. Both somatostatin analogs provide symptomatic relief in 50% to 70% of patients and biochemical improvement in 40% to 60%. They also have antiproliferative effects on tumor cells.[17](A1)

Telotristat is an FDA-approved agent to treat refractory diarrhea not responding to SSA. It inhibits the enzyme tryptophan hydroxylase, which catalyzes a rate-limiting step in the conversion of the tryptophan to serotonin. 

Alternative effective serotonin suppression agents include sirolimus, an mTOR inhibitor, and interferon alpha. The manufacturer discontinued interferon alpha, and it is no longer available in the United States. The evidence to support the use of cytotoxic chemotherapy is limited.[18][19](B3)

Radioligand Therapy

PRRT is a targeted systemic treatment for advanced neuroendocrine tumors that express somatostatin receptors, utilizing radiolabeled somatostatin analogs (eg, lutetium-177) to deliver localized ionizing radiation to tumor cells. PRRT is most effective for well-differentiated, low-to-intermediate grade neuroendocrine tumors, particularly of gastrointestinal and pancreatic origin. Additionally, this treatment has demonstrated significant efficacy in improving progression-free survival and quality of life and is increasingly used in managing such patients.[20][21][22](B3)

Surgical Treatment

Surgery is critical in managing patients with disease that is amenable to cytoreduction. In metastatic midgut tumors, removing over 70% of the tumor burden improves symptoms and overall survival, while resection can be curative in other tumor sites (eg, the bronchus). Elective cholecystectomy may be performed during surgery to prevent biliary complications associated with somatostatin analog therapy. Endoscopic resection of small (≤1 cm) gastric or rectal neuroendocrine tumors can also result in a complete cure, although such tumors are very unlikely to cause carcinoid syndrome.[23][24][25]

Liver-Directed Therapies

For patients with inoperable hepatic metastases, liver-directed therapies can reduce morbidity and improve quality of life. Options include percutaneous hepatic transarterial embolization, radioembolization with yttrium-90 microspheres, and ablation.[26][27](B3)

Prevention and Management of Carcinoid Crisis

Carcinoid crisis is a potentially life-threatening complication characterized by severe hemodynamic instability, flushing, bronchoconstriction, and hypotension, often triggered by surgery, anesthesia, or tumor necrosis. It typically occurs in patients with high levels of circulating vasoactive peptides, eg, serotonin. Prophylactic administration of octreotide is recommended in patients not on SSA as part of treatment. The routine use of preoperative octreotide in patients who are already on long-acting SSA is debatable. During a crisis, a bolus of octreotide followed by an intravenous infusion is recommended. Vasopressors and fluid resuscitation are recommended as well.[28][29][30](A1)

Differential Diagnosis

Carcinoid syndrome tends to present with varying clinical features, which accounts for the wide range of its differential diagnoses.[1] Some essential differential diagnoses that should be considered while establishing a diagnosis of carcinoid syndrome include the following:

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

Prognosis

The prognosis of carcinoid syndrome is dependent on the underlying tumor characteristics, stage, and extent of metastasis, as well as the presence of associated complications, eg, carcinoid heart disease or carcinoid crisis. Well-differentiated neuroendocrine tumors typically exhibit a relatively indolent course. With advances in targeted therapies, including somatostatin analogs, PRRT, and liver-directed treatments, the prognosis for patients with metastatic disease has improved significantly. The presence of carcinoid heart disease, however, markedly worsens the prognosis due to the risk of progressive right-sided heart failure and its associated morbidity. Long-term survival in patients with carcinoid syndrome is variable and depends on the success of symptom management, control of tumor progression, and prevention or treatment of complications. While early-stage, localized tumors have a favorable prognosis with curative surgical resection, advanced or metastatic disease is often associated with a median survival ranging from 3 to 8 years, depending on the tumor burden and response to therapy. Regular follow-up and an interprofessional approach to care are critical in optimizing outcomes and maintaining the quality of life of these patients.[3][6][12]

Complications

One of the most significant complications is carcinoid heart disease, characterized by fibrotic plaque deposition on the endocardium of right-sided heart valves, leading to tricuspid regurgitation, pulmonic stenosis, and eventually right-sided heart failure. Chronic diarrhea can result in dehydration, electrolyte imbalances, and malnutrition. Niacin deficiency due to excessive tryptophan utilization for serotonin synthesis may lead to pellagra, presenting as dermatitis, diarrhea, and dementia. Patients are also at risk for carcinoid crisis. Long-term exposure to elevated serotonin levels can result in retroperitoneal fibrosis, causing ureteral obstruction and renal dysfunction. Additionally, metastatic involvement of the liver and other organs can lead to organ dysfunction and eventual organ failure.[3][6][12]