Definition

Carcinoid tumors are neuroendocrine tumors that arise from the gastrointestinal (GI) tract (67.5% are midgut carcinoids: ileum, appendix, rectum, pancreas) or an extra-GI primary such as lung or bronchi (25.3% are foregut carcinoids). Primary midgut carcinoid tumors metastasize to the liver or regional lymph nodes and may present with bowel obstruction. They may be nonsecreting or may be associated with flushing, diarrhea, cardiac valvular fibrosis, and bronchoconstriction. Tumors synthesize, store, and release up to 40 bioactive mediators, the most prominent being serotonin, 5-hydroxytryptophan, histamine, bradykinin, tachykinins, and prostaglandins. The liver usually inactivates mediators secreted into the portal circulation. As such, carcinoid syndrome results from the direct release of vasoactive amines, polypeptides, proteins, and prostaglandins into the systemic circulation. This may occur with extensive liver metastasis of GI tumors, primary hepatic carcinoid tumors, and primary tumors without portal venous drainage (bronchial, ovarian, retroperitoneal). In carcinoid tumor cells, 70% of tryptophan is converted into serotonin, which is then metabolized in the liver, lungs, and brain by monoamine oxidases to 5-HIAA (5-hydroxyindoleacetic acid) and excreted in the urine. Serotonin uptake and storage also occurs in platelets. Urinary serotonin is usually either normal or slightly increased.

The incidence of carcinoid tumors is between 1.2 and 2.1 in 100,000 persons per year, with autopsy incidental findings as high as 8%. The highest incidence is seen in African American males, 4.5 per 100,000. Between 75% and 80% of patients with carcinoid syndrome have small bowel tumors. Patients with small bowel carcinoids tend to present in the fifth and sixth decades, most often with mass effects from the tumor (e.g., abdominal pain or obstruction). The majority of small bowel carcinoids have metastases at presentation and approximately 5% have the carcinoid syndrome. The 5-year overall survival rate is 80%, which decreases to 20% with distant metastasis.

A life-threatening carcinoid “crisis” is an acute exacerbation of the carcinoid syndrome. It results in profound flushing, hypotension or extreme changes in blood pressure, stupor, diarrhea, confusion, bronchospasm, arrhythmias, and hyperthermia. Such crises can be triggered by tumor palpitation, induction of anesthesia and tracheal intubation, inadequate analgesia, surgical stress, drug-induced mediator release, chemotherapy, and hepatic arterial embolization.

Recognition

Carcinoid syndrome is relatively uncommon, affecting approximately 10% of patients with carcinoid tumors. The diagnosis of carcinoid syndrome is usually suspected by the clinical features and confirmed by identification of the focal primary lesion, localization of metastatic lesions, and detection of increased urinary excretion of the byproduct of serotonin metabolism, 5-hydroxyindoleacetic acid (5-HIAA). A positive result for 5-HIAA has a 73% sensitivity and a 100% specificity for carcinoid tumor. Serum chromagraffin A is a glycoprotein secreted with other hormones by neuroendocrine tumors and is 95% specific and almost 80% sensitive for carcinoid tumors. Diagnosis of a neuroendocrine tumor is confirmed with immunohistochemical markers. Natriuretic peptides (NT-proBNP) can be used as a simple marker for the diagnosis of carcinoid heart disease, which can then be confirmed by two-dimensional echocardiography. Metastatic disease is most commonly diagnosed using abdominal computed tomography with contrast. Deposits appear as isodense, hypervascular lesions. Somatostatin receptor scintigraphy using indium-111–labeled octreotide is also useful.

Clinical features of carcinoid syndrome include the following:

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  Episodic cutaneous vasomotor flushing, telangiectasia, cyanosis

  
  
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  Hypotension/hypertension

  
  
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  Diarrhea and cramping

  
  
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  Bronchospasm

  
  
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  Carcinoid valvular heart disease

There is significant patient variability with regard to the type and severity of symptoms. Bradykinin and histamine may play a prominent role in hypotension and sporadic flushing, which is the hallmark of carcinoid syndrome. A mild burning sensation and reddish color may suddenly appear on the face, neck, and chest that lasts for 30 seconds to 30 minutes. As the disease progresses, flushing lasts longer, and may become more diffuse and cyanotic, with the appearance of telangiectasia in the face. These symptoms may be accompanied by severe hypotension and tachycardia. Triggers include certain foods (e.g., avocados, fruits, nuts, melons), coffee and alcohol, defecation, emotional events, mechanical stimulation, and anesthesia. Flushing may also be accompanied by sweating, wheezing, and shortness of breath.

Serotonin causes secretory diarrhea and abdominal cramping. Other symptoms include bronchoconstriction, hypertension, and bowel ischemia. Serotonin also stimulates fibroblast growth and fibrogenesis leading to peritoneal and cardiac valvular fibrosis. Carcinoid heart disease is characterized by plaque-like deposits of fibrous tissue composed of smooth muscle cells, myofibroblasts, and an overlying endothelial cell layer. These deposits occur most commonly on the endocardium of valvular cusps and leaflets, the cardiac chambers, and occasionally on the intima of the pulmonary arteries or aorta. These changes cause severe tricuspid regurgitation (TR), pulmonary valve abnormalities, and right-sided endocardial disease. The valves and endocardium of the right side of the heart are most often affected because inactivation of humoral substances by the lung protects the left heart. Left-sided heart disease is uncommon and generally associated with bronchial carcinoid or right-to-left intracardiac shunting. Carcinoid heart disease, which eventually occurs in over 50% of patients with carcinoid syndrome, is a major cause of morbidity and mortality. Echocardiography is the standard for detection and quantitation of TR. Elevation of biomarkers chromogranin-A and NT-proBNP (N-terminal probrain natriuretic peptide) are associated with the severity of TR and overall mortality.

Differential diagnosis of severe refractory hypotension may include the following:

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  Serotonin-induced carcinoid crisis

  
  
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  Angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors taken preoperatively

  
  
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  Anaphylaxis/allergic reactions

  
  
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  Sepsis with or without shock

  
  
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  Unrecognized volume depletion or blood-volume deficit from bleeding

  
  
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  Cirrhosis with portal hypertension and low systemic vascular resistance

  
  
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  Adrenal insufficiency

  
  
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  Etomidate, large IV dose of propofol, wrong drug

  
  
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  Mechanical caval compression

  
  
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  Air/embolic embolism to the right ventricle

  
  
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  Carcinoid heart failure, coronary ischemia, arrhythmia

  
  
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  Biochemical environment: hyponatremia, hyperkalemia, metabolic/respiratory acidosis

The most common treatment approach for perioperative hypotension is to verify the blood pressure, check Sp o ₂ (oxygen saturation), reduce the depth of anesthesia, and administer IV fluids and a bolus dose of pressor drug (phenylephrine, ephedrine, epinephrine, or vasopressin). For hypotension resistant to the initial resuscitation efforts, a review of the patient’s medical history and surgical technique; patient assessment for flushing, rash, hives, or bronchospasm; and verifying that the IV is patent are necessary. Usually, the most likely diagnosis will determine subsequent interventions that may include a pressor infusion, colloid, blood transfusion, steroids, or cardiac evaluation with transesophageal echocardiography (TEE). Carcinoid crisis presenting as refractory hypotension is a diagnosis of exclusion. For patients with known or suspected carcinoid tumors, the most appropriate treatment for severe intraoperative hypotension would be vasopressin, octreotide bolus/infusion, and fluids.

Risk Assessment

Carcinoid tumors occur relatively frequently, but are only rarely symptomatic. Without treatment, the median duration of survival with malignant carcinoid syndrome ranges from 12 to 38 months from the onset of symptoms. The estimated 5-year survival for localized disease is 75% to 93%. With cardiac involvement and symptomatic right-sided heart failure (New York Heart Association class III or IV), the prognosis is poor, with a median survival of less than 1 year. Patients with carcinoid heart disease have much higher (twofold to fourfold) values for serum and plasma serotonin, platelet serotonin, and urine 5-HIAA than those without cardiac involvement. Levels of CgA and NT-proBNP are also associated with overall mortality. Survival at 5 years is 81% in patients with normal CgA levels, 44% in those with elevated CgA but normal NT-proBNP levels, and 16% in those with elevations in both CgA and NT-proBNP.

Implications

Anesthesia can precipitate carcinoid crisis in patients with carcinoid syndrome. As has been described, this syndrome is characterized by flushing, extreme changes in blood pressure, bronchoconstriction, arrhythmias, and confusion or stupor, which can be fatal. Preoperative assessment should include history and physical and evaluation for volume depletion, malnutrition, anemia, and electrolyte imbalance due to secretory diarrhea. Carcinoid heart disease occurs in over 50% of patients with carcinoid syndrome. As such, cardiac evaluation should include a baseline echocardiogram, electrocardiogram, and chest x-ray, especially when NT-proBNP is elevated.

Octreotide acetate (Sandostatin) has simplified the perioperative management of patients with carcinoid tumor and is widely considered the standard treatment for carcinoid symptoms and crises. Control of carcinoid symptoms with an octreotide analog should be a goal before surgery, and meticulous perioperative care is required. Large doses of somatostatin are often necessary in the perioperative and postoperative periods. Octreotide is a synthetic octapeptide analog of somatostatin with an elimination half-life of about 1.5 hours following subcutaneous administration. Octreotide-LAR (monthly injection) may prevent the release of bioactive amines by binding to the sstr-2 subtype of somatostatin G protein–coupled receptors. Octreotide acetate exerts pharmacologic actions similar to the natural hormone somatostatin, but it is an even more potent inhibitor of growth hormone, glucagon, and insulin. Similar to somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin-releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide. Octreotide has widespread effects including QT prolongation, bradycardia, conduction defects, abdominal cramps, nausea, and vomiting. Symptoms are relieved in more than 80% of patients, although the average response lasts only 18 months. Insulin release in response to hyperglycemia is inhibited as well, which can complicate glucose management in obese patients or non–insulin-dependent diabetics. Unfortunately, octreotide does not prevent or delay cardiac valve disease.