Carcinoid tumors are rare, slow-growing neuroendocrine tumors that are derived from the enterochromaffin cells, or Kulchitsky cells, of the neuroendocrine system [1]. Carcinoid tumors are now referred to as well-differentiated neuroendocrine tumors [2]. The incidence is estimated to be ~ 2–4 per 100,000 people per year [3, 4]. Carcinoid tumors are associated with multiple endocrine neoplasia (MEN) type 1 syndrome [5, 6].

Carcinoid tumors most commonly present in the gastrointestinal tract (65%), less often in the tracheobronchial tree or lungs (25%), and rarely other areas of the body (i.e., ovaries, pancreas) (10%). In the gastrointestinal (GI) tract, carcinoid tumors most commonly arise in the small bowel (40%) and appendix (19%) [2].

These tumors release a variety of vasoactive substances including serotonin, dopamine, norepinephrine, histamine, bradykinins, tachykinins, and prostaglandins that lead to the symptoms of carcinoid syndrome [4–6].

Carcinoid syndrome is caused by tumor release of vasoactive substances into the systemic circulation leading to the development of a variety of symptoms, including cutaneous flushing, diarrhea, bronchospasm, abdominal cramping, and right-sided heart failure. Flushing and diarrhea are the most commonly experienced symptoms [6, 7], with 90% of patients experiencing flushing and 70% with diarrhea, where those with wheezing (20%) and bronchospasm (10%) are far less common [7]. The flushing of carcinoid syndrome primarily involves the face, neck, and chest and may be associated with a burning sensation.

Carcinoid syndrome is only experienced by ~10% of patients with carcinoid tumors [3, 8, 9]. This is because carcinoid syndrome is most commonly seen in patients with primary tumors of the gastrointestinal system that have metastasized to the liver. Prior to hepatic metastases, the hormones and peptides released by the primary tumor of the GI system are inactivated by hepatic metabolism via the portal circulation. Once the primary tumor has metastasized to the liver, these chemical substances bypass hepatic metabolism and are released directly into the systemic circulation and cause the symptoms of carcinoid syndrome.

Carcinoid syndrome may develop in the absence of hepatic metastases when the primary tumor releases vasoactive substances directly into the systemic circulation. This is true for primary carcinoid tumors located outside of the gastrointestinal tract, as is the case with bronchial, ovarian, and pancreatic tumors [5].

A thorough preoperative history and physical exam are necessary to identify patients with carcinoid syndrome, as they may be at higher risk of developing intraoperative carcinoid crisis. This includes assessing for history of flushing, diarrhea, wheezing, shortness of breath, and bronchospasm. It is imperative to evaluate for symptoms associated with carcinoid heart disease and right-sided heart failure (i.e., jugular venous distension, hepatomegaly, peripheral edema, fatigue, etc.), as this significantly increases the patient’s risk of morbidity and mortality associated with the procedure [10]. It is important to ascertain how long a patient has been symptomatic, as 50% of patients with carcinoid syndrome will develop carcinoid heart disease [11], and this usually occurs within 24–28 months after onset of carcinoid syndrome [12]. Lastly, one should evaluate whether the patient is treated with octreotide and their current dose. Patients receiving octreotide at baseline may require higher doses to treat symptoms if they develop in the perioperative period [3].

Physical exam should include assessment for wheezing, presence of telangiectasias, signs of right-sided heart failure, presence of murmur, and evaluation of volume status given the risk of volume depletion in the setting of frequent diarrhea.

Laboratory evaluation to aid in the diagnosis of a carcinoid tumor includes serum measurement of chromogranin A and 24-h urine measurement of 5-hydroxyindole-3-acetic acid (5-HIAA). Chromogranin A is a glycoprotein secreted by carcinoid tumors and is elevated in 56–100% of people with carcinoid tumors [13]. Because this level correlates with bulk of disease, it can be followed serially to evaluate for disease progression or response to treatment [13]. 5-HIAA is a metabolite of serotonin and is frequently elevated in patients with carcinoid disease, especially in patients with hepatic metastases, and may therefore be normal in patients who have gastrointestinal carcinoid without metastatic disease. Elevated concentration of 5-HIAA is positively correlated with disease progression and worsened prognosis [12]. High levels of 5-HIAA preoperatively has also been demonstrated to be a risk factor for increased perioperative complications and death [10].

An octreotide scan, or somatostatin receptor scintigraphy, is the most sensitive imaging modality for identifying the presence of carcinoid tumors and metastatic disease [14]. Radiolabeled octreotide is injected into the body and binds to the somatostatin receptors of carcinoid tumors, which can then be viewed on imaging. Conventional MRI and CT scan should also be reviewed to evaluate for the presence of metastatic disease.

Carcinoid heart disease (CHD) occurs in more than 50% of patients with known carcinoid syndrome [11] and may be the presenting symptom of carcinoid syndrome in up to 20% of patients [15]. CHD is associated with an increase in morbidity and mortality in patients with carcinoid disease [15–18]. Patients with CHD have a 31% 3-year survival rate compared to 60% in patients without CHD [12]. Given the increased morbidity and mortality associated with CHD, these patients are at increased risk of perioperative complications, and it is critical to identify these patients in the preoperative setting.

CHD is classically characterized by plaque-like deposits of fibrous tissue on the endocardial surfaces of valve leaflets, chordae tendineae, papillary muscles, and cardiac chambers [16]. High concentrations of serotonin, along with other vasoactive substances, released by carcinoid tumors into the vena cava and, subsequently, the right heart, are implicated in triggering the pathological formation of these plaque-like deposits [15, 16]. These mediators then pass through the pulmonary circulation and are degraded before they are able to trigger the same pathological response in the left heart [15, 16]. As a result, the valves of the right heart are affected in >90% of patients with CHD, with only 10% of patients having evidence of left heart involvement [15, 16]. Left heart involvement is more commonly seen in patients with a patent foramen ovale, allowing flow of these mediators into the left heart prior to their degradation by the pulmonary circulation [15, 16]. The most common valvular abnormalities seen in CHD are tricuspid insufficiency and pulmonary stenosis.

Clinically, patients may initially have subtle, nonspecific symptoms of fatigue or dyspnea on exertion. As the valvular disease progresses, more classic signs and symptoms of right-sided heart failure may be evident. A focused physical exam should be performed to evaluate for the presence of murmur, elevated jugular venous pressure, peripheral edema, hepatosplenomegaly, and ascites [15]. Having frequent episodes of daily flushing (>3 episodes/day) has been shown to be an independent risk factor for development and progression of CHD [18].

Laboratory evaluation of patients with carcinoid tumors can help to identify patients who are more likely to have CHD. Higher levels of 5-hydroxyindole-3-acetic acid (5-HIAA) in the urine have been correlated with increased risk of developing CHD and progression of CHD on echocardiography [15, 16, 18]. N-terminal pro-brain natriuretic peptide (NT-proBNP), a natriuretic peptide released by the atria and ventricles in response to increased wall stress secondary to volume and/or pressure overload, has been shown to have a high sensitivity (87%) and specificity (80%) in predicting CHD, even in patients without carcinoid syndrome. An NT-proBNP >260 pg/mL can be used to rule out significant carcinoid heart disease [15–17].

Patients who have carcinoid syndrome, especially with frequent flushing episodes, symptoms or exam findings concerning for CHD, high levels of 5-HIAA or NT-proBNP, should be further evaluated with transthoracic echocardiography to better evaluate for and/or characterize the severity of the patient’s CHD.

As outlined above, serum chromogranin A, 24-h urine collection of 5-HIAA, and, in some cases, NT-proBNP are useful in characterizing the burden of disease in patients with carcinoid. In addition to these studies, a chemistry panel should be obtained to evaluate for the presence of volume depletion, electrolyte abnormality, and hyperchloremic metabolic acidosis in the setting of diarrhea. Imaging studies, including octreoscan, should be reviewed to evaluate for the presence of liver metastases and burden of disease. If you suspect carcinoid heart disease, obtaining an electrocardiogram and transthoracic echocardiogram is prudent to better characterize cardiac function.

One should obtain large bore intravenous access given the potential need for fluid resuscitation in the event of carcinoid crisis. This is even more critical if there is a high risk of blood loss with the planned surgical procedure. Preinduction intra-arterial monitoring is necessary, given the need for continual hemodynamic monitoring during induction of anesthesia and the remainder of the procedure. Central venous access may also be necessary, especially when vasopressor support is likely, as may be the case in patients with carcinoid heart disease or other significant medical comorbidities.

Carcinoid crisis is a more severe, and potentially life-threatening, manifestation of the signs of carcinoid syndrome, where release of vasoactive substances from the carcinoid tumor or metastases leads to the development of severe flushing, bronchospasm, tachycardia, and/or hemodynamic instability to the point of complete vascular collapse [1].