Carcinoid Tumors: Pathophysiology and Natural History

Carcinoid tumors originate from endocrine cells anywhere in the gastrointestinal tract and other organs. They are classified based on organ site and cell of origin and occur most frequently in the gastrointestinal tract (67%), where they are most common in the small intestine (25%).¹ Changes in nomenclature have attempted to alleviate the confusion surrounding the diversity of the clinical prognosis of carcinoid tumors, and most carcinoid tumors are now described as well-differentiated neuroendocrine tumors (NETs).² Recent research demonstrates a significant increase in the reported incidence of NETs over the past several decades (P<.001), suggesting that these tumors are more prevalent than previously believed. Nevertheless, they remain rare enough that they are still considered "orphan" tumors. According to an analysis of Surveillance, Epidemiology, and End Results (SEER) program data, the 29-year limited-duration prevalence of NETs on January 1, 2004 in the United States was 103,312 cases.³

Cells of carcinoid tumors can harbor secretory granules, which secrete a variety of hormones and biogenic amines ⁴. The release of these substances into the systemic circulation results in unique systemic syndromes. Differences in these systemic syndromes are associated with differences in the location of the primary tumor and account for the diverse clinical presentations of patients with carcinoid tumors.⁵ It should be noted that most carcinoid tumors do not harbor secretory granules that are associated with carcinoid syndrome. These tumors are often referred to as non-functioning tumors.

Although gastrointestinal carcinoid tumors are considered slow growing tumors, they can behave aggressively.¹ Factors that determine the clinical course and outcome of patients with gastrointestinal (GI) carcinoid tumors are complex and include⁶:

Incidence and origin of carcinoid symptoms

Carcinoid syndrome is a consequence of vasoactive peptides such as serotonin, histamine, or tachykinins released into the circulation and is manifested by symptoms of episodic flushing, diarrhea, wheezing, and, potentially, the eventual development of carcinoid heart disease.⁷ In patients with carcinoid syndrome, diarrhea is found in 83% of cases, flushing in 49%, dyspnea in 20%, and bronchospasm in 6%.⁸ The relationship between diarrhea and flushing is variable. One can occur without the other, and there may be no temporal relationship between the two. These symptoms can have a significant effect on patients if not controlled by treatment.⁶ Most symptoms of carcinoid syndrome can be expected to become more severe when a secreting tumor spreads to the liver and the over-secreted hormones spread more freely via the circulatory system.

Not all carcinoid tumors with carcinoid syndrome produce the same variety of chemicals and hormones, and it is not yet entirely clear which of the substances is responsible for each of the symptoms of the carcinoid syndrome. However, almost all of these tumors make the following⁸:

In carcinoid tumors, neurotensin is elevated in 43% of patients, substance P in 32% of patients. Hormones and peptide produced by the tumor are also markers of the relative primary tumor location.⁹

Prognosis

While the general prognosis for carcinoid tumors is excellent compared with that of other visceral cancers,¹⁰ Davis and colleagues reported a mean survival of 38 months from the first episode of flushing, with only 25% of patients living for more than 6 years. With regional lymph node involvement, the figure falls to approximately 14 months, and with urinary 5-HIAA in excess of 150 mcg per 24 hours or inoperable tumors, median survival is only 11 months.⁸

Many patients with carcinoid syndrome will develop irreversible valvular cardiac complications consisting of tricuspid regurgitation or pulmonary stenosis. The development of carcinoid heart disease results in much poorer prognosis compared with its absence.¹

Carcinoid heart disease: A dangerous complication

Carcinoid heart disease occurs in up to two thirds of patients with carcinoid syndrome and is responsible for one third of patient deaths.¹ The lesions are characterized by plaquelike, fibrous endocardial thickening, involving predominantly the right side of the heart (tricuspid and pulmonic valves). Right-sided heart failure is irreversible and can lead to significant morbidity and mortality. It is caused by the exposure of the heart to elevated concentrations of serotonin and other vasoactive substances released in patients with carcinoid syndrome.¹¹ Patients with carcinoid heart disease have a 5-year survival of approximately 20% versus approximately 50% for those without carcinoid heart disease (Figure 1).¹²

Carcinoid heart disease and serotonin

The development of carcinoid heart disease is influenced not only by high levels of serotonin, but also by the duration of exposure to serotonin, indicating how important it is to exert biochemical control in patients with high levels of serotonin as soon as possible. Moller and colleagues have also found that not only is serotonin related to the progression of carcinoid heart disease, but the risk of progressive heart disease is higher in patients who received chemotherapy.¹¹

Controlling the vasoactive peptide release by the tumors is essential. It is likely that the control of carcinoid syndrome reduces the risk of progressive carcinoid heart disease.¹¹ Biochemical markers (ie, CgA, urinary 5-HIAA, and others depending on the primary site of the tumor) should be monitored on a regular basis (every 3 to 6 months) and the trend followed for information on disease progression and response to therapy.^8,13 It is noteworthy that patients with carcinoid tumors with no symptoms may develop functional hormone secretion during tumor progression.¹⁴

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