Carcinoid syndrome

Signs and symptoms

Flushing of the skin, usually of the head and upper thorax, occurs in about 85% of people and may be triggered by diet, activity, or stress. Diarrhea, the second most common finding, affects about 80% and may involve abdominal cramping and pain. Bronchoconstriction is relatively rare, occurring in about 15%, and often accompanies flushing, sneezing, and shortness of breath.

Cardiac complications develop in 60–70% of those affected, mainly involving fibrosis of the right-sided tricuspid and pulmonic valves, which may be heard as a murmur and contribute to fatigue. Less common symptoms include malabsorption (leading to pellagra), fatigue, muscle loss, and cognitive impairment. Late complications may include mesenteric and retroperitoneal fibroses.

Pathophysiology

Carcinoid syndrome occurs secondary to neuroendocrine tumors, which arise mostly in the gut and less commonly in the lungs, pancreas, kidneys, or other organs. These tumors secrete over 40 biologically active substances, primarily amines and peptides; the exact contribution of each is unknown, but serotonin appears to have the greatest role. Symptoms result from the action of these substances on blood vessels.

The liver normally metabolizes and inactivates these substances via first-pass metabolism, so the syndrome most often occurs when the tumor has metastasized to the liver, allowing substances to bypass this process. Tumors arising in the bronchi can cause manifestations without liver metastases because their products reach the systemic circulation before passing through the liver. Tryptophan metabolism is altered: conversion to serotonin shifts from the normal 1% to as high as 70%, increasing gut motility and contributing to diarrhea and flushing.

Tryptophan is also needed for niacin synthesis, which can lead to pellagra. In pulmonary tumors or metastases, histamine and kallikrein are the vasoactive mediators. Carcinoid crisis is an extreme exacerbation triggered by stressful procedures such as anesthesia, surgery, or radiation, resulting in flushing, hypotension, arrhythmia, and bronchospasm.

Diagnosis

With clinical suspicion, the most useful initial test is a 24-hour urine level of 5-HIAA, the end product of serotonin metabolism. Chromogranin A, a glycoprotein released by neuroendocrine tumors, can detect non-secreting tumors. Imaging should focus on the abdomen and pelvis, as the causative tumors largely arise in the gut. Nuclear medicine gamma camera imaging using radioactive somatostatin analogues such as indium-111 pentetreotide localizes the tumor; PET scan can also find the primary site.

Bronchoscopy with biopsy is performed if a pulmonary tumor is suspected. For patients with serotonin elevated five times the upper limit of normal or more, an echocardiogram is recommended to evaluate for carcinoid heart disease. Other conditions to consider include irritable bowel syndrome, celiac disease, and Ogilvie syndrome.

Treatment

Treatment focuses on controlling tumor proliferation and symptoms with somatostatin analogues octreotide or lanreotide. For refractory symptoms, increasing the dose or switching to another analogue such as pasireotide may be effective; if still refractory, mTOR inhibitors like everolimus may be used. The TPH inhibitor telotristat ethyl can help control diarrhea. Peptide directed radiotherapy (PRRT) using radioactive somatostatin analogues such as 177Lu-Dotatate or 90Y-Edotreotide is an alternative for patients who failed somatostatin analogue therapy, effective for metastatic disease but studied over about six-month periods.

Cytoreductive surgery with 131I-MIBG may control symptoms starting 6–15 months post-procedure and lasting up to 39 months. Liver-directed procedures such as radiofrequency ablation or radioembolization deliver targeted therapy via catheters, especially for liver metastases. For carcinoid heart disease, detection via echocardiography with color doppler is key; treatment follows heart failure management, with definitive treatment being surgical valve repair or replacement. Disease progression is difficult to ascertain because metastases can be too small to identify; markers like chromogranin-A are imperfect.

Did You Know?

• In nonhuman animals, common signs include vomiting, diarrhea, and weight loss, though flushing, hypotension, and diarrhea can also occur.