Carcinoid syndrome: what is it, signs, treatment, prognosis

What is carcinoid syndrome?

Carcinoid syndrome refers to a group of symptoms caused by the systemic release of various types of humoral factors, such as polypeptides, biogenic amines and prostaglandins, mainly from well-differentiated neuroendocrine tumors. Previously, well-differentiated neuroendocrine tumors were known as carcinoid tumors. Neuroendocrine tumors originate from enterochromaffin cells that are ubiquitous in our body. It is reported that only about 10% of neuroendocrine tumors result in carcinoid syndrome.

Signs and symptoms

Carcinoid syndrome occurs in about 10% of carcinoid tumors and occurs when vasoactive substances from tumors enter the systemic circulation, avoiding destruction by the liver. If the primary tumor is from the gastrointestinal tract (hence the release of serotonin into the hepatic portal circulation), carcinoid syndrome usually does not occur until the disease has developed enough to suppress the liver's ability to metabolize released serotonin.

• Redness: The most important clinical sign is flushing of the skin, usually of the head and upper chest.
• Diarrhea: May be associated with abdominal cramps. This symptom is associated with the action of serotonin, histamine and gastrin.
• Abdominal pain: arises from hepatomegaly, obstruction of the small intestine, or lack of oxygen in the small intestine.
• Bronchospasm, which can be caused by histamine or serotonin, affects about 15% of patients with carcinoid syndrome and is often accompanied by redness of the skin, sneezing and shortness of breath.
• Carcinoid heart disease: 19% to 60% of patients with carcinoid syndrome develop carcinoid heart disease. Serotonin causes fibrosis of the right heart valves, especially the tricuspid valve.

Causes

Carcinoid syndrome is most commonly caused by midgut neuroendocrine tumors that metastasize to the liver. Neuroendocrine tumors of the anterior and posterior colon also rarely cause carcinoid syndrome. Neuroendocrine tumors most often occur in the gastrointestinal tract (about 70%), and then in the respiratory tract (about 25%). Neuroendocrine tumors rarely occur in other areas such as the ovaries, testes, and kidneys.

Epidemiology

Neuroendocrine tumors are relatively rare tumors. As mentioned above, only about 10% of neuroendocrine tumors result in carcinoid syndrome. SEER (National Cancer Institute's Surveillance, Epidemiology and Outcomes Program is a source of epidemiological information on incidence and survival of cancer in the United States), the incidence of neuroendocrine tumors in the non-pancreatic zone, adjusted for age, is 4.7 per 100 000. The incidence of neuroendocrine tumors is growing. The incidence of neuroendocrine tumors, including non-pancreatic and pancreas, increased from 1.09 to 5.25 per 100,000 between 1973 and 2004 (according to SEER). This increase in morbidity in recent decades is likely due to an increase in the number of endoscopic and radioimaging studies. The incidence depends on gender and race. Recent data show that the incidence of neuroendocrine tumors is higher in black men than in Europeans (6.46 versus 4.6 per 100,000). The ratio of the incidence of tumors in men and women is almost the same, in men it is slightly higher. The average age at diagnosis of neuroendocrine tumors is from 55 to 60 years.

Pathophysiology

The pathophysiology of carcinoid syndrome is based on the fact that biologically active amines and peptides enter the systemic circulation and escape from the first pass metabolism in the liver. Usually, these biologically active products are inactivated in the liver. However, in cases of neuroendocrine tumors with liver metastases, these biologically active products either enter the systemic circulation directly or are not inactivated due to liver dysfunction.

Less commonly, carcinoid syndrome can occur without liver metastases in conditions such as a primary bowel tumor with widespread metastases in the retroperitoneal lymph nodes, ovarian tumor or bronchial carcinoid, which release bioactive amines directly into the systemic blood flow.

Neuroendocrine tumors secrete about 40 types of biologically active amines and peptides. The most common are serotonin, histamine, tachykinins, kallikrein, and prostaglandins. Most of the clinical manifestations are associated with serotonin, which is an end product of tryptophan metabolism.

Usually only 1% of tryptophan is converted to serotonin. However, in the case of neuroendocrine tumors, up to 70% of tryptophan is metabolized to serotonin. Serotonin undergoes oxidative reactions that lead to the formation of 5-hydroxyindoleacetic acid (5-HIAA) via aldehyde dehydrogenase, which is then excreted in the urine.

Serotonin causes increased motility and excessive secretion of the gastrointestinal tract, leading to diarrhea. Since most of the tryptophan is directed to the serotonin pathway by neuroendocrine tumors, this leads to a deficiency of tryptophan, which is necessary for the synthesis of niacin. Hence, niacin deficiency results in pellagra, which is manifested by the triad dermatitis, dementia and diarrhea. Prostaglandins are also involved in increasing intestinal motility and fluid secretion in the gastrointestinal tract, causing diarrhea.

Carcinoid tumors of the foregut and lungs lack the aromatic L-amino acid decarboxylase enzyme, which metabolizes 5-hydroxytryptophan to serotonin. Thus, carcinoid tumors of the lungs and foregut do not produce serotonin. On the other hand, hindgut neuroendocrine tumors usually do not produce bioactive hormones.

Pulmonary carcinoid tumors primarily produce histamine, which can cause atypical flushing and itching. Tachykinins (substance p, neurokinin A, neuropeptide k) are also responsible for erythema due to their vasodilating action.

Diagnostics

For some degree of clinical suspicion, the most useful initial test is determination of the level of 5-hydroxyindoleacetic acid, the end product of serotonin metabolism, in daily urine. Patients with carcinoid syndrome typically excrete more than 25 mg of 5-HIAA per day.

- Visualization studies.

For the localization of both primary lesions and metastases, the initial imaging method is octreoscan, where the labeled indium-111 somatostatin analogs (octreotide) are used in scintigraphy to detect tumors expressing receptors somatostatin. The median detection rate with octreoscan is about 89%, in contrast to other imaging techniques such as computed tomography (CT) and MRI, with a detection rate of about 80%. Gallium-68 labeled somatostatin analogs such as 68Ga-DOTA-Octreotate (DOTATATE) performed on a PET / CT scanner are superior to conventional octreoscan.

Typically, CT scans show arachnoid / crab-like changes in the mesentery due to fibrosis caused by the release of serotonin. PET / CT with 18F-FDG, which measures increased glucose metabolism, can also help localize carcinoid lesions or assess metastases. Chromogranin A and platelet serotonin are elevated.

Transthoracic echocardiogram shows valve thickening and decreased valve mobility. Cardiac MRI is useful for showing the anatomy and function of the ventricles.

- Localization of the tumor.

Tumor localization can be extremely complex. Swallowing barium and subsequent examination of the intestines may sometimes show swelling. Recently, capsule video endoscopy has been used to localize the tumor. Laparotomy is often the definitive way to localize the tumor. Octreoscan is another form of tumor localization. Indium-111 is injected into a vein where tumors take up the indium-111 radionuclide and become visible on the scanner. Only the tumors take up the somatostatin substance indium-111, which makes the scan effective.

Treatment

There are various treatments for carcinoid syndrome, which include somatostatin analogs, therapeutic therapy aimed at liver, surgical removal in the early stages of low-grade neuroendocrine tumors and chemotherapy for the treatment of poorly differentiated neuroendocrine tumors or refractory carcinoid syndrome.

Surgery plays a vital role in the treatment of carcinoid syndrome with or without metastases. If possible, always consider surgical resection of the primary tumor as well as nodular and liver metastases to reduce tumor burden.

- Medical management.

Two somatostatin analogs are available for medical treatment: octreotide and lanreotide. Somatostatin is an amino acid peptide that is an inhibitory hormone that is synthesized by paracrine cells found throughout the gastrointestinal tract. It inhibits the release of most endocrine hormones from the gastrointestinal tract. About 80% of neuroendocrine tumors have somatostatin receptors. The use of a somatostatin analogue inhibits the release of biogenic amines, resulting in control of symptoms such as hot flushes and diarrhea.

Octreotide is available as a short-acting subcutaneous injection, as well as a depot for intramuscular injection (Sandostatin® LAR), which can be administered monthly. Patients should start with 20–30 mg IM every four weeks and may need to gradually increase the dose. Short-acting octreotide can be used in patients with severe or refractory symptoms.

Lanreotide is a long-acting drug (depot somatulin) that is administered at a dose of 60 to 120 mg every four weeks. It has the same potency as octreotide.

Both somatostatin analogues provide symptom relief in 50–70% of patients and biochemical responses in 40–60% of patients. Many studies have shown that octreotide and lanreotide also inhibit tumor cell proliferation.

The most common side effects associated with somatostatin analogs are nausea, bloating and steatorrhea caused by pancreatic malabsorption. Pancreatic enzyme supplements usually help relieve adverse symptoms. Due to decreased motor skills and contraction gallbladder due to the inhibitory effect of somatostatin, patients are at risk of developing bile sediment and gallstones.

- Surgery.

In patients with neuroendocrine tumors of the bronchi with carcinoid syndrome diagnosed at an early stage, surgical resection of the tumor leads to a complete cure of the carcinoid syndrome. In patients with surgically resectable liver metastases, surgical resection, or partial hepatectomy, symptoms improve. It has been reported that in patients with severe tumor burden and extensively metastatic disease palliative cytoreductive surgery or surgery to remove the tumor improves symptoms, morbidity and mortality. Selective cholecystectomy may also be suggested during surgery to prevent formation deposits of the biliary tract and the formation of gallstones, which can occur with analog therapy somatostatin. Endoscopic resection of early neuroendocrine tumors of the stomach and rectum (less than 1 cm) can lead to complete recovery from carcinoid syndrome.

In patients with neuroendocrine cardiac tumors with severe tricuspid regurgitation, tricuspid valve replacement may reduce mortality.

A patient who is not a candidate for surgery but has a higher tumor burden, especially with liver metastases, transarterial chemoembolization.

- Refractory symptoms.

The following therapy options are available for a patient with refractory symptoms:

1. Additional doses of short-acting octreotide or more frequent depot doses of octreotide or lanreotide (every three weeks instead of every four weeks).
2. Telotristat: An oral tryptophan hydroxylase inhibitor recently approved for the treatment of carcinoid syndrome for use in combination with somatostatin analogues to control diarrhea. It is prescribed in a dose of 250 mg 3 times a day with meals.
3. Interferon: Interferon-alpha can be used in a patient who does not respond to a somatostatin analog. Interferon works by stopping the cell cycle in tumor cells, stimulating T cells, and inhibiting tumor cell angiogenesis, resulting in tumor necrosis.
4. Antidiarrheals such as loperamide, lomotil, cholestyramine (especially for those who have had bowel surgery).
5. Systemic therapy. The most common cytotoxic chemotherapy used for carcinoid syndrome is everolimus, which is an mTOR inhibitor. Everolimus has been shown to improve symptoms by increasing the clearance of 5-HIAA, but studies have shown no improvement in disease-free survival.
6. Radioligand therapy with peptide receptors for the delivery of targeted radiation to tumors expressing the somatostatin receptor.

- Prevention and treatment of carcinoid crisis.

Carcinoid crisis: patients with carcinoid syndrome may experience severe hemodynamic instability due to severe acute attacks of persistent hyperemia with bronchospasm and hypotension. Factors that can trigger a carcinoid crisis are sedatives, anesthetics, catecholamines, surgery, and tumor necrosis. This is due to the sudden release of the overwhelming amount of vasoactive compounds.

In all patients with metastases, daily urinary 5-HIAA levels should be determined. With an increase, octreotide should be prescribed as a prophylactic measure. In patients with functioning tumors or with liver metastases, preoperative administration of octreotide from 300 to 500 μg IM / is mandatory to prevent carcinoid crisis. Additional dosing may be required during surgery. It is necessary to avoid adrenergic drugs for blood pressure control, which can have a paradoxical effect.

If a carcinoid crisis occurs, octreotide 500–1000 mcg intravenously should be given as a bolus followed by continuous infusion at a dose of 50–200 mcg / hour. In the case of intraoperative hypotension, calcium and catecholamines should be avoided, as they impair the release of mediators from the tumor.

- Echocardiogram recommendations.

Patients with a significant increase (more than five times the upper limit of normal) serum serotonin / 5-HIAA in urine, signs and symptoms of carcinoid heart disease, or if major surgery is planned, it should be performed echocardiogram.

Forecast

The prognosis varies from patient to patient. It ranges from 95% 5-year survival for localized disease to 80% 5-year survival for patients with liver metastases. The median survival time since the start of octreotide treatment has increased to about 12 years.