bubble_chart Overview

Carcinoid, also known as carcinoid tumor, is a group of neoplasms originating from chromaffin cells in the gastrointestinal tract and other organs. Their clinical, histochemical, and generation and transformation characteristics may vary depending on the site of occurrence. These tumors can secrete biologically active factors such as serotonin (5-hydroxytryptamine), kinins, and histamine, leading to vasomotor disturbances, gastrointestinal symptoms, and cardiac or pulmonary lesions, collectively known as carcinoid syndrome.

bubble_chart Epidemiology

This disease is rare, accounting for 1.5% of gastrointestinal tumors. Japanese statistics show that it accounts for 0.14% to 1.8% of autopsy cases and 0.06% to 0.16% of surgical cases. It can occur at any age, with appendiceal carcinoids appearing at a younger average age of 30, while carcinoids in other locations have an average onset age of around 50. Except for appendiceal carcinoids, most carcinoid tumors occur more frequently in males.

bubble_chart Etiology

The etiology of this disease has not yet been elucidated. Carcinoid tumors are neoplasms capable of producing small-molecule polypeptides or peptide hormones, i.e., APUD cell tumors. They act by increasing cyclic adenosine monophosphate (cAMP) in target cells and can secrete highly physiologically active substances such as serotonin (5-hydroxytryptamine, 5-HT), kallikrein, and histamine. Some may also secrete other peptide hormones, including adrenocorticotropic hormone (ACTH), catecholamines, growth hormone, parathyroid hormone, calcitonin, antidiuretic hormone (ADH), gonadotropin, insulin, glucagon, prostaglandins, gastrin, and motilin. The primary substances responsible for carcinoid syndrome are serotonin and bradykinin, with histamine also playing a partial role.

Serotonin exerts a direct vasoconstrictive effect on peripheral and pulmonary blood vessels, as well as a strong bronchoconstrictive effect. It stimulates preganglionic vagal nerves and ganglion cells in the gastrointestinal tract, enhancing peristalsis and secretion.

Bradykinin has a potent vasodilatory effect. Some carcinoid tumors, particularly gastric carcinoids, can produce large amounts of vasoactive substances such as bradykinin and histamine, leading to cutaneous flushing. Elevated circulating serotonin levels can also cause endocardial fibrosis.

Under normal circumstances, only about 2% of dietary tryptophan is utilized for serotonin (5-HT) synthesis, while 98% is metabolized into niacin and protein synthesis pathways. However, in patients with carcinoid syndrome, up to 60% of tryptophan may be taken up by tumor cells, resulting in increased 5-HT synthesis and reduced niacin production. Within tumor cells, 60% of the ingested tryptophan is catalyzed by tryptophan hydroxylase into 5-hydroxytryptophan (5-HTP), which is then converted to 5-HT by dopa decarboxylase. Some of this 5-HT is stored in secretory granules within the tumor cells, while the remainder enters the bloodstream directly. In the blood, free 5-HT is largely degraded by monoamine oxidase (MAO) in the liver, lungs, and brain into 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in urine. In carcinoid tumors originating from the midgut system, serum 5-HT levels are elevated, and urinary 5-HIAA excretion increases, constituting the typical carcinoid syndrome. This type accounts for over 75% of carcinoid syndrome cases. Foregut carcinoid tumors often lack dopa decarboxylase, preventing the conversion of 5-HTP to 5-HT. Consequently, 5-HTP is released directly into the bloodstream, leading to elevated serum 5-HTP levels without a corresponding increase in 5-HT. In these patients, urinary excretion of 5-HTP and 5-HT is increased, while 5-HIAA levels show little change, resulting in atypical carcinoid syndrome.

bubble_chart Pathological Changes

More than 90% of carcinoid tumors occur in the gastrointestinal tract, primarily in the appendix, terminal ileum, and rectum, with a minority occurring in the colon, stomach, duodenum, Meckel's diverticulum, as well as the biliary tract, pancreatic duct, gonads, lungs, and bronchi. The predominant sites of carcinoids may vary among different ethnic groups. In Japanese cases, carcinoids of the stomach, duodenum, and colon are more common than in European and American cases, while small intestine carcinoids are less frequent. This is speculated to be related to differences in the distribution of chromaffin cells in various organs between Japanese and Europeans/Americans.

Godwin reviewed 2,837 cases of carcinoids and found that 85.5% were located in the gastrointestinal tract. Extragastrointestinal sites included the bronchi, lungs, larynx, liver, pancreas, uterine cervix, parotid gland, urethra, and even the testes or ovaries. Orloff summarized the distribution of 3,000 gastrointestinal carcinoid cases from the literature, in descending order: appendix (47.0%), ileum (27.5%), rectum (17.0%), stomach (2.5%), colon (2.0%), jejunum (1.5%), duodenum (1.3%), Meckel's diverticulum (1.0%), and gallbladder (0.2%). The appendix is the most common site, with the appendix, ileum, and rectum together accounting for over 90% of all gastrointestinal carcinoids.

Typical gastrointestinal carcinoids often present as small, yellow or gray submucosal nodular masses, either solitary or multiple, with an intact mucosal surface. Their morphology varies, appearing as nodular, polypoid, or annular. A few tumors may develop surface ulcers, resembling adenocarcinomas, and often invade the muscular and serosal layers. Some patients may have multicentric carcinoid tumors. Ileal carcinoids are frequently multiple and small, usually less than 3.5 cm in diameter, averaging around 1.5 cm. A domestic study of 78 cases found that rectal carcinoids were all located within 10 cm of the anal verge, with tumor sizes ranging from 0.2 to 2.5 cm, mostly less than 1.0 cm, resembling polyps but lacking a stalk. On cross-section, they appear gray-white or gray-yellow, firm, and well-demarcated.

Under the microscope, carcinoid cells appear square, columnar, polygonal, or round. The nuclei are uniform with rare mitotic figures, and the cytoplasm contains eosinophilic granules. Electron microscopy reveals that the granules in carcinoid cells from different parts of the gastrointestinal tract exhibit distinct morphologies and histochemical properties. Small intestine carcinoid cells contain large, pleomorphic granules that are argyrophilic (silver stain-positive). Gastric carcinoid cells have round granules that require an exogenous reducing agent for a positive silver stain reaction, making them argentaffin. Rectal carcinoid cells have large, round, uniform granules that are non-reactive to both argyrophilic and argentaffin stains.

The histological hallmark of carcinoids is the diverse arrangement of tumor cells. Soga et al. classified the patterns into five types based on their arrangement.

**Type A**: Carcinoid cells aggregate into nodular solid nests, with mostly round cells arranged irregularly, forming cords that infiltrate the surrounding tissue. This type is most typical of midgut-derived carcinoids.

**Type B**: Tumor cells form trabecular structures, arranged in a single layer like a shell, with nuclei at the periphery in a palisading or ribbon-like pattern. This type is common in foregut-derived carcinoids.

**Type C**: Square cells arrange into gland-like structures without lumens or form rosette-like patterns.

**Type D**: Tumor cells are irregular in shape and arrangement, forming large medullary structures. Types C and D are often seen in hindgut-derived carcinoids.

**Type E**: A mixture of the above four types.

The atypical hyperplasia and mitotic figures of carcinoids are not obvious, making it generally difficult to judge their malignancy based on cellular morphology alone. The following can be referenced: ① The size of the carcinoid. Based on data from 843 surgical cases, those with a maximum diameter below 1 cm showed a benign course in 90–100% of cases. For those between 1–2 cm, 30–50% had metastases. For those with a diameter >2 cm, 80–100% had metastases. ② The degree of invasion. Statistics show that carcinoids that have invaded the muscular layer of the gastrointestinal tract have a 90% metastasis rate. ③ The location of growth. Appendiceal carcinoids almost always follow a benign course, and even if they have infiltrated the serosa, metastasis remains rare (<2%).

The metastasis rate of small intestine carcinoids is 30%, while that of colon carcinoids is 38%. Malignant carcinoids in the duodenum and stomach are less common than those in the small intestine.

The pathways of carcinoid metastasis include direct invasive growth, penetration through the serosa into surrounding tissues, as well as lymphatic or hematogenous metastasis. There have also been rare reports of hematogenous metastasis occurring without local lymph node involvement. Hematogenous metastasis most frequently involves the liver, but it can also spread to bones, lungs, and the brain. Other less common metastatic sites reported in the literature include the ovary, epididymis, skin, bone marrow, retroperitoneum, orbit, adrenal gland, spleen, pancreas, kidney, thyroid, bladder, prostate, and uterine cervix. There have also been reports of metastasis to the breast, with clinical signs closely resembling those of primary breast cancer.

Carcinoid cells originate from enterochromaffin cells (also known as Kulchitsky cells) in the APUD cell system. These cells are derived from the embryonic neural crest and are widely distributed throughout the digestive tract. They contain chromaffin and argentaffin granules and can produce various peptide and amine hormones. In recent years, advances in immunohistochemical techniques have confirmed the presence of multiple hormones in tissue sections. Carcinoid syndrome results from serotonin and various vasoactive substances metabolized by the liver, which then enter the bloodstream and reach the lungs and heart. This leads to pulmonary valve and subendocardial fibrous tissue proliferation. Approximately half of the cases are associated with right-sided valvular lesions, including thickening, shortening, rigidity, and adhesion of the pulmonary valve and tricuspid valve. Fibrous thickening may also occur in the endocardium and chordae tendineae, causing pulmonary valve stenosis and tricuspid valve insufficiency. Left-sided endocardial lesions may present with focal or diffuse fibrous proliferation in the elastic fiber layer, particularly in bronchial carcinoids, where fibrosis of the left heart, pulmonary valve, tricuspid valve, and aortic valve is more commonly observed.

bubble_chart Clinical Manifestations

Carcinoid tumors themselves have inconspicuous symptoms or only local symptoms, while carcinoid syndrome often presents with significant systemic symptoms. Rectal carcinoids are frequently discovered incidentally during screenings.

(1) Local symptoms of carcinoid tumors

1. Right lower abdominal pain: Appendiceal carcinoids can cause luminal obstruction, often leading to appendicitis, manifested as right lower abdominal pain.

2. Symptoms of intestinal obstruction: Small intestine carcinoids and their metastatic masses can cause intestinal obstruction, presenting with abdominal pain, abdominal distension and fullness, borborygmus, nausea, vomiting, and other symptoms.

3. Abdominal mass: A few carcinoids may develop into abdominal masses. Malignant carcinoids invading surrounding tissues or metastasizing often result in abdominal masses.

4. Gastrointestinal bleeding: Gastric or duodenal carcinoids may cause upper gastrointestinal bleeding; intestinal carcinoids can also present with hematochezia or occult bleeding, leading to anemia.

5. Respiratory symptoms: The most common manifestations of bronchial carcinoids are respiratory symptoms such as cough, expectoration, hemoptysis, chest pain, etc.

(2) Systemic symptoms of carcinoid syndrome: Mostly caused by malignant small intestine carcinoids metastasizing to the liver, but can also arise from carcinoids in the bronchus, stomach, pancreas, thyroid, ovary, and other locations.

1. Skin flushing: 63–94% of patients may experience this symptom, mostly occurring in the upper body, particularly the face and neck. The skin exhibits episodic bright red changes. Gastric carcinoids, due to potential histamine secretion, may present with skin flushing patches resembling urticaria. Flushing episodes may be accompanied by feverish sensations, tearing, palpitations, hypotension, and facial and periorbital edema. The severity and duration of episodes vary, typically lasting 1–5 minutes, but may extend to several hours in chronic cases. Initially, episodes may occur every few days or weeks, later increasing to several times a day. Triggers include emotional stress, physical activity, alcohol consumption, ingestion of tyramine-rich foods, or injection of calcium or catecholamine drugs. After years of episodes, chronic localized dilation of skin capillaries and venules may lead to fixed cyanotic skin changes, often seen on the face and nasolabial area, resembling long-term mitral stenosis patients.

2. Gastrointestinal symptoms: Mainly characterized by hyperactive intestinal motility, leading to episodic colicky abdominal pain, borborygmus, diarrhea ranging from loose stools to episodic watery stools, and tenesmus. Gastrointestinal symptoms occur in 68–84% of patients, often accompanied by episodic skin flushing, with only 15% of patients lacking flushing symptoms. A few patients may develop malabsorption syndrome, resulting in significant nutritional decline.

3. Respiratory symptoms: Small bronchial spasms may occur, causing episodic asthma. Seen in 8–25% of patients. This symptom may appear earlier than others, leading to misdiagnosis as allergic disorders. Like skin flushing, it can be triggered by emotional stress or physical activity.

4. Cardiovascular symptoms: Observed in 11–53% of cases. Long-term illness may lead to endocardial fibrosis, affecting the valves, predominantly in the right heart, with milder left heart involvement. Clinically, in late stages, half of the cases may exhibit valvular disease, with tricuspid insufficiency and pulmonary valve stenosis being more common, potentially causing right heart failure. Endocardial fibrosis may result from serotonin released by carcinoids. The lungs contain abundant monoamine oxidase, which can inactivate serotonin, so left heart involvement is rare unless right-to-left shunting or bronchial carcinoids are present. Left ventricular involvement primarily manifests as mitral valve disease, resembling rheumatic heart disease. Cardiac complications are often the primary cause of death in carcinoid patients.

5. Other Manifestations Over 90% of patients have liver metastases, often presenting with signs of hepatomegaly. In some cases during the late stage [third stage], brownish-yellow skin pigmentation and hyperkeratosis may occur, resembling pellagra-like changes. Myopathy can also develop, characterized by atrophy of type I and II muscle fibers. Arthropathy manifests as joint stiffness and pain during movement. X-ray imaging may reveal erosion of the interphalangeal joints, multiple cystic lucent areas within the phalanges, and osteoporosis in the periarticular regions of the interphalangeal and metacarpophalangeal joints.

Clinically, the possibility of carcinoid tumor should be considered under the following circumstances: ① A right abdominal mass, prolonged weight loss, and a history of diarrhea should raise suspicion of small intestine carcinoid; ② Unexplained intermittent diarrhea, facial telangiectasia, paroxysmal flushing, asthma, or psychiatric symptoms suggest carcinoid syndrome, and the presence of hepatomegaly further supports this diagnosis; ③ Chronic low intestinal obstruction with hematochezia, a relatively long course, and generally good condition should prompt consideration of colonic carcinoid; ④ A young patient with no smoking history presenting with a lung mass, long-term survival, and exclusion of other lesions suggests bronchopulmonary carcinoid.

(3) Classification of Carcinoid Tumors Williams categorized carcinoid tumors into three types based on their origin, each differing in cytology, histochemistry, biochemistry, and clinical manifestations, as well as treatment (Table 1).

Table 1 Classification of Carcinoid Tumors

	Foregut Type	Midgut Type	Hindgut Type
Site of Origin	Bronchus, stomach, pancreas	Duodenum to transverse colon	Descending colon to rectum
Histology	Cells arranged in cords, nodules, or pseudoglandular patterns	Cells arranged in solid nests	Mixed arrangement, tending toward cord-like patterns
Argentaffin Reaction	-	+	-
Argyrophilic Reaction	+	+	-
Tumor Cell Content
5-HT	Low	High	Absent
Histamine	Present	Absent	Absent
Secretory Granules	Present	Present	Present
Carcinoid Syndrome	Common	Frequent	Absent
Urinary 5-HIAA	High	High	Absent
5-HTP Secretion	Common	Rare	Absent
Bone and Skin Metastases	Common	Rare	Common

bubble_chart Auxiliary Examination

(1) 5-HT Measurement The serum 5-HT levels in patients with carcinoid syndrome are often significantly elevated, mostly ranging from 83 to 510 μmol/24h (normal range: 11–51 μmol/24h).

(2) 5-HIAA Measurement Patients with carcinoid syndrome exhibit increased urinary excretion of 5-HIAA, often exceeding 78.5 μmol/24h, typically between 156.9 and 3138 μmol/24h (normal value <47.1 μmol/24h).

(3) Flushing Provocation Test ① Add 10 ml of ethanol to 15 ml of orange juice and administer orally; within 3–5 minutes, approximately one-third of patients develop skin flushing. ② Intravenously inject 15–20 μg of norepinephrine or 5–10 μg of epinephrine. These two provocation tests provide some diagnostic assistance. However, caution is advised for patients with a history of arrhythmia, cardiac insufficiency, or asthma.

bubble_chart Diagnosis

Carcinoid tumors lack specific signs, making diagnosis quite difficult. Clinically, they are often overlooked or misdiagnosed as appendicitis, Crohn's disease, intestinal cancer, and other conditions. When carcinoid syndrome occurs, diagnosis becomes easier. Typical manifestations include skin flushing, diarrhea, abdominal pain, asthma, right-sided valvular heart disease, and hepatomegaly. Elevated serum 5-HT levels and increased urinary excretion of 5-HIAA are diagnostically significant; if the latter exceeds 261.5–523 μmol/24h, the diagnosis can be confirmed. Histological examination of the tumor provides definitive confirmation.

To determine the primary site of the carcinoid tumor and whether metastasis has occurred, the following examinations should be selected based on the clinical scenario: ① Gastrointestinal endoscopy and biopsy; ② Bronchoscopy can localize bronchial carcinoids; ③ Selective angiography is helpful for intestinal carcinoids; ④ Ultrasound or CT can assess liver metastasis; ⑤ Digital rectal examination and proctoscopy aid in diagnosing rectal carcinoids.

bubble_chart Treatment Measures

(1) Surgical Treatment

Surgical removal of the primary lesion is the most effective treatment method. Early surgery yields particularly good results, but even in cases of metastasis, excising large primary lesions can alleviate or eliminate symptoms. Metastasis is rare in appendiceal carcinoid tumors, and it is generally considered sufficient to perform a simple appendectomy. Expanded radical surgery is only considered when there is visible metastasis or the tumor diameter exceeds 2 cm. Small intestine carcinoids have a high malignancy rate, and aggressive radical surgery is recommended.

Small, asymptomatic rectal carcinoids can be treated with local excision. Orloff reported that rectal carcinoids larger than 1 cm in diameter are prone to spread to regional lymph nodes, while those smaller than 1 cm usually do not extend beyond the submucosal layer. Radical surgery is thus limited to cases where the tumor exceeds 2 cm in diameter, invades the muscle layer, or recurs after local excision.

For gastric and duodenal carcinoids, local excision is sufficient if the diameter is less than 1 cm. If the diameter exceeds 1 cm, partial gastrectomy and omentum removal should be performed. Carcinoids in the second or third part of the duodenum may require pancreaticoduodenectomy, but due to the high mortality rate of this procedure, it should be approached with caution.

For liver metastases, the best palliative treatment is lobectomy or metastatic tumor resection. Reports indicate that removing large isolated liver metastases can significantly relieve symptoms, reduce urinary 5-HIAA levels, and prolong survival for years. When surgical resection is not feasible, hepatic artery catheter embolization or perfusion therapy may be considered.

Carcinoid tumor surgery carries many complications, including a high risk of anesthesia accidents. Tumor exploration during surgery can trigger carcinoid crisis, and manipulation or compression of the tumor often leads to severe hypotension. Therefore, preoperative preparation is essential, including administering high-dose antiserotonin drugs and having vasoactive medications on hand to promptly correct hypotension. Avoid using catecholamine drugs and use thiopental sodium cautiously for induction.

There have been reports that cardiac valve lesions in patients with carcinoid syndrome can be significantly improved through repair surgery.

(2) Medical Treatment

This primarily targets the various vasoactive substances released by carcinoid tumors, along with symptomatic management and supportive therapy.

1. Serotonin synthesis inhibitors: Parachlorophenylalanine inhibits tryptophan hydroxylase activity, blocking serotonin synthesis. The dose is 2–4 g daily, divided into four oral doses, which can completely relieve diarrhea and reduce episodes of skin flushing. This drug is now rarely used and has been replaced by 5-fluorotryptophan, which has similar effects but fewer side effects. The dose is 600 mg, divided into three oral doses, with a 6–8-day cycle showing significant reduction in urinary 5-HIAA. Methyldopa and 4-deoxypyridoxine HCl inhibit serotonin decarboxylation, blocking serotonin synthesis. These are effective in relieving abdominal pain and diarrhea, especially for gastric carcinoid syndrome symptoms, at doses of 250–500 mg, 3–4 times daily. However, they are ineffective for most serotonin-producing carcinoids and may cause hypotension as a side effect.

2. Serotonin antagonists: There are three types:

(1) Methysergide: 6–24 mg orally per day. For acute episodes, 1–4 mg can be administered intravenously once, or 10–20 mg diluted in 100–200 ml of saline can be infused over 1–2 hours. This effectively controls flushing, asthma attacks, and diarrhea, with stronger antidiarrheal effects than cyproheptadine. Side effects include hypotension, syncope, fatigue, and drug resistance. Long-term use may lead to retroperitoneal fibrosis, cardiac valve fibrosis, other fibrotic tissue damage, and fluid retention.

(2) Cyproheptadine (Periactin): 6-30 mg/day orally. For acute symptom relief, 50-75 mg may be administered intravenously in 100-200 ml of normal saline. Its efficacy is similar to that of methylergotamide, but it is superior in controlling flushing. The side effects are similar to those of methylergotamide, but it does not cause fibrotic sexually transmitted disease changes.

(3) Noznam: Can decompose 5-HT, commonly administered as 2.5g intravenous injection.

3. Kallikrein Inhibitors The following drugs may be selected:

(1) Aprotinin (trasylol): Can inhibit kallikrein, acting the fastest and strongest, rapidly destroying bradykinin in the blood and alleviating hypotension. Commonly administered as 25,000–125,000 units intravenously, with up to 2.5 million units permitted within 24 hours.

(2) 6-Aminocaproic acid: Can counteract kallikrein. Initially administered as 5g intravenous drip, followed by 1g/hr for maintenance.

(3) Iniprol (Cy66): Also inhibits kallikrein. Can be administered as 1 million units intravenously, with the dose increased if necessary.

(4) Phenoxybenzamine: 10–30mg/day. Can inhibit the release of kallikrein.

4. Application of Other Drugs

(1) Antihistamines: May help control flushing in cases with elevated histamine levels.

(2) Corticosteroids: Prednisone 15–40mg/day can be administered, showing significant efficacy for foregut-type carcinoids with carcinoid syndrome but ineffective for other types.

(3) Prochlorperazine: 10mg 3–4 times daily, occasionally helpful in controlling flushing. Phenothiazine has some efficacy in alleviating endocrine symptoms of foregut-type carcinoids.

(4) Methyldopa (Aldomet): 250–500mg every 6–8 hours, helps alleviate diarrhea.

(5) Somatostatin analogue Sandostatin: Recent literature reports that Sandostatin can effectively control carcinoid syndrome symptoms and shrink tumors. Administered as 250μg subcutaneously 2–3 times daily, it rapidly controls skin flushing and diarrhea within a short time, with serotonin levels dropping quickly, demonstrating good palliative efficacy.

5. Chemotherapy Both Adriamycin and 5-Fu have an efficacy rate of around 20%. The combination of streptozotocin and 5-Fu achieves a 33% efficacy rate, with a median effective duration of 7 months. Recent reports indicate that α-interferon therapy can alleviate carcinoid syndrome symptoms. Administered as 3–6 million units intramuscularly daily, the efficacy rate is 47%, with a median effective duration of 34 months.

6. Supportive Therapy Food should be rich in nutrients and calories, supplemented with protein and sufficient vitamins. Avoid foods that may trigger skin flushing and diarrhea, such as dairy products, eggs, and citrus fruits.

bubble_chart Prognosis

The prognosis of this disease depends on the location of the primary tumor, the extent and degree of metastasis, and the effectiveness of surgical treatment. It is generally believed that carcinoid tumors grow slowly, and even in advanced stages, surgical resection should be attempted whenever possible, as the outcomes remain relatively favorable. Carcinoid tumors of the appendix and rectum often show no metastasis and are easily resected with curative intent, resulting in the best prognosis. The 5-year survival rates post-surgery are 99% and 83%, respectively. Patients with carcinoid syndrome caused by gastric and ileal carcinoids also have a relatively good prognosis, surviving 5 to 25 years after radical treatment. In contrast, carcinoid syndrome caused by bronchial and colonic carcinoids has a poorer prognosis, with survival times of only 1 to 2 years, often due to heart, lung, or liver failure.

bubble_chart Differentiation

The following diseases should be differentiated from carcinoid tumors and carcinoid syndrome:

1. Appendiceal carcinoid should be differentiated from appendicitis or Crohn's disease. Barium meal contrast examination of the digestive tract and measurements of 5-HT and 5-HIAA can aid in differentiation.

2. Small intestine carcinoid should be differentiated from other small intestine tumors. Barium meal contrast examination, small intestine endoscopy, and measurements of 5-HT and 5-HIAA can help in making the distinction.

3. Rectal carcinoid should be differentiated from rectal adenoma or adenocarcinoma. Rectoscopy with biopsy is of definitive diagnostic value.

4. Carcinoid syndrome should be differentiated from systemic mastocytosis. The latter is characterized by skin flushing lasting 20–30 minutes or longer, often accompanied by cutaneous pruritus and pigmentary urticaria. Bone marrow smear examination may reveal abnormal proliferation of mast cells.