A. Introduction

1. Carcinoid tumors are often indolent, asymptomatic tumors
   1. Tumors derived from neuroendocrine cells, usually in gut tissue
   2. Symptoms manifest by secretion of vasoactive compounds or from mass effects
2. Carcinoid Syndrome occurs when tumors make bioactive compounds which cause symptoms
3. Most carcinoids are detected because of symptoms due to the syndrome
4. Annual incidence is ~10 per 1 million population

B. Primary Carcinoid Tumor Locations

1. Small Intestine - usually ileum; about 35% of small intestinal tumors are carcinoids
2. Appendix - most common tumor type of the appendix
3. Colon - less than 1% of colonic tumors
4. Lung - about 2% of primary lung cancers, usually perihilar
5. Stomach
   1. Usually gastrinomas (associated with hyperacidity)
   2. Type I: associated with chronic atrophic gastritis (CAG)
   3. Type II: develops in patients with multiple endocrine neoplasia I (MEN I) or Zollinger-Ellison
   4. Type III: sporadic
6. Pancreas - usually produce VIP (see below)
7. Overall, ~90% of tumors are within gastrointestinal tract
   1. Associated with Multiple Endocrine Neoplasia Type 1 Syndrome in ~10% of cases
   2. Localization usually by CT scan or octreotide scintography

C. Symptoms (Due to Serotonin) [4]

1. Flushing ~90%
2. Diarrhea ~70%
3. Chronic abdominal pain ~40% or chest pain with hemoptysis (lung tumors)
4. Valvular Heart Disease [17]
   1. Tricuspid disease, usually manifesting intially with murmur ~30%
   2. Mitral (or aortic) valve disease suggests pulmonary carcinoid ~10%
   3. Progression to heart failure can occur
   4. Progression of heart disease related to levels of serotonin during course of disease
   5. Progression of coronary disease is also increased in patients who received chemotherapy
5. Telangiectasias (facial) ~25%
6. Wheezing ~15%
7. Niacin Deficiency (Pellagra) symptoms reported ~5% (diarrhea, dermatitis, dementia)
8. Carcinoid Crisis [4]
   1. Hypotension, occasionally hypertension
   2. Tachycardia (arrhythmias)
   3. Severe wheezing
   4. Flushing
   5. Central nervous system (CNS) anomalies
   6. Precipitated by anesthetic or interventional procedure in patients with carcinoid
9. Hormones other than serotonin produce specific symptoms

D. Pathogenesis [5]

1. Pathology of Carcinoid Tumors
   1. These neuroendocrine tumors are solid and yellow tan
   2. Tumor cells have faint pink granular cytoplasm with round nuclei, few mitoses
   3. Tumor cells take up and reduce silver ("argentaffin" cells)
   4. Also stain with potassium chromate (so-called "enterochromaffin" cells)
   5. All carcinoids convert tryptophan to 5-hydroxytryptamine (serotonin)
2. Carcinoid Syndrome
   1. Due mainly to secretion of various hormones by carcinoid tumors
   2. Serotonin (5-hydroxytryptamine) - most common
   3. Vasoactive Intestinal Polypeptide (VIP) - usually pancreatic carcinoids (VIPoma)
   4. Substance P - vasodilator, tachykinin
   5. Gastrin - especially in patients with chronic gastritis Type A [14]
   6. Somatostatin
   7. Corticotropin
   8. Other vasoactive compounds: histamine, catecholamines, prostaglandins
   9. Islet cell tumors - insulinoma, glucagoma, somatostatinoma
3. Etiology of Symptoms of Carcinoid Syndrome
   1. Syndrome manifests only if tumor products bypasses liver
   2. Many carcinoids arise in gut
   3. Venous blood drains to liver, which will remove many of the tumor products
   4. Symptoms occur only in patients with liver metastases or with lung carcinoids
   5. Left sided cardiac valve lesions imply pulmonary involvement
   6. Gastrinomas lead to primarily peptic ulcer disease (multiple ulcers)
4. Cardiac Disease
   1. Metabolites from liver lesions cause endocardial fibrosis
   2. This leads to valvular lesions due to high concentration in right heart circulation
   3. Result is marked regurgitation, usually of tricuspid valve
   4. Normally, lung monoamine oxidase reduces carcinoid metabolites
   5. Lung carcinoids can cause left sided valvular disease, leading to (mitral) regurgitation
   6. High output congestive heart failure can occur
5. Appatite Suppressants and Carcinoid Pathology [6,11,12,13]
   1. Likely related to serotonin effects on valves
   2. Valvular lesions are similar to those seen with serotonergic anorexic drugs
   3. Pulmonary hypertension also occurs in ~5% of patients on some anorexic agents
   4. Serotonin is a vasoconstrictor and may affect pulmonary
   5. Fenfluramine, dexfenfluramine, phentermine implicated and withdrawn from market
   6. Unclear if there is a genetic predisposition to these effects in certain obese patients

E. Diagnosis

1. Urinary 5-HIAA Level
   1. 24 hour measurement for this metabolite of serotonin
   2. Highly specific for carcinoid
   3. Elevations also occur with bananas and avocados
2. Serum Tumor Markers
   1. Chromogranin A - protein made in secretory granules
   2. About 80% of patients with carcinoid have elevated chromogranin A levels
   3. Neuron specific enolase elevated in ~40% of patients with carcinoid
   4. Gastrinoma detected by administering secretin (SecreFlo®) to stimulate gastrin
3. Serum Hormone Levels
   1. Helpful to measure these levels to predict symptoms, outcomes, and therapy
   2. Gastrin
   3. Substance P
   4. Calcitonin
   5. Neuropeptide K
   6. VIP
   7. Pancreatitic polypeptide
   8. Serum chromagranin A levels can be very highly elevated (particularly in MEN I) [3]
   9. These measurements also permit ruling out other neuroendocrine tumor types
4. Imaging Studies
   1. CT or MRI Scan
   2. Endoscopy including endoscopic ultrasonography
   3. Somatostatin-receptor scintigraphy (111-indium or 99-technetium)
5. Tumor Biopsy
   1. Confirmation of diagnosis requires biopsy
   2. Special stains, electron microscopy may be needed
   3. Biopsy not helpful to predict metastatic potential
6. Echocardiography on all patients
   1. Look for characteristic tricuspid valve changes
   2. Right ventricular hypertrophy and dilation common
   3. Prognosis for heart failure
7. Tumor metastatic in 10% of cases at presentation
   1. Liver metastases are most commonly found
   2. Abdominal CT should be performed to evaluate for metastatic disease
   3. Liver function tests are not reliable

F. Treatment [7]

1. Multidisciplinary therapy required
   1. Surgery
   2. Hormonal blockade
   3. Symptomatic treatment
   4. Cardiac therapy
   5. Chemotherapy
2. Surgical Resection
   1. Surgical removal of masses can be curative
   2. Conservative resection / debulking may be undertaken
3. Liver transplantation has been used following hepatectomy for metastatic disease
4. Hepatic Artery Embolization (with hepatic disease) [8]
   1. Surgically or by catheterization
   2. Chemotherapy may be added with improvement in disease
   3. Regression occurs in nearly all patients
5. Octreotide (Sandostatin®)
   1. Long acting analog of somatostatin
   2. Often relieves symptoms of disease
   3. Causes regression of Types II and III gastric carcinoids [15]
   4. Intravenous octreotide bolus 50-100µg and 50µg/hr for carcinoid crisis
   5. Sandostatin® LAR intramuscular injection 20mg q 4 weeks
   6. Lanreotide - another long acting somatostatin analog
   7. Yttrium-90 labelled octreotide ablates tumor cells, may be of benefit
6. Chemotherapy [7,9,16]
   1. 5-FU combined with streptozosin first line
   2. Doxorubicin
   3. Dacarbazine (DTIC)
7. Interferon alpha has shown some activity [16]
8. External beam radiation can be used for local disease paliation
9. Followup
   1. Serial CT Scans and scintigraphy
   2. Measure serum hormone and tumor marker levels
   3. Monitor cardiac function with Echocardiography

F. VIPoma

1. Secrete vasoactive intestinal polypeptide
2. Symptoms
   1. Some nausea, steatorrhea
   2. VIP level increases leading to diarrhea
3. Treatment
   1. Somatostatin analogue Octreotide (Sandostatin®) [10]
   2. Octreotide will increase small bowel transit but won't affect gastric emptying time
   3. This is a long acting form of somatostatin, used at ~300µg per day
   4. Chemotherapy of minimal benefit - usually streptozotocin + fluorouracil

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