AUTHOR INFORMATION

Section 1 of 8

Authored by Cameron K Tebbi, MD, Medical Director, Department of Pediatric Hematology-Oncology, Tampa Children's Hospital

Cameron K Tebbi, MD, is a member of the following medical societies: American Society of Clinical Oncology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, Florida Association of Pediatric Tumor Programs, Histiocyte Society, International Society of Paediatric Oncology, and International Union Against Cancer

Edited by Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Timothy P Cripe, MD, PhD, Associate Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; and Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center

Author's Email:	Cameron K Tebbi, MD
Editor's Email:	Kathleen Sakamoto, MD

eMedicine Journal, March 3 2007, VOLUME 8, Number 3

INTRODUCTION

Section 2 of 8

Background:

Origin and general involvement and presentation

Carcinoid tumors are derived from primitive stem cells in the gut wall but can be seen in other organs (Broaddus, 2003), including the lungs (Moraes, 2003), mediastinum, thymus (Soga, 1999) liver, pancreas, bronchus, and ovaries (Piura, 1995). In children, most cases occur in the appendix, and most are benign and asymptomatic.

Although rare, aggressive and metastatic disease (eg, to the brain [Hlatky, 2004] do occur. Even tumors in the appendix can metastasize (Volpe, 2000). Depending on size and location, carcinoid tumors can cause various symptoms, including carcinoid syndrome. Carcinoid tumors of the ileum and jejunum, especially those larger than 1 cm, are most prone to produce this syndrome, at least in adults.

Classification

Carcinoid tumors generally are classified on the basis of the location in the primitive gut (ie, foregut, midgut, hindgut) that gives rise to the tumor.

Foregut carcinoid tumors are divided into sporadic primary tumors and those secondary to achlorhydria. Sporadic primary foregut tumor encompasses carcinoids of the bronchus, stomach, proximal duodenum, and pancreas.

Midgut tumors are derived from the second portion of the duodenum, the jejunum, the ileum, and the right colon. These account for 60-80% of all carcinoid tumors in adults and are also seen in children (Schmittenbecher, 2001), especially those of the appendix and distal ileum. Appendicular carcinoid tumors are most common (Bethel, 1997; Pelizzo, 2001). In children, more than 70% of these tumors occur at the tip of the appendix, and they are often an incidental finding in appendectomy specimens. In one study, carcinoid tumors were found in 0.169% of 4747 appendectomies (Doede, 2000). Bulky tumors are relatively rare and require somewhat extensive cecectomy or, when tumor infiltration is beyond the cecum, ileocecal resection (Soreide, 2000; D’Aleo, 2001; Pelizzo, 2001).

Hindgut carcinoid tumors include those of the transverse colon, descending colon, and rectum.

Carcinoid tumors also can arise from the Meckel diverticulum, cystic duplications, and the mesentery. Each of these entities has distinctive clinical, histochemical, and secretory features. For example, foregut carcinoids are argentaffin negative and have low serotonin content, but they secrete 5-hydroxytryptophan (5-HTP), histamine, and several polypeptide hormones. These tumors can metastasize to bone, and they may be associated with atypical carcinoid syndrome, acromegaly, Cushing disease, other endocrine disorders, telangiectasia, or hypertrophy of the skin in the face and upper neck.

Midgut carcinoids are argentaffin positive and can produce high levels of serotonin 5-hydroxytryptamine (5-HT), kinins, prostaglandins, substance P (SP), and other vasoactive peptides. These tumors have a rare potential to produce corticotropic hormone (previously adrenocorticotropic hormone, ACTH). Bone metastasis is uncommon.

Hindgut carcinoids are argentaffin negative and rarely secrete 5-HT, 5-HTP or any other vasoactive peptides. Therefore, they do not produce related symptomatology. Bone metastases are not uncommon in these tumors.

Pathophysiology: Carcinoid tumors are of neuroendocrine origin and derived from primitive stem cells, which can give rise to multiple cell lineages. In the intestinal tract, these tumors develop deep in the mucosa, growing slowly and extending into the underlying submucosa and mucosal surface. This results in the formation of small firm nodules, which bulge into the intestinal lumen. These tumors have a yellow, tan, or gray-brown appearance that can be observed through the intact mucosa. The yellow color is a result of cholesterol and lipid accumulation within the tumor. Tumors can have a polypoid appearance and occasionally become ulcerated. With expansion and infiltration through the submucosa into the muscularis propria and serosa, carcinoid tumors can involve the mesentery. Metastases to the mesenteric lymph node and liver, ovaries, peritoneum, and spleen can occur.

On histologic examination, carcinoid tumors have 5 distinctive patterns: (1) solid, nodular, and insular cords; (2) trabecular or ribbons with anastomosing features; (3) tubules and glands or rosettelike patterns; (4) poorly differentiated or atypical patterns; and (5) mixed patterns. A combination of these patterns is often observed. Tubules can contain mucinous secretions, and individual tumor cells can contain mucin-positive material, which includes the various acidic and neutral intestinal mucin. Rarely do tumors have eosinophilic stroma. Capillaries are often prominent. Cells are uniformly round or polygonal with a central nucleus and punctate chromatin, as well as small nucleoli and infrequent mitosis. The cytoplasm can be slightly acidophilic, basophilic, or amphophilic. Eosinophilic granules may be present.

In midgut carcinoids, cells are arranged in closely packed, round, regular, monomorphous masses. In the appendix, carcinoids appear as discrete yellow nodules in the lumen. Lesions associated with diffuse wall thickening are relatively uncommon. Carcinoid tumors commonly affect the tip of the appendix. Most carcinoid tumors invade the wall of the appendix, and lymphatic involvement is nearly universal. About 75% of patients have evidence of peritoneal involvement. However, only a few patients have regional or distant dissemination. The size of the tumor can be correlated with outcome of the disease in that tumors smaller than 1.5 cm in diameter (after formalin fixation) rarely result in distant metastases or recurrences.

Carcinoid tumors can be associated with concentric and elastic vascular sclerosis resulting in obliteration of vascular lumina and ischemia. A common finding is elastosis and fibrosis that surround nests of the tumor cells and that result in matting of the involved tissues and lymph nodes. Fibroblastic proliferation may result from the stimulation of fibroblast cells by growth factor. This stimulation may be a result of a local release of tumor growth factor (TGF)-beta, beta–fibroblast growth factor (beta-FGF), and platelet-derived growth factor.

Other products of carcinoid tumors include the following:

• Acid phosphatase

• Alpha-1-antitrypsin

• Amylin

• Atrial natriuretic polypeptide

• Calbindin-D28k

• Catecholamines

• Dopamine

• Fibroblast growth factor

• Gastrin

• Gastrin-releasing peptide (bombesin)

• Glucagon, glicentin

• 5-Hydroxyindoleacetic acid (5-HIAA)

• 5-Hydroxytryptamine (5-HT)

• Histamine

• Insulin

• Kallikrein

• Kinins

• Motilin

• Neuropeptide

• Neurotensin

• Pancreastatin

• Pancreatic polypeptide

• Platelet-dermal growth factor

• Prostaglandins

• Pyroglutamyl-glutamyl-prolinamide

• Secretin

• Serotonin

• Somatostatin (ie, SRIF)

• Tachykinins

• Neuropeptide K

• Neuropeptide A

• Substance P (SP)

• Transforming growth factor-beta

• Vasoactive intestinal polypeptide (VIP)

CLINICAL

Section 3 of 8

History: Signs and symptoms of carcinoid tumors vary greatly and depend on the location and size of the tumor and on the presence of metastases. Findings range from no tumor-related findings to full symptoms of carcinoid syndrome. Because carcinoid tumors are rare in children, clinicians rely on reports of adult patients to understand the full scope of the manifestations of the disease.

• Anatomic distribution


• • In general, carcinoid tumors are found in a variety of locations, including the lungs (Lal, 2005; Fink, 2001), trachea, bronchus (Fauroux, 2005), thymus, liver, rectum, appendix, midgut (with metastasis), prostate, ovaries, and testes.
  
  
  
  • Approximately 80% of appendicial tumors are discovered incidentally during surgery for other indications, but some cause or coexist with acute appendicitis.
  
  
  
• Diagnosis and differential diagnosis


• • Because symptoms can be vague and intermittent, diagnosis may be delayed, especially true in children, in whom the tumor is rare and the diagnosis unexpected. Diagnostic difficulties may arise in patients who have flushing without a large tumor or metastases and in those without symptoms. The diagnosis is sometimes made because of unrelated findings, such as anemia, endocrine, or autoimmune disease. Tumors in the chest can produce symptoms because of their location, or they can be discovered in a chest radiograph. In the absence of positive imaging findings and biochemical markers, consider differential diagnoses such as an adverse reaction to medications, other malignant disorders (eg, chronic myelogenous leukemia), mastocytosis, and other tumors. The availability of octreotide-receptor scintigraphy allows for the detection of the tumor and metastases. When results are positive, they may also allow for therapy by using octreotide with large doses of therapeutic radioactive agents.
  
  
  
• Clinical presentations and symptoms


• • The most common clinical presentation for a small intestinal carcinoid is periodic abdominal pain, which can be caused by fibrosis of the mesentery, kinking of the bowel, or intestinal obstruction. A constellation of symptoms called malignant carcinoid syndrome is often associated with this tumor.
  
  
  
• Production of VIP may produce symptoms similar to those of neuroblastoma, which is far more prevalent than carcinoid in children.


• • Ectopic ACTH and Cushing syndrome observed with foregut carcinoid tumors must be differentiated from other tumors that produce these symptoms.
  
  
  
  • Likewise, rare acromegaly caused by the carcinoid tumors must be differentiated from pituitary tumors.
  
  
  
  • Carcinoid crisis can occur spontaneously or as a response to stress, such as anesthesia or chemotherapy. Symptoms may include intense flushing, diarrhea, abdominal pain, tachycardia, hypertension or hypotension, altered mental status, and coma. This condition can be life threatening, but treatment with somatostatin analog SMS-201-995 has improved the outcome of patients with carcinoid crisis.
  
  
  
• An early and frequent (94%) symptom of carcinoid tumors, especially those of midgut with metastases, is cutaneous flushing, which typically affects the head and neck. Striking color changes range from pallor or erythema to cyanosis. Episodes are often associated with an unpleasant warm feeling, itching, palpitation, upper-body erythema and edema, salivation, diaphoresis, lacrimation, and diarrhea. Exercise, stress, or certain foods (eg, cheese) may trigger an attack, though the flushes can also be spontaneous and unrelated to any stimulation. Initial attacks are short, lasting only a few minutes. With time, the duration increases to hours. Flushes are reported to be longest in association with bronchial carcinoids. Some patients develop a constant red or cyanotic discoloration.



• Diarrhea and malabsorption occur in up to 84% of patients. Stools are watery, frothy, bulky, or in the form of steatorrhea. Diarrhea may or may not be associated with abdominal pain, flushing, and cramps. It may be profuse and often colicky.

• Wheezing or asthma-like syndrome is caused by bronchial constriction and may occur in as many as 25% of patients.

• Other symptoms are those of valvular heart lesions. Cardiac manifestations are observed in as many as 60% of patients. Fibrosis of the endocardium, which often involves the right side of the heart, is observed. The fibrous deposit usually involves the ventricular aspect of the tricuspid valve and associated chordae. Fibrosis of the pulmonic valve is relatively uncommon and results in regurgitation or stenosis. Cardiac lesions may lead to heart failure. The mitral valve is infrequently involved.

• Relatively uncommon complaints include joint pain, arthritis, lacrimation, confusion and changes in mental status, ophthalmologic findings associated with flushing or secondary to vascular occlusion, retroperitoneal fibrosis, obstruction of ureter, intra-abdominal fibrosis, and male sexual dysfunction.

• Skin hyperkeratosis and pigmentation and arthritis are also relatively uncommon.



• Associated conditions: Carcinoid tumors have occurred in association with other familial or genetic disorders, such as multiple endocrine neoplasia type 1 (MEN 1) and Peutz-Jegher syndrome.

Causes: The etiology of carcinoid tumors is not known, but genetic abnormalities are suspected. Reported chromosomal abnormalities include changes in chromosomes, such as loss of heterogeneity, and numerical imbalances.

• MEN 1 is an autosomal dominant disorder characterized by the occurrence of multiple tumors, particularly in the pancreatic islets, parathyroid and pituitary glands, and neuroendocrine tumors.


• • Germline mutations in the MEN 1 gene can be identified in the general population.
  
  
  
  • Multiple carcinoid tumors occurring in association with MEN 1 have been reported (Yazawa 1998).
  
  
  
  • Although the MEN 1 gene locus is known to be involved in neuroendocrine tumors, the genetic events underlying the neoplastic process are basically unknown.
  
  
  
  • Although familial cases other than those associated with MEN 1 are rare, they do occur (Hemminki, 2001).
  
  
  
  • In several studies, loss of heterozygosity (LOH)at the MEN1 locus has been reported (Vageli, 2006; D'adda, 2002; Pizzi, 2002; Jakobovitz, 1996).
  
  
  
  • Genetic abnormalities involving chromosome 11 are most common. These can be seen as a part of MEN 1, or indepenedent of MEN1 abnormalities (Jakobovitz, 1996). In 5 of 9 typical carcinoid tumors of the lung, 3 distinct regions of allelic loss were identified at bands 11q13.1 (D11S1883), 11q14.3-11q21 (D11S906), and 11q25 (D11S910).
  
  
  
  • Some atypical carcinoids have LOH at band 11q13 between markers PYGM and D11S937 and at bands 11q14.3-11q21 (D11S906), 11q23.2-23.3 (D11S939), and 11q25 (D11S910).
  
  
  
  • The region of band 11q13 bearing the MEN 1 gene can also be affected in some atypical carcinoid tumors more than it is in typical carcinoid tumors. Therefore, band 11q13 appears to be important in these tumors. Aggressive atypical carcinoid tumors, defined by high mitosis, vascular invasion and organ metastasis, also appear to be have more allelic losses than other tumors.
  
  
  
  • The MEN 1 gene is located on band 11q13 and likely functions as a tumor-suppressor gene. In a study of 46 sporadically occurring tumors, 78% had LOH at this site, with almost the entire allele missing in 5 cases. In the remaining cases, genetic heterozygosity had a discontinuous pattern. Some have postulated that sporadically occurring carcinoid tumors evolve after inactivation of a tumor-suppressor gene on chromosome 11 as well as genetic mutations that affect DNA-mismatch repair.
  
  
  
• Gastric neuroendocrine tumors are associated with a high incidence of LOH at chromosomal arm 8p and a lowered frequency of LOH at 7q. Chromosomal arm 8p is suspected to be the possible location of the tumor-suppressor gene associated with the genesis of gastric neuroendocrine tumors.



• LOH on the X chromosome is seen in 15% of malignant carcinoid tumors (Pizzi, 2002).



• Numerical imbalances of chromosomes have been observed in carcinoid tumors.


• • In 1 study of midgut carcinoids, numerical changes were found in 16 of the 18 tumors.
  
  
  
  • The most common aberrations were losses of bands 18q22-qter (67%), 11q22-q23 (33%), and 16q21-qter (22%) with a gain of band 4p14-qter (22%). Rates of alterations were substantially more common in metastases than in primary tumors.
  
  
  
• Losses of chromosomal arms 18q and 11q were found in the primary tumors and metastases, whereas loss of 16q and gain of 4p were present only in metastases.



• One postulate is that loss of chromosomal arms 18q and 11q may represent an early event and that the loss of 16q and gain of 4p occur as a late event in midgut carcinoids.

WORKUP

Section 4 of 8

Lab Studies:

• Laboratory diagnosis of carcinoid tumors depends on the identification of the characteristic biomarkers of the disease.


• • Measurement of biogenic amines levels, such as serotonin, 5-HT, catecholamines, histamine, and its metabolites in the platelets, plasma, and urine of patients can be helpful in diagnosis.
  
  
  
• Urinary 5-HIAA levels are usually increased and aid in the assessment of carcinoid tumors (Moertel 1983, 1987, and 1987; Delcore 1994; Mani, 1994; Kulke, 1999).



• • Measurement of urinary 5-HIAA can help in diagnosing carcinoid syndrome, but it may not help in detecting tumors at an early stage of development when they are potentially curable with resection.
  
  
  
• Although the detection of urinary 5-HIAA is the single best screening method for carcinoid tumors, the level is not always elevated, and the measurement of other peptides (eg, SP, neuropeptide K, chromogranin) may be necessary for diagnosis and follow-up.


• • Fasting plasma 5-HIAA assay is more stable than whole-blood serotonin assay and is more convenient than 24-hour urine collection (Carling, 2002). Substances produced by carcinoid tumors are listed in Pathophysiology above.
  
  
  
• In 1 study, CDX2 was highly indicative of GI carcinoid, whereas TTF-1 had high specificity for pulmonary tumors (Saqi, 2005).



• • One (17%) of 6 gastric carcinoids stained with CDX2, whereas 8 (53%) of 15 pulmonary carcinoids stained with TTF-1. None of the GI tumors stained with TTF-1.
  
  
  

Imaging Studies:

• A number of imaging modalities have been used to detect carcinoid tumors. These modalities include plain radiography, upper- and lower-GI radiography with the use of oral contrast agents, CT, MRI, angiography, positron emission tomography (PET), scintigraphy with metaiodobenzylguanidine [MIBG] (Monsieurs, 2001) and octreotide (Shi, 1998), radionuclide imaging with somatostatin analogs attached to the radioactive tracer, and technetium-99m bone scanning. Depending on the location of the tumor and metastasis, a combination of these may be used.



• GI series, CT, and MRI may be helpful in some situations.


• • For the diagnosis of chest tumors, CT combined with scintigraphy with octreotide is preferred.
  
  
  
  • In the large bowel, the disease is often detected with colonoscopy and does not provide an imaging challenge. Imaging diagnosis of small-bowel carcinoids is relatively difficult. Small tumors in this location are difficult to detect on upper-GI series and CT scans, and other techniques are required.
  
  
  
  • Mesenteric invasion and liver metastasis are often detected on CT scans. MRI can also be helpful in the diagnosis of hepatic disease but is less sensitive than CT in detection of extrahepatic lesions.
  
  
  
• With advances in imaging studies, angiography is rarely used and is reserved for equivocal situations.



• PET scanning can be helpful and is increasingly used for diagnosis and follow-up of the tumors.



• Scintigraphy with MIBG and octreotide scanning have been used to successfully detect carcinoid tumors (Kaltsas, 2001).



• • Octreotide scanning appears to be more sensitive than MIBG imaging.
  
  
  
• Radionuclide imaging with somatostatin analogs attached to radioactive tracer can be used to advantage for diagnosis of carcinoid tumors.


• • Radiotracers current used are indium-111 diethylenetriamine pentaacetic acid (DTPA) and yttrium. Most neuroendocrine tumors have receptors for somatostatins. Five somatostatin receptor subtypes, designated SSTR-1 to SSTR-5, are identified. Binding affinity of somatostatin analogs to these subtypes may vary, with highest affinity for SSTR-2, medium affinity for SSTR-2 and SSTR-5, and lowest affinity for SSTR-1 and SSTR-4. Carcinoid tumors often express SSTR-1 to SSTR-3 and, infrequently, SSTR-2. Nevertheless, for tumors > 1 cm in diameter, the sensitivity of ¹¹¹In-DTPA octreotide imaging reaches 80-90%.
  
  
  
  • This technique can be used identify primary and metastatic disease and is approved for radionuclide scanning of carcinoid tumors. An advantage is that, if the result is positive, this technique can be used as a treatment modality.
  
  
  
  • In a study of 40 patients, somatostatin-receptor scintigraphy (SRS) helped in detecting localized tumors in 78% of patients versus 82% with CT scanning. However, SRS helped in identifying primary tumors in 2 patients missed on CT scanning. In 16% of patients, SRS depicted lesions not found with other modalities. No false-positive results were observed.
  
  
  
  • Overall, SRS appears to be the imaging method of choice for localizing and evaluating the extent of carcinoid tumor.
  
  
  
  • Bone metastasis is not uncommon in carcinoid tumors. In a study of 12 patients, 11 of whom had liver metastasis, 8 had bone involvement, as detected on SRS.
  
  
  
• 99mTc bone scanning can aid in the detection of metastases.

Procedures:

• Endoscopy, including bronchoscopy, esophagogastroscopy, gastroscopy, and colonoscopy, can be used for biopsy and diagnosis.

TREATMENT

Section 5 of 8

Medical Care: If metastasie occurs and surgical excision is not suitable, consider treatment with currently recommended chemotherapy.

• Chemotherapeutic agents currently used in clinical trials to palliate metastatic carcinoid disease include the following:


• • Alkylating agents
  
  
  
  • Doxorubicin
  
  
  
  • 5-Fluorouracil

  • Dacarbazine

  • Actinomycin D

  • Cisplatin

  • Etoposide

  • Streptozotocin

  • Interferon alfa

  • Somatostatin analogs with a radioactive load
  
  
  
• A combination of the agents listed above is typically used.

• In 1 study, 8 adults with carcinoid tumor metastatic to liver were treated with intra-arterial 5-fluorouracil and embolization of hepatic tumors with bovine collagen fiber admixed with iohexol, cisplatin, mitomycin C, and doxorubicin. This treatment resulted in symptomatic relief and in tumor regression in 4 patients, and it stabilized the disease in the rest of the patients.

• Octreotide, a somatostatin analog, is highly effective in reducing symptoms; however, in the pediatric age group, stunt linear growth is of concern.
  • Octreotide reduces the amount of the growth factor produced and thus theoretically impairs growth.

  • Intermittent and continuous infusion of octreotide administration are reported, with superior results obtained with the latter.

  • Such treatment can result in near-normalization of the plasma insulin-like growth factor I and partial suppression of plasma growth hormone-releasing hormone (GHRH) (Lefebvre, 1995).

  • The availability of a long-acting somatostatin analog that can be given once a month has eliminated the need for injections 2-3 times per day, with equal efficacy (Rubin, 1999).

  • In metastatic carcinoid tumors, long-term use of octreotide is reported. However, receptor alteration induced during the use of this agent requires consecutive drug dosage increase to control the symptoms (Corleto, 2000).

  • At present, no formal, well-designed study has been performed to systematically measure the effects of this modality of therapy. Although experience is limited, adverse effects in children have been similar to those in adults. Adverse effects include gallstones and steatorrhea, which may sometimes require pancreatic enzyme replacement. Local irritation at the injection site is a common complaint. These adverse effects must be weighted against the potential benefits.

• In situ targeted therapy with somatostatin analogs (eg, octreotide attached to a radioactive load using yttrium-90 or ¹¹¹Indium-labeling agents) provides promise for patients with unresectable tumors.


• • This therapy is currently used on an experimental basis in adults and children.
  
  
  

Surgical Care: The treatment of choice is surgical excision, if feasible. The surgical technique may vary according to the type or location of the tumor.

• In most appendiceal tumors, simple appendectomy is sufficient for treatment. In intestinal carcinoids, block resection of the tumor with adjacent lymph nodes must be attempted. In the bronchial location, aggressive surgical resection, and not bronchoscopic removal, is recommended (Fink, 2001; Fauroux, 2005).



• In localized tumors, surgical resection can result in a cure with 70-90% survival rate.



• When total resection is not possible, debulking may provide symptomatic relief.



• For hepatic tumors, surgical ligation of the hepatic artery can potentially deprive blood supply to the tumor cells and cause necrosis while preserving most of the normal live cells. However, new blood vessels develop over time and restore circulation.



• Intra-arterial infusion of chemotherapeutic agents with chemoembolization of the hepatic artery may also provide effective, albeit short term, relief of symptoms due to hepatic metastasis in cases of carcinoid tumors.



• If hepatic metastasis is present but resectable, surgical resection is preferred.

FOLLOW-UP

Section 6 of 8

Complications:

• The most serious complication of carcinoid tumors is carcinoid crisis, which is often observed in patients who have foregut tumors and high levels of 5-HIAA.

Prognosis:

• The prognosis for patients with completely resected localized disease is excellent. However, patients with metastasis do poorly (Spunt, 2000).



• In general, the survival rate of patients with carcinoid tumors is directly related to the size of the primary tumor and to the degree of distant metastasis. Tumors larger than 2 cm, positive lymph nodes, and atypical histologic features are often associated with a poor prognosis.

TEST QUESTIONS

Section 7 of 8

CME Question 1: Which one of the following is not a substance that carcinoid tumors produce?

A: 5-hydroxyindoleacetic acid (5-HIAA)
B: 5-hydroxytryptamine (5-HT)
C: Vasoactive intestinal peptide (VIP)
D: Delta–amino levulinic acid (delta-ALA)
E: Histamines

The correct answer is D: Many carcinoid tumors produce 5-HIAA, 5-HT, VIP, and histamines. In fact, levels of these substances can be measured as markers to diagnose the tumor, and they are responsible for the symptoms of carcinoid syndrome.

CME Question 2: Which chromosomal change is reported in carcinoid tumors?

A: 11(11p13) deletion
B: 12(12p14) deletion
C: t(9;22)
D: t(14:18)(q21;q32)
E: t(12;22)

The correct answer is A: MEN 1 gene for multiple endocrine neoplasia type 1 (MEN 1) is located in chromosomal band 11p13 and is likely to function as a tumor-suppressor gene. In 1 study of 46 sporadically occurring tumors, 78% had a loss of heterozygosity (LOH) at this site.

Pearl Question 1 (T/F): Most carcinoid tumors in the pediatric age group are located in the tip of the appendix and are asymptomatic.

The correct answer is True: Carcinoid tumors occur most often in the appendix and are incidentally found during appendectomy.

Pearl Question 2 (T/F): Measurement of urinary isovaleric acid levels is the most reliable test for detecting carcinoid tumors in children.

The correct answer is False: Isovaleric acid is not one of the metabolites found in carcinoid tumors.

Pearl Question 3 (T/F): Cutaneous flushing, diarrhea, wheezing, and symptoms of valvular heart lesions can be signs of a carcinoid tumor.

The correct answer is True: Cutaneous flushing, asthma-like syndrome, diarrhea, abdominal pain, and cardiac symptoms are due to substances carcinoid tumors produce and are a part of carcinoid syndrome.

Pearl Question 4 (T/F): Carcinoid tumor has occurred in association with multiple endocrine neoplasia type 1 (MEN 1) or Peutz-Jegher syndrome.

The correct answer is True: Several reports describe carcinoid tumors occurring in association with MEN 1 and/or Peutz-Jeghers syndrome. The reason for these associations is not known.

BIBLIOGRAPHY

Section 8 of 8

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