Carcinoid Tumor  Author: Cameron K Tebbi, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  

Updated: Apr 3, 2013

PathophysiologyCarcinoid 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.

Upon 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. Tumors rarely 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. Immunohistochemically, these tumors have a strong positive reaction to keratin and neuroendocrine markers. These include chromogranin and synaptophysin.

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; 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 that results 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)

Classic carcinoid tumor cells are argentaffinic and argyrophilic. At present, immunostain and hormonal markers are used for diagnosis. Carcinoid tumors of mediastinum can be misclassified as thymoma.

Carcinoids may have somatostatin receptors. Five identified somatostatin receptors are members of the G-protein receptor family. Five distinct genes on chromosomes 11, 14, 16, 17, and 20 encode somatostatin receptors. Somatostatin receptors are used to advantage for diagnosing and treating this disease.

Carcinoid tumors have high potential for metastasis. These cells produce a significant amount of beta-catenin, which enables the tumor cell adhesion, thus promoting metastasis. Induction of Raf1 results in decreased adhesion of carcinoid cells and may be important in the metastatic process.[15]

HistorySigns 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 distributiono In general, carcinoid tumors are found in various locations, including the lungs,[18, 19] trachea, bronchus,

[20] thymus, liver, rectum, appendix, midgut (with metastasis), prostate, ovaries, kidneys,[6] and testes.[21]

o Approximately 80% of appendicial tumors are incidentally discovered during surgery for other indications, but some cause or coexist with acute appendicitis.

Diagnosis and differential diagnosiso Because symptoms can be vague and intermittent, diagnosis may be delayed, especially in children,

in whom the tumor is rare and the diagnosis is unexpected.o Diagnostic difficulties may arise in patients who have flushing without a large tumor or metastases and

in those without symptoms.o The diagnosis is sometimes made because of unrelated findings, such as anemia, endocrine disease,

or autoimmune disease.

o Tumors in the chest can produce symptoms because of their location or can be discovered using chest radiography.

o 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.

o 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 symptomso 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.

o Production of vasoactive intestinal peptide (VIP) may produce symptoms similar to those of neuroblastoma, which is far more prevalent than carcinoid in children.

o Ectopic adrenocorticotropic hormone (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.

o 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.

o 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, although 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.

o Diarrhea and malabsorption occur in as many as 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.

o Wheezing or asthmalike syndrome is caused by bronchial constriction and may occur in as many as 25% of patients. Some tremors are relatively indolent and result in chronic symptoms such as cough, shortness of breath and dyspnea.[22] Bronchopulmonary carcinoid tumor presenting with Cushing syndrome has been reported.[23]Behavior of bronchial carcinoid tumor can range from benign to aggressive with metastasis.[24] A child with a carcinoid tumor who had late relapse in mediastinum and metastasis to cerebellum 16 years after the initial diagnosis with atypical carcinoid tumor has been reported.[24]

o Other symptoms of carcinoid tumors may include 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.

Othero 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.

o Skin hyperkeratosis and pigmentation and arthritis are also relatively uncommon.o Carcinoid tumors have occurred in association with other familial or genetic disorders, such as multiple

endocrine neoplasia type 1 (MEN 1) [25]   and Peutz-Jeghers syndrome.o Multicenteric tumor involving more than one organ (eg, larynx and thyroid) has been reported.[26, 27]

o A second primary tumor in association GI carcinoids can occur. A case of hepatocellular carcinoma post diagnosis of carcinoid tumor has been reported.[28] These secondary tumors tend to be aggressive. In all cases of carcinoid tumor, care should be given to evaluate and follow patients for possible second malignancies.

CausesThe 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.[29]

o Germline mutations in the MEN 1 gene can be identified in the general population.o Multiple carcinoid tumors occurring in association with MEN 1 have been reported.[30]

o Although the MEN 1 gene locus is known to be involved in neuroendocrine tumors, the genetic events underlying the neoplastic process are basically unknown.

o Familial cases other than those associated with MEN 1 are rare, but do occur.[31]

o In several studies, loss of heterozygosity (LOH) at the MEN 1 locus has been reported.[32, 33, 34, 35, 36, 37]

o Genetic abnormalities involving chromosome 11 are most common. These can be seen as a part of MEN 1 or independent of MEN 1abnormalities.[36, 37] 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).

o 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).

o 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 have more allelic losses than other tumors.

o 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 patients. 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.[34, 35]

Numerical imbalances of chromosomes have been observed in carcinoid tumors.o In one study of midgut carcinoids, numerical changes were found in 16 of the 18 tumors.o 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.

HER2 expression has been reported in intestinal, but not gastric, tumors.[38]

Some studies have implicated homeobox gene Hoxc6 through activation of the oncogenic activator protein-1 signaling pathway and via interaction withJunD in carcinoid uemorigenesis.[39] Mutation in the home domain of Hoxc6, which blocks this interaction, results in inhibition of the carcinoid tumor cell proliferation in vitro.

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.

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