Aggressive and metastatic disease, while rare, has been reported. Depending on the size and location, it can produce various symptoms, including carcinoid syndrome. At least in adults, carcinoid tumors of the ileum and jejunum, especially when larger than 1 cm, are more prone to produce this syndrome.

Carcinoid tumors generally are classified based on the primitive gut that gives rise to the tumor (ie, foregut, midgut, hindgut). Foregut carcinoid tumors are divided into sporadic primary and tumors secondary to achlorhydria. The sporadic primary foregut tumor encompasses carcinoids of the bronchus, stomach, proximal portion of the 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, especially those of the appendix and distal ileum. Hindgut carcinoid tumors include those of the transverse colon, descending colon, and rectum.

In addition to the above, carcinoid tumors also can arise from 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 a low content of serotonin, but they secrete 5-hydroxytryptophan (5-HTP), histamine, and several polypeptide hormones.

These tumors have the potential for bone metastasis and may be associated with atypical carcinoid syndrome, acromegaly, Cushing disease, other endocrine disease, 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 rare potential for adrenocorticotropic hormone (ACTH) production. Bone metastasis is uncommon. Hindgut carcinoids are argentaffin negative and rarely have 5-HT or secrete 5-HTP or vasoactive peptides; thus, they do not produce related symptomatology. Bone metastasis is 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 can ulcerate. With expansion and infiltration through the submucosa into the muscularis propria and serosa, carcinoid tumors can involve the mesentery. Metastasis to the mesenteric lymph node and liver, ovaries, peritoneum, and spleen can occur.

Histologically, carcinoid tumors have 5 distinctive patterns, as follows: (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 often is 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 often are prominent. Cells are uniformly round or polygonal with a central nucleus and punctate chromatin with small nucleoli and infrequent mitosis. 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 within the lumen. Diffuse wall thickening lesions are less common. Carcinoid tumors commonly affect the tip of the appendix. Most carcinoid tumors invade the wall of the appendix, and lymphatic involvement is nearly universal. In 75% of cases, evidence of peritoneal involvement is present; however, only a few patients have regional or distant dissemination. Size of the tumor can correlate with outcome of the disease, with a tumor less than 1.5 cm in diameter (after formalin fixation) rarely resulting in distant metastasis or recurrences.

In carcinoid tumors, concentric elastic vascular sclerosis of vessels resulting in obliteration of vascular lumens and ischemia can be observed. Elastosis and fibrosis surrounding nests of the tumor cells resulting in matting of involved tissues and lymph nodes also is common. The fibroblastic proliferation may result from the effects of growth factors stimulating fibroblast cells. Specifically, this may be as a result of local release of tumor growth factor–beta (TGF-beta), beta–fibroblast growth factor (beta-FGF) and platelet-derived growth factor. Other products of carcinoid tumors are listed below.

Table 1. Substances Produced by Carcinoid Tumors

Classic carcinoid tumor cells are argentaffinic, argyrophilic, and can be used for pathological evaluations; currently, immunostain and hormonal markers are used for diagnosis.

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

History:

• Signs and symptoms of carcinoid tumors vary greatly, depending on the location, size, and existence of metastasis. These range from no tumor-related findings to full symptoms of carcinoid syndrome. With carcinoid tumors being rare in children, reliance is made on adult literature regarding the full scope of the disease manifestation. Although uncommon in the pediatric age group, carcinoid tumors have been found in a variety of locations, including the lungs, trachea, bronchus, thymus, liver, rectum, appendix, midgut with metastasis, prostate, ovaries, testis, and unknown primary site. In addition, carcinoid tumors in association with other familial or genetic disorders (eg, multiple endocrine neoplasia type 1 [MEN 1] and Peutz-Jeghers syndrome) have been reported. Approximately 80% of appendicial tumors are discovered incidentally during surgery for other indications, but some cause or coexist with acute appendicitis and, as a rule, do not form metastasis.

• The most common clinical presentation for a small intestinal carcinoid is periodic abdominal pain. This can be caused by fibrosis of mesentery, kinking of the bowel, or intestinal obstruction. With the vague and intermittent symptoms, the diagnosis is delayed. This is especially true in children, where the tumor is rare and diagnosis unexpected. Clinical findings in carcinoid tumors in other locations depend on the site, size of the tumor, and presence or absence of metastasis and complications. A constellation of symptomatologies called malignant carcinoid syndrome often is associated with this tumor. Diagnostic difficulties may arise in patients who have flushing without a large tumor or metastasis and in those without symptoms. Imaging studies, endoscopy, increased urinary 5-HIAA, and biopsy often disclose the nature of the tumor. Measurement of other biogenic amines, such as serotonin, 5-HT, catecholamines, histamine, and its metabolites in the platelets, plasma, and urine of patients can be helpful in
  diagnosis.

• At times, the diagnosis is made because of unrelated findings such as anemia, endocrine, or autoimmune disease. Tumors located in the chest can produce symptoms because of their location, or they can be discovered in a chest x-ray film. In the absence of positive imaging studies and biochemical markers, consider differential diagnosis, such as adverse reaction to medications, other malignant disorders (eg, chronic myelogenous leukemia), mastocytosis, and other tumors. Availability of octreotide receptor scintigraphy allows detection of the tumor and metastasis. This technique, when positive, also may allow an alternative therapy with this agent attached to larger doses of therapeutic radioactive doses.

• The most serious complication of carcinoid tumors is carcinoid crisis. This often is observed in patients who have foregut tumors and very high levels of 5-HIAA. Carcinoid tumors, as described before, can secrete a number of other gastrointestinal peptides, such as ACTH, gastrin, somatostatin, insulin, motilin, growth hormone, calcitonin, neurotensin, beta-MSH, gastrin-releasing peptide, pancreatic polypeptide, and vasoactive intestinal peptide, each of which can produce unique symptoms.

• Production of VIP may produce symptoms similar to neuroblastoma, which is far more prevalent in children. Ectopic ACTH and Cushing syndrome observed with foregut carcinoid tumors need to be differentiated from other more common tumors producing these symptoms. Likewise, rare acromegaly caused by the carcinoid tumors needs to be differentiated from pituitary tumors. The crisis can occur spontaneously or as a response to stress such as anesthesia or chemotherapy. Symptomatology may include intense flushing, diarrhea, abdominal pain, tachycardia, hypertension or hypo, altered mental status, and coma. This can be life threatening, but treatment with somatostatin analog SMS-201-995 has improved the outcome of carcinoid crisis.

• Carcinoid syndrome is related to hormonal products of the tumor.

• An early and frequent symptom of carcinoid tumors, especially those of midgut with metastasis, is cutaneous flushing, typically of the head and neck, with striking color changes ranging from pallor or erythema to cyanosis. Other symptoms include a profuse and often colicky diarrhea, asthmatic wheezing, and symptoms of valvular heart lesion.

• Less common complaints include joint pain, arthritis, lacrimation, changes in mental status, ophthalmologic findings associated with flushing or secondary to vascular occlusion, and retroperitoneal fibrosis.

• Patients may develop Cushing syndrome, which is caused by the release of ACTH, and acromegaly, with is caused by the release of growth hormone.

• Flushing attacks are most common, occurring in as many as 94% of patients, sometimes during the course of the disease. These often are 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 the attack. Nevertheless, the flushes can be spontaneous and unrelated to any stimulation. Initially, flushing attacks are short, lasting only a few minutes. With time, the duration of attacks increases to hours. Flushes are reported to be longer lasting in bronchial carcinoids.

• Some patients develop a constant red or cyanotic discoloration.

• Diarrhea and malabsorption occur in up to 84% of the cases, sometimes during the course of the disease. Stools are watery, frothy, bulky, or in the form of steatorrhea. Diarrhea may or may not be associated with abdominal pain, flushing, and cramps.

• Wheezing or asthmalike syndrome is caused by bronchial constriction and may occur in up to 25% of the patients.

• Cardiac manifestation is observed in as many as 60% of the patients. Fibrosis of endocardium, often involving the right heart, is observed. The fibrous deposit usually involves ventricular aspect of the tricuspid valve and associated chordae. Less commonly, fibrosis of the pulmonic valve is seen, resulting in regurgitation or stenosis. Cardiac lesions may lead to heart failure. The mitral valve is less frequently involved.

• Skin hyperkeratosis and pigmentation and arthritis are less common.

• Confusion and changes in mental status can occur.

• Ophthalmological manifestations, including vessel occlusion, have been reported.

• Retroperitoneal fibrosis, obstruction of ureter, intra-abdominal fibrosis, and male sexual dysfunction can occur.

Causes:

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

• Multiple endocrine neoplasia type 1 (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. MEN1 gene germline mutation carriers can be identified in the general population. Although the MEN1 gene locus is known to be involved in neuroendocrine tumors, the genetic events that derive the neoplastic process are basically unknown.

• Loss of heterozygosity was found in 13 of 20 neuroendocrine lung tumors.

• In 5 of 9 "typical" carcinoid tumors of the lung, 3 distinct regions of allelic loss (band 11q13.1 [D11S1883], bands 11q14.3-11q21 [D11S906], band 11q25 [D11S910]) were identified.

• "Atypical" carcinoids had loss of heterozygosity (LOH) at band 11q13 between markers PYGM and D11S937, bands 11q14.3-11q21 (D11S906), band 11q23.2-23.3 (D11S939), and band 11q25 (D11S910).

• The region of band 11q13 bearing the MEN1 gene was more affected in atypical than typical carcinoid tumors; therefore, band 11q13 appears to be of significance in these tumors. It also appears that more aggressive atypical carcinoid tumors, defined by high mitosis, vascular invasion and organ metastasis, have more allelic losses.

• The MEN1 gene is located on chromosome 11 (band 11q13) and likely functions as a tumor suppressor gene. In one study of 46 sporadically occurring tumors, 78% displayed LOH at this site, with almost the entire allele missing in 5 cases. In the remaining cases, genetic heterozygosity displayed a discontinuous pattern. It is postulated that sporadically occurring carcinoid tumors are monoclonal, and tumorigenesis involves inactivation of a tumor suppressor gene on chromosome 11 and DNA mismatch repair gene mutations.

• Gastric neuroendocrine tumors are shown to have a high incidence of LOH on 8p chromosome and a lower frequency of LOH on 7q. Chromosome 8p is suspected to be the possible location of the tumor suppressor gene associated with the genesis of gastric neuroendocrine tumor.

• Numerical imbalances of chromosomes have been observed in carcinoid tumors. In one study of midgut carcinoids, numerical changes were found in 16 of the 18 tumors. The most common aberrations were losses of band 18q22-qter (67%), band 11q22-q23 (33%), and band 16q21-qter (22%) and gain of band 4p14-qter (22%). Metastasis has significantly higher alterations than the primary tumors. Losses of chromosome arms 18q and 11q were found in the primary tumors and metastasis, while loss of 16q and gain of 4p were present only in metastasis. It is postulated that loss of chromosome arms 18q and 11q may represent an early event and loss of 16q and gain of 4p occur as a later event in midgut carcinoids.

Lab Studies:

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

• In midgut tumors, 5-HTP is rapidly converted to 5-HT by dopa-decarboxylase and is stored in neurosecretory granules or released. A significant portion of 5-HT is taken up and stored in the secretory granules of platelets. The free segment of 5-HT is mostly converted to 5-HIAA by monoamine oxidase and by aldehyde dehydrogenase and secreted in the urine. As noted before, the level of 5-HIAA depends on the cellular origin of the lesion, with foregut tumors having a relatively small amount of 5-HIAA and large quantities of 5-HTP. Presumably these tumors are deficient in dopa-decarboxylase; thus, the conversion of 5-HTP to 5-HIAA is largely impaired, and only a modest increase in urinary 5-HT and 5-HIAA metabolites is observed.

Surgical Care:

• The treatment of choice is surgical excision, if feasible. In most appendiceal tumors, a simple appendectomy is sufficient treatment. In intestinal carcinoids, block resection of the tumor with adjacent lymph nodes must be attempted. When total resection is not possible, debulking may provide symptomatic relief. Intra-arterial chemotherapy infusion with chemoembolization of the hepatic artery may provide effective, albeit short-term, relief for hepatic metastasis in carcinoid tumors. If hepatic metastasis is present but resectable, surgical resection is preferred.
• Therapeutic agents effective in treatment of carcinoid tumors include the following (a combination of agents often is used):
  • Alkylating agents
  • Doxorubicin
  • 5-Fluorouracil
  • Dacarbazine
  • Actinomycin D
  • Cisplatin
  • Etoposide
  • Streptozotocin
  • Interferon alfa
  • Somatostatin analogues with radioactive load

• In one study, 8 adult patients with carcinoid tumor metastatic to liver were treated with intra-arterial 5-fluorouracil and hepatic tumor embolization with bovine collagen fiber admixed with iohexol, cisplatin, mitomycin C, and doxorubicin. This resulted in symptomatic relief and in regression of tumor in 4 patients and stabilization of disease in the rest of the patients. Octreotide, a somatostatin analogue, is highly effective in reducing symptoms; however, in the pediatric age group, stunt linear growth is a major adverse effect. Other adverse effects of this therapy include steatorrhea, which at times may require pancreatic enzyme replacement, and development of gallstones. Local irritation at the site of injection is a common complaint.

• In situ targeted therapy with somatostatin analogues (eg, octreotide attached to a radioactive load using yttrium-90 [⁹⁰Y] or ¹¹In labeling agents) can provide promising therapy for patients with unresectable tumors. This therapy currently is used on an experimental basis in adults and children.

Prognosis:

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