Carcinoid Tumor, Intestinal

Synonyms and related keywords: intestinal carcinoid tumor, intestinal carcinoid tumour, gastroenteropancreatic neoplasm, GEP, GEP neoplasm, well-differentiated gastrointestinal neuroendocrine cancer, neuroendocrine tumor, neuroendocrine tumour, argentaffinoma, carcinoid syndrome, small bowel malignancy, irritable bowel syndrome, IBS, idiopathic flushing, intestinal tumor, intestinal tumour, GI tumor, GI tumour, gastrointestinal tumor, gastrointestinal tumour, intestinal malignancy


INTRODUCTION

Background: Carcinoid, a term first applied to hormonally active tumors by Oberndorfer in 1907, follows a more benign clinical course than most other malignancies. Carcinoid of the small intestine, a well-differentiated neuroendocrine tumor, is the most common distal small bowel malignancy, with an occurrence rate of 1 case per 300 autopsies.

Carcinoid tumors of the appendix account for 0.2-0.7% of all appendicectomies, and they are the most common tumor of the appendix, accounting for 80% of appendiceal growths (Marshall, 1993). Even though the frequency of the primary tumor is high, the incidence of metastasis is quite low (1 metastasis per 300,000 incidences). Common sites of metastatic spread include the regional mesenteric and para-aortic lymph nodes and the liver. With distant spread, especially to the liver, carcinoid syndrome can develop.

The association of flushing, diarrhea, bronchoconstriction, and cardiac disease with carcinoid tumors was first reported by Thorson and colleagues in 1954. The findings that 5-hydroxytryptamine (serotonin) was present in carcinoid tumors and that patients with carcinoid syndrome excrete increased quantities of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), led to the hypothesis that the humoral manifestations of carcinoid syndrome could be attributed to the overproduction of serotonin by these tumors. However, serotonin is not the only mediator of the clinical syndrome. Other substances, such as the tachykinins, play a significant role in the different clinical characteristics of affected patients.

Pathophysiology: Enterochromaffin cells stain yellow-brown after chromate fixation and are diffusely distributed in the tissues derived from the primitive gut. Intestinal enterochromaffin cells are the Kulchitsky cells in the crypts of Lieberkühn of the small intestine. Carcinoid tumors arise from the enterochromaffin cells. Tumor cells and Kulchitsky cells both reduce silver salts (argentaffin reaction); thus, the term argentaffinoma is used to describe carcinoid tumors.

Endocrine cells in the pituitary gland, thyroid gland, lungs, pancreas, and gastrointestinal tract secrete polypeptides and share common cytochemical and ultrastructural characteristics. Pearse developed the concept of the amine precursor uptake and decarboxylation system because these cells take up and decarboxylate amino acid precursors of biogenic amines such as serotonin and catecholamines. Included in this system are the enterochromaffin cells responsible for carcinoid tumors.

This system of cells has a common embryonic origin from the neuroectoderm. Related cells are present in the adrenal medulla, sympathetic ganglia, paraganglia, and chemoreceptor system. Because of the apparent common embryologic ancestry of these cells, a unique concept of dysplasia of the neuronal ectoderm has been proposed to explain the occurrence of multiple endocrine neoplasia and the multipotentiality of neoplastic cells derived from this system to produce a variety of peptide hormones.

Consistent with the aforementioned concept, histologic similarities among carcinoid tumors, islet cell tumors, and medullary carcinoma of the thyroid have been recognized. In addition, carcinoid tumors may coexist with other endocrine tumors. Tumors that histologically appear to be carcinoids may also produce gastrin, calcitonin, insulin, vasoactive intestinal peptide, neurotensin, catecholamines, and corticotropin (adrenocorticotropin hormone).

Common embryonic ancestry may also explain the occurrence of more than one primary carcinoid tumor in a single patient. In most instances, carcinoid tumors do not occur in association with other endocrine neoplasms, and they usually do not secrete hormones normally produced by cells other than enterochromaffin cells.

Clinical, biochemical, morphological, and cytochemical heterogeneity of carcinoid tumors are related to the site of origin. One classification is based on whether the tumor arose from the embryonic foregut (ie, bronchus, stomach, pancreas, duodenum), midgut (ie, ligament of Treitz to mid transverse colon), or hindgut (ie, mid transverse colon, descending colon, rectum). Classification can also include whether oversecretion of amine or peptide hormones is present (secretors vs nonsecretors).

Characteristically, midgut-derived carcinoid tumors secrete serotonin, and patients with these tumors have elevated urinary excretion of 5-HIAA. Patients with foregut carcinoid tumors frequently have low activity of L-amino acid decarboxylase, which converts 5-hydroxytryptophan (5-HTP) to serotonin. Thus, these tumors primarily secrete 5-HTP. Midgut tumors may secrete 5-HTP in addition to serotonin. After 5-HTP is secreted, it is converted to serotonin and its metabolites by other tissues in the body. Therefore, although foregut carcinoid tumors do not usually directly secrete large quantities of serotonin, elevated urinary 5-HIAA levels are found in patients with these tumors. In contrast, hindgut carcinoid tumors do not usually secrete large amounts of either 5-HTP or serotonin, and patients with these tumors do not have elevated urinary excretion of 5-HIAA.

Endocrine aspects of carcinoid neoplasm

The term carcinoid syndrome is used to describe the hormonal manifestations of carcinoid tumors. These are flushing, diarrhea, bronchoconstriction, and cardiac disease. Most patients with carcinoid tumors do not develop carcinoid syndrome. The frequency of hormonal manifestations is greatest for midgut primary tumors and varies with the site of tumor origin.

Of patients with small intestinal and proximal colonic carcinoids, 40-50% experience the syndrome. Carcinoid syndrome occurs less frequently in patients with bronchial carcinoids, is rarely observed in association with appendiceal carcinoids, and does not occur in patients with rectal carcinoids, even when the rectal carcinoid is in an advanced stage and has metastasized.

The development of carcinoid syndrome is also a function of total tumor mass and the extent of metastasis. Development is unusual in patients with a small tumor burden. Patients with the syndrome almost invariably have hepatic metastases. The association with hepatic metastases may be related to the efficient inactivation by the liver of hormones released from an abdominal tumor into the portal circulation.

In contrast, venous drainage from a metastatic tumor in the liver goes directly into the systemic circulation and bypasses hepatic inactivation. Consistent with this concept is the fact that the tumors most likely to be associated with carcinoid syndrome in the absence of hepatic metastasis are ovarian teratomas and bronchial carcinoids, which release mediators directly into the systemic circulation rather than the portal circulation.

Nonhormonal symptoms

Recognition of nonhormonal symptoms early in the course of disease enhances the likelihood of diagnosis before distant metastasis or endocrine manifestations have occurred.

Bronchial carcinoid tumors may be associated with respiratory complaints (eg, cough, dyspnea, hemoptysis), which leads to roentgenologic evaluation and bronchoscopy.

Rectal carcinoids are usually asymptomatic in the absence of advanced disease.

Patients with midgut carcinoids frequently have symptoms for long periods (ie, 2-5 or more y) before a specific diagnosis is made. In this group of patients, early diagnosis can potentially lead to a cure by surgical resection of the primary tumor. The most common symptoms and signs of an intestinal carcinoid are abdominal pain, intermittent obstruction, and a palpable abdominal mass, each of which occurs in nearly 50% of patients.

Obstruction usually occurs after invasion of the mesentery, and the resulting desmoplastic reaction with scarring and matting of small bowel loops, in turn, can produce a mass and intermittently obstruct the intestine. The clinical picture of recurrent intermittent intestinal obstruction should raise the suggestion of carcinoid tumor. Because this process is extraluminal, results of the roentgenological examination may be normal approximately half the time.

Frequency:

• In the US: The frequency of carcinoid tumor is 1 case per 300 individuals. For carcinoid syndrome, it is 1 case per 300,000 individuals.

Mortality/Morbidity: Survival is dependent on the primary site and the size of the primary tumor. Patients with metastatic disease arising from midgut (ie, distal small intestine/cecal) primary tumors generally live longer than those with the foregut (ie, bronchial, gastric, pancreatic) and hindgut (ie, rectal) as primary sites. The 5-year survival rate from the time of diagnosis of metastatic disease is 67%. No therapy to date has been shown in any randomized clinical trial to prolong survival for patients with metastatic carcinoid tumors, and therapy remains palliative.

Race: No racial differences in the incidence of carcinoid tumors are known.

Sex: The incidence of carcinoid is similar between males and females (Surveillance, Epidemiology, and End Results [SEER] Program, 2001).

Age: The occurrence rate of carcinoid tumors peaks at approximately age 62 years. Carcinoid tumors are rare in young persons, particularly because the argentaffin cells from which this tumor develops are only identified in children older than 4 years (Deans, 1995).

CLINICAL

History: Clinical symptoms can arise from the primary tumor, from the sequelae of metastatic disease, or from the carcinoid syndrome. Many intestinal carcinoids are small and asymptomatic. They are found incidentally or at autopsy.

• Symptoms of partial intestinal obstruction can be the result of an intense desmoplastic reaction characteristic of carcinoid tumors.

• Lower gastrointestinal bleeding can result from ulceration of the mucosa overlaying the tumor.

• Intestinal ischemia or infarction can occur secondary to mesenteric angiopathy characterized by a desmoplastic mesenteric reaction.

• Constitutional symptoms are common to the clinical presentation. They involve anorexia, weight loss, and fatigue. This is usually related to disease metastasis to regional lymph nodes or the liver, which is present in up to 90% of patients at the time of diagnosis.

• Malignant carcinoid syndrome develops with carcinoid of the small bowel only with massive hepatic replacement by metastatic tumor.

• Serotonin and other vasoactive substances secreted by the hepatic metastases escape hepatic degradation and enter the systemic circulation directly, with resultant symptoms.

• Approximately 10% of patients with an intestinal carcinoid tumor develop carcinoid syndrome.

• Metastatic carcinoid neoplasm can be difficult to diagnose early in its natural history because the patient generally complains of vague abdominal symptoms or flushing. The disease is estimated to have been present for more than 8 years before diagnosis.

• Patients with carcinoids have commonly been diagnosed with irritable bowel syndrome or idiopathic flushing.

• The syndrome is characterized by hepatomegaly, diarrhea, and flushing in 80% of patients; right heart valvular disease in 50%; and asthma in 25%.

• Malabsorption and pellagra (ie, dementia, dermatitis, and diarrhea) are occasionally present and are thought to be caused by the excessive diversion of dietary tryptophan to serotonin.

• Cutaneous flushing is a common manifestation (~80% of patients) and is often the earliest sign of the syndrome. Flushing can occur spontaneously, typically in the head and neck. It may be triggered by excitement, exercise, some types of food, or alcohol. Flushing is mediated by the vasoactive peptides secreted by the tumor.

• Diarrhea is the most common feature (~80% of patients) of carcinoid syndrome. It is usually episodic, often occurring after meals. The elevated circulating levels of serotonin stimulate the secretion of small bowel fluid and electrolytes and increase intestinal motility, resulting in diarrhea.

• Carcinoid abdominal crisis is a rare acute abdominal syndrome characterized by severe abdominal cramping without a mechanical bowel obstruction. The mechanism of the crisis is believed to be intestinal ischemia caused by vasoactive substances elaborated by the carcinoid tumor, combined with a decreased mesenteric blood supply due to a perivascular fibrosis.

• Right-sided cardiac valvular disease usually develops only after many years of the syndrome and manifests in approximately half the patients with long-standing carcinoid syndrome. Serotonin stimulation induces irreversible endocardial fibrosis of the tricuspid and pulmonary valves, resulting in valvular dysfunction (stenosis or incompetence). The lungs metabolize serotonin and protect the left heart from fibrosis. Carcinoid heart disease may ultimately result in cardiac insufficiency, usually with right-sided heart failure.

• Asthma (~25% of patients) is due to bronchoconstriction, which may be attributed to serotonin, bradykinin, or substance P elaborated by the carcinoid tumor. The treatment of asthma associated with carcinoid syndrome must be conducted very carefully because adrenergic drugs may cause the release of humoral agents from the tumor that may cause status asthmaticus.

Physical: Physical examination findings may be normal, and the patient may appear healthy. Patients in carcinoid crises can have face, neck, and upper chest flushing lasting for hours to days. They can have hypotension, increased lacrimation, and fever and can be in moderate-to-severe distress. The typical patient is aged 61-66 years and experiences flushing when performing a Valsalva maneuver.

• Skin

• Facial telangiectasias, usually bimalar

• Extremity rash, usually in severe, uncontrolled, end-stage disease, thus implying niacin deficiency

• Lungs - Wheezing

• Heart - Usually normal but with prolonged, uncontrolled serotonin secretion, tricuspid valve regurgitation, and, less commonly, pulmonic stenosis

• Abdomen

• May be distended and nontender

• Bowel sounds normal or high pitched

• Hepatomegaly possible

• Extremities - Bilateral lower extremity edema

Causes: Risk factors are unknown, and the results of a genetic linkage analysis are inconclusive. Environmental toxins remain unidentified.

DIFFERENTIALS

Irritable Bowel Syndrome
Malignant Neoplasms of the Small Intestine
Mastocytosis, Systemic
Thyroid, Medullary Carcinoma


WORKUP

Lab Studies:

• Unfortunately, as already mentioned, most patients with carcinoid tumors present with metastatic disease. Only approximately 20% of patients are diagnosed with potentially resectable disease (Sugimoto, 1995).

• Urinalysis

• In persons with carcinoid syndrome, levels of urinary 5-HIAA are usually greatly increased. This is because tryptophan metabolism is diverted from protein and nicotinic acid metabolism to serotonin, with consequent breakdown to 5-HIAA. A very high (usually >5 times normal values) level of urinary 5-HIAA in a 24-hour collection is diagnostic, provided that avocados, bananas, plums, walnuts, pineapples, tomatoes, eggplants (aubergines), and cough medicines are excluded from the diet for 24 hours before the collection is made.

• In very rare cases, usually in bronchial carcinoids or gastric tumors (derived from the foregut), the tumor cells lack the aromatic amino acid decarboxylase enzyme, and hence the secretion of 5-HTP is increased. If this is the situation, then 5-HIAA urinary excretion would be normal and the diagnosis is confirmed by measuring total 5-hydroxyindole excretion. Such measurement includes 5-HTP, serotonin, and 5-HIAA.

Imaging Studies:

• Ultrasound

• Ultrasound has limited use, particularly in lesions smaller than 1 cm.

• Endoscopic ultrasound is useful for detecting duodenal lesions; experience in this technique is mainly in detecting duodenal gastrinomas and is highly operator dependent (Ruszniewski, 1995).

• CT scan

• Noncontrast CT scan is the investigation of choice for carcinoid tumors because metastatic carcinoid tumors are usually extremely vascular; consequently, they tend to become isodense in the presence of contrast (Sugimoto, 1995).

• CT scan can also detect mesenteric involvement with tumor in 50% of patients with metastatic disease.

• MRI

• In the past, availability and the speed of the procedure initially limited use of this investigation. Another dilemma was the difficulty in distinguishing between small (less than 2 cm) vascular intrahepatic lesions and benign hemangiomas.

• With technical improvements, MRIs are increasingly being used as the supplemental abdominal investigation of choice.

Other Tests:

• Endoscopy: Standard gastroscopy is of limited use except in patients with multiple gastric carcinoids.

TREATMENT

Medical Care: Medical care is usually only for symptomatic relief.

• Chemotherapy

• Response rates are variable but rarely exceed 30%. Results are usually short-lived (ie, less than 1-y duration). 5-Fluorouracil and streptozocin (Zanosar)–based regimens are commonly used in patients with metastatic carcinoid tumors. The value of using newer agents (eg, taxanes, gemcitabine [Gemzar], irinotecan [Camptosar]) remains unproven.

• Chemotherapeutic regimens are only for palliative purposes; if eligible, patients should be put on a clinical trial of investigational therapy.

• Radiation: This only has a palliative role, particularly for painful bony metastasis.

• Other modalities

• High doses of sodium iodine-131–labeled metaiodobenzylguanidine, low-dose interferon alfa, and octreotide have all been used, with some reduction in symptoms; however, tumor reduction is rarely observed. When reductions occur, they are only transient (Gordon, 1989; Diaco, 1995).
• Patients with problematic diarrhea usually find benefit from antidiarrheal medication. Cyproheptadine and histamine-2 receptor blockers may be of benefit because they suppress the production of vasoactive amines or block their peripheral effects.

Surgical Care: Surgical resection is the standard therapeutic modality.

• Appendiceal carcinoids

• For tumors smaller than 1.5 cm in greatest diameter that are confined to mucosa, appendicectomy is adequate, with no need for follow-up care. Cure rates are 100%.
• Tumors 2 cm or larger in diameter, those at the base of the appendix, or those with mesenteric lymphadenopathy are not common but are considered potentially malignant. Consider more aggressive surgery in the form of a right hemicolectomy and lymphadenectomy, similar to that performed for colonic adenocarcinoma.
• Invasion of only the mesoappendix does not alter the long-term prognosis, but cecal involvement necessitates further surgery.

• Small bowel carcinoids

• At laparotomy, perform a thorough examination of the small bowel because multiple lesions are fairly common.
  
• Macroscopic tumor size is a fairly good indictor of malignant potential. For tumors smaller than 1 cm in diameter, a local resection is usually adequate. Tumors larger than 1.5 cm have a risk of recurrence, hence the need for a segmental bowel resection with lymphadenectomy.

• Rectal carcinoids

• Tumor size again is of essence with regard to the extent of resection.
• Tumors of up to 1 cm in diameter require only local excision or fulguration, with cure rates close to 100% (Mani, 1994). Consider large tumors (>2 cm) malignant, and manage them similar to adenocarcinoma of the rectum, ie, with extensive resection. Tumors of 1-2 cm can be treated either by limited or more aggressive resection, but each case is guided according to the size, invasive nature, and anatomical location.
• All patients, except for those with lesions smaller than 1 cm, need conscientious follow-up care.

• Metastatic intestinal carcinoid - Possible options

• Surgery is considered worthwhile in most cases because this is the best form of palliation regardless of whether the tumor is of the secretory type. Tailor the procedure accordingly, and avoid attempts at major debulking procedures.
• All patients with advanced-stage carcinoid tumors should be evaluated for possible multimodal surgical therapy. Primary tumors should be resected, even in the presence of distant metastases to prevent future intestinal obstruction. The "wait and see" method of management of this slow-growing cancer no longer has merit.

• Obstructive small bowel lesions could be resected (if possible) or bypassed.

• Multiple liver metastases in patients with carcinoid syndrome are resected, cauterized, or ablated with percutaneous alcohol injections because this usually results in a dramatic relief of symptoms.
• Hepatic artery ligation or embolization (eg, collagen fibers, gel foam, alcohol) can result in significant tumor necrosis and is of value in patients with bulky, inoperable, or symptomatic liver metastasis, with up to a 60% reduction of tumor bulk in some cases. This form of treatment can be combined with intrahepatic chemotherapeutic infusion. However, it can result in toxic effects, particularly fever, nausea, vomiting, and abdominal pain. Occasionally, the carcinoid symptoms may worsen (Carrasco, 1986).

MISCELLANEOUS

Medical/Legal Pitfalls:

• Because patients with carcinoid tumors present with a plethora of symptoms, diagnosis is usually delayed. This delay can be the basis of litigation.