Carcinoid tumors are slow-growing tumors arising from neuroendocrine cells and capable of secreting a variety of peptides and neuroamines. The common primary sites are the gastrointestinal (GI) tract (60%) followed by the tracheobronchial tree (25%), but other primaries may occur in the ovaries or kidneys. The most common location of carcinoids is the small intestine. The term carcinoid is usually used for well-differentiated and low to intermediate grade neuroendocrine tumors, and the term neuroendocrine carcinoma is used for the less frequent, poorly differentiated and high-grade neuroendocrine tumors. We will focus on gastrointestinal (GI) carcinoid tumors in this chapter.
Carcinoid tumors are endodermal in origin and arise from enterochromaffin cells of the aerodigestive tract. GI carcinoids occur most frequently in the small bowel, followed by rectum, appendix, and stomach. It has been proposed that paracrine agents and growth factors induce cell proliferation, and form fertile ground for mutations in oncogenes and tumor suppressor genes. Carcinoids can also rarely be seen in patients with familial MEN1 syndrome.
The annual incidence is estimated to be 2.5 to 5 per 100,000 people per year, and prevalence is 35 per 100,000. The highest incidence is reported in patients around 50 to 70 years of age, with no gender predilection. With improved techniques for tumor detection, the incidence has increased.
Carcinoid tumors are commonly classified based on their embryologic origins and the vascular supply of the GI tract into the foregut, midgut, and hindgut carcinoids. Functional carcinoids can secrete various vasoactive substances such as serotonin, histamine, tachykinins, and prostaglandins. Presentation with carcinoid syndrome usually indicates underlying hepatic metastatic disease, indicating loss of the ability of the liver to inactivate these substances, but foregut carcinoids can release vasoactive amines directly into the systemic circulation and can present with carcinoid syndrome without liver metastases. Embryonic hindgut carcinoids are rarely associated with a hormonal syndrome.
The tumors are usually small, polypoid and solid, slow growing, often invading transmurally and spread to the lymphatics and adjacent mesentery. The tumor cells are arranged in nests or trabeculae and characterized by lightly eosinophilic cytoplasm, variable nuclear grade and round to oval finely granular nuclei. Immunostaining for general markers of neuroendocrine tumors such as chromogranin A and synaptophysin are frequently done for diagnostic confirmation.The WHO (2010) classified all neuroendocrine tumors, including carcinoids into three grades based on the mitotic rate, or Ki-67 index:
The presentation of carcinoids depends on where they are located, hormonal activity and aggressiveness of the tumor. Carcinoid syndrome from hypersecretion of vasoactive amines is most common with small intestinal carcinoids (up to 80%) but can also occur in foregut carcinoids in the lung and ovaries. The most common clinical manifestations are episodic flushing (84%), watery diarrhea (70%) and heart disease (37%). Most of the episodic flushing occurs spontaneously, but physical and emotional stress, alcohol, and tyramine-containing foods like blue cheese, chocolate, and red wine can provoke it. Flushing associated with carcinoids is characteristically dry flushing, as opposed to common causes of flushing such as panic attacks and menopause which are associated with sweating. Leonine facies may result over time due to telangiectasia and hypertrophy of the skin. Diarrhea is secretory in nature and key in the history is its persistence with fasting. Other presentations could be bronchospasm, arthropathy, neuropathy, and edema. Bowel ischemia with abdominal pain and bleeding could result from mesenteric fibrosis associated with midgut carcinoids. Local mass effect of the tumor can cause bowel obstruction.
Chronic exposure to these amines can cause fibrous endocardial thickening of the right side of the heart with resultant tricuspid and pulmonary valve regurgitation leading to right heart failure. Left heart disease is uncommon due to the clearance of 5HT by monoamine oxidase present in the lung.
Patients can also present with Pellagra as tryptophan is diverted from niacin synthesis to serotonin synthesis. These patients present with glossitis, angular stomatitis, characteristic skin rash with rough, scaly skin, and confusion.
The diagnosis of these tumors is often delayed by five to seven years as these patients are often asymptomatic or present with non-specific symptoms. Metastases occur in 30% of patients at the time of diagnosis and can be as high as 70% in midgut carcinoids. The diagnosis is mainly based on clinical suspicion and biochemical evaluation. Imaging is often used for localization and assessment of tumor spread.
It is recommended that all patients with carcinoid tumors have chromogranin A, pancreastatin and 24-hour urine for 5-hydroxyindoleacetic acid (5-HIAA) checked. Chromogranin A, a non-specific neuroendocrine marker, can be useful in the screening and follow-up of both functioning and non-functioning carcinoids, like other neuroendocrine tumors. Levels should be obtained while fasting and exercise should be avoided before testing. Chromogranin A levels correlate with tumor volume and may provide prognostic information, and be a useful tool for monitoring response to therapy. Small tumors may be associated with a normal level, and thus missed. False-positive measurements can occur with severe hypertension, chronic gastritis, proton pump inhibitor use and renal insufficiency. Results from different laboratories are not directly comparable, and it is important to send samples to the same laboratory when chromogranin A is used for serial monitoring. Pancreastatin, a post-translational processing product of chromogranin A, appears less susceptible to assay artifacts and use of proton pump inhibitors, may be a negative prognostic indicator and has the potential to be an alternate biomarker.24 hour urine collection for 5-HIAA, a serotonin breakdown product is useful for the diagnosis and follow-up of carcinoid tumors secreting serotonin: mainly midgut carcinoids. It is important to avoid certain foods (rich in serotonin and tryptophan) and medications that can result in false elevations of 5-HIAA, for three days before and during collection.Serum serotonin is not useful due to variability from daily activities. Measurement of single fasting plasma 5-HIAA level is convenient but needs further study.Foregut carcinoids being deficient in dopa-decarboxylase (converts 5-hydroxytryptophan to serotonin) lead to only modest elevations of 5-HIAA.
CT with multiphase contrast study, MRI, somatostatin receptor scintigraphy with Octreoscan and PET scan with DOTATOC are useful imaging modalities for localizing carcinoid tumors and assessing metastatic spread. CT is insensitive for small liver metastases for which MRI with hepatocyte-specific contrast agent is a better imaging modality. FDG-PET is not useful due to the low proliferative activity of carcinoid tumors. Upper and lower GI endoscopy are useful for direct visualization and biopsy of accessible lesions. CT enterography can also be used. Small bowel enteroscopy and pill-cam endoscopy are useful for small bowel tumors beyond the reach of standard endoscopy. Pill-cam can be retained at the tumor site with resultant small bowel obstruction, and therefore routine use is not recommended. An echocardiogram is useful for detecting carcinoid valvular disease and should be done before any surgery. Octreotide scan is useful for predicting treatment response to octreotide treatment.
In many patients with carcinoid have nonspecific symptoms, and diagnosis is delayed, and metastatic disease is present at diagnosis. Goals of treatment are to resect primary tumor and associated regional lymph nodes and to control carcinoid syndrome when present.
Surgical removal of the tumor is curative in localized disease, although finding the primary when small can be challenging. The goal of surgery in midgut carcinoids is complete curative en bloc resection of the primary tumor and extensive mesenteric lymph node dissection. Subserosal-injected methylene blue helps identify surgical margins for midgut carcinoids. Small intestinal carcinoids can cause a severe desmoplastic reaction and deeply infiltrative lymph nodes around major vessels and thus complete surgical resection is seldom achieved, but cytoreductive surgery (resection of 90% of the tumor) from an experienced surgical team results in improved symptomatic outcomes. Surgery should not be delayed until symptoms occur because this makes cytoreductive surgery more difficult. As most patients with midgut carcinoids require treatment with somatostatin analogues at some point and these agents are associated with biliary stasis and cholelithiasis, cholecystectomy should be performed at the time of initial surgery. Small bowel obstruction is also an indication for surgery and is treated with resection of the involved segments and mesentery. All patients with metastatic carcinoids should be evaluated for multimodality approach involving surgery, medical therapy, and radiotherapeutic techniques.Metastasectomy can also be curative in isolated metastasis and can also be used to decrease tumor bulk to provide relief in symptomatic patients. Liver-directed therapies for palliative control of advanced metastatic disease include chemoembolization and radioembolization.
Somatostatin analogues (SA) are the mainstay of medical therapy for carcinoid syndrome due to high expression of somatostatin receptors (SSTR) on these tumors. Octreotide and lanreotide bind to SSTR-2 and -5 and reduce diarrhea and flushing in up to 80% of patients. Somatostatin analogues have been shown to control the growth of well-differentiated neuroendocrine tumors and to increase progression-free survival. Pancreatic malabsorption can occur with use of SAs and benefits from pancreatic enzyme supplementation. Tolerance to somatostatin analogues develops over time requiring dose escalation. Refractory diarrhea may benefit from the use of loperamide. It has been recommended that all patients with functional or nonfunctional neuroendocrine tumors (including carcinoids) be considered for treatment with somatostatin analogues and have routine tumor surveillance. Interferon-alpha has a potential role for refractory symptoms of carcinoid syndrome despite somatostatin analogue treatment. The role of mTOR inhibitors in the management of carcinoids needs further study. As carcinoids are slow growing, traditional chemotherapy is ineffective.
Peptide receptor radiotherapy (PRRT) utilizing somatostatin analogue chelated to beta emitting cytotoxic isotope, 90-Yttrium or 177-Lutetium is an emerging therapeutic modality that utilizes somatostatin receptor as a target. I 131 MIBG therapy is being used for metastatic neuroendocrine tumors with intense uptake and needs further studies.
Carcinoid crisis can occur due to excessive release of neuropeptides during stress and can present with hemodynamic instability, shock, arrhythmia, hyperthermia, bronchospasm, or flushing. It can also occur pre-op, intra-procedural or post-op due to manipulation of the tumor. Patients with carcinoid syndrome and large bulky tumors or metastatic carcinoid may be at higher risk of carcinoid crisis and should be given perioperative continuous intravenous octreotide. Adrenergic blocking agents like clonidine, chlorpromazine (kinin antagonist), corticosteroids (blocks kallikrein release) and aprotinin (a kallikrein inhibitor) have also been used in carcinoid crisis. Before surgery, patients should undergo echocardiography for carcinoid valve disease, valve repair considered, and be given prophylaxis with somatostatin analogues.