Carcinoid tumors are rare malignancies first described over 100 years ago. The term “carcinoid” was replaced with “well-differentiated endocrine neoplasm” by the World Health Organization in the year 2000; more appropriately descriptive of these typically slow-growing neuroendocrine tumors (NETs). The majority of NETs occur sporadically and are nonhereditary, with the ability to secrete various vasoactive substances.1 Despite their sporadic occurrence, carcinoid tumors may be associated with hereditary syndromes like multiple endocrine neoplasia (MEN); the mutation of the MEN1 gene being the most common somatic mutation in sporadic tumors like carcinoids. For example, some of the foregut tumors may show a loss of heterozygosity at 11q13. Poorly differentiated NETS may show loss of heterozygosity for p53 or the adenomatous polyposis coli tumor suppressor gene.2
Carcinoid tumors are rarely found in adults with an estimated annual incidence of 5 per 100,000; which reflects significant increase over the past 15 years.3,4 The incidence in children and adolescents is lower at 2.8 NETs per million under the age of 30 years.5 Despite their low numbers, carcinoid tumors represent the most frequent tumor of the gastrointestinal tract in children6 and the most frequently diagnosed primary pulmonary tumor in children and adolescents.5,7,8 These tumors are often classified based on their embryonic gut origin. The foregut is the precursor site for bronchial and gastric tumors; the midgut is the precursor site for small intestinal and appendiceal tumors, and the hindgut, the precursor site for rectal tumors. Nearly 68% of carcinoid tumors develop in the gastrointestinal tract, with the appendix being the most common location, and another 25% occurring in the bronchopulmonary system.9 Other sites of occurrence include the thymus, gonads, breast, and other areas within the gastrointestinal tract.5,10
There have been several series investigating carcinoid and the other NETs in pediatric patients. Spunt et al11 analyzed pediatric patients at St Jude over a 22-year period and found 8 patients treated there for carcinoid tumors. These lesions were more likely to be found in female patients (75%) and whites (87.5%). The median age of presentation was 12.7 years. In a case series of childhood carcinoid tumors in Brazil over an 11-year period, 9 patients were found to have carcinoid tumors. 66.6% were female patients, and mean age was 12.2 years. Locations for the tumors were the appendix (n=8) and bronchus (n=1).12 Similarly, an Austrian review of appendiceal carcinoid tumors in children found 36 patients diagnosed with these tumors over a 30-year period. Again, the tumors were more likely to be found in female patients (69.4%), and the median age at diagnosis was 12.3 years.13 Dall’Igna et al14 reviewed appendiceal carcinoid tumors in Italy over a period of 15 years. Fourteen patients were diagnosed with appendiceal carcinoid tumors during this time. The median age was 13.5 years, and 64.3% were female. Over a period of 50 years, 22 patients under 20 years of age presented with appendiceal carcinoid tumors at MD Anderson. The mean age at presentation was 14.6 years.6 A recent review of SEER data for the period 1975 to 2006 confirms these findings with 28% of all NETs in the lung, 18% in the breast, and 18% in the appendix. The SEER data confirm the female:male predominance of 2:1.5 Analysis of SEER data demonstrated that breast, ovarian, and cervical NETs account for the increased female incidence.5
Investigating bronchial carcinoid tumors in pediatric patients, Wang et al8 reviewed a 59-year period during which time 17 patients between 10 and 21 years of age were diagnosed with bronchial carcinoid tumors. The average age at diagnosis was 17 years, with a median duration of symptoms of 8.5 months.
Broaddus et al15 reviewed cases of 13 NETs in extra-appendiceal sites during childhood and adolescence: 8 tumors were carcinoid tumors and 5 were classified as neuroendocrine carcinoma. Of the carcinoid tumor patients, 62.5% were female, whereas all of the neuroendocrine carcinoma patients were male. The mean age at presentation was 12.7 years.
Symptoms associated with carcinoid tumors are related to the location, size, and extent of spread of the tumor. In pediatric patients, appendiceal carcinoids are often found incidentally, but occasionally they are associated with lower quadrant abdominal pain and other symptoms of acute appendicitis.13,14,16,17 In a series of 23 patients with appendiceal carcinoid tumors, 18 patients presented with symptoms of an acute abdomen.16 In another series of 36 patients, acute right lower quadrant pain was present in 75%, and chronic right lower quadrant pain was present in the other 25%. Just over one third of the patients had appendicitis at the time of appendectomy.13 Moertel et al17 reviewed 150 patients with appendiceal carcinoid tumors and found that tumors that were smaller than 2.0 cm in greatest dimension were not associated with any metastatic disease. The incidence of metastatic disease increased with an increased size of tumor. Younger age seemed to be associated with larger tumors and greater risk of metastases.
Bronchial carcinoids may present with signs of cough, dyspnea, hemoptysis, or pleuritic pain. In a series of 17 patients by Wang et al8 symptoms included wheezing, hemoptysis cough, dyspnea, and chest pain (20% to 30% of patients), weight loss of 3 to 14 kg over a period of weeks to months (30% of patients), and a hoarse voice in 1 patient. Nearly 50% of patients presented with pneumonia in which no organism was identified. No patient was completely asymptomatic at the time of diagnosis.
The classic “carcinoid syndrome,” which consists of some combination of wheezing, flushing, diarrhea, hypotension, and/or abdominal pain, is rare in pediatric patients. This is because most young patients with carcinoid tumors do not have metastatic disease to the liver. Symptoms of carcinoid syndrome are related to the variable catecholamine expression of carcinoid tumors. Specific substances that may be secreted alone or in combination include 5-serotonin (5-HT), adrenocorticotropic hormone, substance P, gastrin, catecholamines, and 5-hydroxytryptophan (5-HTP).18 In general, foregut tumors have a low content of serotonin (5-HT) but often secrete its precursor, 5-HTP. They also often secrete histamine and many different polypeptide hormones. Midgut carcinoids typically have high serotonin content and rarely secrete the precursor, 5-HTP. These tumors may also produce adrenocorticotropic hormone and vasoactive substances such as kinins, prostaglandins, substance P, and neurokinin A. Hindgut carcinoids rarely secrete vasoactive substances, serotonin, or 5-HTP, thus making them less likely to be associated with carcinoid syndrome.18–20
One of the more serious side effects of carcinoid is carcinoid heart disease.21–23 When carcinoid tumors secrete vasoactive substances, the substances are usually inactivated by the liver. However, when a patient has disease in the liver itself, the vasoactive substances are not inactivated and are allowed to reach the systemic circulation The vasoactive substances are able to travel through the circulation, reaching the right heart, which is associated with fibrous tissue that deposits on the endocardial surfaces of the heart. Initial studies investigating carcinoid heart disease reported a rate as high as 70% in patients with carcinoid syndrome, but more recent studies suggest that the current rate of carcinoid heart disease may be lower for reasons that are not quite clear.23 Symptoms of carcinoid heart disease are related to the signs and symptoms of right heart failure. Patients may present with worsening shortness of breath, fatigue, and lower extremity edema. The right heart valves are damaged by the vasoactive substances, resulting in a combination of tricuspid regurgitation and stenosis. The pulmonary valve is less often involved, and left-sided lesions may occur in up to 10% to 15% of cases, thought to be due to a patent foramen ovale, bronchial carcinoid, or high levels of vasoactive substances. The presence of carcinoid heart disease has been shown to shorten survival in those patients with metastatic disease.23
The World Health Organization has provided a recent classification of NETs, to include 5 major categories: well-differentiated endocrine tumors (benign or low-grade malignancy), well-differentiated endocrine carcinomas, poorly differentiated endocrine carcinomas (small cell carcinomas), mixed exocrine and endocrine carcinomas, and tumor-like lesions. This differentiation is based on the tumor’s histology, tumor size, morphology, and the presence or absence of local invasion or metastases.24 When analyzing the histologic features of carcinoid tumors, they are frequently separated into “typical” and “atypical” groups. By definition, typical histologic features include neuroendocrine differentiation with a classic architecture of clusters of cells in trabecular, insular, or ribbon-like patterns. When the tumors appear more aggressive or poorly differentiated with increased mitotic activity and perhaps limited necrosis, they are considered atypical, and therefore may be more clinically aggressive. Some tumors exhibit more “aggressive” features, such as invasion into the lymphatic or vascular spaces or into the fat surrounding the primary tumor. The histologic pattern of the tumor should be taken into account when making clinical decisions for patient care.
By staining tumor cells for Ki-67, the clinician can get some objective evidence as to the inherent aggressiveness of the tumor, and all carcinoid tumors should be stained for this marker. Well-differentiated tumors tend to have minimal areas of atypical cytology and <2% Ki-67–positive cells. Alternatively, poorly differentiated carcinoid tumors have more malignant potential with more necrosis and atypia present, with closer to 15% of cells showing Ki-67 positivity. Other tumor biology markers such as CD-44 and nm-23 have also shown some association with more aggressive and more malignant carcinoid tumors.25,26 In general, these well-differentiated NETs have positive immunohistochemical staining for chromogranin A, synaptophysin, and neuron-specific enolase. However, the embryonic origin of the tumor may affect some of its staining features. For example, midgut carcinoids are likely to be argentaffin positive, whereas foregut and hindgut tumors will stain argentaffin negative.27
Certain chromosomal alterations may be clues for the clinician that a more significant endocrine disorder, such as MEN is present. For example, some of the foregut tumors may show a loss of heterozygosity at 11q13, leading the provider to think that MEN type 1 may be present. Other poorly differentiated tumors may show loss of heterozygosity for p53 or the adenomatous polyposis coli tumor suppressor gene.25
In pediatric and young adult patients, the insidious presentation of carcinoid tumors make it difficult to get “baseline” levels of typical carcinoid tumor markers to follow long term. However, if carcinoid syndrome or a carcinoid tumor is suspected based on clinical symptoms or imaging studies, it is best to obtain several laboratory studies before proceeding with surgical biopsy or resection. Chromogranin A is thought to be one of the most common and reliable serum tests for carcinoid tumors. It is thought to be elevated in as many as 80% of patients with carcinoid cancer, and often an elevation of chromogranin A may predict a radiologic or clinical relapse of the disease. The chromogranin A elevation is very specific for disease recurrence, but unfortunately has a sensitivity of around 63%, with higher levels found in secreting tumors and in patients with metastatic disease.20 Pancreastatin has also been analyzed as a reliable serum test for carcinoid tumors. It has been shown to be an effective marker in the follow-up of patients who require hepatic artery chemoembolization and for those patients who may have metastatic disease.28–30
The most useful urine test is a 24-hour urine collection for 5-hydroxyindoleacetic acid, which is a metabolite of 5-HT. When performed correctly, elevated levels of 5-hydroxyindoleacetic acid in urine is specific (100%) but not very sensitive (35%) in patients with disease due to the manner in which levels are influenced by foods such as bananas, avocados, walnuts, pineapples, etc.31 Other groups have advocated looking for other “tumor markers” when evaluating for carcinoid disease, to include serotonin, gastrin, neuron-specific enolase, and neurokinin A.20 Some of these laboratories are of more benefit than others, depending on the location of the tumor and the patient’s symptoms at presentation. For example, gastrin may only be useful in evaluating masses that may arise from enterochromaffin-like cells, whereas none of the tests may be useful in nonsecreting hindgut tumors.
The types of studies used to detect this type of tumor depend largely on the location of the lesion and the associated symptoms of the patient. Bronchial carcinoid tumors are likely to be discovered on computed tomography (CT) or magnetic resonance imaging (MRI) imaging. Rectal or gastric carcinoids are most likely to be visualized directly by endoscopy procedure, unless they are large enough in size to be detected by more routine imaging. Small intestinal tumors are the most difficult to localize by imaging studies and are usually only found in this manner after they have metastasized to other regions. Fortunately, the majority of pediatric and young adult carcinoid tumors are found incidentally during appendectomy or evaluation for other disease processes. In these cases, once a patient has been diagnosed with a carcinoid tumor, the patient must receive a thorough evaluation, not only of the primary tumor location but also for any potential metastatic disease. Local evaluation usually consists of a CT or MRI of the primary tumor site. Ideally, CT imaging should be done with a multidetector CT because it has high temporal and spatial resolution, high-quality reformatted images, and a precise timing of the scan through bolus-tracking capability. For the liver in particular, the best imaging will include dual-phase imaging with both arterial and portal venous phases. Often, metastatic disease to the liver will show early enhancement with washout during the portal venous phase because the tumor is so hypervascular.32 For metastatic disease, the most common and easy test with an excellent positive predictive value is somatostatin receptor scintigraphy (considered the imaging study of choice, especially in those with gastroenteropancreatic NETs).33 111In-DTPA-octreotide combined with CT (single-photon emission computed tomography/CT) can be used to localize disease anywhere in the body. Recent studies have looked at combining a newer somatostatin analog, 68Ga-DOTA-tyrosine3-octreotide (DOTATOC), with positron emission tomography imaging. This form of imaging has shown a sensitivity of 97%, specificity of 92%, and an accuracy of 96% in patients with suspected NETs imaged with this modality. The detection rate with 68Ga-DOTATOC positron emission tomography/CT is higher than with 111In-DTPA-octreotide single-photon emission computed tomography/CT. Unfortunately, the availability of this test is limited.34
The specific treatment regimen used for carcinoid cancer is influenced by the tumor location, but invariably all these tumors need some sort of surgical resection. The patient’s best chance for cure comes from a complete resection of all known disease. Patients who present with larger tumors, more aggressive features on histology, residual disease, or metastatic disease may require more close monitoring and potentially further treatment. One thing that must be kept in mind when performing a surgical procedure on any patient with known carcinoid tumors is that a “carcinoid crisis” may be induced by anesthesia or significant stress to the patient. Having an experienced anesthesiologist, aware of the potential for a carcinoid crisis is imperative to ensure that the patient is prepared adequately for surgery.
Small appendiceal tumors make up 18% of disease found in pediatric and adolescent patients, and these tumors are typically discovered when the appendix is being removed for some other reason. In cases where the tumor is small (<1.5 cm in size), without atypical or invasive histologic features, and without positive surgical margins, primary appendectomy is a sufficient therapy. However, if the tumor shows more aggressive features (atypical histology, size ≥2 cm) or has positive surgical margins, a second surgery should be performed. In pediatric patients, many surgeons will perform an ileocecal resection, whereas in adult patients most surgeons perform hemicolectomies. In both groups, it is not uncommon to recommend regional lymph node sampling. It is well established that patients with tumors ≥2 cm in size are more likely to have regional or even metastatic spread of disease.
The method of resection of bronchial tumors varies based on the tumor location and surgeon performing the procedure. An earlier review of pediatric bronchial carcinoid tumor patients by Wang et al8 showed that the majority of patients were treated with some variation of a lobectomy (13 of the 17 patients), whereas the others had lesions that were best treated by other means due to their specific anatomic location. Brokx et al35 has recently proposed an initial bronchoscopic treatment for those patients with intraluminal bronchial carcinoids. This approach may be more “tissue sparing” and still leads to a high cure rate from surgery alone. In their treatment of 72 adult patients, 37.5% had a complete response after an initial bronchoscopic treatment strategy, and another 11% had a complete response after a second bronchoscopic treatment. Of these 33 patients, 2 experienced recurrence of their diseases, which were then easily treated by an open surgical procedure.
The use of somatostatin analogs has shown to be of some help in patients with residual disease and significant symptoms of carcinoid syndrome. Treatment regimens vary from subcutaneous injections administered daily to monthly injections of long-acting depopreparations of somatostatin. Interferon-α has also been used in patients with more indolent disease, but the side effects of the therapy are usually poorly tolerated, often leading to a lower quality of life for a patient with a relatively slow-growing tumor.36 Chemotherapy in general is relatively unhelpful for patients with carcinoid tumors. Those who may benefit from therapy include those with a large tumor burden and more aggressive tumors as determined by histology. For example, tumors with higher levels of Ki-67 may respond better to cytotoxic chemotherapy than those with Ki-67 levels <2%. There have been many chemotherapeutic agents tried for treatment in adults; they include 5-fluorouracil, cisplatin, doxorubicin, dacarbazine, and various combinations of these agents. None however, have shown an extended response to treatment. The median length of response to treatment is typically 3 to 6 months.37
Various medical treatments have been tried in adults with residual or metastatic carcinoid disease. One of the most common sites of metastatic disease and greatest source of substance production leading to carcinoid syndrome and future carcinoid heart disease is the liver. There have been several methods proposed to reduce the bulk of tumor that may be present in the liver, ranging from simple tumor excision, liver transplantation, systemic chemotherapy agents, and hepatic embolization. Clinicians may use selective arterial embolization or chemoembolization for patients with significant liver metastases. Chemoembolization has been shown to improve symptoms in more than 50% of patients with relatively mild side effects from the therapy. Difficulty arises when patients have tumor burden of >60% of liver mass by Doppler ultrasound, because a significant amount of tumor necrosis may lead to a compensatory release of vasoactive substances leading to a carcinoid crisis.38,39 Also, the duration of benefit can be quite short, ranging from 4 to 24 months.40,41 One of the most promising therapies for carcinoid tumor treatment involves radionuclear treatment coupled with somatostatin analogs. Many groups have developed different radioactive analogs, coupling octreotide with 111Indium, Yttrium 90 DOTATOC, and 177Lu-octreotate to name a few. Each analog has shown some success in patients with difficult-to-treat disease, but none have been actively studied in pediatric patients.42–44 A phase I study children and young adults who have tumors that are positive for somatostatin receptors by somatostatin receptor scintigraphy is currently underway.
The North American Neuroendocrine Tumor Society recently published guidelines to improve NET disease management. Although these guidelines include specific details for management of well differentiated, poorly differentiated, and more unusual forms of NETs in adults, they can also serve as a great reference to any provider with an unusual pediatric, adolescent, or young adult case.45
Although carcinoid tumors are rare in pediatric and adolescent patients, they do occur and may be associated with significant morbidity. The majority of these patients will be cured completely by surgical resection. These patients with small, localized disease still deserve adequate follow-up to assess for the possibility of recurrence. Disease presentation is often insidious so that it is difficult to get “baseline” levels of typical carcinoid tumor markers to follow long term. For those with more extensive metastatic disease at presentation, aggressive treatment of their tumors with surgical resection when possible, somatostatin analogs, hepatic chemoembolization, and perhaps novel therapeutic agents such as radioactive analogs may be indicated. It is recommended that all patients with carcinoid tumors have a history and physical examination after surgery, with tumor marker monitoring, and appropriate local area imaging studies (CT, MRI). Some patients may require an Octreoscan at diagnosis as well (nonappendiceal tumors). Patients with ≤2 cm appendiceal tumors generally require no further follow-up. Patients with rectal tumors ≥2 cm will require proctoscopy at regular intervals to be determined by individual patient profile. Proctoscopy is recommended at 6 and 12 months, then as clinically indicated. Most other patients with larger tumors or tumors in other locations will require follow-up with history/physical, tumor markers, and/or imaging studies on a regular interval within the first 3 years of diagnosis and subsequently as clinically determined.
Patients of all ages, who have carcinoid tumors, especially in association with carcinoid syndrome, are at risk for carcinoid heart disease and should be monitored appropriately. This is especially so for patients with metastatic disease. Additional imaging recommended for heart disease includes triple phase technique CT and MRI. In the absence of any evidence of metastatic disease, observation, screening for tumor markers, and imaging are recommended 3 to 6 months, or till disease shows up. Enrollment in clinical trials is a palliative measure that remains an option for patients with unresectable metastatic disease.
The sporadic occurrence of carcinoid tumors make primary prevention difficult, with logistic and cost implications associated with any attempts at screening for this rare cancer. Similarly, their occurrence in unusual sites results in missed diagnoses, inadvertent neglect and therefore delayed intervention.
In pediatric and young adult patients, it is rare for the provider to suspect carcinoid cancer before the tumor has been resected, so that at best, secondary prevention may be achieved with complete resection of tumors that are localized at diagnosis. Knowledge of the association of carcinoid tumors with MEN1 may aid clinicians in anticipating carcinoid tumors and institute early interventions. Genetic counseling is of relevance in this group of patients. In patients with functioning carcinoid tumors with the classic carcinoid syndrome, long-acting release octreotide is recommended for chronic prevention.
With the increased awareness of medical staff and potential increase in incidence of carcinoid tumors, clinicians need to be knowledgeable about diagnosis, treatment, and management options for these patients with a tumor that sometimes presents a challenging management. Clinical trials remain an effective means to improve management of tumors like carcinoids.
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