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Childhood Carcinoid Tumor

Carcinoid tumors can be encountered in all age groups. They are accompanied by a polymorphic clinical presentation and can originate from the gut wall, lungs, kidneys, thymus, ovaries, prostate, testis, pancreas, liver, bronchus or mediastinum. Localized disease implicates a good prognosis, but they have a high potential for metastasis and metastatic cases are more difficult to treat.


Presentation

The tumor in itself, as well as metastatic disease cause symptoms, ranging up to the carcinoid syndrome. Most pediatric cases of carcinoid tumor originate in the gut. Appendicular tumors can be asymptomatic (especially when they are non-functioning) and discovered incidentally or can cause acute appendicitis. Pediatric intestinal carcinoid tumors cause abdominal pain due to intestinal obstruction or kinking or mesentery fibrosis. Abdominal pain can also be caused by appendicular perforation [1].

Clinical signs can also be caused by the hormones and other substances that the tumor secretes, such as bradykinin, serotonin, vasoactive intestinal peptide, 5-hydroxytryptophan and histamine or adrenocorticotropic hormone. Frank carcinoid syndrome, the most severe presentation of a carcinoid tumor is very infrequent in children [2]. It occurs more often in children with functioning tumors that have metastasized to the liver and it consists of a constellation of signs and symptoms, such as cutaneous flushing of the head and neck, tachycardia, and palpitations, lacrimation, diaphoresis, hypersalivation, blood pressure disturbances (hypertension or hypotension), abdominal pain, diarrhea and decreased mental state. Flushing can be accompanied by edema and itching and the erythema can progress to cyanosis. The duration of these episodes is initially short (minutes) but as the disease progresses, they may last up to several hours.

The stools may range from watery diarrhea to steatorrhea and patients may suffer from malabsorption. Bronchial carcinoid tumors may cause asthma-like symptoms, such as wheezing, dyspnea, cough or shortness of breath [3] and may be accompanied by signs of Cushing syndrome [4].

The heart may also be affected by the disease. Carcinoid tumors may cause endocardial fibrosis often involving the right cavities and the tricuspid valvular apparatus. Other valves, such as the pulmonary may also be involved, resulting in stenosis or regurgitation. Disease progression may cause heart failure.

Patients sometimes also complain about joint pain secondary to arthritis, sexual dysfunction or visual abnormalities caused by vascular occlusion. Skin hyperkeratosis can occur, but it is considered to be an uncommon finding, as is laryngeal involvement [5].

Patients affected by Peutz-Jeghers syndrome or multiple endocrine neoplasia type 1 can develop a carcinoid tumor. Also, secondary malignancies such as hepatocellular carcinoma can be encountered in carcinoid tumor patients [6].

Fever
  • These leukemias can cause bone and joint pain, fatigue, weakness, pale skin, bleeding or bruising, fever, weight loss, and other symptoms.[cancer.org]
  • However, parents must watch for signs of problems, like fever, nausea, vomiting, or diarrhea. A child with a high fever should see a doctor right away.[kidshealth.org]
  • Neoplastic fever: a neglected paraneoplastic syndrome. PMID 15864658 Rees JH (2004). “PARANEOPLASTIC SYNDROMES: WHEN TO SUSPECT, HOW TO CONFIRM, AND HOW TO MANAGE”. J. Neurol. Neurosurg.[ja.wikipedia.org]
Diarrhea
  • The stools may range from watery diarrhea to steatorrhea and patients may suffer from malabsorption.[symptoma.com]
  • In addition to the use of octreotide or lanreotide to control diarrhea, conventional anti-diarrheal medications such as Lomotil and Imodium may be helpful. Cyproheptadine (Periactin) may also help the diarrhea as well as flushing.[carcinoid.org]
  • However, parents must watch for signs of problems, like fever, nausea, vomiting, or diarrhea. A child with a high fever should see a doctor right away.[kidshealth.org]
  • Diarrhea and malabsorption (84%): Watery, frothy, or bulky stools, gastrointestinal (GI) bleed or steatorrhea; may or may not be associated with abdominal pain, flushing, and cramps Cardiac manifestations (60%): Valvular heart lesions, fibrosis of the[emedicine.medscape.com]
Abdominal Pain
  • Pediatric intestinal carcinoid tumors cause abdominal pain due to intestinal obstruction or kinking or mesentery fibrosis. Abdominal pain can also be caused by appendicular perforation.[symptoma.com]
  • Signs and symptoms seen in larger tumors may include the following: Periodic abdominal pain: Most common presentation for a small intestinal carcinoid; often associated with malignant carcinoid syndrome Cutaneous flushing: Early and frequent (94%) symptom[emedicine.medscape.com]
  • They can cause intermittent abdominal pain and then a change in bowel habits that may lead to intestinal obstruction.[carcinoid.org]
Steatorrhea
  • The stools may range from watery diarrhea to steatorrhea and patients may suffer from malabsorption.[symptoma.com]
  • […] with an unpleasant warm feeling, itching, rash, sweating, palpitation, upper-body erythema and edema, salivation, diaphoresis, lacrimation, and diarrhea Diarrhea and malabsorption (84%): Watery, frothy, or bulky stools, gastrointestinal (GI) bleed or steatorrhea[emedicine.medscape.com]
Regurgitation
  • Other valves, such as the pulmonary may also be involved, resulting in stenosis or regurgitation. Disease progression may cause heart failure.[symptoma.com]
Hypersalivation
  • […] occurs more often in children with functioning tumors that have metastasized to the liver and it consists of a constellation of signs and symptoms, such as cutaneous flushing of the head and neck, tachycardia, and palpitations, lacrimation, diaphoresis, hypersalivation[symptoma.com]
Hypertension
  • Patients may experience periodic abdominal pain, diarrhea, cutaneous flushing affecting the head and the neck, accompanied by an itching sensation, sweating, diaphoresis, lacrimation and salivation; palpitations, tachycardia and hypertension; signs of[symptoma.com]
  • Some children also may have: nausea stomach pain high blood pressure (hypertension) blood in the pee loss of appetite a fever Even though Wilms tumors often are large when found, most have not spread to other areas of the body.[kidshealth.org]
  • […] stools, gastrointestinal (GI) bleed or steatorrhea; may or may not be associated with abdominal pain, flushing, and cramps Cardiac manifestations (60%): Valvular heart lesions, fibrosis of the endocardium; may lead to heart failure with tachycardia and hypertension[emedicine.medscape.com]
Tachycardia
  • It occurs more often in children with functioning tumors that have metastasized to the liver and it consists of a constellation of signs and symptoms, such as cutaneous flushing of the head and neck, tachycardia, and palpitations, lacrimation, diaphoresis[symptoma.com]
  • […] frothy, or bulky stools, gastrointestinal (GI) bleed or steatorrhea; may or may not be associated with abdominal pain, flushing, and cramps Cardiac manifestations (60%): Valvular heart lesions, fibrosis of the endocardium; may lead to heart failure with tachycardia[emedicine.medscape.com]
Palpitations
  • It occurs more often in children with functioning tumors that have metastasized to the liver and it consists of a constellation of signs and symptoms, such as cutaneous flushing of the head and neck, tachycardia, and palpitations, lacrimation, diaphoresis[symptoma.com]
  • […] presentation for a small intestinal carcinoid; often associated with malignant carcinoid syndrome Cutaneous flushing: Early and frequent (94%) symptom; typically affects head and neck; often associated with an unpleasant warm feeling, itching, rash, sweating, palpitation[emedicine.medscape.com]
Cyanosis
  • Flushing can be accompanied by edema and itching and the erythema can progress to cyanosis. The duration of these episodes is initially short (minutes) but as the disease progresses, they may last up to several hours.[symptoma.com]
Arthritis
  • Patients sometimes also complain about joint pain secondary to arthritis, sexual dysfunction or visual abnormalities caused by vascular occlusion.[symptoma.com]
Lacrimation
  • It occurs more often in children with functioning tumors that have metastasized to the liver and it consists of a constellation of signs and symptoms, such as cutaneous flushing of the head and neck, tachycardia, and palpitations, lacrimation, diaphoresis[symptoma.com]
  • […] carcinoid syndrome Cutaneous flushing: Early and frequent (94%) symptom; typically affects head and neck; often associated with an unpleasant warm feeling, itching, rash, sweating, palpitation, upper-body erythema and edema, salivation, diaphoresis, lacrimation[emedicine.medscape.com]
Flushing
  • Flushing can be accompanied by edema and itching and the erythema can progress to cyanosis. The duration of these episodes is initially short (minutes) but as the disease progresses, they may last up to several hours.[symptoma.com]
  • After a while the flush may become persistent in some individuals and may not be felt or noticed by them. The diarrhea may also be chronic and weight loss can occur.[carcinoid.org]
  • Signs and symptoms seen in larger tumors may include the following: Periodic abdominal pain: Most common presentation for a small intestinal carcinoid; often associated with malignant carcinoid syndrome Cutaneous flushing: Early and frequent (94%) symptom[emedicine.medscape.com]
Flushing
  • Flushing can be accompanied by edema and itching and the erythema can progress to cyanosis. The duration of these episodes is initially short (minutes) but as the disease progresses, they may last up to several hours.[symptoma.com]
  • After a while the flush may become persistent in some individuals and may not be felt or noticed by them. The diarrhea may also be chronic and weight loss can occur.[carcinoid.org]
  • Signs and symptoms seen in larger tumors may include the following: Periodic abdominal pain: Most common presentation for a small intestinal carcinoid; often associated with malignant carcinoid syndrome Cutaneous flushing: Early and frequent (94%) symptom[emedicine.medscape.com]
Skin Lesion
  • More infrequent signs: mental disturbances and pellagra with scale-like skin lesions. Useful laboratory tests include the determination of histamine, catecholamines, serotonin, chromogranin-A and 5-hydroxyindoleacetic acid.[symptoma.com]
  • lesions, diarrhea and mental disturbances Carcinoid crisis can be the most serious symptom of the carcinoid tumors and life threatening.[emedicine.medscape.com]
Hyperkeratosis
  • Skin hyperkeratosis can occur, but it is considered to be an uncommon finding, as is laryngeal involvement. Patients affected by Peutz-Jeghers syndrome or multiple endocrine neoplasia type 1 can develop a carcinoid tumor.[symptoma.com]
Confusion
  • Some children, however, do experience fast heartbeats and palpitations, episodes of face and neck redness and warm feeling or itching (flushing), impaired breathing, abdominal pain, diarrhea, restlessness, dizziness, confusion, or blood pressure variations[symptoma.com]
  • […] are worse when waking up in the morning and go away within a few hours Headaches that get worse with coughing or exercise, or with a change in body position Headaches that occur while sleeping and with at least one other symptom such as vomiting or confusion[medlineplus.gov]
  • First, and most important, each of these syndromes, though having different features, can prominently include flushing and/or diarrhea and be confused with Carcinoid Syndrome.[carcinoid.org]
Sexual Dysfunction
  • Patients sometimes also complain about joint pain secondary to arthritis, sexual dysfunction or visual abnormalities caused by vascular occlusion.[symptoma.com]

Workup

Childhood carcinoid tumor workup includes blood and urine tests, as well as several imaging methods. Certain tests such as 5-hydroxyindoleacetic acid [7], histamine, catecholamines, serotonin, chromogranin, neuropeptide K and 5-5-hydroxytryptamine have been proved useful, but the diagnosis remains difficult because the level of these substances is not always elevated. False positive results can be eliminated by avoiding serotonin rich foods for two days before urine collection.

Imaging methods that can be used consist of simple radiography, contrast radiography, angiography, computed tomography (CT), magnetic resonance imaging, scintigraphy [8], positron emission tomography (PET) and radionuclide imaging (using yttrium and indium-111 diethylenetriamine pentaacetic acid (111 In-DTPA) as radiotracers), depending on the location of the suspected tumor. PET-CT is considered to have poor sensitivity but good specificity, while scintigraphy combined with computed tomography is optimum for chest tumors discovery. Hepatic lesions can be diagnosed via computed tomography, while this method is relatively unreliable for small bowel tumors. The large bowel can be explored via colonoscopy and the diagnosis is relatively easy to establish. This technique, as well as the upper digestive endoscopy, offers the advantage of being able to obtain biopsies. Bone metastasis is not infrequent and can be diagnosed by technetium-99m bone scanning. Extra-abdominal disease can be diagnosed by scintiscan with Octreotide [9].

Hepatocellular Carcinoma
  • Also, secondary malignancies such as hepatocellular carcinoma can be encountered in carcinoid tumor patients. Childhood carcinoid tumor workup includes blood and urine tests, as well as several imaging methods.[symptoma.com]
  • Gastric carcinoid tumor in association with hepatocellular carcinoma: a case report. South Med J. 2008 Nov. 101(11):1170-2. [Medline]. [Guideline] Dreijerink KM, Roijers JF, van der Luijt RB, et al.[emedicine.medscape.com]

Treatment

The first treatment choice of carcinoid tumors is represented by surgical excision. This is more or less feasible, depending on the location of the pathological process. Appendicular tumors are easy to extract by appendectomy, while block resection is needed in intestinal carcinoids. When the margins of the resection piece are not tumor free, a larger portion of the organ should be excised. Adjacent lymph nodes must also be averted in this instance and the need for reoperation cannot be excluded. Large tumors are infrequent in the pediatric age groups. Bronchial carcinoids should be resected by classic surgery, not by bronchoscope interventional procedures [10]. Endoscopic procedures may be used in adults with rectal tumors, when facing a small tumor located in the mucosa, but even in this age group classical surgical procedures are preferred due to improved survival [11].

Patients with hepatic tumors that cannot be evacuated may benefit for a short period of time from hepatic artery surgical ligation or hepatic artery chemoembolization or cryotherapy. In cases where surgery or interventional procedures are not an option, chemotherapy remains the only alternative. Several chemotherapeutic agents, such as 5-Fluorouracil, Cisplatin, Streptozotocin, Doxorubicin, Etoposide, Dacarbazine and Actinomycin D are widely used, at least for palliative purposes. Octreotide provides symptom decrease, but more studies are needed regarding stunted linear growth and survival improvement. When associated with everolimus, octreotide shows superior results [12]. Experimental data regarding treatment with octreotide attached to a radioactive load like yttrium or indium is currently available and showing positive results.

Prognosis

Exact data regarding the prognosis of childhood carcinoid tumors is unavailable, but the outcome of properly treated appendix located tumor cases seems to be favorable. Tumors that are found in other locations tend to be larger and to have already spread at the time of diagnosis, therefore their prognosis is grimmer. Also, the probability of recurrence is higher in these cases. Metastases are more frequent in patients with periappendiceal or mesoappendix fat invasion [13], but all neuroendocrine tumors are considered to have a high risk for metastases in general [14].

Etiology

Childhood carcinoid tumors derive from stem cells located mainly in the intestinal wall, but the disease may also originate in the respiratory, reproductive or urinary systems, in the mediastinum or in other parts of the digestive tract. The tumors may be argentaffin positive or negative. The cause of tumor development remains unknown, but chromosomal abnormalities are suspected. Reported cases describe chromosomal abnormalities like allelic losses or numerical imbalances. Metastatic cells may lose chromosomal arms 16q, 11q or 18q and gain 4p or losses may be more discrete, involving only certain bands: 16q21-qter, 18q22-qter or 11q22-q23. Homeobox gene Hoxc6 may also be involved in carcinoid etiology [15].

Epidemiology

Carcinoid tumors are more frequent in adults than children and adolescents. Still, in the pediatric age group, carcinoid tumors represent the most frequent type of gastrointestinal epithelial tumor [16]. Their incidence is reported to be around 0.08% of pediatric cancers. 2 to 5 in 100 pediatric appendectomies incidentally discover the presence of a carcinoid [17], but the disease can also be found during a laparotomy [18]. In adults, the incidence is thought to be steadily increasing [19], and this has been speculated to be due to more extensive proton pump inhibitors use.

Sex distribution
Age distribution

Pathophysiology

Carcinoid tumors may have a secretory activity and/or other, mechanical consequences. They may bulge into the intestinal lumen appearing as nodules or polyps that may be ulcerated or not. They may cause vascular sclerosis, leading to intestinal or appendicular ischemia. The secretory activity consists of multiple substance excretion: somatostatin, gastrin, glucagon, alpha-1-antitrypsin, atrial natriuretic polypeptide, catecholamines, dopamine, histamine, insulin, pancreastatin, neuropeptides, serotonin, vasoactive intestinal polypeptide, and so on.

Prevention

Effective prevention methods for childhood carcinoid tumors do not exist at this time. Smoking is thought to represent a risk factor for this disease, so children and adolescents should be strongly advised not to start this habit.

Summary

Pediatric carcinoid tumor patients may be entirely asymptomatic or they may present with various symptoms and clinical signs. Their complaints may be due to the tumor itself, to the substances secreted by the tumor or to its metastases. Patients may experience periodic abdominal pain, diarrhea, cutaneous flushing affecting the head and the neck, accompanied by an itching sensation, sweating, diaphoresis, lacrimation and salivation; palpitations, tachycardia and hypertension; signs of heart failure caused by endocardial fibrosis or valvular lesions; respiratory symptoms may include cough, dyspnea and wheezing. More infrequent signs: mental disturbances and pellagra with scale-like skin lesions.

Useful laboratory tests include the determination of histamine, catecholamines, serotonin, chromogranin-A and 5-hydroxyindoleacetic acid. The location of the tumor can be determined using one or more imaging methods: plain radiographs, ultrasound, endoscopic ultrasound, computed tomography, magnetic resonance imaging, contrast digestive radiography, angiography, scintigraphy, positron emission tomography or radionuclide imaging. Upper and lower digestive endoscopy, as well as bronchoscopy may be necessary in some cases.

Surgical excision is the best therapeutic measure in childhood carcinoid tumor. Metastasis is treated by chemotherapy using etoposide, doxorubicin, dacarbazine, 5-fluorouracil, cisplatin or streptozocin. Interferon alfa, radioactive somatostatin analogs and other experimental agents show promising results.

Patient Information

Childhood carcinoid tumor is a very rare disease, much more rare than the carcinoid tumor found in adults. The tumor is usually located in the appendix or in the intestines, but cases of liver, lungs or pancreas tumors have also been described. The carcinoid grows slowly and may cause no symptoms. Some children, however, do experience fast heartbeats and palpitations, episodes of face and neck redness and warm feeling or itching (flushing), impaired breathing, abdominal pain, diarrhea, restlessness, dizziness, confusion, or blood pressure variations. The physician will conduct a clinical examination and may order several blood tests, to look for substances that may be produced by the tumor and eliminated in the bloodstream. He or she can also ask that a 24 hour urine probe is collected and analyzed. If suspicion persists, the location of the tumor must be established and this is accomplished using imaging methods and procedures. An upper or lower digestive endoscopy or a bronchoscopy may be needed, or the doctor will ask for a computer tomography, a magnetic resonance imaging exam, a radiography, an echography or other, more sophisticated tests: radionuclide imaging, scintigraphy, angiography or positron emission tomography.

The tumor is best removed from the body by a surgeon. However, by the time of diagnosis it may have already spread to other locations. These secondary tumors, called metastases, may not be resectable and, in this case, the patient must undergo chemotherapy. Even if properly treated, the tumor can reappear after some time.

References

Article

  1. Bethel CAI, Bhattacharyya N, Hutchinson C, et al. Alimentary tract malignancies in children. J Ped Surg 1997;32:1004-9.
  2. Robertson RG, Geiger WJ, Davis NB. Carcinoid tumors. Am Fam Physician 2006; 74:429–434
  3. Uskul BT, Turker H, Dincer IS, Melikoglu A, Tasolar O, Tahaoglu C. A primary tracheal carcinoid tumor masquerading as chronic obstructive pulmonary disease. South Med J. 2008; 101(5):546-9.
  4. Atoui R, Almarzooqi S, Saleh W, Marcovitz S, Mulder D. Bronchopulmonary carcinoid tumor associated with Cushing syndrome. Ann Thorac Surg. 2008; 86(5):1688-90.
  5. Lin ZM, Chang YL, Lee CY, Wang CP, Hsiao TY. Simultaneous typical carcinoid tumour of larynx and occult papillary thyroid carcinoma. J Laryngol Otol. 2008;122(1):93-6.
  6. Petrou A, Papalambros A, Papaconstantinou I, et al. Gastric carcinoid tumor in association with hepatocellular carcinoma: a case report. South Med J. 2008;101(11):1170-2.
  7. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med. 1999;18. 340(11):858-68.
  8. Monsieurs MA, Thierens HM, Vral A, et al. Patient dosimetry after 131I-MIBG therapy for neuroblastoma and carcinoid tumours. Nucl Med Commun. 2001;22(4):367-74.
  9. Pasieka JL, McKinnon JG, Kinnear S, et al. Carcinoid syndrome symposium on treatment modalities for gastrointestinal carcinoid tumors: symposium summary. Can J Surg 2001;44:25-32.
  10. Fauroux B, Aynie V, Larroquet M, et al. Carcinoid and mucoepidermoid bronchial tumours in children. Eur J Pediatr. 2005; 164(12):748-52.
  11. Givi B, Pommier SJ, Thompson AK, Diggs BS, Pommier RF. Operative resection of primary carcinoid neoplasms in patients with liver metastases yields significantly better survival. Surgery. 2006; 140(6):891-7; discussion 897-8.
  12. Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011; 378(9808):2005-12.
  13. Gouzi JL, Laigneau P, Delalande JP, et al. Indications for right hemicolectomy in carcinoid tumors of the appendix. Surg Gynecol Obstet 1993;176:543-7.
  14. Broaddus RR, Herzog CE, Hicks MJ. Neuroendocrine tumors (carcinoid and neuroendocrine carcinoma) presenting at extraappendiceal sites in childhood and adolescence. Arch Pathol Lab Med 2003; 127:1200–3.
  15. Fujiki K, Duerr EM, Kikuchi H, et al. Hoxc6 is overexpressed in gastrointestinal carcinoids and interacts with JunD to regulate tumor growth. Gastroenterology. 2008; 135(3):907-16, 916.e1-2.
  16. Copron CA, Black T, Herzog CE, et al. A half century experience with carcinoid tumors in children. Am J Surg 1995;170:606-8.
  17. Doede T, Foss HD, Waldschmith J. Carcinoid tumors of the appendix in children: epidemiology, clinical aspects and procedure. Eur J Ped Surg 2000;10:372-7.
  18. Parkes SE, Muir KR, Al Sheyyab M, et al. Carcinoid tumors of the appendix in children 1957-1986: incidence, treatment and outcome. Br J Surg 1993;80:502-4.
  19. Ellis L, Shale MJ, Coleman MP. Carcinoid tumors of the gastrointestinal tract: trends in incidence in England since 1971. Am J Gastroenterol. 2010;105 (12):2563-9.

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Last updated: 2019-07-11 20:33