An 18 month old female presents to the office for her well-child examination. A third year medical student is allowed to take the history and perform the initial examination. On a routine ophthalmoscopy exam, the student notices that the child does not have a red reflex in the right eye. This is reported to the physician who confirms the exam finding. There is no history of weight loss, anorexia, crossed eyes, fever, or irritability.
Exam: VS T 37.0, P 110, R 26, BP 92/42. Height, weight, head circumference are all at the 40th percentile. She is alert and active. Leukocoria is present in the right eye. A normal red reflex observed in the left eye. Pupils are equal and reactive. The eyes are conjugate. Facial function is good. The remainder of the physical examination is negative.
Clinical Course: The child is referred to an ophthalmologist. An ophthalmoscopy exam performed under general anesthesia reveals a tumor in the posterior pole of the right eye. An orbital CT demonstrates that the tumor is confined to the globe (i.e., no spread outside the eye). Since the tumor is small it is treated with laser photoablation. Careful follow ups are scheduled to monitor for recurrences or development of secondary tumors.
This chapter will cover the four most common malignant solid tumors of childhood: retinoblastoma, osteosarcoma, neuroblastoma and Wilms' tumor.
Retinoblastoma is a slow growing malignant tumor of the retina that may be confined to the eye for up to months or even years. In the United States it is the seventh most common pediatric malignancy (1). About 90% of cases occur before the age of 5. Bilateral tumors occur at an earlier age than unilateral tumors. The mean age of diagnosis in bilateral tumors is 12 months whereas unilateral tumors occur at a mean of 24 months of age (2).
The exact molecular pathogenesis has been elucidated for retinoblastoma, which results when there is a mutation in the retinoblastoma gene found on the long arm of chromosome 13 at band 14 (13q14). The gene is a tumor suppressor gene that is involved in regulating the cell cycle. In order for retinoblastoma to manifest, both Rb alleles must be mutated (the essence of the two hit hypothesis). In the hereditary form of retinoblastoma, the individual inherits a mutant Rb gene from the germ line. Another mutation must occur in a somatic retinal cell in order for retinoblastoma to manifest itself. In the nonhereditary form, both mutations must occur in the same somatic retinal cell. When both are mutated, defective intracellular transcription and unchecked cell proliferation leads to malignant transformation (3).
If it is not detected during the routine ophthalmoscopic exam or suspected due to family history, the first presenting sign may be a white pupillary reflex called leukocoria, which is frequently noted on flash photography as a white reflex instead of the usual flash photography "red eye". Parents will often notice this and bring this to the attention of the child's physician, usually after a significant delay. This sign is present in approximately 60% of the patients and is attributed to the formation of a central posterior pole tumor. Another 20% may present instead with strabismus due to tumor involvement of the macula. Retinal detachment may also be detected. The patient may also present with a red, painful eye, poor vision, unilateral pupil dilation, heterochromia (the iris color of each eye are not the same), or nystagmus. If the tumor is in an advanced stage, the patient may present with constitutional symptoms and signs as well as neurologic defects, orbital mass, proptosis, or blindness (1).
Leukocoria is difficult to detect during a routine exam. If it is not detected during the exam, yet the parent reports an abnormal pupil, a referral should still be made to an ophthalmologist. Ophthalmoscopy done by a specialist through dilated pupils is the most important test performed to diagnose retinoblastoma. If the child is young, this must be done under general anesthesia. Parents and siblings should also have a dilated ophthalmoscopic examination to rule out unsuspected or dormant tumors (2). A CT scan can also be used to detect intraocular calcification, optic nerve involvement, and extraocular extension of the tumor (4).
Careful examination is required to rule out any other disorders that resemble retinoblastoma. The differential for a mass should include astrocytic hamartomas and granulomas of Toxocara canis, Coat's disease, retinopathy of prematurity, and persistent hyperplastic primary vitreous should be suspected when there is retinal detachment (1).
Treatment options for retinoblastoma include enucleation, external beam radiation, plaque radiation, laser photoablation, thermotherapy, cryotherapy, and chemotherapy. The choice of treatment will ultimately depend on the size, location, and extent of the tumor, whether it is bilateral or unilateral, if there is visual potential, or if extraocular disease or metastasis is present.
Enucleation is performed on large unilateral tumors that have led to severe visual impairment. Individuals with optic nerve invasion, secondary glaucoma, and seeding into the pars planta have also undergone enucleation (5). In the past, enucleation was performed on the eye with the most advanced disease in bilateral tumors. However, chemotherapy and local therapy have successfully replaced this practice (2).
In the past, standard therapy for the least involved eye in bilateral tumors has been external beam radiation. However, long term consequences such as cataract formation, radiation retinopathy, optic neuropathy, and the development of secondary tumors has lead to the search for alternative treatments. Radioactive plaque therapy (or brachytherapy, in which radioactive seeds are implanted close to the tumor) has since been employed to restrict the area of the orbit exposed to radiation. This procedure has reduced the harsh consequences of radiation. Brachytherapy has also been used to treat unilateral tumors. Small tumors have also responded well to other types of local therapy, in particular cryotherapy and laser photoablation (5).
Chemotherapy is also a common therapy used in the treatment of retinoblastoma. In the past, it was used basically to treat advanced extraocular disease. Today, it is used when there is extraocular extension, metastasis, and positive cerebrospinal fluid findings. It is also used if accidental dissemination of tumor cells has occurred. For example if a previous intraocular procedure was done before the diagnosis of retinoblastoma was made, the patient may be treated prophylactically with chemotherapy (5).
The extent of optic nerve involvement, extension of the tumor, and choroidal involvement directly influences mortality. The outcome has been excellent in individuals suffering from unilateral intraocular tumors. Individuals with optic nerve extension beyond the lamina cribrosa have only a 40% 5 year survival rate (4). A cure rate of greater than 90% has been seen after enucleation of unilateral intraocular tumors. The use of local ablation with or without chemotherapy is also usually successful (3).
Patients with a germ line mutation of the Rb gene fare a worse outcome. These are individuals who were born with one mutant Rb gene and sustained a subsequent spontaneous mutation in a somatic Rb gene. They have poor survival rates and have a reduced likelihood of salvage of vision. If they survive retinoblastoma they are at an increased risk for developing a secondary cancer. More than 90% will develop a secondary cancer within 32 years after treatment (1). This is because the retinoblastoma gene is linked to nonocular tumors, most notably osteosarcoma (1).
Osteosarcoma is a malignant mesenchymal tumor of bone with resultant osteoid formation. It is the third most common cancer in children and adolescents (6). It has a bimodal incidence with the first peak occurring in the second decade of life and the second peak occurring in the elderly. It is more common in boys than in girls. The common sites of involvement are the metaphyseal regions of the distal femur, proximal tibia, and proximal humerus (7).
The exact cause of osteosarcoma is unknown, but it has been linked to a variety of syndromes and genetic changes. Most notably, it has been strongly correlated with a germ line mutation of the Rb gene. Patients with retinoblastoma have a significantly increased risk for the development of osteosarcoma. If these individuals were treated with radiation, their susceptibility increases further (7). Alkylating agents and other antineoplastic drugs, have also been reported to increase the risk of developing this neoplasm. Individuals suffering from Li-Fraumeni syndrome, a familial cancer syndrome associated with a germ line mutation, are also predisposed (8).
Patients usually present with pain and swelling most commonly at the knee. The pain may be intermittent and most commonly occurs at night causing it to be often dismissed as growing pains. Since individuals afflicted with this disease are commonly going through their "growth spurt", this conclusion seems rational. It may further be mistaken by the patient as a sports injury. However, not all patients present with a history of trauma. Physicians must take care not to make the same assumptions. Additional clinical findings may help them distinguish this disease from benign growing pains. These findings include a palpable mass, limited range of motion, tenderness, and warmth (8). However, since none of these findings may be present initially, an imaging study is often necessary to diagnose osteosarcoma during its earliest stage.
The diagnosis of osteosarcoma can be made on: x-ray of the affected bone, MRI, CT scan, radionuclide bone scan, and biopsy. Radiographs may display a mixed lytic and blastic lesion. In more advanced cases, a sunburst pattern of new bone formation and lifting of the bony cortex may create what is called a Codman triangle (4). An MRI of the lesion and the entire bone is done to evaluate the tumor's proximity to nerves and blood vessels as well as its extension into a joint or soft tissue. CT of the chest, and bone scintigraphy detects sites of metastasis (6). After all of these procedures are done, a biopsy can be performed to make the definitive diagnosis. Together, these procedures should help to differentiate osteosarcoma from other bone disorders such as histiocytosis, Ewing's sarcoma, lymphoma, and osteomyelitis (8).
In the past, osteosarcoma was treated with surgery alone. However, the survival rate was poor even for nonmetastatic cases, since most patients have non-detectable micrometastases at presentation. Surgical treatment combined with chemotherapy has greatly improved the survival rate. Treatment options available today include chemotherapy, amputation, and limb salvage procedures (7).
Previously, surgical treatment meant amputation of the affected bone. The bone would be amputated 7 cm proximal to the proximal border of the tumor to minimize recurrence. The patient would then undergo chemotherapy. However, with the advent of even more effective chemotherapeutic agents, limb salvage treatment is the new therapeutic approach to osteosarcoma. The patient undergoes preoperative chemotherapy to induce primary tumor necrosis and treat micrometastatic disease (6). A block excision of the tumor and prosthetic replacement is then performed (7). Contraindications for limb salvage therapy include involvement of a neurovascular bundle by the tumor, immature skeletal age (especially for the lower limb), infection in the region of the tumor, and extensive muscle involvement that would result in poor functionality (4).
This multi-agent approach has greatly improved survival rates. Approximately 75% of patients with nonmetastatic osteosarcoma of the extremity are cured. Even individuals with lung metastases have shown a 20% to 30% cure rate when treated aggressively with chemotherapy and resection of lung nodules (8). This is an improvement because pulmonary metastasis has been the major obstacle in curing patients with osteosarcoma.
Neuroblastoma is a neoplasm of childhood that arises from neural crest cells involved in the development of sympathetic nervous tissue. It is the most common extracranial solid tumor of childhood, occurring at a rate of 1 case per 10,000 persons. Young children are the primary targets, with the median age of diagnosis occurring at 2 years of age. It rarely occurs in children over 10 years of age and it has a slight predilection for boys (2).
The exact cause of neuroblastoma is unknown, but it has been associated with various disorders and mutations. It has been tied to disorders that involve neural crest development such as Hirschsprung's disease and neurofibromatosis type I. It has also been linked with several different types of genetic changes. These changes include n-myc proto-oncogene amplification, chromosome 1p deletion and chromosome 17q gain (9). It is believed that the 1p deletion and 17q gain are the result of an unbalanced translocation between these two sites (10). The exact role of these changes in the pathogenesis of neuroblastoma has not been elucidated.
Neuroblastoma develops from sympathetic neuroblasts anywhere along the sympathetic chain ganglia or in the adrenal medulla. Spontaneous malignant transformation is believed to occur when sympathetic neuroblasts fail to differentiate. When there is complete failure of differentiation, a neuroblastoma forms.
Primary tumors occur 50% in the adrenal gland, 30% in retroperitoneal sympathetic ganglia, and 20% in cervical and thoracic ganglion (9). The patient's clinical presentation depends on the location of the primary tumor, the size of the tumor, and if it has metastasized. The typical constitutional symptoms of cancer, fever, general malaise, and pain, are present. Complicating the patient's clinical presentation is the fact that approximately 75% of patients will present with metastatic disease at the time of diagnosis. Common sites of metastasis are lymph nodes, bone marrow, liver, skin, orbit, or bone (especially facial bones, skull, and appendicular bone) (2).
Adrenal and retroperitoneal tumors present as an abdominal mass extending from the flank to the midline of the abdomen. The mass is usually firm, irregular, and nontender. If the mass begins to enlarge and extend further in the cavity, abdominal distention, anorexia and weight loss occur. The mass may also be a result of hepatomegaly due to tumor metastasis, so physicians must take care not to miss this diagnosis. Retroperitoneal tumors may extend into the paraspinal area and compress on the spinal cord. Thoracic tumors may compress the spinal cord and cause paraplegia. Lower lumbar tumors may cause cauda equina syndrome (10).
Thoracic and cervical ganglion may also compress on surrounding structures. Thoracic masses may be an incidental finding on a chest x-ray done to evaluate dyspnea or other upper respiratory problems. A cervical tumor presents as a hard, fixed mass associated with Horner's syndrome or tracheal compression (10). These patients may present with myosis, ptosis, anhydrosis, flushing, and apparent enophthalmos.
On the initial visit, the patient may also present with bone or ocular problems that indicate metastasis to these regions. The bone metastasis may manifest as bone pain with refusal to walk and reported tenderness, swelling, or the finding of a localized lump. If the tumor extends into the marrow, bone marrow suppression may occur. This manifests as anemia and weakness. Periorbital metastasis is associated with orbital ecchymosis and proptosis, also described as "raccoon eyes" (10).
Clinical manifestations may also be a result of substances released from the tumors. Release of vasoactive intestinal peptide (VIP) may cause intractable secretory diarrhea leading to hypokalemia and dehydration. Release of catecholamines from the tumors is rare and may cause hypertension, tachycardia, palpitations, profuse sweating, and flushing (9). Another mysterious syndrome associated with neuroblastoma is opsomyoclonus (also called opsoclonus). This syndrome consists of myoclonic jerks and random eye movements sometimes associated with cerebellar ataxia. It is sometimes called the dancing eyes and dancing feet syndrome because of its physical presentation. The exact mechanism is unknown but hypotheses implicate either a peptide produced by the tumor or immunologic cross reactivity between the tumor and cerebellar neurons (10).
Bone pain may resemble symptoms seen in rheumatoid arthritis, rheumatic fever, osteomyelitis, and acute leukemia. Abdominal masses are also present in Wilms' tumor, lymphoma, mesenteric cysts, hydronephrosis, and splenomegaly. Intractable diarrhea may be due to malabsorptive states (11).
If the historical and physical findings lead to the suspicion of neuroblastoma, a complete blood count, urinalysis, and imaging studies should be done. A CBC may show anemia and thrombocytopenia indicating extension into the bone marrow. Special urine chemistry may pick up catecholamine metabolites such as homovanillic acid (HVA) and vanillylmandelic acid (VMA), break down products of the catecholamines secreted by the tumor. The skeletal survey may discover bone metastases. MRI may also detect bone metastases as well as intraspinal tumors (11). At initial presentation, ultrasound is useful for diagnosing intra-abdominal tumors and can display calcifications (11), but ultrasound interpretation requires skilled expertise. Falsely negative studies are misleading for the clinician unless an alternate imaging study such as a CT scan is done to make the diagnosis.
The diagnosis must be confirmed by histologic examination. Neuroblastoma is known as one of the small, blue, round cell tumors of childhood. Histologically, it is characterized by undifferentiated neuroblast aggregates that are separated by fibrovascular septae. Neuroblastomas that mature into benign ganglioneuromas due to spontaneous regression or therapy-induced maturation may have a mixture of undifferentiated and differentiated cells (10). Some neuroblastomas (especially in infants) may undergo spontaneous regression, even if widely disseminated at initial presentation.
Treatment depends on the stage of the tumor and its histology. Surgical resection is the primary treatment for those who have a localized tumor that is resectable. This includes patients with tumors that are localized to one side of the midline or those which cross the midline without encasement of major blood vessels. Radiation is indicated in those with localized, unresectable tumors that have not responded to initial chemotherapy. Chemotherapy is used in patients with advanced stages of neuroblastoma (2).
The main prognostic factors for neuroblastoma are the age of the patient, the stage of the disease, presence of n-myc amplification, and chromosome 1p deletion. Children who are younger than 1 year old and have favorable histology have better survival rates for all stages than those older than 1 year. For example, a child older than 1 year with stage 2 disease has an 85% disease-free survival whereas a child younger than 1 year with stage 2 disease has nearly a 95% disease-free survival (10).
Wilms' tumor is a malignant embryonic neoplasm of the kidney most commonly seen in young children. It is the second most common abdominal tumor in children (neuroblastoma is more common). It peaks at ages 1 through 3 years with the median age of diagnosis occurring at 3.5 years in those with unilateral involvement (13). Bilateral involvement presents at an earlier age than unilateral involvement.
The exact cause of Wilms' tumor is unknown, but mutations in the short arm of chromosome 11 have been detected in approximately 30% of the patients (15). The Wilms' tumor suppressor gene (WT1) is located on locus 11p13 and acts to regulate transcription of other genes during normal renal development (16). Mutation of WT1 predisposes an individual to nephrogenic rests, benign clusters of blastemal and stromal cells, which may be subjected to further mutation leading to malignant transformation (2). Deletion of this locus has been linked to the WAGR (see below) and Denys-Drash syndromes. These are syndromes that consist of various congenital anomalies in conjunction with Wilms' tumor. Individuals with the WAGR syndrome present with Wilms' tumor, aniridia, genitourinary malformations, and mental retardation (15). Those who suffer from Denys-Drash syndrome have Wilms' tumor, nephropathy, and genital abnormalities (15).
A second locus has recently been discovered at the 11p15 locus. It is denoted as the WT2 gene, but its exact functions have not been elucidated. Some hypothesize that the gene is actually IGF2 (insulin growth factor 2), which encodes for a growth factor found in abundance in Wilms' tumor (2). The Beckwith-Wiedemann syndrome has been linked to this locus. Patients with Beckwith-Wiedemann syndrome display organomegaly (liver, kidney, adrenal, and pancreas), macroglossia, omphalocele, and hemihypertrophy (15). Individuals with this syndrome have a 10-20% incidence of tumor development, including Wilms' tumor (16).
This neoplasm most commonly presents as an asymptomatic abdominal mass discovered by parents during bathing or by a doctor during a routine exam. The mass is usually smooth, firm and rarely crosses the midline. Individuals who are symptomatic may present with abdominal pain, fever, anemia, hematuria, and hypertension. The tumor may compress on the renal artery causing renal ischemia leading to renin secretion with resulting hypertension (2). Post-streptococcal glomerulonephritis may be mistakenly diagnosed in cases presenting with hematuria and hypertension. Individuals may also present with abnormalities that may link them with the syndromes associated with Wilms' tumor (WAGR, Denys-Drash, Beckwith-Wiedemann). Rarely, a paraneoplastic syndrome may arise in which erythropoietin is released causing polycythemia (15).
An abdominal mass is linked with a variety of diseases all of which needs to be included in the differential. Those that are of importance include neuroblastoma, rhabdomyosarcoma, leiomyosarcoma, renal cell sarcoma, fibrosarcoma, hydronephrosis, polycystic kidney, adrenal hemorrhage, and renal vein thrombosis (13).
Imaging studies (ultrasound or CT) are required to confirm the presence of a renal mass. Once a Wilms' tumor is suspected, a complete blood count, liver and kidney function tests, skeletal survey, and chest x-ray should also be done. Ultrasound or CT helps localize the mass, identifies associated genitourinary abnormalities, confirms function of the contralateral kidney, and indicates if there is extension to the inferior vena cava (16). CT scan is better at detecting subtle intra-abdominal abnormalities such as tumor spread, lymph node enlargement, vascularity, etc. Chest x-rays are done to look for evidence of lung metastasis. A definitive diagnosis is made based on biopsy results (13).
The National Wilms' Tumor Study Group Staging System is the most common criteria used to stage a tumor. This system stages tumors according to information gathered by clinicians, surgeons, and pathologists.
The first line of treatment is surgical resection whenever possible. During the procedure the surgeon should remove the tumor taking precautions to prevent tumor spillage. While the abdomen is open, the contralateral kidney should be inspected to detect involvement. The liver should also be inspected for evidence of metastasis. The renal vein should be checked to see if the tumor has extended to this area. Lastly, a retroperitoneal lymph node sample should be obtained for histopathology. If the tumor is inoperable either due to large size or the presence of invasion, a biopsy should be taken and other forms of therapy started (15). This tumor is sensitive to chemotherapy and radiation so either of these treatment options are possible therapeutic choices.
If there is bilateral Wilms' tumor, complete resection is not an option since dialysis or a renal transplant would be required to prevent uremia. Instead, renal sparing surgery is preferred. First, a biopsy must be done to confirm bilateral involvement and to get histologic data to grade the tumors. Next, preoperative chemotherapy, appropriate for the stage of the tumor, is begun which lasts for up to six weeks. An abdominal CT scan is then done to determine if resection is possible. If it looks good, surgical excision is done. If it does not appear to be resectable, a second-look procedure is done in which another biopsy is taken and a partial resection is attempted. If a partial resection is not possible, then chemotherapy is utilized with or without radiation (16).
The prognosis of the patient is based on the histology (grade) and stage of the tumor. A favorable histology is one in which blastemal, stromal, and epithelial elements may be seen. An unfavorable histology is an anaplastic one detectable by the presence of gigantic polypoid nuclei within the tumor sample (14). Four year Wilms' tumor survival (4): Stage I with favorable histology (96%), stage II with favorable histology (92%), stage III with favorable histology (87%), stage IV with favorable histology (83%), unfavorable histology (60%).
1. A 2 year old boy presents with a large right flank mass, fever, weight loss, proptosis of the right eye, and ecchymosis around the right eye. The most likely diagnosis is:
. . . . . a. Wilms' tumor
. . . . . b. Neuroblastoma
. . . . . c. Hydronephrosis
. . . . . d. Metastatic neuroblastoma
2. What is the most common secondary tumor that develops after survival of retinoblastoma?
. . . . . a. Neuroblastoma
. . . . . b. Soft tissue sarcoma
. . . . . c. Osteosarcoma
. . . . . d. Acute lymphocytic leukemia
3. Which one of the syndromes in the following list is not associated with Wilms' tumor?
. . . . . a. Beckwith-Wiedemann syndrome
. . . . . b. Li-Fraumeni syndrome
. . . . . c. WAGR syndrome
. . . . . d. Denys-Drash syndrome
4. If a teenager comes in complaining of night pain in his knee, which disorder should be at the top of your differential? Which would be the most likely, and which would be the most serious likely consideration?
. . . . . a. Juvenile Rheumatoid Arthritis
. . . . . b. Osteosarcoma
. . . . . c. Paget's Disease
. . . . . d. Stress fracture
. . . . . e. Growing pains
5. Retinoblastoma is often detected by:
. . . . . a. Primary care physicians performing routine ophthalmoscopy checks for a red reflex, but finding a white reflex instead.
. . . . . b. Flash photography of infants and children done by family members.
. . . . . c. Incidental finding on CT scans done for head trauma.
. . . . . d. Genetic counseling and risk analysis.
. . . . . e. Detection of an orbital bruit.
1. Mahoney DH. Chapter 135 - Retinoblastoma. In: Johnson KB, Oski FA. Oski's Essential Pediatrics. 1997, Philadelphia: Lippincott-Raven Publishers, p 378-380.
2. Abeloff MD, Armitage JO, Lichter AS, et al. Chapter 80 - Pediatric Tumors. In: Abeloff MD, Armitage JO, Lichter AS, et al (eds). Clinical Oncology, 2nd edition. 2000, New York: Churchill Livingstone, pp. 2346-2394.
3. Gilchrist GS, Robertson DM. Chapter 508 - Retinoblastoma. In: Behrman RE, Kliegman RM, Jenson HB (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1561-1562.
4. Albano EA, Foreman NK, Greene BS, et al. Chapter 27 - Pediatric Tumors. In: Hay WW, Hayward AR, Levin MJ, et al (eds). Current Pediatric Diagnosis and Treatment, 16th edition. 2003, New York: Lange Medical Books/McGraw-Hill, pp. 793-819.
5. O'Brien JM, Uusitalo M, Wheeler S. Ocular oncology: New approach in the clinical management of retinoblastoma. Ophthamol Clin North Am 1999;12(2):255-264.
6. Wittig JC, Bickles J, Priebat D, et al. Osteosarcoma: A multidisciplinary approach to diagnosis and treatment. Am Fam Phys 2002;65(6):1123-1132.
7. Hurwitz RL. Chapter 136 - Malignant Bone Tumors In Children. In: Johnson KB, Oski FA (eds). Oski's Essential Pediatrics. 1999, Philadelphia: Lippincott-Raven Publishers, pp.380-381.
8. Gilchrist GS, McManus MJ. Chapter 507 - Osteosarcoma. In: Behrman RE, Kliegman RM, Jenson HB (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1558-1560.
9. Grier HE. Chapter 20.9 - Osteosarcoma. In: Rudolph AM, Rudolph CD (eds). Rudolph's Pediatrics, 21st edition. 2002, New York: McGraw-Hill Companies, pp.1610-1611.
10. Alexander F. Pediatric urologic oncology: Neuroblastoma. Urol Clin North Am 2000;27(3):383-392, vii.
11. Dreyer ZE, Fernbach DJ. Chapter 133 - Neuroblastoma. In: Johnson KB, Oski FA (eds). Oski's Essential Pediatrics. 1999, Philadelphia: Lippincott-Raven Publishers, pp. 375-376.
12. Gilchrist GS, McMannus MJ. Chapter 504 - Neuroblastoma. In: Behrman RE, Kliegman RM, Jenson HB (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1552-1554.
13. Fernbach DJ, Steuber CP. Chapter 134 - Wilms' Tumor. In: Johnson KB, Oski FA. Oski's Essential Pediatrics. 1999, Philadelphia: Lippincott-Raven Publishers, p. 374.
14. Greene DM. Chapter 20.12 - Wilms' Tumor. In: Rudolph AM, Rudolph CD (eds). Rudolph's Pediatrics, 21st edition. 2002, New York: McGraw-Hill Companies, pp. 1614-1616.
15. Anderson PM. Chapter 505.1 - Wilms' Tumor. In: Behrman RE, Kliegman RM, Jenson HB (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: W.B. Saunders Company, pp. 1554-1556.
16. Neville HL, Ritchey ML. Wilms' tumor: Overview of national Wilms' tumor study group results. Urol Clin North Am 2000;27(3):435-442.
Answers to questions
4. Growing pains (e) are ill-defined, but are supposedly very common, so from a numerical standpoint, this diagnosis is probably the most common. However, since this age group is one of the peak ages for osteosarcoma (b) and since this is a serious condition that should be diagnosed as early as possible, osteosarcoma is the most serious likely consideration.
5. a, b, and d are correct.