Pediatric Solid Tumors
Summary of Key Points
Osteosarcoma
Primary Therapy
• The primary tumor is managed surgically with a limb-sparing operation or amputation.
• Adjuvant chemotherapy incorporating high-dose methotrexate is used preoperatively for presumed micrometastatic disease; response will guide further therapy.
• Methotrexate responders have a more than 80% chance of cure.
• Primary pulmonary metastatic disease is managed surgically, although adjuvant chemotherapy may reduce the extent of resection.
Ewing Sarcoma Family Tumors
Differential Diagnosis
• Osteomyelitis must be ruled out, especially when the patient has a fever.
• Lesions to be excluded include benign tumors of bone that manifest as lytic lesions (e.g., eosinophilic granuloma, giant cell tumor), malignant tumors (e.g., osteosarcoma, primary lymphoma of bone), and metastatic lesions from a nonosseous tumor (e.g., neuroblastoma).
Primary Therapy
• The primary tumor should always be treated with multimodality therapy consisting of chemotherapy, radiation therapy, surgery, or a combination of these treatments.
• Specific local treatment depends on the primary site. Surgical extirpation may be considered with tumors in expendable bones (proximal part of the fibula, rib, clavicle, iliac wing).
• Unresectable tumors generally necessitate a combined approach of chemotherapy, radiation therapy, and surgery.
• Localized disease is curable with combined therapy in more than 70% of cases. Metastatic disease is curable in 30% to 40% of cases.
Neuroblastoma
Differential Diagnosis
• Disseminated bone disease can resemble systemic infection, inflammatory disease, osteomyelitis, or rheumatoid arthritis.
• Paraneoplastic syndromes associated with neuroblastoma (vasoactive intestinal peptide syndrome, opsoclonus-myoclonus-ataxia syndrome) must be differentiated from primary inflammatory bowel disease and neurologic disease.
• Neuroblastoma must be differentiated from other small, round, blue cell neoplasms of childhood (e.g., Ewing sarcoma, primitive neuroectodermal tumor, non-Hodgkin lymphoma, undifferentiated soft-tissue sarcoma).
• In as many as 10% of tumors, catecholamines are not produced. In 1%, the absence of an obvious primary lesion confounds the diagnosis.
Staging Evaluation
• Staging evaluation includes a complete history and physical examination, CBC, serum chemistry analysis (including determination of lactate dehydrogenase level), quantitative urine catecholamines, bone marrow examination, radionuclide scintigraphy, and imaging studies of the primary tumor and chest.
Primary Therapy
• Specific treatment depends on stage of disease, age of the patient, and biological features of the tumor.
• With few exceptions (completely resected primary tumor, localized tumor with/without complete excision and favorable tumor biological features, infants with stable stage 4S disease), multiple-agent chemotherapy is the backbone of multimodality treatment.
• Survival depends on stage and biological features of the tumor (e.g., histopathological subtype, MYCN gene amplification).
• The overall survival rate for asymptomatic patients with favorable biology stage 1, 2a, or 2b tumors is greater than 90%.
• Overall survival among patients with advanced-stage 3 or 4 with MYCN gene amplification disease is poor. Less than one-third of children with high risk disease are long-term survivors.
Wilms Tumor
Etiology and Epidemiology
• Mean age at diagnosis is 44 months for unilateral tumors and 31 months for bilateral tumors.
• Familial cases account for 1.5% of cases of Wilms tumor.
• Associated with Wilms tumor is a syndrome comprising aniridia, genitourinary anomalies, and mental retardation (WAGR syndrome); Denys-Drash syndrome; and Beckwith-Wiedemann syndrome.
• No firmly established environmental factors have been identified.
Pathology and Tumor Biology
• The main histologic subtypes are favorable and anaplastic.
• Major implicated genes and loci include WT1 (11p13), IGF2 (11p15), FAM123B/WTX (Xq11), and CTNNB1/β-catenin (3p22).
• Mutations of the p53 gene (TP53) are associated with anaplastic tumors.
• Loss of heterozygosity (LOH) at chromosomes 1p and 16q and gain of chromosome 1q are associated with adverse prognosis.
Differential Diagnosis
• Neuroblastoma is the main consideration in the differential diagnosis.
• Other tumors to be excluded are renal neoplasms (clear cell sarcoma, rhabdoid tumor, congenital mesoblastic nephroma, renal cell carcinoma).
• Benign renal processes (nephrogenic rests, multicystic or polycystic kidneys, hydronephrosis, renal carbuncles, hemorrhage) also should be ruled out.
Staging Evaluation
• Evaluation begins with complete history and physical examination, with careful attention to blood pressure and assessment for associated congenital anomalies.
• Other components of the staging evaluation include CBC, serum chemistry analysis, urinalysis, abdominal ultrasonography, abdominal/pelvic computed tomography (CT) or magnetic resonance imaging (MRI), and chest CT.
Primary Therapy
• Surgery: Surgical resection of the primary tumor usually precedes chemotherapy in the approach taken by the Children’s Oncology Group (COG). Presurgical chemotherapy is used in the approach taken by the International Society of Pediatric Oncology (SIOP).
• Chemotherapy: Agents used depend on disease stage and favorable versus anaplastic histology: stages I and II, favorable histology—vincristine, actinomycin D; stages III and IV, favorable histology, and stage I, anaplastic histology—vincristine, doxorubicin, actinomycin D; stages II through IV, anaplastic histology—vincristine, cyclophosphamide, doxorubicin, carboplatin, etoposide.
• Radiation therapy: Radiation therapy is included in management for stages III and IV, favorable histology, and stages II through IV, anaplastic histology.
• Recurrent disease is effectively managed with radiation therapy and chemotherapy with agents not used for initial treatment.
• Patients who initially received aggressive treatment may respond to cyclophosphamide or ifosfamide-, carboplatin-, and etoposide-based regimens.
Complications
• Renal failure is seen in less than 1% of patients with unilateral tumors and 12% in patients with bilateral tumors.
• Congestive heart failure may occur in patients who receive doxorubicin (occurs in 4.4% of patients).
• Pregnancy-related complications in adulthood have occurred in girls who receive flank irradiation.
• A second malignant neoplasm also may develop (6.7% cumulative incidence of solid malignancies at age 40 years).
Rhabdomyosarcoma
Primary Therapy
• Primary therapy is chemotherapy with surgery, radiation therapy, or both. Specific treatment depends on age of the patient, tumor primary site and histologic subtype, and extent of disease.
• Mutilating surgery usually can be avoided because the tumor is sensitive to both chemotherapy and radiation therapy.
• The overall survival rate exceeds 70%, but survival will depend on extent of disease. More than 90% of patients with localized, resectable, favorable histology tumors survive, but less than 20% of patients with metastatic disease survive.
Nonrhabdomyosarcoma Soft-Tissue Sarcoma
Primary Therapy
• Surgical excision with or without radiation therapy is indicated for patients with resectable tumors.
• Chemotherapy may provide some benefit for patients with high-grade tumors larger than 5 cm in diameter and for those with unresectable or metastatic tumors.
• Survival depends on the size and grade of the tumor and extent of disease. Patients with localized tumors 5 cm or less in diameter or localized low-grade tumors larger than 5 cm in diameter that can be resected have a survival rate exceeding 85%. Approximately 50% of patients with high-grade tumors larger than 5 cm or with unresectable disease survive. The survival rate is approximately 10% among patients with metastatic disease.
Retinoblastoma
Incidence and Clinical Forms
• Among children younger than 5 years of age,11 new cases occur per 1 million population per year.
• The two clinical forms of retinoblastoma are as follows: (1) Hereditary, bilateral or multifocal (40% of cases)—This form, characterized by germline mutations of RB1, may be inherited from an affected survivor or a silent carrier parent or may be the result of a new germline mutation. (2) Nonhereditary, unilateral or unifocal (60% of cases)—15% of unilateral cases represent germline mutations.
Staging Evaluation
• Approach to staging depends on tumor size and on the presence or absence of intraocular and extraocular extension.
• Indirect ophthalmoscopic examination of both eyes with the patient under general anesthesia is essential.
• Imaging studies helpful in staging include ultrasonography, orbital and cerebral CT, and MRI.
• Bone marrow biopsy and cerebrospinal fluid examination are reserved for patients with extraocular disease, optic nerve involvement, or choroid invasion.
Treatment
• Treatment must be individualized and depends on laterality, potential for vision, and tumor extent.
• Enucleation is reserved for cases in which no potential for useful vision remains. Cryotherapy and photocoagulation are useful for management of small primary or recurrent tumors.
• Radiation therapy is the treatment modality of choice for controlling local disease and preserving vision with larger tumors.
• Use of chemotherapy is restricted to patients with advanced intraocular disease or with extraocular disease.
Hepatoblastoma
Staging Evaluation
• Staging evaluation includes a complete history and physical examination, with careful assessment for any congenital abnormalities or signs of precocious puberty.
• Laboratory tests typically include CBC, serum chemical analysis, and α-fetoprotein and α-human chorionic gonadotropin assays.
• Diagnostic imaging may include CT or MRI of the abdomen and chest CT.
Primary Therapy
• Cure is possible only when complete surgical excision is performed. If complete excision is not feasible, liver transplantation should be considered.
• Adjuvant chemotherapy (cisplatin-based, in conjunction with doxorubicin or 5-fluorouracil) is useful preoperatively for achieving resectability and postoperatively for preventing distant metastasis.
1. What is the most common primary site in osteosarcoma in children?
2. Which one of the following syndromes is not associated with the development of osteosarcoma?
3. Which one of the following drugs is not commonly used in the treatment of osteosarcoma?
4. What is the most common genetic abnormality in Ewing sarcoma?
5. What is the most common site of metastatic spread in Ewing sarcoma?
6. Which of these clinical and biological factors are associated with increased risk of treatment failure in neuroblastoma?
7. Which is a true statement regarding stage 4S neuroblastoma?
A Chemotherapy is always first-line therapy
B Metastatic disease to the liver, skin, and skeleton is common
C It can be diagnosed in any age group
D Limited chemotherapy may be considered in selected cases when there is organ impairment
8. Which of these clinical and biological factors is/are associated with increased risk of relapse in Wilms tumor?
B Blastemal predominant histology after chemotherapy
9. Which is a true statement regarding pediatric renal cell carcinoma?
A Immunotherapy with interferon is first-line therapy.
B As in adults, clear cell histology is most common.
C Renal cell carcinoma (RCC) in children usually occurs in infants and toddlers.
D Vascular endothelial growth factor-targeted therapy should be considered for patients with metastatic disease.
10. Which of the following genetic syndromes is not associated with an increased risk of rhabdomyosarcoma?
11. Prognosis is generally favorable when rhabdomyosarcoma arises at which of the following anatomic sites?
12. Which of the following operations is appropriate for a newly diagnosed patient with suspected rhabdomyosarcoma?
A Wide resection of a 3 cm tumor of the thigh
B Fine-needle aspiration biopsy to establish the diagnosis
13. In what way do nonrhabdomyosarcoma soft-tissue sarcomas (NRSTSs) differ from rhabdomyosarcoma?
A NRSTSs occur in younger children
B NRSTSs are more sensitive to radiation therapy
C NRSTS rarely spreads to the bone marrow
D NRSTS more often requires chemotherapy as part of multimodality therapy
14. Which of the following is not a known risk factor for NRSTS?
15. All of the following factors predict outcome in pediatric NRSTS except:
16. A 2-year-old girl is referred to you by ophthalmology after having been enucleated for unilateral retinoblastoma. An MRI of the brain and orbits fails to show any orbital or intracranial disease, and review of the enucleated specimen by pathology shows extension no evidence of invasion of the choroid, anterior chamber, or optic nerve. What would be the most appropriate treatment for this child?
A Irradiation of the orbital socket and chiasm
C Irradiation of the orbital socket alone
E Adjuvant chemotherapy and irradiation of the orbital socket
17. Which of the following neoplasms is more common in survivors of bilateral retinoblastoma?
18. Which statement is most accurate regarding the treatment of hepatoblastoma?
A Complete surgical resection is required for cure, even if the tumor is responsive to chemotherapy.
B Front-line chemotherapy includes irinotecan.
C The presence of lung metastases at diagnosis is a contraindication to liver transplantation.
D High-dose therapy with autologous stem cell rescue is accepted management for recurrent disease.
19. What is the most common endocrine syndrome associated with adrenocortical tumors in children?
20. Which of the following statements is not true about childhood nasopharyngeal carcinoma?
1. Answer: D. The most common primary site in osteosarcoma is the distal femur, followed by proximal tibia and proximal humerus.
2. Answer: C. Beckwith-Wiedemann syndrome is associated with the development of several embryonal malignancies, such as hepatoblastoma, Wilms tumor, adrenocortical carcinoma and rhabdomyosarcoma, but not osteosarcoma.
3. Answer: C. Actinomycin D is used in the management of several malignancies in children, such as rhabdomyosarcoma and Wilms tumor, but is not typically part of the treatment of osteosarcoma.
4. Answer: D. EWS rearrangements are the most common abnormality in Ewing sarcoma, and their presence in the context of typical pathology defines the disease.
5. Answer: A. The lungs are the most common metastatic site in Ewing sarcoma. Involvement of bone and bone marrow is also common. Involvement of liver and lymph nodes is extremely rare.
6. Answer: D. Studies by Shimada et al. have shown that poorly differentiated histology is a predictor of disease aggressiveness. Similarly the overall survival rate for patients that have MYCN amplified tumors is inferior to those without MYCN amplification. Overall older children with neuroblastoma have higher stage disease and poorer outcomes. Historically an age cutoff of 12 months was considered prognostically important; more recent studies suggest that children between the ages of 12 and 18 months have comparable excellent outcomes.
7. Answer: D. Stage 4S (MS) neuroblastoma is a distinct clinical entity that occurs in children younger than 12 months age. It is characterized by a localized primary tumor but with metastases limited to the liver, skin, and minimal bone marrow involvement (<10%). Patients may be seen with massive hepatomegaly (“Pepper syndrome”), skin nodules (“blueberry muffins”) and respiratory distress that may lead to organ impairment (kidney failure, mechanical ventilation). Patients may have spontaneous tumor regression and thus chemotherapy is not usually the first line of treatment but will require supportive care in the interval. In selected cases minimal chemotherapy provides an opportunity for disease regression and less morbidity. In the majority of cases, survival is excellent.
8. Answer: D. Anaplastic histology remains the most powerful predictor of outcome. The overall survival rate for anaplastic histology is approximately 50%, compared with 90% for nonanaplastic Wilms tumor. The SIOP-9 study demonstrated that blastemal-predominant histology after 4 to 6 weeks of chemotherapy is associated with adverse outcome with outcomes almost as poor as for anaplastic histology. NWTS-5 demonstrated that loss of heterozygosity at 1p and 16q predict unfavorable outcome among patients with favorable histology tumors.
9. Answer: D. In contrast to adult RCC, clear cell histology is distinctly uncommon in children and adolescents. The translocation and papillary histologies are most common. These subtypes do not typically respond to immunotherapy, although responses to tyrosine kinase inhibitors that target vascular endothelial growth factor have been reported. When RCC arises in children, it typically affects older children and teenagers, in contrast to Wilms tumor, which has a mean age at diagnosis of 3 years.
10. Answer: C. Down syndrome, or trisomy 21, carries an increased risk of leukemia but not a risk of rhabdomyosarcoma. Costello syndrome, caused by germline HRAS gene mutations, is characterized by developmental delay, intellectual impairment, short stature, distinctive facial features, structural heart defects, and hypertrophic cardiomyopathy, along with a notably increased risk of rhabdomyosarcoma. Li-Fraumeni syndrome, associated with TP53 and CHEK2 germline mutations, greatly increases the risk of several types of cancer, including bone and soft-tissue sarcomas, brain tumors, leukemias, breast cancer, and adrenocortical carcinoma. Beckwith-Wiedemann is an overgrowth syndrome characterized by hemihypertrophy, omphalocele, macroglossia, visceromegaly, and neonatal hypoglycemia. These children are at an increased risk of developing rhabdomyosarcoma, Wilms tumor, and hepatoblastoma.
11. Answer: D. Anatomic site is an important prognostic feature in childhood rhabdomyosarcoma and is a component of the staging systems used throughout the world for this disease. Favorable anatomic sites include the orbit, nonparameningeal head and neck sites (such as the cheek, nasal cavity, and scalp), genitourinary sites other than bladder/prostate, and the biliary tract. All other sites, including parameningeal head and neck sites (such as the infratemporal fossa and nasopharynx), extremities, and bladder/prostate, are unfavorable and tumors arising in these locations have an inferior prognosis.
12. Answer: A. The diagnosis of rhabdomyosarcoma is best made by incisional biopsy, multiple core-needle biopsies, or tumor resection to ensure adequate tissue retrieval for pathological classification and molecular testing. Fine-needle aspiration biopsy cannot reliably establish the histologic subtype of rhabdomyosarcoma (alveolar or embryonal) and therefore should not be used to establish the diagnosis. At the time of initial diagnosis, wide resection of rhabdomyosarcoma should be performed if doing so would not compromise form or function. For patients with embryonal histology tumors, an adequate resection also eliminates the need for radiotherapy. Because radiotherapy is necessary after a marginal resection and the dose delivered for microscopic residual disease is similar to that used for gross residual disease, it is rarely appropriate to resect rhabdomyosarcoma when microscopic residual disease is expected or when permanent functional abnormalities can be anticipated from surgery (such as in tumors of the infratemporal fossa, where cranial nerve deficits may occur). Similarly, tumor debulking is not recommended at the time of initial diagnosis because it does not improve outcome.
13. Answer: C. NRSTSs differ from rhabdomyosarcoma in that they predominate in adolescents rather than in young children, virtually never involve the bone marrow, and are less sensitive to both chemotherapy and radiotherapy. Surgery is the mainstay of treatment for NRSTS; chemotherapy is used primarily for higher risk patients, including those with large, high-grade tumors that are likely to metastasize, and those with unresectable or metastatic disease. The indications for radiotherapy in pediatric patients are evolving, but radiation plays an important role in the treatment of patients with residual disease after maximal surgery.
14. Answer: B. Klinefelter syndrome, the most common sex chromosome aneuploidy in males, carries an increased risk of mediastinal germ cell tumor and, in adulthood, breast cancer. The syndrome is not associated with NRSTS. Patients with neurofibromatosis type I are at risk for developing malignant peripheral nerve sheath tumors, along with optic pathway and other gliomas. Patients with hereditary retinoblastoma may develop various types of NRSTSs, as well as other cancers such as osteosarcoma. Radiation-induced soft-tissue sarcomas are a known complication of radiation exposure, including therapeutic radiation for cancer.
15. Answer: A. The most important predictors of outcome in pediatric NRSTS are extent of disease (nonmetastatic vs. metastatic), tumor size, histologic grade, and extent of surgical resection. Although NRSTSs are more common in males, outcomes do not differ by gender.
16. Answer: B. High-risk histopathologic signs are invasion of the optic nerve beyond the lamina cribrosa, massive choroidal involvement, or involvement of the sclera or anterior segment structures. In the absence of those factors, enucleation alone is curative in >95% of the cases. Adjuvant chemotherapy is indicated for high risk histology, and irradiation is used for extraocular disease (transscleral or orbital disease, or involvement of the optic nerve at the cut end).
17. Answer: C. Patients with germline RB1 mutation are at increased risk of developing cancer. Almost any malignancy has been described in retinoblastoma survivors. However, bone (and soft-tissue) sarcomas either inside or outside the radiation field, are the most frequent second malignancies.
18. Answer: A. One of the basic principles of hepatoblastoma treatment is that surgical resection is required for cure, even if resection entails liver transplantation. Chemotherapy can facilitate surgical resection, but is not a substitute for removal of the tumor. Front-line chemotherapy includes cisplatin, with or without other agents such as vincristine/5-fluoruracil, carboplatin, and doxorubicin. Irinotecan has produced responses in small series and is currently being evaluated in the phase II setting; it is not considered standard front-line treatment at this time. Patients with lung metastases responsive to chemotherapy have been cured with liver transplantation. If the lung disease can be eradicated, liver transplantation should be considered.
19. Answer: C. The vast majority of children with adrenocortical tumors present with virilization. Cushing syndrome or a mixed virilization and Cushing syndrome is also common.
20. Answer: A. Childhood nasopharyngeal carcinoma is a neoplasm of the second decade of life and it is very rare among young children. It is almost always associated with EBV and presents with WHO type III histology. In the United States, its incidence is higher among African Americans.
