Information about the molecular pathology of the Ewing sarcoma family of tumors now allows us to recognize Ewing sarcoma of bone, extraosseous Ewing sarcoma, and peripheral primitive neuroectodermal tumor as a single tumor type. These tumors share the genetic lesion EWS-FLI1 [t(11:22)(q24;q12)], which produces a fusion protein with aberrant transcriptional activation properties that can transform NIH3T3 cells.[51,52] Some Ewing sarcomas contain other translocations involving the EWS gene on chromosome 22. Molecular tests for these abnormalities allow accurate diagnosis, sensitive detection of metastatic disease in the bone marrow, and detection of minimal residual disease. The EWS abnormalities may also offer a target for future therapies.[53]
Before the introduction of systemic chemotherapy, few patients survived Ewing sarcoma. The Intergroup Ewing Sarcoma Study (IESS) introduced the first successful combined-modality therapy.[54] Another major contribution was the principle that the primary tumor site dictates the local control measure—for example, complete surgical removal of tumors in expendable bones (rib, clavicle, fibula). Risk-adapted irradiation of the primary site is based on the degree of resection and the response to chemotherapy. In addition, irradiation of pulmonary metastasis may improve survival in a subset of patients, as shown in Figure 6.[55] More recently, ifosfamide(Drug information on ifosfamide) and etoposide(Drug information on etoposide) were shown to benefit patients with high-risk features.[56] More than 70% of localized Ewing sarcoma is curable with combined therapy. Metastatic disease remains a challenge, and high-dose chemotherapy and immunotherapy regimens are under investigation.
Before the introduction of systemic chemotherapy, few patients survived Ewing sarcoma. The Intergroup Ewing Sarcoma Study (IESS) introduced the first successful combined-modality therapy.[54] Another major contribution was the principle that the primary tumor site dictates the local control measure—for example, complete surgical removal of tumors in expendable bones (rib, clavicle, fibula). Risk-adapted irradiation of the primary site is based on the degree of resection and the response to chemotherapy. In addition, irradiation of pulmonary metastasis may improve survival in a subset of patients, as shown in Figure 6.[55] More recently, ifosfamide(Drug information on ifosfamide) and etoposide(Drug information on etoposide) were shown to benefit patients with high-risk features.[56] More than 70% of localized Ewing sarcoma is curable with combined therapy. Metastatic disease remains a challenge, and high-dose chemotherapy and immunotherapy regimens are under investigation.
Tumors of the Central Nervous System
Tumors of the CNS are the second most common malignancies in children aged 0 to 14 years.[1] Several unique features of brain tumors present therapeutic challenges, including anatomic constraints on resection, the blood-brain and blood-cerebrospinal fluid barriers, and the sensitivity of the developing brain to toxic insult. With the notable exception of germinoma, brain tumors are relatively unresponsive to chemotherapy and radiation. Consequently, survival rates have not increased dramatically. The past few decades have seen many advances in diagnosis and treatment, however, and survival rates for some pediatric brain tumors, including low-grade glioma, ependymoma, and medulloblastoma, are relatively good. Therapies targeted to the molecular characteristics of pediatric brain tumors should improve outcomes for more patients in the near future.
Many advances over the past 3 decades reflect improved technology, particularly diagnostic imaging. CT and MRI have revolutionized management through accurate diagnosis and staging, advanced neurosurgical treatment planning, and sophisticated radiation therapy.[57] Current CT- and MRI-based treatment planning can precisely identify tumor and critical normal structures to allow optimal delivery of conformal techniques such as intensity-modulated radiotherapy. Proton-beam therapy may further spare normal structures and is likely to be widely implemented.
Low-Grade Glioma
Low-grade glioma is the most common childhood brain tumor and has an excellent prognosis when completely resected. Children with completely resected cerebellar pilocytic astrocytoma, for example, have a long-term survival rate > 95%, without adjuvant radiation or chemotherapy.[58] Tumors that cannot be completely resected, including hypothalamic/optic pathway gliomas, are much more likely to recur. Although radiation can result in prolonged stable disease, it may have severe endocrine and cognitive consequences.
In recent years, chemotherapy has been used to delay radiation, particularly in young children. Effective chemotherapy regimens include the vincristine/carboplatin combination, which induced objective responses or prolonged stable disease in two-thirds of patients with low-grade astrocytoma, although long-term follow-up is needed.[59] Ongoing COG trials are testing the efficacy of additional chemotherapeutic agents, including temozolomide(Drug information on temozolomide) (Temodar) and vinblastine(Drug information on vinblastine).
Ependymoma
Ependymoma is rare but exemplifies the advantages of enhanced imaging capability. In the late 1980s, the 5-year EFS for patients with this neoplasm was approximately 40% and 5-year overall survival, < 60%.[60] High-resolution imaging now allows complete resection, which is crucial even at the cost of cranial nerve deficits, and detection of postoperative residual disease that may require reresection. With complete resection and focal conformal irradiation, 3-year EFS is reportedly > 75% for children with localized ependymoma.[61] Survivors have reasonable functional outcomes, as cranial nerve deficits often improve significantly. Focal conformal irradiation also allows relative sparing of cortical structures and preservation of neurocognitive function.
Remaining challenges in ependymoma management include effective risk stratification, which is impeded by the difficulty of reliably interpreting histologic grade. Insights into the biology of ependymoma, including the adverse significance of ERBB2 and ERBB4 overexpression, may ultimately improve risk stratification.[62] Patients with metastatic or recurrent disease currently fare poorly. Although ependymoma has been considered chemoresistant, current trials are reevaluating the role of chemotherapy for high-risk disease and exploring the efficacy of new agents.
Medulloblastoma
Medulloblastoma is the most dramatic success story in pediatric neurooncology. Overall, long-term survival for patients older than 3 years at diagnosis has improved 20% to 30% over the past 3 decades through routine conformal irradiation of the tumor bed plus craniospinal irradiation (CSI), recognition of the importance of complete resection, and neurosurgical advances that have improved the safety and feasibility of complete resection.
As shown in Figure 7, the addition of chemotherapy has provided a further survival benefit and allowed reduction of the CSI dose for average-risk disease (complete resection with no evidence of metastasis at diagnosis).[63-65] After further refinement of chemotherapy, average-risk patients had 5-year EFS rates > 80% in two recent large trials.[65,66] The SJMB96 regimen (surgical resection and radiation followed by four cycles of high-dose chemotherapy with autologous stem cell support) substantially improved survival for high-risk patients.[66] Further advances will require development of less toxic, more specific therapies based on a thorough understanding of tumor biology.
Analysis of medulloblastoma tumor specimens has shown the histology to be prognostically important: Large-cell anaplastic medulloblastoma is more clinically aggressive, while nodular desmoplastic tumors are much more likely to be cured.[67] Some histologic characteristics are associated with specific molecular derangements (eg, the large-cell anaplastic phenotype and abnormalities of c-myc and n-myc), but even within histologically identical tumors, molecular differences can have prognostic value and may ultimately provide a basis for targeted therapy. Abnormalities of the wnt/beta-catenin pathway are associated with a relatively favorable prognosis, while overexpression of ERBB2 is associated with poor outcomes.[68,69] Microarray technology can now provide the comprehensive molecular profile of a tumor. This technology has been used to create a combined clinical and molecular risk-stratification system for medulloblastoma that will serve as a prototype for similar, but likely more complex, stratification schemes in future clinical trials.
Formidable challenges remain. One-third of patients older than 3 years at diagnosis experience relapse, and very few of these survive. For younger patients, the neurocognitive sequelae of craniospinal irradiation are unacceptable, and therefore outcomes are substantially worse in most series.[70,71] Older patients are less profoundly affected by CSI, but the cognitive, behavioral, and endocrine sequelae can still affect quality of life, school performance, and adult potential. The extent to which CSI can be safely decreased for average-risk disease, and the potential improvement in neurocognitive function, are still unresolved.
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
