Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ®) 3/5 –Health Professional Version - National Cancer Institute

Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ®)–Health Professional Version

Childhood Nonmedulloblastoma Embryonal Tumors

In This Section

• Clinical Presentation
• Cellular and Molecular Classification
  • Subtypes of nonmedulloblastoma embryonal tumors
• Staging Evaluation
• Treatment Option Overview for Childhood Nonmedulloblastoma Embryonal Tumors
• Treatment of Childhood Nonmedulloblastoma Embryonal Tumors
  • Treatment of children aged 3 years and younger
  • Treatment of children older than 3 years
• Treatment of Childhood Embryonal Tumors with Multilayered Rosettes or Medulloepithelioma

Clinical Presentation

For nonmedulloblastoma embryonal tumors, presentation is also relatively rapid and depends on the location of the tumor in the nervous system. Embryonal tumors tend to be fast-growing tumors and are usually diagnosed within 3 months of initial onset of symptoms.

Nonmedulloblastoma embryonal tumors may occur anywhere in the CNS, and presentation is variable. Usually there is significant neurologic dysfunction associated with lethargy and vomiting. Supratentorial embryonal tumors (refer to Figure 1) will result in focal neurologic deficits such as hemiparesis and visual field loss, depending on which portion of the cerebral cortex is involved. They may also result in seizures and obtundation.

Cellular and Molecular Classification

The World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) classifies nonmedulloblastoma embryonal tumors primarily by histologic and immunohistologic features, with the exception of embryonal tumor with multilayered rosettes (ETMR) and atypical teratoid tumor with rhabdoid features.[1] By definition, these tumors arise in the cerebral hemisphere, brain stem, or spinal cord and are composed of undifferentiated or poorly differentiated neuroepithelial cells that may display divergent differentiation. This classification, based on the histopathological characteristics and location of the tumor, is as follows:

• ETMR, C19MC-altered.
• ETMR, not otherwise specified (NOS).
• Medulloepithelioma.
• CNS neuroblastoma.
• CNS ganglioneuroblastoma.
• CNS embryonal tumor, NOS.
• Atypical teratoid/rhabdoid tumor.
• CNS embryonal tumor with rhabdoid features.

CNS embryonal tumors that demonstrate distinct areas of neuronal differentiation are termed cerebral neuroblastomas and, if ganglion cells are present, ganglioneuroblastomas. Likewise, medulloepitheliomas have a specific histologic pattern and remain a separate entity.[1,2]

Genomic molecular characterizations of embryonal tumors and pineoblastomas have demonstrated substantial heterogeneity among these tumors. These tumors are also molecularly different from medulloblastomas.[3,4]

Although the WHO classification system does not yet use molecular findings to classify nonmedulloblastoma embryonal tumors, future classification will most likely be based on both histological and molecular findings and, possibly, site of origin in the nervous system.

Subtypes of nonmedulloblastoma embryonal tumors

A study applying unsupervised clustering of DNA methylation patterns for 323 nonmedulloblastoma embryonal tumors found that approximately one-half of these tumors diagnosed as nonmedulloblastoma embryonal tumors showed molecular profiles characteristic of other known pediatric brain tumors (e.g., high-grade glioma, atypical teratoid/rhabdoid tumor [AT/RT]).[4] This observation highlights the utility of molecular characterization to assign this class of tumors to their appropriate biology-based diagnosis.

Among the same collection of 323 tumors diagnosed as nonmedulloblastoma embryonal tumors, molecular characterization identified genomically and biologically distinctive subtypes, including the following:

• Embryonal tumor with multilayered rosettes (ETMR): Representing 11% of the 323 cases, this subtype combines embryonal rosette-forming neuroepithelial brain tumors that were previously categorized as either embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, or medulloepithelioma.[4,5] ETMRs arise in young children (median age at diagnosis, 2–3 years) and show a highly aggressive clinical course, with a median progression-free survival (PFS) of less than 1 year and few long-term survivors.[5-7]
  ETMRs are defined at the molecular level by high-level amplification of the microRNA cluster C19MC and by a gene fusion between TTYH1 and C19MC.[5,8,9] This gene fusion puts expression of C19MC under control of the TTYH1 promoter, leading to high-level aberrant expression of the microRNAs within the cluster. The World Health Organization (WHO) allows histologically similar tumors without C19MC alteration to be classified as ETMR, not otherwise specified (NOS).
• Central nervous system (CNS) neuroblastoma with FOXR2 activation (CNS NB-FOXR2): Representing 14% of the 323 cases, this subtype is characterized by genomic alterations that lead to increased expression of the transcription factor FOXR2.[4] CNS NB-FOXR2 is primarily observed in children younger than 10 years, and the histology of these tumors is typically that of CNS neuroblastoma or CNS ganglioneuroblastoma.[4] There is no single genomic alteration among CNS NB-FOXR2 tumors leading to FOXR2 overexpression, with gene fusions involving multiple FOXR2 partners identified.[4] This subtype has not been added to the WHO diagnostic lexicon.
• CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC): Representing 4% of the 323 cases, this subtype is characterized by genomic alterations affecting CIC (located on chromosome 19q13.2), with fusion to NUTM1 being identified in several cases tested.[4] CIC gene fusions are also identified in extra-CNS Ewing-like sarcomas, and the gene expression signature of CNS EFT-CIC tumors is similar to that of these sarcomas.[4] CNS EFT-CIC tumors generally occur in children younger than 10 years and are characterized by a small cell phenotype but with variable histology.[4] This subtype has not been added to the WHO diagnostic lexicon.
• CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1): Representing 3% of the 323 cases, this subtype is characterized by gene fusions involving MN1 (located on chromosome 22q12.3), with fusion partners including BEND2 and CXXC5.[4] The CNS HGNET-MN1 subtype shows a striking female predominance and tends to occur in the second decade of life.[4] This subtype contained most cases carrying a diagnosis of astroblastoma as per the 2007 WHO classification scheme.[4] This subtype has not been added to the WHO diagnostic lexicon.
• CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR): Representing 3% of the 323 cases, this subtype is characterized by internal tandem duplications of BCOR,[4] a genomic alteration that is also found in clear cell sarcoma of the kidney.[10,11] While the median age at diagnosis is younger than 10 years, cases arising in the second decade of life and beyond do occur.[4] This subtype has not been added to the WHO diagnostic lexicon.

The contribution of DNA methylation profiling to correctly diagnose supratentorial embryonal tumors was demonstrated in a clinical trial of patients with supratentorial primitive neuroectodermal tumors of the CNS (CNS-PNET) and pineoblastoma.[12] For the pineoblastoma cases, there was high concordance between the diagnosis made by methylation profiling and the diagnosis made by central pathology review diagnosis (26 of 29). However, for the remaining 31 patients, the diagnosis made by methylation profiling was high-grade glioma in 18 patients, AT/RT in 2 patients, and RELA-fusion–positive ependymoma in 2 patients. Adjudication of discrepancies between the diagnosis made by central review pathology and the diagnosis made by methylation profiling was in favor of methylation profiling in the ten cases that were re-examined.

Medulloepithelioma

Medulloepithelioma with the classic C19MC amplification is considered an ETMR, C19MC-altered (refer to the ETMR information above). However, when a tumor has the histological features of medulloepithelioma, but without a C19MC amplification, it is identified as a histologically discrete tumor within the WHO classification system and called medulloepithelioma.[13,14] Medulloepithelioma tumors are rare and tend to arise most commonly in infants and young children. Medulloepitheliomas, which histologically recapitulate the embryonal neural tube, tend to arise supratentorially, primarily intraventricularly, but may arise infratentorially, in the cauda, and even extraneurally, along nerve roots.[13,14]

Intraocular medulloepithelioma is biologically distinct from intra-axial medulloepithelioma.[15,16]

Staging Evaluation

Patients with nonmedulloblastoma, nonmedulloepithelioma embryonal tumors are staged in a fashion similar to that used for children with medulloblastoma; however, the patients are not assigned to average-risk and high-risk subgroups for treatment purposes (refer to the medulloblastoma Staging Evaluation section of this summary for more information).

Medulloepitheliomas frequently disseminate to the neuraxis.[17] Medulloepithelioma is staged in the same way as medulloblastoma; however, the patients are not assigned to average-risk and high-risk subgroups for treatment purposes (refer to the medulloblastoma Staging Evaluation section of this summary for more information).

Treatment Option Overview for Childhood Nonmedulloblastoma Embryonal Tumors

Table 4 describes the standard treatment options for newly diagnosed and recurrent childhood nonmedulloblastoma, nonmedulloepithelioma embryonal tumors and medulloepithelioma.

Table 4. Standard Treatment Options for Childhood Nonmedulloblastoma, Nonmedulloepithelioma Embryonal Tumors and Medulloepithelioma

Treatment Group		Standard Treatment Options
Newly diagnosed childhood nonmedulloblastoma, nonmedulloepithelioma embryonal tumors	Children aged 3 years and younger	Surgery
		Adjuvant chemotherapy
	Children older than 3 years	Surgery
		Adjuvant radiation therapy
		Adjuvant chemotherapy
Newly diagnosed childhood embryonal tumors with multilayered rosettes or medulloepithelioma		Surgery and adjuvant therapy
Recurrent childhood nonmedulloblastoma embryonal tumors		There are no standard treatment options. (Refer to the Treatment of Recurrent Childhood Medulloblastoma and Other CNS Embryonal Tumors section of this summary for more information.)

Treatment of Childhood Nonmedulloblastoma Embryonal Tumors

(Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for more information about the treatment of CNS atypical teratoid/rhabdoid tumors.)

(Refer to the Treatment of Childhood Embryonal Tumor With Multilayered Rosettes or Medulloepithelioma section of this summary for information about the treatment of medulloepithelioma.)

Treatment of children aged 3 years and younger

Standard treatment options for children aged 3 years and younger with newly diagnosed nonmedulloblastoma, nonmedulloepithelioma embryonal tumors include the following:

1. Surgery.
2. Adjuvant chemotherapy.

Treatment of children aged 3 years and younger with nonmedulloblastoma, nonmedulloepithelioma embryonal tumors is similar to that outlined for children aged 3 years and younger with medulloblastoma. (Refer to the medulloblastoma Treatment of children aged 3 years and younger section of this summary for more information).

With the use of chemotherapy alone, outcome has been variable, with survival rates at 5 years ranging between 0% and 50%.[18-20]; [21][Level of evidence: 2Di] The addition of craniospinal irradiation to chemotherapy-based regimens may successfully treat some children but with anticipated neurodevelopmental decline.[22][Level of evidence: 2A]

Treatment of children older than 3 years

Standard treatment options for children older than 3 years with newly diagnosed nonmedulloblastoma, nonmedulloepithelioma embryonal tumors include the following:

1. Surgery.
2. Adjuvant radiation therapy.
3. Adjuvant chemotherapy.

Surgery

Evidence (surgery):

1. Attempting aggressive surgical resection is the first step in the management of newly diagnosed nonmedulloblastoma embryonal tumors. Although previous studies did not demonstrate that the extent of resection is predictive of outcome,[23-25] one study demonstrated an improved survival when the tumor was completely resected.[26][Level of evidence: 2A] A published study (COG-ACNS0332 [NCT00392327]) of molecularly classified nonmedulloblastoma embryonal tumors revealed improved overall survival (OS) for patients who had less than 1.5 cm2 of residual disease compared with patients who had more than 1.5 cm2 of residual disease.[12][Level of evidence: 1iiA]
2. Nonmedulloblastoma embryonal tumors are often amenable to resection; in reported case series, 50% to 75% of patients were totally or near-totally resected.[23,24]; [12][Level of evidence: 1iiA]

Adjuvant radiation therapy

After surgery, children with nonmedulloblastoma embryonal tumors usually receive treatment similar to that received by children with high-risk medulloblastoma.

Conventionally, patients are treated with radiation to the entire neuraxis with local boost radiation therapy, as given for medulloblastoma.[25] However, the local boost radiation therapy may be problematic because of the size of the tumor and its location in the cerebral cortex. Also, there is no definitive evidence that craniospinal radiation therapy is superior to radiation to the primary tumor site alone in children with nondisseminated lesions.[23-25]

Adjuvant chemotherapy

The chemotherapeutic approaches during and after radiation therapy are similar to those used for children with high-risk medulloblastoma. Three-year to 5-year OS rates of 25% to 50% have been noted.[23-25]; [26,27][Level of evidence: 2A]; [28][Level of evidence: 3iiiB]

In a published study of nonpineal tumors that were diagnosed as CNS primitive neuroectodermal tumors (PNETs) by traditional pathology, 71% of these cases were revealed to be glioblastoma or another diagnosis by DNA methylation studies. Patients with nonmedulloblastoma embryonal tumors (n = 36) (including pineoblastomas, n = 26) had a 5-year OS of 78.5% (95% confidence interval [CI], 62.2%–94.8%). In contrast, the patients with glioblastoma had a 5-year OS of 12% (95% CI, 0%–24.7%). The study showed no benefit for children who received carboplatin or isotretinoin.[12][Level of evidence: 1iiA] This study highlights the importance of molecular classification of tumors traditionally termed CNS-PNET.[4]

Treatment of Childhood Embryonal Tumors with Multilayered Rosettes or Medulloepithelioma

There are few data on which to base treatment of newly diagnosed medulloepithelioma and embryonal tumor with multilayered rosettes (ETMR). Treatment considerations are usually the same as those for children with high-risk medulloblastoma and for children aged 3 years and younger at diagnosis with other embryonal tumors. (Refer to the Treatment of children older than 3 years with high-risk medulloblastoma and the Treatment of children aged 3 years and younger sections of this summary for more information.)

References

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