Cellular Classification of Central Nervous System (CNS) Embryonal Tumors

The classification of a childhood brain tumor is based on both the histopathologic characteristics of the tumor and its location in the brain.[1-3] The histopathological classification of childhood central nervous system (CNS) embryonal tumors remains somewhat controversial. These tumors all develop on the background of an undifferentiated round cell tumor but show a variety of divergent patterns of differentiation. Although it has been proposed that these tumors be merged under the term primitive neuroectodermal tumor, histologically similar tumors in different locations in the CNS demonstrate different genetic alterations.[4-8] In the 2007 World Health Organization (WHO) classification, embryonal tumors include the following:[2,9]

• Medulloblastoma.
• CNS primitive neuroectodermal tumors (PNETs).
• Medulloepithelioma.
• Ependymoblastoma.
• Atypical teratoid/rhabdoid tumor. Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumors for more information.

Pineoblastoma, a tumor histologically similar to CNS embryonal tumors, is reviewed in this summary, although pineoblastoma is grouped with tumors of the pineal region in the WHO classification.

By definition, medulloblastomas must arise in the posterior fossa.[1-3] Five different subtypes of medulloblastoma are recognized by the WHO classification and includes the following:

• Classic.
• Desmoplastic/nodular.
• Medulloblastoma with extensive nodularity.
• Large cell.
• Anaplastic.[1]

Significant attention has been focused on medulloblastomas that display anaplastic features, including increased nuclear size, marked cytological pleomorphism, numerous mitoses, and apoptotic bodies.[10,11] Classification is a complicated matter because most medulloblastomas have some degree of anaplasia, foci of anaplasia may appear in tumors with histologic features of both classic and large cell medulloblastomas, and there is significant overlap between the anaplastic and large cell variant.[10-13] The incidence of medulloblastoma with desmoplastic variant is higher in infants, is less common in children, and increases again in adolescents and adults. The desmoplastic variant subtype is different from medulloblastoma with extensive nodularity; the nodular variant having an expanded lobular architecture. The nodular subtype occurs almost exclusively in infants and carries an excellent prognosis.[13]

CNS PNETs generally arise in the cerebrum or suprasellar region, but may arise in the brain stem and spinal cord.[14] According to the 2007 WHO classification, tumors demonstrating areas of distinct neuronal differentiation are termed cerebral neuroblastomas and, if ganglion cells are also present, ganglioneuroblastomas. The pineoblastoma is histologically similar to the medulloblastoma; however, according to the WHO, its histogenesis is linked to a pineal cell, the pineocyte. Histologically different from the pineocyte, a pineal parenchymal tumor of intermediate differentiation showing elements of pineoblastoma and pineocytoma is recognized, although its natural history is variable and poorly characterized.[1,2] Genome-wide characterization of PNETs and pineoblastomas has demonstrated substantial molecular heterogeneity among these tumors.[8]

Both medulloepithelioma and ependymoblastoma are identified as histologically discrete tumors within the WHO classification system.[9,15] Medulloepithelioma and ependymoblastoma 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 extraneural, along nerve roots.[9,15]

The existence of ependymoblastomas as a discrete entity has been questioned, although it remains in the most recent WHO classification. Ependymoblastoma is characterized by the presence of true multilayered (or ependymoblastic) rosettes.[16,17] The tumor has a supratentorial predilection, but like medulloepithelioma, it may occur in the spine, especially in the sacrococcygeal region. Histologically, the tumor shares features with other embryonal tumors and with a rare tumor type, the "embyronal tumor with abundant neuropil and true rosettes" (ETANTR).[16-19] The latter entity is characterized by young age at diagnosis (median age approximately 2 years), primarily supratentorial presentation, poor prognosis, and tumors showing true multilayered/ependymoblastic rosettes within a background of abundant neuropil-like areas.[17,19,20] In addition to sharing clinical characteristics (i.e., age, primary site, and prognosis), ependymoblastoma and ETANTR show common genomic alterations, including chromosome 2 gain and focal amplification at chromosome band 19q13.42. The latter chromosome region contains a cluster of microRNA coding genes,[21] and its amplification appears to be present in virtually all pediatric embryonal tumors with true multilayered rosettes (i.e., ependymoblastoma and ETANTR).[20-22] By contrast, 19q13.42 amplification has not been detected in more than 300 other pediatric brain tumors, suggesting that it may be a useful diagnostic marker for ependymoblastoma and ETANTR.[20]

The pathologic classification of pediatric brain tumors is a specialized area that is evolving. Immunohistochemical staining is now a routine component of evaluation.[10,11] Molecular genetic profiles are also being incorporated into evaluation and may radically alter classification in the future.[23-26] For example, gene expression profiling divides medulloblastoma into distinctive biological subtypes that differ in their clinical presentation, their underlying genomic abnormalities, and their immunohistochemical staining pattern.[25-27]

Subgroups include the following:

• Medulloblastoma with aberrations in the WNT pathway: These cases occur most commonly in older children and are characterized by beta-catenin nuclear immunoreactivity, monosomy 6, classic medulloblastoma histology, and have a highly favorable outcome in children.[24-26]

• Medulloblastoma with aberrations in the sonic hedgehog (SHH) pathway: These cases represent the majority of medulloblastoma arising in young children (age <3 years) and also occur commonly in older adolescents and adults. They are characterized by chromosome 9q deletions, by desmoplastic/nodular histology, and by mutations in SHH pathway genes including PTCH1, as well as PTCH2, SMO, and SUFU. The primary histology for these cases is desmoplastic. Outcome is relatively favorable for these cases.[23-26]

  Patients with desmoplastic tumors with extensive nodularity should be carefully evaluated for stigmata of Gorlin syndrome, which is generally associated with mutations in PTCH1. One report observed that medulloblastoma with extensive nodularity (MBEN) was associated with Gorlin syndrome in 5 of 12 cases.[13] Gorlin syndrome is an autosomal dominant disorder, also known as the nevoid basal cell carcinoma syndrome, in which those affected are predisposed to the development of basal cell carcinomas later in life, especially in the radiation portal after radiation therapy. The syndrome can be diagnosed early in life by characteristic dermatological and skeletal features such as keratocysts of the jaw, bifid or fused ribs, macrocephaly, and calcifications of the falx.[13] Germline SUFU mutations have been observed among children younger than 3 years with the desmoplastic/nodular histology and may be most common among young children with MBEN.[28] While SUFU germline mutations may also be associated with Gorlin syndrome, young children with such mutations who develop medulloblastoma appear to often lack stigmata of Gorlin syndrome.[28,29]

• Medulloblastoma associated with other genomic alterations: These other subgroups defined by gene expression profiling are enriched for isochromosome 17q (k17q) and for poor biological prognostic factors such as MYC and MYCN amplification. These subgroups include cases with classic, as well as large cell and anaplastic histology and include most medulloblastoma cases that present with metastatic disease.[23-25]

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