Cellular and Molecular Classification of CNS Embryonal Tumors
- Medulloblastoma (commonly referred to as classic medulloblastoma).
- Anaplastic medulloblastoma.
- Large cell medulloblastoma.
- Desmoplastic/nodular medulloblastoma.
- Medulloblastoma with extensive nodularity (MBEN).
Significant attention has been focused on medulloblastomas that display anaplastic features, including increased nuclear size, marked cytological pleomorphism, numerous mitoses, and apoptotic bodies.[3,4] Using the criteria of anaplasia is subjective 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.[3,4] One convention is to consider medulloblastomas as anaplastic when anaplasia is diffuse (variably defined as anaplasia occurring in 50% to 80% of the tumor).
The incidence of medulloblastoma with the 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 MBEN; the nodular variant has an expanded lobular architecture. The nodular subtype occurs almost exclusively in infants and carries an excellent prognosis.[5,6]
Biologically/molecularly defined subtypes of medulloblastoma
Multiple medulloblastoma subtypes have been identified based on gene expression profiles.[7-21] As of 2012, there was a general consensus that medulloblastoma can be molecularly separated into at least four subtypes; however, it is likely that further subclassification will occur.[20-22]
- Subtype 1: WNT tumors (medulloblastoma with aberrations in the WNT signaling pathway). Subtype 1 shows a WNT signaling gene expression signature and beta-catenin nuclear staining. They are usually histologically classified as classic medulloblastoma tumors and rarely have a large cell/anaplastic appearance. They are infrequently metastasized at diagnosis. Genetically, these tumors have 6q loss and CTNNB1 mutations and have activated WNT signaling; there may be occasional MYC overexpression.
The WNT subset is primarily observed in older children, adolescents, and adults and does not show a male predominance. The subset is believed to have brain stem origin, from the embryonal rhombic lip region. Subtype 1 tumors are associated with a very good outcome.
- Subtype 2: Sonic hedgehog (SHH) tumors (medulloblastoma with aberrations in the SHH pathway). Subtype 2 tumors are characterized by chromosome 9q deletions; desmoplastic/nodular histology; and mutations in SHH pathway genes, including PTCH1, PTCH2, SMO, SUFU, and GLI2.
Subtype 2 tumors show a bimodal age distribution and are observed primarily in children younger than 3 years and then later in life in older adolescence and adulthood. The tumors are believed to emanate from the external granular layer of the cerebellum. Prognosis for patients with SHH medulloblastoma appears to be negatively affected by other molecular genetic changes, such as chromosome 17p loss, chromosome 3q gain, chromothripsis, p53 amplification, TP53 mutation, and the finding of large cell/anaplastic histology.[21,25] The outcome for patients with SHH medullolastoma is relatively favorable, primarily in children younger than 3 years and adults. This is likely because of the type of mutation present in the SHH pathway, given that patients with upstream mutations such as PTCH1, PTCH2, and SUFU have a more favorable prognosis than do patients with downstream mutations, such as GLI2. Overall outcome in adolescents and young adults with SHH medulloblastoma is not different from that seen in patients with non-WNT pathway–activated tumors, except for patients with TP53 mutations and downstream SHH pathway mutations. Patients with unfavorable molecular findings have an unfavorable prognosis, with less than 50% of patients surviving after conventional treatment.[23,25-27]
- Subtype 3 (Group 3): Histology of Subtype 3 tumors is either classic or large cell/anaplastic and these tumors are frequently metastasized at the time of diagnosis. A variety of different mutations have been noted in these tumors including the presence of i17q and, most characteristically, MYC amplification.
Subtype 3 tumors occur throughout childhood and may occur in infants. Males outnumber females in a 2:1 ratio in this medulloblastoma subtype. Patients with subtype 3 tumors have a variable prognosis. Patients with MYC amplification or MYC overexpression have a poor prognosis, with less than 50% of these patients surviving 5 years after diagnosis. This poor prognosis is especially true in children younger than 4 years at the time of diagnosis. However, patients with subtype 3 tumors without MYC amplification or MYC overexpression who are older than 3 years have a prognosis similar to most patients with medulloblastoma, with a 5-year progression-free survival rate greater than 70%.
- Subtype 4 (Group 4): Subtype 4 tumors are either classic or large cell/anaplastic tumors. Metastasis at diagnosis is common, but not as frequent as is seen in Subtype 3 tumors. Molecularly, they have a CDK6 amplification and MYCN amplification and may also have an i17q abnormality.
Subtype 4 tumors occur throughout infancy and childhood and into adulthood. They also predominate in males. The prognosis is better than Subtype 3 tumors but not as good as Subtype 1 tumors. Prognosis for Subtype 4 patients is affected by additional factors such as the presence of metastatic disease and chromosome 17p loss.[20,21]
Optimal ways of identifying the four core medulloblastoma subtypes for clinical use is under active study, and both immunohistochemical methods and methods based on gene expression analysis are under development.[24,28] It is likely that the classification of medulloblastoma into four major subtypes will be altered in the near future. Further subdivision within subgroups based on molecular characteristics is likely, although there is no consensus regarding an alternative classification.[20,22]
Whether the classification for adults with medulloblastoma has similar predictive ability in children is unknown.[21,23] In one study of adult medulloblastoma, MYC oncogene amplifications were rarely observed and tumors with 6q deletion and WNT activation (as measured by nuclear beta-catenin staining) did not share the excellent prognosis seen in pediatric medulloblastomas, although another study did confirm an excellent prognosis for WNT-activated tumors in adults.[21,23]
CNS Primitive Neuroectodermal Tumors (PNETs) and Pineoblastoma
Genome-wide molecular characterization of PNETs and pineoblastomas has demonstrated substantial heterogeneity among these tumors.
Pineoblastoma is histologically similar to medulloblastoma; however, according to the WHO, its histogenesis is linked to the pineocyte (a type of pineal cell).
CNS PNETs generally arise in the cerebrum or suprasellar region, but may arise in the brain stem and spinal cord. 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.
Biological subtypes of CNS PNETs
Integrative genomic analysis has been used to molecularly subdivide CNS PNETs, with subtypes defined primarily based on their gene expression profiles. In a study of 142 hemispheric tumors, the following three molecular subsets were identified:
- Group 1 (Neural): Group 1 tumors showed gene expression profiles enriched for genes associated with embryonic or neural stem cells and occurred more commonly in young children (median age of 2.9 years) with a female predominance (1.7:1.0). Other subtypes of CNS PNETs have been identified within the group 1 tumors, including embryonal tumors with multilayered rosettes.
- Group 2 (Oligoneural): Group 2 tumors showed upregulation of expression of genes associated with oligoneural differentiation, had no clear-cut sex predominance, and had a median age at presentation of 7.9 years.
- Group 3 (Mesenchymal): Group 3 tumors showed reduced expression of neural differentiation genes and upregulation of epithelial and mesenchymal differentiation genes. They occurred more frequently in males (1.6:1.0), with a median age at presentation of 5.9 years.
Survival was shortest for Group 1 tumors, although treatment varied among all three groups. Group 3 tumors showed the highest rate of metastatic disease at diagnosis. Loss of INI1 protein expression in the absence of rhabdoid cell morphology has been identified in a small subset of CNS PNETs.[Level of evidence: 3iB]
Medulloepithelioma is identified as a histologically discrete tumor within the WHO classification system.[34,35] 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 extraneural, along nerve roots.[34,35]
Ependymoblastoma is identified as a histologically discrete tumor within the WHO classification system; however, the existence of ependymoblastoma as a discrete entity has been questioned by others. Ependymoblastoma tumors are rare and tend to arise most commonly in infants and young children. Ependymoblastoma is characterized by the presence of true multilayered (or ependymoblastic) rosettes.[36,37] 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 embryonal tumor with abundant neuropil and true rosettes (ETANTR).[36-39] The latter entity is characterized by young age at diagnosis (median age of approximately 2 years), primarily supratentorial presentation, poor prognosis, and tumors showing true multilayered/ependymoblastic rosettes within a background of abundant neuropil-like areas.[37,39,40]
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, and its amplification appears to be present in virtually all pediatric embryonal tumors with true multilayered rosettes (i.e., ependymoblastoma and ETANTR).[40-42] 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.
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