Primitive Neuroectodermal Tumor

In 2016, the World Health Organization (WHO) published a revised classification of central nervous system (CNS) tumors using molecular parameters. In this classification, some tumors previously recognized in the 2007 classification had been renamed or eliminated. The primitive neuroectodermal tumor (PNET) is no longer recognized. CNS embryonal tumors are now classified using specific genetic/molecular characteristics. Using molecular analysis, many tumors that were previously reported as PNET are now reclassified into know tumors with specific genetic characteristics.  Medulloblastomas are the most common embryonal tumors and have their own genetic/molecular defined groups (SHH-activated TP53-mutant, SHH-activated TP53-wildtype, WNT-activated, non-SHH/WNT group three, and non-SHH/WNT group four) in addition to their histologically defined groups (classic, desmoplastic/nodular, medulloblastoma with extensive nodularity, and large cell/anaplastic). A combination of the genetic profile and the histology determines the prognosis of these tumors. The sonic hedgehog protein, important in cell specialization and growth, is encoded in the SHH gene at chromosome 7. The WNT gene family in the chromosome 12q13 region encode for signaling proteins that regulate cell proliferation, cell fate, and embryogenesis. All other embryonal tumors are classified depending if they have an amplification of the C19MC region (19q13.42) on chromosome 19. If they have the amplification, they are called embryonal tumor with multilayered rosettes, C19MC-altered (WHO 9478/3*). If they do not have the amplification, they are called embryonal tumor with multilayered rosettes, NOS (WHO 9478/3). The other embryonal tumors are classified as medulloepithelioma (9501/3), CNS neuroblastoma (9500/3), CNS ganglioneuroblastoma (9490/3), and atypical teratoid/rhabdoid tumor (ATRT) with alterations of INI1 or in rare occasions BRG1. Immunohistochemical staining for INI1 or BRG1 expression is used to distinguish them. Those tumors that do not have alterations of either INI1 or BRG1 are classified as embryonal tumors with rhabdoid features (WHO 9508/3). Those embryonal tumors without amplification of the C19MC, no alterations of INI1 or BRG1, and no rosettes, are called embryonal tumor, NOS (WHO 9473/3). This last group is a wastebasket category for the tumors previously called PNET, which can not be classified under a genetic/molecular group. In tumors with the “NOS” designation (not otherwise specified), there is insufficient information for classification. Some of these tumors were previously named embryonal tumor with abundant neuropil and true rosettes. Concurrent with the publication of the WHO 2016 classification, a group recognized four new categories for PNET. They reviewed their previously classified PNET database and found that based on molecular analysis of the tumor samples, most of them were indistinguishable from known CNS supratentorial tumors and were classified into those known CNS supratentorial tumors. The small group of other tumors which can not be attributed to known CNS supratentorial tumors were classified into the four new categories. The new categories include CNS neuroblastoma with Forkhead Box R2 (FOXR2) activation, CNS Ewing sarcoma family tumor with CIC alteration, CNS high-grade neuroepithelial tumor with meningioma 1 gene (MN1) alteration, and CNS high-grade neuroepithelial tumor with BCL6 Corepressor (BCOR) alteration. The small number of tumors that did not show any molecular specificity to be included in a specific category were called CNS embryonal tumors, NOS. This group is similar to the wastebasket category of the WHO 2016 classification. The significance of these results have yet to be analyzed and incorporated in a future WHO classification. These four new groups had also been confirmed by a Polish study in 2020.