Molecular diagnostics in embryonal brain tumors

Abstract

Embryonal brain tumors are a heterogeneous group of neoplasms united by the presence of poorly differentiated stem-like cells. Molecular details are increasingly being used to separate them into biologically and clinically meaningful groups. For medulloblastoma, integrated mRNA expression profiling and DNA analysis by a number of research groups defines 4-6 distinctive molecular variants. A subset with prominent Wnt activity is associated with good clinical outcomes and classic histology. Medulloblastomas showing a Hedgehog gene expression signature are frequently of the desmoplastic/nodular subtype. Interestingly, Hedgehog activity is found in tumors arising either in infants or older teenagers and adults. The association of clinically aggressive medulloblastoma with MYC expression, large cell/anaplastic change and high levels of photoreceptor differentiation transcripts has also been noted in several studies. Immunohistochemical analysis of just one or two genes per molecular medulloblastoma variant may be sufficient for accurate classification, and this would be of great practical utility if validated. Advances have also been made in the classification of central nervous system (CNS) Primitive Neuroectodermal Tumors (PNET), as several groups have identified an amplicon at chromosome 19q13.41-42, which appears to define a unique PNET subtype associated with prominent true rosettes, young age and very poor outcomes.

Figure 1

Embryonal brain tumor histopathology. A. “Classic” medulloblastoma lack distinctive features and are comprised of sheets of poorly differentiated cells. B. Desmoplastic/nodular medulloblastoma contain scattered pale islands of differentiated cells (asterisk) surrounded by more pleomorphic internodular zones. C. Medulloblastoma with extensive nodularity contain back to back nodules which can extend into elongated streams of neuropil surrounding rows of small round tumor cells. D. Large cell medulloblastoma are characterized by plump, round, discohesive tumor cells with prominent nucleoli (asterisk), while in anaplastic medulloblastoma nuclei are angular and molded (right side). As seen in this panel, both patterns can co‐exist in a single tumor. E. Atypical teratoid/rhabdoid tumors often have a “jumbled” appearance, and rhabdoid cells can be hard to find. F. Central nervous ystem (CNS) primitive neuroectodermal tumors (PNET) can have a variety of appearances; this supratentorial case contains anaplastic foci (asterisks). G. Embryonal tumors with abundant neuropil and true rosettes (ETANTR) feature multilayered rosettes often arising from paucicellular regions rich in tumor neuropil. H. Other regions of ETANTR can lack the distinctive rosettes and neuropil. (Original magnification 400 × for all images).

Figure 2

Molecular classification of medulloblastoma.