Molecular pathology of tumors of the central nervous system

Abstract

Since the update of the 4th edition of the WHO Classification of Central Nervous System (CNS) Tumors published in 2016, particular molecular characteristics are part of the definition of a subset of these neoplasms. This combined 'histo-molecular' approach allows for a much more precise diagnosis of especially diffuse gliomas and embryonal CNS tumors. This review provides an update of the most important diagnostic and prognostic markers for state-of-the-art diagnosis of primary CNS tumors. Defining molecular markers for diffuse gliomas are IDH1/IDH2 mutations, 1p/19q codeletion and mutations in histone H3 genes. Medulloblastomas, the most frequent embryonal CNS tumors, are divided into four molecularly defined groups according to the WHO 2016 Classification: wingless/integrated (WNT) signaling pathway activated, sonic hedgehog (SHH) signaling pathway activated and tumor protein p53 gene (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH-activated. Molecular characteristics are also important for the diagnosis of several other CNS tumors, such as RELA fusion-positive subtype of ependymoma, atypical teratoid rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes, and solitary fibrous tumor/hemangiopericytoma. Immunohistochemistry is a helpful alternative for further molecular characterization of several of these tumors. Additionally, genome-wide methylation profiling is a very promising new tool in CNS tumor diagnostics. Much progress has thus been made by translating the most relevant molecular knowledge into a more precise clinical diagnosis of CNS tumors. Hopefully, this will enable more specific and more effective therapeutic approaches for the patients suffering from these tumors.

Keywords: CNS tumor; embryonal tumor; glioma; integrated diagnosis; medulloblastoma; molecular pathology.

Figure 1.

The integrated diagnostic workflow used in CNS tumor diagnostics depicted here is based on novel molecular platforms for next-generation sequencing (NGS) and genome-wide DNA methylation profiling besides conventional microscopy. Microscopy for standard histological evaluation includes panels of immunohistochemical staining (IHC) and in some laboratories also FISH analyses. NGS panels with selected genes allow for the detection of mutations, copy number variations (CNVs) and gene fusions. Genome-wide DNA methylation profiling is a novel approach with high potential as a support tool for a more refined and robust classification of CNS tumors.

Figure 2.

The pathological diagnosis of CNS tumors is a multi-step process starting with tumor tissue and in some cases also blood samples being analyzed with multiple tests to provide an integrated diagnosis. Evaluation and discussion of the pathological diagnosis by a multidisciplinary board of specialists from radiology, surgery, oncology, and (neuro)pathology is crucial for translating the findings into optimal therapeutic management for individual patients.