Ask the Expert: How the 2016 World Health Organization (WHO) classification affects the diagnosis and management of brain tumours

The World Health Organization (WHO) provides an internationally recognized classification of brain tumours that is used by neuropathologists around the world to diagnose these diseases. Since the previous WHO update in 2007, there have been a number of significant advances in our understanding of the molecular characteristics and behaviour of certain types of brain tumours.

The most recent WHO Classification (WHO2016), released this year, is the result of two years of hard work by international experts in the fields of neuropathology, neuro-oncology, and molecular pathology. WHO2016 combines new information about molecular characteristics and importantly, it also affects the way oncologists treat these diseases. 
 
Examples of molecular characteristics include mutations in a gene called isocitrate dehydrogenase (IDH1/2), or the loss of genetic material on chromosomes 1 and 19. Chromosomes are thread-like strands that come in pairs and contain the genes responsible for hereditary information.  Most humans have 23 pairs and each strand has a short (p) and a long (q) arm. Characteristic changes in tumours affect how we diagnose the various types of gliomas, including astrocytoma, oligodendroglioma and glioblastoma
 
In the past, classification of gliomas was based primarily on how tumour cells and tissue looked under a microscope (“histology”) and how fast cells grew and how much tumour cells resembled or were different from the non-cancer cells of origin (“grade”). For gliomas, the main histological types have included oligodendrogliomas and astrocytomas. The grade of the tumour ranges from the most benign (grade I) to the most malignant (grade IV). 
 
Brain tumours rarely metastasize or leave the central nervous system and are therefore not “staged” as other cancers are. Staging refers to how extensively the cancer has spread beyond the original site of disease. This occurs commonly with some cancers, like lung and breast, but very infrequently with brain cancer.
 
WHO grade II and III gliomas (also called infiltrating gliomas because of their tendency to invade brain tissue) include those with cells that look like astrocytomas or oligodendrogliomas. The majority of these carry IDH1/2 mutations. In addition, many of these are characterised by a change in an amino acid in position 132 (R132H) in the IDH1 gene.  Amino acids are the building blocks of proteins and are found in every cell of the body. This change can be clearly identified by pathology testing and provides an accurate diagnosis of an infiltrating glioma.  
 
Oligodendrogliomas were previously identified by the way the tissues looked, including a cellular appearance resembling  “fried eggs,” and a fine network of blood vessels that look like “chicken wire.” However, diagnosis by these histological features alone failed to accurately predict how these tumours behaved. Oligodendrogliomas are expected to respond well to treatment, but sometimes they behave like more aggressive tumours.  Some oligodendroglial tumours are characterized by changes in their genes. The loss of genetic material on the p arm of chromosome 1 and the q arm of chromosome 19 is associated with a tumour that does behave well; those tumours that do not have this loss of genetic material tend to behave more malignantly and do not respond as well to treatment. As a result of this discovery, a more accurate diagnosis can be made.
 
The WHO2016 classification system continues to include histological descriptions that have been used for the past 100 years, but it gives priority to more precise molecular characteristics such as the presence or absence of IDH mutation and the loss or retention of 1p19q chromosomal material. In the 2016 classification, there are three new subtypes of tumours: 
  1. IDH mutated, 1p19q- codeleted (which have the best response to treatment) ;
  2. IDH mutated, 1p19q- retained (which have an intermediate response to treatment);
  3. No IDH mutation (the worst responders, and the poorest prognosis).

"Mixed" gliomas, also called oligoastrocytomas, are no longer recognized. 

These and other elements of the new classification system allow us to better predict a patient’s prognosis and help us choose the most appropriate therapy for an individual patient.  The diagnostic categories in WHO2016 have been adopted in B.C. and will become the new standard in pathology labs in brain tumour centres around the world. 
Special thanks to Stephen Yip, M.D., Ph.D., FRCPC, Neuropathologist, Vancouver General Hospital and BC Genome Sciences Centre for his assistance with this article.
 
References:
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H.  
Wiestler OD, Kleihues P, Ellison DW (2016). The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathologica 131:803–820 DOI 10.1007/s00401-016-1545-1
 
The Cancer Genome Atlas Research Network. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. New England Journal of Medicine 2015; 372: 2481-2498.

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