core functions of the World Health Organization (WHO) is to develop global diagnostic guidelines to ensure the appropriate use of available scientific evidence in support of global public health and equality. For almost a decade, Prof. Pieter Wesseling, a neuropathologist affiliated with Amsterdam UMC and Princess Máxima Center for Pediatric Oncology in Utrecht, has been at the forefront of developing, inventorizing, reviewing, and summarizing diagnostic criteria of tumors that arise from the central nervous system, including brain tumors.
The digital version of the fifth edition of the WHO ‘Classification of Tumors of the Central Nervous System’ was published in November 2021, and the printed WHO ‘Blue Book’ of this classification in January 2022. It is an elaborate book of over 600 pages that provides comprehensive and detailed information about cancers of the central nervous system (CNS). It covers primary CNS tumor types and subtypes, starting from the definition / localization of tumors and the cells of origin, macro- and microscopic pathology, and molecular features, to how patients usually present themselves, epidemiological data, and disease prognosis. Moreover, a table with diagnostic criteria is included for each tumor type to greatly facilitate the accurate diagnosis of a CNS tumor.
A global team effort
“This state-of-the-art, in-depth collection of information on tumor classification is the product of real teamwork,” says Professor Wesseling. “On one hand, you consider all the research results generated over the years by thousands of colleagues all over the world. On the other, there are over 200 contributing authors and 12 expert members, including myself, who guide and oversee the WHO classification.”
Professor Pieter Wesseling
“Starting with the incorporation of molecular characteristics in the definition of brain tumors in 2016, the WHO classification of CNS tumors has revolutionary changed. This is a giant leap forward, and hopefully one that can soon be translated into improved outcome for the patients suffering from these tumors."
Professor Wesseling’s involvement in the WHO expert panel is a recognition of his considerable expertise in pathology analyses and many years of research on the characterization of tumors of the central nervous system.
Pinpointing a tumor diagnosis without a microscope: A revolutionary development
In 2019, Professor Wesseling organized a meeting in the Netherlands with over two dozen international experts. The mission of this meeting was to find out how to optimally include molecular tumor features in the diagnosis of brain tumors and thereby provide a basis for the fifth edition of the WHO classification of these tumors. It was clear that tumor-specific, including epigenetic, DNA modifications could provide novel and valuable diagnostic insights for classifying these tumors, the diagnosis of which previously was based solely on microscopic analysis (histology).
Professor Wesseling further argued this rationale by referring to an article in the prestigious scientific journal Nature in 2018. He explains: “A new molecular tool allows us to look at 850,000 locations along the chromosomes to see the distribution of methyl groups (the ‘methylation fingerprint’). If you do that systematically in a large cohort of tumors, you can match new tumor samples with DNA modification patterns from previous samples. This overlap in DNA modification patterns often allows for classification of brain tumor without even looking through a microscope. Furthermore, such a molecular-based classification frequently is more precise and less error-prone in comparison to the discerning ability of a pathologist's eyes. This molecular-based diagnosis of brain tumors is a revolutionary development.”
This molecular-based diagnosis of brain tumors is a revolutionary development.” Prof. Pieter Wesseling
While there are still are many tumors where you ’precisely can hit the nail on the head’ and can deduce an accurate diagnosis through microscopic analysis, in many other cases histological features provide only clues, and additional molecular markers are needed to precisely pinpoint the nature of the tumor.
Global differences
The world-wide standardization of diagnostic hallmarks provided by WHO is of immense value. It defines a common ‘language’ and empowers transparency, the sharing of research findings, and the implementation of standardized treatments based on the latest science across the world.
“There is also a political aspect to publishing new WHO classifications. Not everyone has access to modern analytical tools,” says Prof. Wesseling. “So, some people say, 'you should only update or change the classification if we can apply it worldwide'. That’s a challenge, because WHO principles are aimed at equality - but at the same time at raising medical standards worldwide.”
Worldwide inequality means that more developed nations will continue to advance insights on their own, resulting in diverging standards and an inability to compare findings with countries that do not have access to the latest diagnostic equipment. One way to deal with this reality is to translate molecular tumor features discovered through e.g. DNA methylation analysis into so-called surrogate markers: relatively simple and cheap tools (such as immunohistochemistry) that enable quite accurate tumor characterization in less privileged nations.
Prof. Wesseling adds: “It is better to know what you do not know. So in situations where the molecular (or surrogate marker) analysis required for a precise brain tumor diagnosis could not be performed, ‘not otherwise specified’ can be added to the diagnosis. This helps to better understand the records for research on treatment and disease outcome.”
Future outlook
The pathology classification is now somewhat ahead of our clinical practice regarding treatment. Prof. Wesseling: “Previously, categories were less well defined and a mix of tumor (sub)types were grouped together under one diagnosis. As a result, responses to treatment that were recorded in the past may not be representative for the different types we now distinguish molecularly. It is important to now work on a better understanding of which brain tumor (sub)types are more sensitive to radiation or other forms of treatment, including targeted therapies.”
“The tools that we now have to molecularly characterize tumors are really powerful,” concludes Prof. Wesseling. “Starting with the incorporation of molecular characteristics in the definition of brain tumors in 2016, the WHO classification of CNS tumors has revolutionary changed. This is a giant leap forward, and hopefully one that can soon be translated into improved outcome for the patients suffering from these tumors.”
For more information contact Professor Pieter Wesseling.
Text by Henri van de Vrugt