The World Health Organization (WHO) sponsors a group of pathologists and clinicians who are experts in brain and spinal cord tumors to develop the criteria for how brain tumors are classified and graded. As the scientific field continues to better understand the biology of brain tumors, a separate organization, cIMPACT (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy), periodically reviews and updates new recommendations that guide the WHO’s brain tumor classifications.
The latest round of revisions to the WHO classifications for brain tumors will officially be published later this year, and leaders of the process to update the classification have just published a review article that previews the updates. Here’s what patients and caregivers need to know now.
Is this good news?
Yes! Science continues to advance and is helping researchers and doctors understand brain tumors better than ever before. The WHO experts have now able to apply the latest knowledge to further refine how we classify and grade brain tumors. While this is not the end of the story, it’s a significant and positive step forward for the brain tumor community.
Why are updates to brain tumor classifications important?
These periodic updates make brain tumor classifications more accurate. This is important for three reasons:
- The diagnosis and care of patients – More precise classifications leads to more accurate diagnoses for patients. More accurate diagnoses can lead to better estimates of prognosis and predicting how a tumor is going to “behave” or respond to treatment, which therefore can also help guide what course of care a patient should receive.
- Conducting and interpreting brain tumor research and clinical trials – All clinical trials rely on accurate classification, and our understanding of experimental studies (whether in mice, petri dishes, or in human clinical trials) depends on the accurate classification of what is being studied.
- Population-level research, disease trends, and funding – Truly understanding the population of people affected by various tumor types, the trends of these diagnoses, and potentially uncovering common elements that may point to causes and risk factors all depend on accurate classifications of tumors.
So what’s in the new updates?
This fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5) builds on the 2016 updates and the cIMPACT updates—incorporating molecular data with histology (how tumors look under a microscope) in classifying brain tumors.
Four key takeaways that the brain tumor community should know are:
- Some updates help clarify how the field talks about brain tumor grades. Other updates revise how certain tumor types are classified based on their molecular features. Together, these changes group brain tumors into more biologically and molecularly defined groups and introduce new types of tumors and subtypes, especially in the pediatric population. Some top-line numbers:
- 22 new entities (tumor types) have been added — seven in the glioma category, three in the glioneuronal category, four each in the ependymal and embryonal groups, three sarcomas, and one new pituitary tumor.
- 13 entities will have revised terminology; for example, the tumor currently known as “supratentorial ependymoma, RELA fusion-positive” will now be referred to as “supratentorial ependymoma, ZFTA fusion-positive.”
- Three types of tumors that were formerly subtypes or variants are now recognized as their own distinct full tumor type.
- There will now be grading within tumor types. For example, IDH-mutant and 1p/19q-co-deleted oligodendrogliomas will now be given a specific CNS grade of 2 or 3. This essentially means the term “anaplastic” will no longer be used to distinguish more aggressive tumors of the same origin.
- Adult and pediatric glioma classifications continue to be refined to reflect that the types of gliomas that occur in infants, children, adolescents, and young adults often differ in their molecular make-up and behavior from their adult counterparts of the same name. Therefore, there will now be a division of diffuse gliomas into groups that occur primarily in adults and those that occur mainly in children:
- Adult-type diffuse gliomas
- Astrocytoma, IDH-mutant (grades 2 through 4)
- Oligodendroglioma, IDH-mutant and 1p/19q-co-deleted (grades 2 and 3)
- Glioblastoma, IDH-wildtype (grade 4)
- Pediatric-type diffuse low-grade gliomas
- Diffuse astrocytoma, MYB- or MYBL1-altered
- Angiocentric glioma
- PLENTY (polymorphous low-grade neuroepithelial tumor of the young)
- Diffuse low-grade glioma, MAPK pathway-altered
- Pediatric-type diffuse high-grade gliomas
- Diffuse midline glioma, H3 K27-altered
- Diffuse hemispheric glioma, H3 G34-mutant
- Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype
- Infant-type hemispheric glioma
- There will be some significant changes to tumors classified as glioblastoma, as well as other grade 4 tumors:
- Previously, tumors were classified as glioblastoma based on certain characteristics pathologists would identify when looking at biopsy samples under the microscope, and this was true for tumors both with and without mutations to their IDH genes. Now, glioblastoma diagnoses will be reserved exclusively for tumors without IDH mutations (“IDH-wildtype” tumors) that have certain features under the microscope. Conversely, tumors that have similar features under the microscope but are IDH-mutant will now be classified as astrocytoma, IDH-mutant grade 4.
- In some situations, molecular information can be used for grading (as opposed to just using microscopic features).
- For instance, astrocytomas that don’t necessarily look like glioblastomas under a microscope, but are IDH-wildtype, will also be classified as glioblastoma if they have one or more of three other molecular characteristics— (1) TERT promoter mutation, (2) EGFR gene amplification, (3) combined gain of entire chromosome 7 and loss of entire chromosome 10 (+7/-10).
- In addition, for IDH-mutant adult diffuse astrocytomas that test positive for what’s known as a “CDKN2A/B homozygous deletion” will automatically be labeled grade 4, regardless of their appearance under the microscope.
These updates underscore the importance of patients and caregivers knowing their particular tumors, and the need for comprehensive molecular testing at diagnosis and recurrence. Now more than ever before, the types of genetic and molecular changes that occur in different tumors will define how they are classified and diagnosed.
For newly diagnosed patients, consider seeking care at a medical center that has experience and expertise in diagnosing and treating brain tumor patients (such as most large academic-affiliated teaching hospitals and/or National Cancer Institute-designated cancer centers of excellence), appropriate molecular testing should be available. If patients are/were not able to receive an initial diagnosis at a center that has access to adequate molecular tumor testing capabilities, however, it is important to ask the team there if they’d be able to send your biopsy sample out to a capable lab in another hospital or to a private company such as Foundation Medicine or Caris Life Sciences to get a full workup completed.
When the full updates are published by the WHO (in a publication known as “the Blue Book,” expected later this summer or early fall), NBTS will provide a more detailed overview of the changes with leaders from the WHO CNS group who developed the classifications as well as key neuro-oncologists who can explain how these changes impact patients.
How does this affect me if I’m a survivor or still living with a tumor that was previously diagnosed?
It’s important to note that while the terminology used to classify certain tumor types may change to more accurately describe its molecular features, in a vast majority of cases, these updates will not impact your treatment or quality of care. It is common for basic science to move faster than breakthroughs in the clinic. It’s our expectation that research will continue to improve our understanding of brain tumors, further refine diagnostic criteria, and help guide the development of more effective and personalized clinical trials, and ultimately new precision treatments.
If you have any questions or concerns about how your care and treatment plans may be impacted, consult your medical team, who should be aware of the new classification. Some questions to consider asking are:
- Should I have my tumor tissue tested to determine if it should be reclassified?
- Is there any tumor tissue left from my initial biopsy and diagnosis? Is it able to be retested?
- Does this medical center have the capabilities to do advanced molecular testing?
- If not, would you be able to send my sample out to an appropriate lab for additional testing?
- How might these updates affect my potential eligibility to participate in clinical trials now or in the future?
This might be particularly true for patients who’ve recently had a recurrence or who are currently in “wait-and-watch” protocol.
When and how will these updates be implemented?
Like any tumor classification system, these are works in progress, and science continues to evolve. It is incumbent upon the research and medical community to use these new criteria to ensure that each individual patient is receiving the best care possible.
NBTS will be encouraging academic and biopharma industry researchers designing clinical trials to review the new classification and seek opportunities to expand clinical trials eligibility appropriately, and we will be reviewing health care coverage policy implications.
NBTS looks forward to sharing more information on the strides being made to better classify brain tumors. As always, please contact the National Brain Tumor Society’s Personalized Support and Navigation team at patientnavigator@braintumor.org for individual support.
