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PubMed This is a summary of 22 peer-reviewed journal articles Updated
Oncology · Ependymoma

Ependymoma Subtypes and the 2021 WHO Classification

At a Glance

In 2021, the WHO updated ependymoma classification to focus on molecular subtypes rather than microscopic appearance. Tumors are now categorized by location and genetics, such as PFA, PFB, or ZFTA-fused, which more accurately predicts tumor behavior and helps guide personalized treatment plans.

For decades, doctors looked at ependymoma cells through a microscope and assigned them a “grade” (I, II, or III) based on how aggressive the cells appeared [1]. However, in 2021, the World Health Organization (WHO) fundamentally changed this approach [2]. We now know that the tumor’s molecular subgroup—the specific genetic and chemical changes inside the tumor—is a much more accurate predictor of how the disease will behave than its appearance under a microscope [3][4].

A Major Shift in Classification

The 2021 WHO update moved away from simple “histology” (microscope appearance) toward a system that categorizes tumors by their location and their molecular fingerprint [2]. In fact, the old distinction between “classic” and “anaplastic” (Grade III) ependymoma has largely been dropped because molecular profiling is more reliable for predicting outcomes [5][6].

1. Supratentorial Ependymomas (Upper Brain)

Tumors in the upper part of the brain are now primarily defined by their gene fusions—where two genes that should be separate are stuck together [7]. These tumors are officially named using an acronym system to denote their location and genetic driver [7].

  • ST-EPN-ZFTA (ZFTA-fused, formerly RELA-fused): (ST for Supratentorial, EPN for Ependymoma, and ZFTA for the fused gene). These are the most common in children [8]. They are often aggressive and are driven by a specific signaling pathway called NF-κB [9]. Doctors often use a marker called L1CAM to help identify these tumors [10].
  • ST-EPN-YAP1 (YAP1-fused): These are rarer and tend to occur in very young children [8]. They often have a more favorable outlook compared to ZFTA-fused tumors [8].

2. Posterior Fossa Ependymomas (Lower Brain)

The most common site for ependymoma in children is the posterior fossa (at the back of the head). These are divided into two main groups [11]:

Subgroup Typical Patient Molecular Profile Outlook
Group A (PFA) Young children (avg. age 3) “Silent” genome; loss of a chemical mark called H3K27me3 [12] Generally more aggressive. While it requires intensive treatment, specialized multidisciplinary teams have specific protocols—like aggressive gross-total resection and access to clinical trials—designed to fight it [13][14].
Group B (PFB) Older children and adults Many chromosomal gains and losses [11] Generally more favorable with higher survival rates [11].

3. Spinal Ependymomas (Spinal Cord)

The 2021 classification introduced a critical new category for spinal tumors and updated an old one [2]:

  • SP-EPN-MYCN (MYCN-amplified): This is a rare, recently discovered subtype that is very aggressive [15]. It is defined by having too many copies (amplification) of the MYCN gene [16]. These tumors have a high risk of spreading through the cerebrospinal fluid [16].
  • Myxopapillary Ependymoma (MPE): Historically, this was considered a “Grade 1” (slow-growing) tumor. However, the 2021 guidelines officially upgraded it to Grade 2 [5]. This shift happened because experts realized MPE can be more aggressive than once thought, sometimes spreading to other parts of the spine or brain [17][18].

Why Molecular Subtypes Matter

Your care team uses this molecular information for three main reasons:

  1. Tailored Treatment: Some subtypes, like ST-EPN-ZFTA, are being studied for specific targeted therapies that might not work on other types [19].
  2. Surgical Planning: For aggressive types like PFA, achieving a “gross-total resection” (removing 100% of the visible tumor) is the single most important factor for survival [14][20].
  3. Better Forecasting: Knowing the subgroup helps your doctor understand the risk of the tumor coming back, allowing for a more personalized schedule of follow-up MRI scans [11][21].

If your pathology report only lists “ependymoma” without a molecular subgroup, ask your doctor if DNA methylation profiling is available to provide a clearer picture of the tumor’s biology [11][22]. You can learn more about how to audit your medical records in Decoding Your Pathology and Surgical Reports.

Common questions in this guide

What does the 2021 WHO classification mean for my ependymoma diagnosis?
The 2021 WHO update shifted diagnosis from relying purely on how cells look under a microscope to identifying the tumor's genetic makeup. Your diagnosis will now likely include a specific molecular subtype, which helps doctors predict tumor behavior and tailor your treatment.
What is the difference between a PFA and PFB ependymoma?
PFA and PFB are the two main molecular subgroups of ependymoma found in the posterior fossa, or lower brain. PFA typically occurs in younger children and usually requires intensive treatment, while PFB is more common in older children and adults and generally has a more favorable outlook.
Why was myxopapillary ependymoma upgraded to a Grade 2 tumor?
Historically considered a slow-growing Grade 1 tumor, myxopapillary ependymoma was upgraded to Grade 2 in 2021. Experts recognized that it can act more aggressively than previously thought, occasionally spreading to other areas of the spine or brain.
What is a ZFTA-fused ependymoma?
A ZFTA-fused ependymoma is a type of tumor located in the upper brain (supratentorial). It is driven by a specific genetic change where two genes are joined together, and it is the most common ependymoma type found in children.
Why is DNA methylation profiling important for ependymoma?
DNA methylation profiling is a specialized test that identifies the exact molecular fingerprint of your tumor. It confirms the specific WHO subtype, which is essential for determining the most effective targeted therapies, surgical approach, and follow-up plan for your case.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What is the molecular subgroup of the tumor (e.g., PFA vs. PFB, or ZFTA-fused)?
  2. 2.Has DNA methylation profiling been performed on the tumor tissue to confirm the 2021 WHO classification?
  3. 3.Does the tumor show MYCN amplification, and how does that change the treatment approach?
  4. 4.If the diagnosis is myxopapillary ependymoma, how does the new Grade 2 classification affect the plan for follow-up imaging?
  5. 5.Is our surgical plan aimed at 'gross-total resection' based on the specific behavior of this molecular subtype?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

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This page explains the 2021 WHO classification of ependymoma subtypes for educational purposes. Always consult your neuro-oncologist to interpret your specific pathology report and treatment plan.

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