Most types of brain tumor are, individually, rare. While all primary central nervous system tumors taken together occur at a rate of roughly 30 new cases per 100,000 people each year, the vast majority of specific subtypes fall well below the threshold that defines a rare disease, which is fewer than 6 new cases per 100,000 per year.1PubMed Central. Rare Primary Central Nervous System Tumors in Adults: An Overview That means doctors treating a chordoma, an atypical teratoid rhabdoid tumor, or a primary CNS lymphoma are often working with a thin evidence base and a small community of specialists. Yet the past decade has reshaped how these tumors are understood, diagnosed, and treated, in some cases dramatically.
Why Classification Changed So Much
For most of the twentieth century, brain tumors were classified almost entirely by how they looked under a microscope. Two tumors that appeared identical could behave very differently in different patients, and nobody had a satisfying explanation. That changed when molecular tools became cheap and fast enough to use routinely. The 2021 fifth edition of the WHO Classification of Tumors of the Central Nervous System made molecular diagnostics central to how brain tumors are named and grouped.2PubMed Central. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary For many tumor types, an “integrated” diagnosis that combines both the tissue appearance and the molecular profile is now required.3Neuro-Oncology. Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline
This matters for rare brain tumors in a concrete way. When you can define a tumor by its genetic alterations, you sometimes discover that what looked like several different diseases are actually one, or that what seemed like one disease contains distinct subtypes needing very different treatments. The reclassification also opened the door to targeted therapies, because once you know the specific molecular change driving a tumor’s growth, you can look for drugs designed to block it.4Interdisciplinary Neurosurgery. Molecular markers in Gliomas: A practical review and algorithm proposal
Diffuse Midline Gliomas
Among the most feared rare brain tumors are diffuse midline gliomas, a category that includes what was once called DIPG (diffuse intrinsic pontine glioma), a childhood tumor centered in the brainstem. Up to about 80 percent of pediatric diffuse midline gliomas carry a mutation in a histone protein gene that swaps a single amino acid at a critical position.5PubMed Central. Detection of histone H3 K27M mutation and post-translational modifications in pediatric diffuse midline glioma via tissue immunohistochemistry informs diagnosis and clinical outcomes Tumors with this mutation respond more poorly to treatment and carry a worse prognosis than those without it, which is why identifying the mutation is now part of the formal diagnosis. The WHO reclassified the entire group and broadened the definition after researchers found that several related molecular alterations can produce similar effects on the histone.6Indian Journal of Neurosurgery. H3 K27M-Altered Diffuse Midline Gliomas: A Review
The prognosis remains grim for most patients, with median survival typically measured in months. Surgery is rarely an option because the tumors grow diffusely through deep brain structures. Radiation can buy time but is not curative. The molecular reclassification has, however, opened new clinical trial avenues: if you know the precise molecular driver, you can design trials around it rather than treating every brainstem glioma as interchangeable.
Craniopharyngiomas
Craniopharyngiomas sit near the base of the brain, usually close to the pituitary gland and the optic nerves. They develop from embryonic tissue remnants and, despite being classified as low-grade, cause serious problems because of where they grow. Symptoms commonly include vision loss, hormonal disruption, increased pressure in the skull, and dysfunction of the hypothalamus, the brain region that regulates hunger, temperature, and sleep.7PubMed Central. Endocrine Disorder in Patients With Craniopharyngioma
Surgery has traditionally been the first-line treatment, but it comes with a harsh trade-off: the more aggressive the surgery, the greater the risk of permanent hormonal damage and hypothalamic obesity. Studies show that rates of pituitary dysfunction, diabetes insipidus, and hypothalamic obesity all climb significantly after surgery, and these complications tend to be worse in the adamantinomatous subtype and in patients who experience tumor recurrence.8PubMed Central. Characteristics and factors influencing hypothalamic pituitary dysfunction in patients with craniopharyngioma This is why the recent success of targeted drug therapy for the papillary subtype has generated so much excitement, which we will get to shortly.
Chordomas
Chordomas are slow-growing tumors that arise from leftover cells of the notochord, the embryonic structure that eventually becomes the spine. They tend to appear at the base of the skull or along the sacrum. Growth is slow but relentless, and chordomas are notorious for coming back after surgery. Nearly all chordomas express a protein called Brachyury, which serves as a useful marker for diagnosis.9PubMed Central. Brachyury: A sensitive marker, but not a prognostic factor, for skull base chordomas The degree of surgical removal remains the strongest predictor of whether a chordoma recurs and how long patients survive.
Research has also shown that when Brachyury levels are especially high, patients tend to have shorter times before the tumor grows back. Almost half of chordomas carry extra copies of the Brachyury gene, and the number of copies tracks closely with how much of the protein the tumor makes. Importantly, the growth-promoting PI3K/Akt signaling pathway appears to be turned up in tumors with high Brachyury, which suggests a potential drug target.10PubMed. Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma In laboratory chordoma cells, blocking PI3K signaling reduced Brachyury levels and slowed growth.
Two Other Rare Subtypes Worth Knowing
Atypical teratoid rhabdoid tumors (AT/RT) are aggressive cancers that mainly strike young children. In nearly all cases, the underlying cause is loss of a gene called SMARCB1, which normally acts as a brake on cell growth. In rare instances a related gene, SMARCA4, is involved instead. One analysis of 89 cases at a single institution found zero instances where both genes were altered simultaneously, underscoring how unusual co-occurrence is.11PubMed Central. A rare case of atypical teratoid rhabdoid tumor (AT/RT) with homozygous SMARCB1 loss and one concurrent somatic heterozygous SMARCA4 variant Identifying the specific gene affected matters because treatment strategies and clinical trials increasingly hinge on the precise molecular profile.
Primary central nervous system lymphoma (PCNSL) is a cancer of immune cells that forms in the brain rather than in lymph nodes or blood. High-dose methotrexate is the backbone of initial treatment because it is one of the few chemotherapy drugs that reliably crosses the blood-brain barrier. A systematic review found that overall response rates to methotrexate-based regimens cluster around 70 to 76 percent, and two-year progression-free survival ranges from roughly 50 to 55 percent, with some evidence that adding rituximab improves both numbers.12PubMed Central. A Systematic Review of High-Dose Methotrexate for Adults with Primary Central Nervous System Lymphoma
Liquid Biopsy for Brain Tumors
Getting a tissue sample from a brain tumor means surgery, which is invasive, risky, and sometimes not recommended at all. Liquid biopsy sidesteps this by looking for fragments of tumor DNA floating in cerebrospinal fluid (CSF). In brain tumors, the approach holds particular promise because a single surgical biopsy may miss important genetic diversity within a tumor, while CSF can capture DNA shed from multiple regions at once.13Brain. The coming of age of liquid biopsy in neuro-oncology
Beyond initial diagnosis, CSF liquid biopsy can track whether a tumor is responding to treatment, detect new genetic changes that open the door to targeted drugs, and catch early signs of recurrence. The technology is not yet standard of care, but clinical adoption is growing, particularly for patients whose tumors sit in locations where a needle biopsy would be too dangerous.14PubMed. Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases
Targeted Therapies That Changed Expectations
Some of the most striking recent results in rare brain tumors come from drugs that target specific molecular mutations. For papillary craniopharyngiomas, which frequently carry a BRAF V600E mutation, a combination of BRAF and MEK inhibitors produced objective responses in 15 of 16 patients in a recent trial, with a median tumor volume reduction of about 91 percent.15PubMed Central. BRAF-MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas For a tumor that previously required radical surgery with significant side effects, the prospect of shrinking it by nine-tenths with pills is transformative.
The same BRAF V600E mutation shows up in other rare brain tumors, including pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma. In a case series, patients with these tumors experienced near-complete or substantial radiographic responses after just eight weeks of dual BRAF/MEK therapy.16Journal of Neurosurgery. Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity A larger study of adults with BRAF-mutant glial and glioneuronal tumors found that about 39 percent achieved a partial or complete response, with a median tumor reduction of 78 percent in responders, and their progression-free survival on the targeted drugs exceeded what they had achieved on first-line therapy.17PubMed. Sustained Tumor Control With MAPK Inhibition in BRAF V600-Mutant Adult Glial and Glioneuronal Tumors
These results depend entirely on the tumor carrying the right molecular target. A craniopharyngioma without the BRAF mutation will not respond to a BRAF inhibitor. This is why molecular profiling at diagnosis, not just at relapse, is becoming standard practice.
Getting Drugs Past the Blood-Brain Barrier
The brain is shielded by a tightly sealed network of blood vessels that keeps most drugs out, which is a major reason brain tumors are so hard to treat. One of the more promising workarounds involves focused ultrasound combined with tiny microbubbles injected into the bloodstream. When ultrasound waves hit the microbubbles, they vibrate and temporarily loosen the junctions between cells lining the blood vessels, creating a window for drugs to slip through.18PubMed Central. Focused ultrasound-mediated enhancement of blood-brain barrier permeability for brain tumor treatment: a systematic review of clinical trials The opening is reversible, usually closing within hours.
In animal models, this technique roughly doubled the delivery of doxorubicin (a common chemotherapy drug) to targeted tumor regions compared to what conventional methods achieved.19Scientific Reports. Evaluation of blood-tumor barrier permeability and doxorubicin delivery in rat brain tumor models using additional focused ultrasound stimulation Clinical trials in humans are underway for several tumor types. The approach is non-invasive, can be aimed at specific brain regions, and does not require the patient to undergo open surgery just to get chemotherapy where it needs to go.
Advances in Surgery and Radiation
Surgeons treating skull-base tumors increasingly operate through the nose using endoscopes, avoiding large craniotomies. One challenge in these procedures is distinguishing tumor from normal tissue in real time. A technique called “second-window ICG” uses a near-infrared dye that passively accumulates in tumors over about 24 hours. In early results, skull-base tumors including craniopharyngiomas, chordomas, and pituitary adenomas all lit up under near-infrared imaging, producing clear contrast against the surrounding tissue.20PubMed Central. Near-Infrared Optical Contrast of Skull Base Tumors During Endoscopic Endonasal Surgery
A different fluorescent agent, 5-ALA, is well-established for high-grade gliomas but showed poor results in endoscopic skull-base surgery. In a multicenter study, only 2 of 28 skull-base tumors showed any fluorescence at all, making 5-ALA largely unhelpful in this setting.21Journal of Neurosurgery. Limited utility of 5-ALA optical fluorescence in endoscopic endonasal skull base surgery: a multicenter retrospective study The contrast between these two fluorescence approaches highlights that no single imaging tool works for every brain tumor scenario.
On the radiation side, proton beam therapy offers a physical advantage over conventional X-ray radiation for tumors near sensitive structures. Because protons deposit most of their energy at a precise depth and then stop, they can deliver high doses to the tumor while largely sparing the optic nerves, pituitary gland, and brainstem that sit millimeters away. Published reports support a benefit for craniopharyngiomas, chordomas, skull-base sarcomas, and certain meningiomas.22Cancer Control. Clinical Benefits of Proton Beam Therapy for Tumors of the Skull Base
Immunotherapy and CAR T Cells
Immunotherapy has revolutionized treatment for melanoma and some other solid cancers, but progress in brain tumors has been slower. CAR T-cell therapy, which re-engineers a patient’s own immune cells to recognize and attack tumor cells, is being tested in early-phase trials for pediatric brain tumors. In one completed Phase 1 trial, four children with high-grade gliomas or AT/RT received CAR T cells infused directly into their brain or spinal fluid. No dose-limiting toxicities occurred, and side effects were mild, though three of the four patients still had disease progression.23Neuro-Oncology. Locoregional infusion of EGFR806-CAR T cells for recurrent or refractory pediatric CNS tumors: Results of the completed BrainChild02 phase 1 clinical trial One patient with a spinal cord diffuse midline glioma showed what could have been tumor response or pseudoprogression, followed by a complete response to subsequent chemotherapy.
Results like these are humbling but expected at the Phase 1 stage, where the primary goal is to demonstrate safety. The brain is an immunologically privileged site, meaning the immune system’s usual tools are dampened there, and many brain tumors actively suppress immune responses in their local environment. Getting CAR T cells into the brain, keeping them active, and preventing the tumor from evading them are all active research problems.
Why Running Clinical Trials Is So Difficult
Rare tumors face a paradox: they need clinical trials the most (because existing treatments are often inadequate) but are the hardest tumors to study (because there aren’t enough patients to fill traditional trial designs). A standard randomized trial for a tumor that affects a few hundred people per year in an entire country could take a decade to enroll enough participants.
One solution gaining traction is the basket trial. Instead of grouping patients by tumor type, basket trials group them by molecular alteration. A patient with a BRAF-mutant chordoma and a patient with a BRAF-mutant craniopharyngioma could join the same trial, because the drug targets the mutation, not the tissue of origin.24Neurotherapeutics. Accelerating discovery: Transformative clinical trial models in neuro-oncology This approach is especially attractive for rare CNS tumors, where a targetable mutation might appear in too few patients with any single histology to ever power a traditional disease-specific trial.
Preclinical Models and Drug Screening
Before a drug reaches patients, it has to be tested in models that mimic the tumor’s behavior. For rare brain tumors, two models have become increasingly important. Patient-derived organoids are three-dimensional clusters of tumor cells grown from an individual patient’s tissue, preserving many features of the original tumor’s biology and microenvironment.25PubMed Central. Patient-derived complex organoids are a critical tool to understand and explore pediatric malignant brain tumors These can be used for high-throughput drug screens, testing hundreds of compounds to see which ones slow growth.
When organoids are combined with orthotopic xenograft models, where patient-derived tumor cells are implanted into the brains of mice, researchers can validate drug responses in a living system. Studies have shown that these paired models reproduce clinically meaningful responses, including sensitivity to temozolomide in tumors with the right epigenetic profile and responsiveness to targeted inhibitors in tumors carrying specific mutations.26Acta Neuropathologica. Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology For rare tumors where clinical trial data is thin, these models are sometimes the best evidence available to guide individual treatment decisions.
AI-Assisted Imaging and Diagnosis
Rare brain tumors pose a diagnostic challenge simply because most radiologists see very few of them. Artificial intelligence tools trained on large imaging databases can help. For craniopharyngiomas, a systematic review and meta-analysis of AI-based models found strong performance in diagnosis, tumor boundary identification, and classification of tumor subtypes.27PubMed. Artificial Intelligence-Based Radiomic Model in Craniopharyngiomas: A Systematic Review and Meta-Analysis on Diagnosis, Segmentation, and Classification AI is also being applied more broadly to other rare brain tumors, including pediatric tumors and extra-axial tumors, with promising early results in detection and prognosis prediction.28Insights into Imaging. Clinical applications of artificial intelligence and radiomics in neuro-oncology imaging
The appeal here is straightforward. A community radiologist in a rural hospital may encounter a chordoma once in a career. An AI model trained on thousands of cases can flag the possibility immediately, prompting earlier referral to a specialized center. These tools are not replacing expert neuroradiologists, but they can function as a safety net, catching unusual tumors that might otherwise be misidentified or diagnosed late.
Life After Treatment
Surviving a rare brain tumor, particularly one treated in childhood, often means living with long-term consequences. Cognitive deficits are reported in 40 to 100 percent of childhood brain tumor survivors, depending on the series, with problems frequently showing up in intellectual ability, memory, attention, and academic achievement.29Cancer. Medical and neurocognitive late effects among survivors of childhood central nervous system tumors These are not just short-term side effects of treatment; they can persist and sometimes worsen over years.
Endocrine problems are another major long-term issue, especially for survivors treated with cranial radiation or diagnosed at a young age. Hormonal deficits tend to accumulate with time rather than stabilize, which means a survivor who appears endocrinologically normal at five years post-treatment may develop growth hormone deficiency or thyroid problems a decade later.30PubMed. Endocrine outcome in long-term survivors of childhood brain tumors Lifelong hormonal monitoring is standard practice for these patients, though the reality is that follow-up becomes harder to maintain as children age into adulthood and transition between pediatric and adult care systems.
Where You Get Treated Matters
For rare brain tumors, the hospital you go to can meaningfully affect your outcome. A large nationwide study found that each increase of 10 cases in a hospital’s annual surgical volume was associated with lower one-year mortality after craniotomy for brain tumor removal.31PubMed. Association between surgical volume and outcomes after craniotomy for brain tumor removal: A South Korean nationwide cohort study The volume effect held in both adults and children. An earlier analysis of U.S. data found that large-volume centers had about 25 percent lower in-hospital mortality for craniotomies compared to lighter-caseload hospitals, and the gap was even wider for needle biopsies.32PubMed Central. Surgery for primary supratentorial brain tumors in the United States, 1988 to 2000: the effect of provider caseload and centralization of care
High-volume centers tend to have specialized neuro-oncology tumor boards, experienced neurosurgeons, dedicated neuropathologists capable of performing molecular testing, and access to clinical trials. For a rare tumor, the molecular subtyping that determines whether a targeted therapy is an option may not be available at a community hospital. Trends toward centralization of brain tumor care are already underway and likely reflect the measurable benefits of multidisciplinary treatment at these institutions.33Neurosurgery. High Volume Centers Provide Superior Value of Care in the Surgical Treatment of Malignant Brain Tumor If you or someone you know receives a diagnosis of a rare brain tumor, seeking a second opinion or referral to a major academic medical center is one of the most consequential steps you can take.