Table of Contents
- Key Points
- Background: Why This Update Matters
- How the Experts Grade Evidence and Recommendations
- Newly Diagnosed Brain Lesions: Telling Tumors from Non-Tumors
- Predicting Molecular Information Without Surgery
- Estimating Prognosis in Newly Diagnosed Gliomas
- Mapping Tumor Extent for Treatment Planning
- What This Means for Patients
- Limitations of the Evidence
- Summary of Recommendations
- Frequently Asked Questions
- Source Information
Key Points
- Updated expert recommendations confirm that amino acid PET is superior to glucose PET for diagnosing, planning treatment, and monitoring gliomas.
- Amino acid PET can help differentiate tumors from non-tumors when MRI is uncertain, but a negative scan does not exclude glioma.
- In over 70% of patients with newly diagnosed glioblastomas, [¹⁸F]FET-PET showed larger tumor volumes than the enhancing volume on MRI.
- Amino acid PET is strongly recommended to distinguish tumor recurrence from treatment-related changes when MRI results are equivocal.
- Strong evidence that PET imaging directly improves patient outcomes is still scarce and is a priority for future research.
Background: Why This Update Matters
Over the past 20 years, PET imaging has become increasingly important in the care of patients with gliomas (brain tumors that arise from glial cells). For many clinical questions, amino acid PET has gained broad international acceptance as a supplement to standard MRI (magnetic resonance imaging) and advanced MRI techniques.
This success came from rigorous research. That research produced many publications, which in turn led expert panels to issue recommendations and clinical guidelines for PET imaging in glioma patients. These guidelines are a joint effort of major organizations in neuro-oncology and nuclear medicine. The organizations include the European Association for Neuro-Oncology (EANO) and the Response Assessment in Neuro-Oncology (RANO) working group. The organizations also include the Society of Neuro-Oncology, the European Association of Nuclear Medicine, and the Society of Nuclear Medicine and Molecular Imaging.
The first guideline for PET imaging in glioma patients was published by the RANO working group together with EANO in 2016. That guideline highlighted that amino acid PET is superior to [¹⁸F]fluorodeoxyglucose PET ([¹⁸F]FDG-PET, a glucose-based tracer) for various clinical applications. The 2016 recommendations were based on the most widely used amino acid tracers. These tracers target system L amino acid transport and include:
- [¹⁸F]fluoroethyl-L-tyrosine ([¹⁸F]FET)
- [¹¹C]methionine ([¹¹C]MET)
- 3,4-dihydroxy-6-[¹⁸F]-fluoro-L-phenylalanine ([¹⁸F]FDOPA)
Since 2016, several hundred articles on PET imaging in gliomas have been published. In 2024, the RANO group proposed standardized criteria for assessing response to treatment. Overall, the initial results were confirmed and refined, the level of evidence improved, and newer indications for amino acid PET imaging were established. One example is evaluating the role of PET in pediatric patients with brain tumors. Other radiolabeled amino acids were also introduced for clinical use.
For example, the alicyclic amino acid anti-1-amino-3-[¹⁸F]fluorocyclobutane-1-carboxylic acid (fluciclovine) has been proposed for imaging primary and secondary brain tumors. Fluciclovine transport is mediated by several neutral amino acid transporters, including system ASC and system L. This uptake mechanism distinguishes fluciclovine from [¹⁸F]FET, [¹¹C]MET, and [¹⁸F]FDOPA.
Reimbursement by statutory health agencies for PET imaging with radiolabeled amino acids has now been granted in Germany, Denmark, and France. This reimbursement covers the use of PET to differentiate treatment-related changes from tumor relapse in glioma patients. The panel anticipates that other European countries will soon grant similar reimbursement.
The updated guidelines in this Policy Review aim to serve medical professionals of all disciplines involved in the diagnosis and care of glioma patients. The guidelines also provide a framework for the use of PET in neuro-oncology.
How the Experts Grade Evidence and Recommendations
The RANO working group for PET defined levels of evidence based on how strongly study findings were validated. Any study that confirmed PET findings with neuropathology was considered the highest degree of validation. Neuropathology means histology (tissue examination), molecular information according to the most recent WHO classifications for CNS tumors, and combinations of these.
The second degree of validation was correlation with conventional MRI, when applicable according to RANO criteria, and with the patient's clinical course. Only papers constituting levels 1–3 of evidence according to the Oxford Centre for Evidence-Based Medicine were included as bases for the recommendations.
The evidence levels are defined as follows:
- Level 1: randomized controlled trial
- Level 2: prospective cohort study, ecological studies, or outcomes research
- Level 3: retrospective study or individual case-control studies
The panel also graded the strength of each recommendation for clinical practice. The grade was based on the level of evidence and the body of evidence, including the number of available studies and the consistency and coherence of those studies. The strength categories are:
- Strong: the evidence strongly supports the use of this imaging study
- Moderate: there is moderate evidence supporting the use of this imaging modality
- Weak: the evidence is limited; expert opinion suggests use, but evidence is minimal
The table below compares the evidence levels from the 2016 guideline with those in this 2025 Policy Review.
- Differentiation of neoplastic from non-neoplastic lesions: level 3 in 2016, level 3 in 2025
- Delineation of glioma extent for planning of local therapy options: level 3 in 2016, level 2 in 2025
- Differentiation of glioma recurrence from treatment-related changes (for example, pseudoprogression): level 3 in 2016, level 2 in 2025
- Detection of malignant tumor parts within MRI findings suggestive of non-enhancing gliomas: level 3 in 2016, level 2 in 2025
- Assessment of prognosis in newly diagnosed, untreated gliomas: level 3 in 2016, level 3 in 2025
- Response assessment: level 3 in 2016, level 2 in 2025
- Analysis of cost-effectiveness: not applicable in 2016, level 2 in 2025
- Pediatric patients with gliomas (for differential diagnosis and follow-up after treatment): not applicable in 2016, level 3 in 2025
Newly Diagnosed Brain Lesions: Telling Tumors from Non-Tumors
Neoplastic lesions such as gliomas typically show considerably higher uptake of radiolabeled amino acids than non-neoplastic lesions. This difference can help doctors make a presurgical differential diagnosis.
Studies evaluating the diagnostic performance of PET with [¹⁸F]FET or [¹¹C]MET reported a specificity for a neoplastic diagnosis in the range of 76% to 91%. Specificity means the ability to correctly identify patients who do not have the disease.
In newly diagnosed lesions that look like glioma on imaging, a pathologically increased [¹⁸F]FET uptake has been linked to a positive predictive value of 98% for a neoplastic diagnosis. Positive predictive value means the chance that a positive test result correctly identifies a tumor. A subsequent study reported sensitivity and specificity higher than 90% for diagnosing a tumor of glial origin with [¹⁸F]FET. Sensitivity means the ability to correctly identify patients who do have the disease.
Evidence for other amino acid tracers, such as [¹⁸F]FDOPA or fluciclovine, for differentiating neoplastic from non-neoplastic lesions is scarce.
One important finding stands out: 20–30% of patients with CNS WHO grade 2 gliomas that carry an isocitrate dehydrogenase (IDH) gene mutation show no amino acid uptake. IDH is a gene that, when mutated, is linked to certain glioma types.
Brain lesions without tracer uptake and with MRI findings suggest that CNS WHO grade 2 gliomas might show photopenic defects on amino acid PET. Photopenic means the uptake appears visually lower than that of normal-appearing brain tissue. These lesions might still be gliomas, including some tumors with a higher CNS WHO grade. This effect has also been reported for the radiolabeled amino acids [¹¹C]MET and [¹⁸F]FDOPA.
Although much less common, mild amino acid tracer uptake above background level can occur in non-neoplastic lesions. Examples include brain ischaemia (reduced blood flow to the brain), cerebral abscess, or inflammatory foci. Mild uptake can also be related to epileptic seizures.
To summarize the most relevant clinical aspects for newly diagnosed brain lesions:
- Amino acid PET shows high diagnostic performance in differentiating between neoplastic and non-neoplastic lesions when conventional imaging results remain uncertain.
- A negative amino acid PET scan does not exclude glioma.
- Amino acid PET adds valuable information for the differential diagnosis of suspected CNS lesions, but neuropathological tissue evaluation remains mandatory to provide a final diagnosis.
Predicting Molecular Information Without Surgery
Invasive procedures are required to obtain tissue samples to establish specific molecular information. This requirement has prompted the evaluation of various non-invasive neuroimaging approaches, including amino acid PET, to accurately obtain information at the molecular level.
Such an approach could be useful when molecular test results are inconclusive. It could also help when tumors are in anatomical locations that are difficult to access for resection or biopsy sampling.
The value of dynamic amino acid PET for predicting the IDH genotype has been investigated for the tracers [¹⁸F]FET and [¹⁸F]FDOPA. IDH genotype refers to whether mutations are present in the IDH1 or IDH2 genes. These studies showed that, in gliomas with amino acid uptake, there was a correlation between dynamically acquired PET parameters and the IDH mutational status. A short time-to-peak value was particularly correlated. This finding is potentially helpful for non-invasive prediction of this marker.
Analyses of perfusion and diffusion MRI metrics combined with static parameters derived from [¹⁸F]FET-PET or [¹⁸F]FDOPA-PET also showed predictive value. These static parameters include tumor-to-brain ratios and the biological tumor volume. The combined approach identified the IDH mutational status with an area under the curve greater than 0.9. The area under the curve is a statistical measure of how well a test can distinguish between two groups; a value above 0.9 indicates excellent performance.
The role of amino acid PET for artificial intelligence (AI) and radiogenomics applications is being explored. Radiogenomics is the study of how imaging features relate to genetic information. Studies using PET with [¹⁸F]FET, [¹⁸F]FDOPA, and [¹¹C]MET have shown predictive value in identifying:
- The IDH genotype
- 1p/19q co-deletion (loss of two chromosome regions, a marker of certain glioma types)
- O-6-methylguanine-DNA methyl transferase (MGMT) promoter methylation status (a chemical change that affects how tumors respond to certain chemotherapy drugs)
- Telomerase reverse transcriptase (TERT) promoter mutation status (a genetic change common in some gliomas)
In light of the phase 3 INDIGO trial, PET imaging of therapeutically relevant targets has gained considerable interest, especially for response assessment. These targets include the mutant IDH1 and IDH2 enzymes, which are targets for novel anticancer agents in gliomas. As a result, efforts were initiated to develop selective PET tracers with high specificity for IDH mutations. The goal is to improve the assessment of response to IDH inhibitors such as vorasidenib. This need exists because conventional MRI findings frequently remain unchanged following treatment with these agents.
In 2024, researchers reported successful labeling of the IDH inhibitor ivosidenib with the positron emitter ¹⁸F. Furthermore, the ¹⁸F tracer showed excellent metabolic stability in vivo (in living organisms). However, there was no significant difference in tracer uptake between IDH-mutant and IDH-wildtype tumors in a preclinical mouse model. Further research for PET ligands with high binding selectivity for IDH-mutant gliomas is warranted.
Overall, studies provide initial evidence for a potential role of amino acid PET alone and in combination with MRI for the non-invasive prediction of molecular parameters. However, the validity and generalizability of the results warrant further investigation.
Estimating Prognosis in Newly Diagnosed Gliomas
Static parameters derived from amino acid PET allow an estimation of prognosis. In several studies, these parameters provided prognostic information beyond molecular markers with high prognostic value, such as IDH mutational status. The PET parameters improved predictions of progression-free survival and overall survival. Progression-free survival is the time a patient lives without the disease getting worse.
In patients with CNS WHO grade 2 gliomas, dynamic [¹⁸F]FET parameters might help to identify gliomas at risk for less favorable outcomes. Of note, these studies were performed before the release of the 2021 WHO classification. As a result, prognostication in such studies might have been imprecisely assessed.
[¹⁸F]FET-PET radiomics is an emerging approach in the evaluation of amino acid radiotracer uptake distribution and heterogeneity. Radiomics is the extraction of many quantitative features from medical images. This approach shows potential in obtaining prognostic information and is under investigation.
In summary, static and dynamic parameters obtained from amino acid PET provide valuable adjunctive information. This information helps estimate prognosis in patients with gliomas at the time of initial diagnosis and in the postoperative setting. The following parameters are associated with poorer prognosis:
- High uptake intensity
- Large PET-avid volumes (that is, a large biological tumor volume)
- Short time-to-peak values obtained from amino acid PET
Mapping Tumor Extent for Treatment Planning
Accurate delineation of glioblastoma extent is of utmost importance in prognosis assessment, surgical and radiotherapeutic planning, and follow-up monitoring. Delineation means defining the exact boundaries of the tumor.
Conventional MRI allows the determination of the tumor only to a limited extent. In particular, visualizing tumor boundaries within the oedema (swelling) and non-enhancing glioma parts remains challenging. Emerging data suggest that the extent of spread beyond the enhancement has substantial prognostic implications. This spread constitutes the non-enhancing volume of glioblastomas.
Notably, in over 70% of patients with newly diagnosed glioblastomas, [¹⁸F]FET-PET displayed larger tumor volumes than the enhancing volume observed on MRI.
What This Means for Patients
This updated guideline confirms and strengthens the clinical value of amino acid PET imaging for patients with gliomas. The evidence level improved from 2016 to 2025 for several key indications. These include delineating tumor extent for treatment planning, distinguishing tumor recurrence from treatment-related changes, detecting malignant tumor parts, and assessing response to treatment.
For patients, this means that amino acid PET can provide important information at every stage of the disease:
- At diagnosis: helping to distinguish tumors from non-tumors when MRI results are unclear
- Before biopsy or surgery: guiding the biopsy to the most malignant tumor parts
- For treatment planning: defining the exact tumor extent for surgery and radiotherapy
- During treatment: assessing whether the treatment is working
- After treatment: distinguishing early and late treatment-related changes from actual tumor relapse
The guideline also underscores the superiority of amino acid PET over glucose PET ([¹⁸F]FDG-PET) for these applications. This superiority is important because it means patients receive more accurate information from amino acid tracers.
Reimbursement for amino acid PET has been granted in Germany, Denmark, and France for differentiating treatment-related changes from tumor relapse. Patients in other European countries may soon have similar access.
However, the panel also underscores the scarcity of class 1 evidence showing that incorporating PET imaging into clinical workflows improves patient outcomes. Class 1 evidence comes from randomized controlled trials, the strongest type of medical evidence. This gap highlights priority areas for future clinical studies.
Limitations of the Evidence
The panel identified several important limitations. First, there is a scarcity of class 1 evidence showing that incorporating PET imaging into clinical workflows improves patient outcomes. Most recommendations are based on level 2 or level 3 evidence, not on randomized controlled trials.
Second, a negative amino acid PET scan does not exclude glioma. Between 20% and 30% of patients with CNS WHO grade 2 gliomas carrying an IDH mutation show no amino acid uptake. This means some gliomas may be missed if doctors rely on PET results alone.
Third, mild amino acid tracer uptake can occur in non-neoplastic conditions such as brain ischaemia, cerebral abscess, inflammatory foci, or epileptic seizures. This overlap can complicate the interpretation of PET scans.
Fourth, studies on prognosis in CNS WHO grade 2 gliomas were performed before the release of the 2021 WHO classification. As a result, prognostication in those studies might have been imprecisely assessed.
Fifth, evidence for newer tracers such as [¹⁸F]FDOPA or fluciclovine for differentiating neoplastic from non-neoplastic lesions is scarce. The validity and generalizability of results on non-invasive molecular prediction warrant further investigation.
Finally, efforts to develop PET tracers selective for IDH mutations have not yet succeeded. A ¹⁸F-labeled ivosidenib tracer showed no significant difference in uptake between IDH-mutant and IDH-wildtype tumors in a preclinical mouse model.
Summary of Recommendations
The panel issued the following recommendations for the clinical use of amino acid PET in patients with gliomas:
- Differentiation of neoplastic from non-neoplastic lesions (level 3, moderate): In newly diagnosed brain lesions, amino acid PET can be recommended for differentiating between neoplastic and non-neoplastic lesions when conventional MRI results remain uncertain.
- Delineation of glioma extent for planning of local therapy options (level 2, strong): Amino acid PET is strongly recommended to provide additional information on the delineation of glioma extent.
- Differentiation of glioma recurrence from treatment-related changes (level 2, strong): Amino acid PET is strongly recommended to provide additional information in differentiating glioma relapse from treatment-related changes, such as pseudoprogression, when conventional MRI results remain equivocal.
- Detection of malignant tumor parts within MRI findings suggestive of non-enhancing gliomas (level 2, strong): Amino acid PET is strongly recommended to identify the most malignant glioma components.
- Assessment of prognosis in newly diagnosed, untreated gliomas (level 3, weak): Amino acid PET can be considered for estimating prognosis in patients with gliomas at the time of initial diagnosis.
- Response assessment (level 2, moderate): Amino acid PET can be recommended to assess response to anticancer therapy, such as alkylating chemotherapy or antiangiogenic therapy. In clinical trials, the use of standardized response criteria as provided by the PET RANO 1.0 criteria is strongly recommended.
- Pediatric patients with gliomas (level 3, weak): In pediatric patients with glioma, amino acid PET can be considered for differentiating between neoplastic and non-neoplastic lesions when conventional MRI results remain uncertain, and for follow-up after treatment.
The guideline also provides a framework for the use of PET at any stage of disease. The stages include suspected or newly diagnosed glioma, relapsed glioma on MRI, biopsy or resection planning, radiotherapy or chemoradiotherapy, maintenance therapy, and follow-up.
Frequently Asked Questions
What is amino acid PET and how is it different from a regular PET scan?
Amino acid PET uses radiolabeled amino acids such as [¹⁸F]FET, [¹¹C]MET, or [¹⁸F]FDOPA to image brain tumors. It is different from glucose PET ([¹⁸F]FDG-PET), which uses a sugar-based tracer. Updated expert recommendations confirm that amino acid PET is superior to glucose PET for diagnosing, planning treatment, and monitoring gliomas, giving patients more accurate information.
Can amino acid PET tell whether a newly found brain lesion is a tumor or something else?
Yes, when conventional MRI results are uncertain, amino acid PET can help differentiate between tumors and non-tumors. In studies using [¹⁸F]FET or [¹¹C]MET, specificity for a tumor diagnosis ranged from 76% to 91%. However, a negative scan does not exclude glioma, and tissue evaluation remains mandatory for a final diagnosis.
Does a negative amino acid PET scan mean I definitely do not have a brain tumor?
No. A negative amino acid PET scan does not exclude glioma. Between 20% and 30% of patients with CNS WHO grade 2 gliomas that carry an IDH gene mutation show no amino acid uptake. These lesions might still be gliomas, including some with a higher grade. Therefore, a biopsy or tissue evaluation is still needed for a definitive diagnosis.
How is amino acid PET used to plan brain tumor surgery or radiation?
Amino acid PET helps define the exact boundaries of a glioma, which is important for surgical and radiotherapy planning. In over 70% of patients with newly diagnosed glioblastomas, [¹⁸F]FET-PET showed larger tumor volumes than the enhancing volume seen on MRI. This information helps doctors target the full extent of the tumor.
Can amino acid PET help tell the difference between tumor recurrence and treatment-related changes?
Yes. When MRI results are equivocal, amino acid PET is strongly recommended to differentiate glioma relapse from treatment-related changes such as pseudoprogression. This use has level 2 evidence and strong recommendation. Reimbursement for this indication has been granted in Germany, Denmark, and France, and other European countries may soon follow.
What does it mean if my amino acid PET scan shows high uptake or a large tumor volume?
In studies, high uptake intensity, large PET-avid volumes (large biological tumor volume), and short time-to-peak values on amino acid PET were associated with poorer prognosis in patients with gliomas. These parameters can provide prognostic information beyond molecular markers such as IDH status, helping estimate progression-free and overall survival.
Is amino acid PET available for children with brain tumors?
In pediatric patients with glioma, amino acid PET can be considered for differentiating between tumors and non-tumors when MRI results remain uncertain, and for follow-up after treatment. This recommendation is based on level 3 evidence and is graded as weak. The role of PET in pediatric brain tumors is a newer indication established since 2016.
When should a patient with a suspected or newly diagnosed glioma seek a second opinion on PET imaging?
Amino acid PET adds information when conventional MRI results remain uncertain, including distinguishing tumors from non-tumors, defining tumor extent for surgery and radiotherapy, and separating tumor recurrence from treatment-related changes. Because a negative amino acid PET scan does not exclude glioma, and 20–30% of IDH-mutant grade 2 gliomas show no amino acid uptake, an expert review of imaging and pathology can clarify the diagnosis and treatment plan. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: Update to the RANO working group and EANO recommendations for the clinical use of PET imaging in gliomas
Authors: Norbert Galldiks, Philipp Lohmann, Mariam Aboian, Ramon Barajas, William G. Breen, Jana Ivanidze, et al.
Publication: The Lancet Oncology, Volume 26, Issue 8, August 2025, pages e436–e447
DOI: 10.1016/S1470-2045(25)00193-7
Publisher: Amsterdam UMC
This patient-friendly article is based on peer-reviewed research.
