PET in Brain Tumours

1. The clinical problem

The neuro-oncology team asks five questions of imaging: is this a tumour, where is its most aggressive part, how far does it extend, is new enhancement after treatment tumour or treatment effect, and is treatment working? Magnetic resonance imaging (MRI) answers the anatomical part; positron emission tomography (PET) is added when the answer depends on biology.

Classification in force: WHO CNS5 (2021)

• Integrated diagnosis. The fifth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumours combines histology with molecular markers in a layered report, and grades tumours within each type using Arabic numerals.
• Adult-type diffuse gliomas. Three types remain: astrocytoma, IDH-mutant (CNS WHO grade 2, 3 or 4); oligodendroglioma, IDH-mutant and 1p/19q-codeleted (grade 2 or 3); and glioblastoma, IDH-wildtype (grade 4). IDH is isocitrate dehydrogenase.
• Molecular grading. Homozygous deletion of CDKN2A/B makes an IDH-mutant astrocytoma grade 4. An IDH-wildtype diffuse astrocytic glioma in an adult is a glioblastoma if it has TERT promoter mutation, EGFR amplification or combined gain of chromosome 7 and loss of chromosome 10, even without necrosis or microvascular proliferation.
• Why it matters for PET. Most cut-offs were derived in cohorts graded by the older histological system, and the joint EANM/EANO/RANO/SNMMI guideline notes that uptake data by molecular type are limited; apply grade-based thresholds to CNS5 diagnoses with care.

Response criteria in force: RANO 2.0 (2023)

• One set of criteria. Response Assessment in Neuro-Oncology (RANO) 2.0 replaces separate high-grade and low-grade criteria. For newly diagnosed glioma the post-radiotherapy MRI, not the post-operative MRI, is the baseline.
• Definitions. Partial response is a ≥50% decrease in the sum of products of perpendicular diameters (or ≥65% by volume) sustained for at least 4 weeks on stable or falling steroids. Progression is a ≥25% increase (or ≥40% by volume) from the smallest measurement.
• The 12-week rule. Pseudoprogression occurs in up to 30–40% of glioblastomas in the 12 weeks after chemoradiotherapy. In a clinically stable patient, progression in this window must be confirmed on repeat MRI (for example at 4 or 8 weeks) or by histology.
• Where PET stands. RANO 2.0 states that amino-acid PET may help separate progression from pseudoprogression but needs further validation before formal inclusion. The separate PET RANO 1.0 criteria (section 7) fill that gap for trials.

Why enhancement after treatment is non-specific

Gadolinium enhancement reflects vascular surface area and leakage across a disrupted blood–tumour barrier, not tumour cell number. Radiotherapy, surgery, inflammation and immunotherapy disrupt the barrier; corticosteroids and anti-angiogenic drugs such as bevacizumab restore it, so enhancement can fade while tumour grows (pseudoresponse). T2 and fluid-attenuated inversion recovery (FLAIR) change is no more specific: oedema, radiation injury, demyelination and ischaemia look the same. After stereotactic radiosurgery (SRS) for metastases, radiation injury and recurrence both appear as an enlarging ring-enhancing lesion.

2. Tracers and why they work

¹⁸F-fluoroethyl-L-tyrosine (FET), ¹¹C-methyl-L-methionine (MET) and 3,4-dihydroxy-6-¹⁸F-fluoro-L-phenylalanine (FDOPA) are carried across the blood–brain barrier and into cells by system L amino-acid transport. Gliomas overexpress L-type amino-acid transporters, chiefly LAT1, so tumour-to-background contrast is high and uptake does not depend on barrier breakdown. This is why amino-acid PET shows the non-enhancing parts of a glioma and why it is less affected than MRI by treatment-induced leakage. ¹⁸F-fluorodeoxyglucose (FDG) reports glucose metabolism, which is intense in normal grey matter; this single fact explains most of its failures in the brain.

Physiological uptake and practical points after the EANM/EANO/RANO/SNMMI glioma guideline (2019), the PET-RANO/EANO recommendations (2016) and the joint meningioma guideline (2024).

Avidity by tumour type

• High-grade glioma. More than 95% of WHO grade 3 and 4 gliomas show increased FET uptake.
• Low-grade glioma. About one-third of WHO grade 2 gliomas, and most dysembryoplastic neuroepithelial tumours, are FET-negative. Uptake overlaps widely between grades, and oligodendroglial tumours are often avid; about half of grade 2 oligodendroglial tumours show a decreasing curve, which mimics a high-grade pattern.
• Brain metastases. FET uptake in untreated metastases is highly variable, most of all in melanoma, and small lesions are underestimated because of limited resolution. PET adds little to MRI for detecting metastases; its value is after treatment.
• Meningioma. Meningiomas overexpress SSTR2, giving intense uptake on SSTR ligands against almost no brain background. A few meningiomas take up little tracer, and grade cannot be read from uptake intensity.

When FDG fails and what replaces it

In a meta-analysis of five histology-controlled studies (119 patients), FET detected brain tumours with a pooled sensitivity of 94% and specificity of 88%, against 38% and 86% for FDG; the authors concluded that FET should be preferred for a new isolated lesion. FDG fails because grey-matter uptake hides tumours in or near cortex, grade 2 gliomas are often hypometabolic, and inflammation (abscess, demyelination, fungal infection, neurosarcoidosis) is avid. It keeps three niches: PCNSL, which has a higher maximum standardised uptake value (SUVmax) than glioblastoma unless corticosteroids have reduced it; lymphoma versus opportunistic infection; and recurrence versus radiation injury when no amino-acid tracer is available, read against white matter (more sensitive) or grey matter (more specific), with delayed images at 3–5 h for metastases.

3. Indications by clinical scenario

The PET-RANO/EANO glioma recommendations (2016) included only Oxford level 1–3 studies but gave no grade per indication; the RANO/PET reports on metastases (2019) and meningioma (2017) did give levels.

4. Evidence at a glance

5. Patient preparation and acquisition

Only points that differ from routine FDG practice are listed (2019 glioma, 2025 metastasis and 2024 meningioma guidelines).

• Fasting. At least 4 h before amino-acid PET, because dietary amino acids compete for transport. The 2025 guideline advises postponing the scan if fasting was not respected, to keep serial studies comparable. For FDG it asks for a 6-h fast and postponement if glucose exceeds 8.9 mmol/L (160 mg/dL); the 2019 guideline asks for at least 4 h.
• FDOPA. Carbidopa premedication is not needed; most brain-tumour studies did not use it.
• Steroids. Record the dose. Corticosteroids may slightly lower amino-acid TBRs by raising uptake in healthy brain, and they reduce FDG uptake in lymphoma.
• MRI for fusion. Recent T1 with and without contrast and T2/FLAIR; check co-registration by displaying the scalp and nose.
• Positioning. Head holder, whole brain including the cerebellum in the field, patient watched throughout. A seizure during the uptake phase raises FET and FDG uptake in the affected cortex.
• Timing after treatment. Wait at least 1 month after radiotherapy or surgery for metastases. For a PET RANO baseline, scan within 14 days before treatment starts but as late as possible after surgery.

Activities and timing from the joint EANM/EANO/RANO/SNMMI procedure guidelines (glioma 2019, brain metastases 2025, meningioma 2024).

Reconstruction and the background region

• Reconstruction. Iterative reconstruction with all corrections, one reconstruction meeting EARL harmonisation standards, and optionally a high-resolution brain reconstruction (voxels under 3 mm, resolution under 6 mm). The 2019 glioma guideline advises against resolution modelling (point-spread-function) because of Gibbs artefacts; the 2024 meningioma guideline allows it with that caveat. Use the same scanner and protocol for serial scans, because TBR depends on resolution.
• Background. Draw a large crescent-shaped volume of interest (VOI) in healthy-appearing cortex, including grey and white matter, in the contralateral hemisphere; PET RANO 1.0 prefers the frontal lobe. Use its mean. TBRmax is the lesion SUVmax divided by the background mean; TBRmean is the mean of the tumour VOI divided by the background mean.
• Tumour VOI for curves. For the time–activity curve, use an isocontour around the tumour maximum giving 1–2 mL, or a 1.6-cm circle centred on the maximum, drawn on the 20–40 min (or 10–30 min) sum. Classify the curve as increasing, plateau or decreasing and note the time to peak (TTP).

6. Interpretation: quantification, variants and pitfalls

1. Check motion and PET–MRI alignment before reading anything else.
2. Look first: is uptake visibly above contralateral cortex, and where does it sit relative to enhancement and FLAIR change?
3. Measure against the crescent background: TBRmax, TBRmean and, if needed, the biological tumour volume (voxels ≥1.6 × background).
4. Read the dynamic curve (FET): pattern and TTP, with the healthy-brain curve plotted to exclude technical errors.
5. Compare with the previous PET, done with the same tracer and protocol.
6. Place the result against the clinical question and its own cut-off, the treatment timeline, steroids and MRI, then answer the question asked.

Cut-offs by clinical question

Thresholds depend on the ROI method, scanner, reconstruction and clinical question. They were derived mostly in single centres on older scanners and are not universal; the metastasis guideline advises favouring specificity when choosing a cut-off. TSR, tumour-to-striatum ratio.

Time–activity curve patterns (dynamic FET)

• Pattern I: uptake increases steadily to the end of the acquisition. Seen in WHO grade 2 glioma and typical of treatment-related change (radiation injury, pseudoprogression); also seen in inflammatory lesions.
• Pattern II: early peak (TTP ≤20 min) followed by a plateau.
• Pattern III: early peak followed by a steady decline. Patterns II and III favour grade 3–4 glioma or recurrence.
• Change over time: a switch from an increasing curve to an early peak with decline in a grade 2 glioma indicates malignant transformation.

Normal variants

• FET and MET: slight uptake in venous sinuses and vessels, basal ganglia, cerebellum, skin and salivary glands; occasionally pineal body, choroid plexus and clivus marrow.
• FDOPA: moderate striatal and pituitary uptake. Tumour next to the basal ganglia is easily missed.
• SSTR ligands: high pituitary uptake, which varies with age and sex; slight uptake in vessels, choroid plexus and salivary glands.

Pitfalls and mimics

Occurrence and timings from the 2019 glioma guideline (Table 2), the 2025 metastasis guideline and the 2024 meningioma guideline.

How to word the conclusion

• Answer the question in the first sentence: for example, 'Findings favour treatment-related change rather than recurrent tumour.'
• Give the numbers and method (TBRmax, TBRmean, curve, background region) and the cut-off applied, with its source.
• State certainty ('favours', 'indeterminate: repeat in 4–8 weeks') and the limitation that matters: small lesion, recent bleed, steroids, recent radiosurgery, change of tracer or scanner.

7. Response assessment and follow-up

PET RANO 1.0 (Albert et al., 2024) is the first standard framework for amino-acid PET response in diffuse glioma. It was written for trials, rests largely on expert opinion, is intended first as a secondary or exploratory endpoint, and evaluates static PET alone, volumetrically, without MRI, steroid dose or clinical status.

Response is compared with baseline or with the nadir after a response.

• Timing. Baseline within 14 days before treatment; 4–6 weeks after surgery if no further treatment is planned. Follow-up every 2–3 months for grade 4 and every 3–6 months for grade 2–3 glioma, ideally with MRI. An optional scan 2–4 weeks after starting treatment assesses early metabolic response.
• Equivocal results. Repeat after one or two cycles with the same tracer; if progression is confirmed, backdate it to the first suspicious scan.
• Earlier response signals. The 2019 guideline lists a >20% fall in FET TBRmax 7–10 days into radiochemotherapy, and a >45% fall in biological tumour volume on bevacizumab, as markers of response.
• Brain metastases. PET RANO BM 1.0 (2025) uses the same progression thresholds (≥30% TBRmax, ≥10% TBRmean, ≥40% volume, or a new measurable lesion). In one study, a fall in FET TBR of at least 10% identified responders to immunotherapy or targeted therapy with 82% accuracy.
• Meningioma. No PET response framework exists; response is judged on MRI (RANO or modified Macdonald). After PRRT, the 2024 guideline asks for MRI and SSTR PET about 1 month after the second cycle and 2 months after the fourth.

8. Theranostics and emerging tracers

SSTR-targeted PRRT for meningioma

• Status. Investigational. It is not approved for meningioma by the FDA or the European Medicines Agency, and no randomised trial has reported. The 2024 joint guideline suggests considering it when surgery and radiotherapy are no longer options, after a multidisciplinary decision and preferably within a trial.
• Evidence. In an individual-patient meta-analysis of 111 treatment-refractory meningiomas, disease control was 63% and 6-month progression-free survival was 94%, 48% and 0% for WHO grades 1, 2 and 3. Higher total administered activity was associated with lower risk of progression.
• Regimen. Usually four cycles of 7.4 GBq ¹⁷⁷Lu-DOTATATE (or 3.7 GBq ⁹⁰Y-DOTATOC) 8 ± 2 weeks apart, with lysine–arginine infusion for renal protection. Stop long-acting somatostatin analogues 4–6 weeks before, and taper steroids where possible, because they may downregulate SSTR2.
• Trials. Randomised phase II trials of ¹⁷⁷Lu-DOTATATE against standard care are recruiting: EORTC (NCT06326190) and NRG/RTOG MOMENTUM-1 (NCT06955169). The SSTR antagonist ¹⁷⁷Lu-satoreotide is in phase I/II (NCT04997317).

TSPO, 18-kDa translocator protein; PSMA, prostate-specific membrane antigen; FLT, fluorothymidine; FMISO, fluoromisonidazole.

9. Structured report example

10. Take-home points

1. Use amino-acid PET, not FDG, for glioma; FET has the widest evidence base and, from 2026, US approval for recurrence versus treatment-related change.
2. Fast the patient for 4 h, record the steroid dose, acquire FET dynamically, and use a large contralateral crescent for background.
3. Quote cut-offs for the question asked, with their source; TBRs change with scanner, reconstruction and ROI method.
4. An early peak with washout favours tumour; a steadily rising curve favours treatment-related change or low-grade tissue.
5. A negative FET scan makes high-grade glioma unlikely but does not exclude a grade 2 glioma.
6. After SRS for metastases, combine TBRmean (about 1.9–1.95) with curve shape, and wait at least 1 month after treatment.
7. PET RANO 1.0 defines response for trials: ≥1.6 × background, >0.5 mL measurable, and 30/10/40% changes in TBRmax, TBRmean and volume.
8. In meningioma, read SSTR PET against the normal pituitary; PRRT is investigational and belongs in trials.

Test yourself

5 quick questions. Pick an answer to see the explanation.

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