The Non-Enhancing Tumor: How Does Amino Acid PET Reveal the Hidden Borders of Glioblastoma?

The Non-Enhancing Tumor: How Does Amino Acid PET Reveal the Hidden Borders of Glioblastoma?

Surgery and radiotherapy for glioblastoma are planned largely on contrast-enhanced MRI. But this tumor grows by infiltrating the surrounding brain, and a significant share of the infiltrating cells do not take up contrast on MRI. In a prospective, biopsy-validated study published in Nature Communications on November 6, 2026, 472 tissue samples from 61 patients with IDH-wildtype glioblastoma were analyzed. FET-PET detected tumor in 91.2% of the tumor-containing samples, and contrast-enhanced MRI in 52.6%. Tumor was present in 98.3% of the samples taken from areas that did not enhance but lit up on FET-PET. In this article we explain what FET-PET is, why the results matter, and why it is still too early to say “FET-PET for every patient.” You can find the basics of glioblastoma in our glioblastoma guide (in Turkish).

Why does this matter?

Glioblastoma is the most common and fastest-progressing primary brain tumor in adults. Standard treatment consists of as extensive a surgery as can be done safely, followed by radiotherapy together with temozolomide (new treatments for IDH-wildtype glioblastoma [in Turkish]). Both the area the surgeon removes and the radiotherapy target are drawn largely on the bright ring seen on contrast-enhanced MRI. Yet glioblastoma cells infiltrate beyond this ring into seemingly normal brain tissue. These invisible extensions explain why the tumor so often recurs right at the edge of the surgical cavity.

The FLAIR sequence on MRI shows a wider area; however, because this area contains edema as well as tumor cells, it cannot tell the two apart (brain edema [in Turkish]). A method that shows the true borders of the tumor more accurately could directly affect where a biopsy sample is taken, how surgery is planned and how the radiotherapy field is defined. This is why amino acid PET methods such as FET-PET have long been investigated.

What is FET-PET?

FET-PET is a PET scan in which FET, an amino acid labeled with fluorine-18 (O-(2-[18F]fluoroethyl)-L-tyrosine), is given intravenously. Because glioma cells overproduce amino acid transporters, they take up far more FET than normal brain tissue. As a result, tumor areas become visible even when the blood–brain barrier is intact.

The most commonly used type of PET in cancer is PET-CT with the sugar-like FDG; however, because normal brain tissue also uses a great deal of sugar, FDG falls short of showing the borders of brain tumors (What is PET-CT? [in Turkish]). Normal brain tissue, on the other hand, takes up amino acids only to a limited extent. This is why the difference between tumor and normal tissue is much clearer with amino acid tracers such as FET. FDOPA and methionine PET are also used for a similar purpose.

Why does MRI miss some tumor areas?

The blood vessels of the brain are surrounded by a tight wall called the blood–brain barrier. The gadolinium-containing contrast agent used in MRI cannot cross this wall; it leaks into the tissue and appears bright only where the tumor has disrupted the vessel structure. The dense, fast-growing center of a glioblastoma breaks down this barrier; however, tumor cells that infiltrate the surrounding tissue one by one usually do not. These cells are invisible on contrast-enhanced MRI. FET, unlike the contrast agent, is taken directly into cells by amino acid transporters; so it can show tumor cells whether or not the barrier is intact.

How was the study done?

The study was carried out prospectively at a single center in Germany, by the neurosurgery and nuclear medicine teams of Ludwig Maximilian University (LMU) of Munich. A total of 61 patients with IDH-wildtype glioblastoma were included; 44 of them were newly diagnosed and 17 were patients with recurrent disease for whom surgery or biopsy was planned (IDH and molecular diagnosis [in Turkish]). Before surgery, every patient had both FET-PET and contrast-enhanced MRI. During surgery or stereotactic biopsy, a total of 472 tissue samples were taken from points matched in location to the images. A pathologist decided under the microscope whether each sample contained tumor; the performance of the images was calculated against this “gold standard” (what is a biopsy? [in Turkish]).

What was found?

Of the tumor-containing samples, 91.2% were positive on FET-PET, whereas contrast-enhanced MRI showed contrast uptake in only 52.6% of the same samples. The absolute difference is about 39 percentage points; in relative terms, FET-PET captured tumor tissue about 1.7 times more often. The most striking finding, however, was in the non-enhancing areas: when FET-PET was positive in these areas, 98.3% of the samples taken contained tumor. In other words, tissue where FET-PET said “there is tumor here” but MRI looked normal was almost always truly tumor.

According to the abstract the researchers presented at the ASCO congress in May 2026, the advantage of FET-PET was preserved in a similar way in newly diagnosed and recurrent patients, in the surgery and biopsy groups, and in both the dense and the infiltrating parts of the tumor. The same abstract reported FET-PET's rate of correctly showing non-tumor tissue as negative (specificity) as 82.5%, versus 33.3% for contrast-enhanced MRI, and the sensitivity of FLAIR as 85.3%. Although FLAIR's sensitivity is high, this sequence alone is not sufficient to define the borders, because it cannot tell tumor from edema.

How should we read the results?

The findings are strong and biologically coherent; however, there are some important limits. First and most important: 472 samples are not 472 separate patients. On average about 8 samples were taken per patient. Samples taken from the same patient's tumor resemble one another; therefore, proportions calculated at the sample level can make the uncertainty at the patient level look smaller than it is. Second, the study was carried out at a single experienced center; reading FET-PET and matching images during surgery require expertise, and the results need to be reproduced in other centers. Third, the points to be biopsied were not random but chosen according to the images; this may affect sensitivity calculations (reading research news correctly [in Turkish]).

The most important limit is this: this study is a diagnostic accuracy study. It proves that FET-PET shows the tumor better; but it does not show that a wider surgery or a differently drawn radiotherapy field based on this information makes patients live longer or better. A wider surgery can also increase the risk of permanent damage in regions that control functions such as speech and movement. In glioblastoma, promising laboratory or imaging findings have not always translated into patient benefit as easily as expected (laboratory findings and clinical reality [in Turkish]). That is why “seeing more tumor” and “benefiting the patient more” are not the same thing.

What could change in clinical practice?

Targeting the biopsy

For deep-seated tumors that cannot be removed surgically, diagnosis relies on needle (stereotactic) biopsy. If the sample is not taken from the most active part of the tumor, the diagnosis can remain incomplete or the grade of the tumor can be underestimated. The area with the highest FET-PET uptake is a good target for biopsy; this use is also included in international recommendations. The concern that a biopsy spreads the tumor is not supported by science (does a biopsy spread cancer? [in Turkish]).

Surgical planning

Some centers, where it is safe, are investigating the removal of FET-PET-positive tissue beyond the contrast-enhancing area as well (“supramaximal” or “supramarginal” resection). In a small retrospective study, a large volume of FET-PET-positive tissue remaining after surgery was associated with shorter survival; but such associations do not prove that the surgery itself prolongs survival (what is a surgical margin? [in Turkish]). The benefit of extensive surgery has to be balanced against preserving functions such as speech, movement and vision; loss of function after surgery directly affects quality of life and adherence to later treatments (rehabilitation in brain tumors [in Turkish]).

Radiotherapy planning

Although drawing the radiotherapy target with FET-PET seems logical, this idea was tested in a randomized trial and the expected result was not obtained. In the GLIAA trial, conducted at 15 centers in Germany, 200 patients with recurrent glioblastoma were assigned to groups whose re-irradiation was planned with FET-PET or with contrast-enhanced MRI. Median progression-free survival was 4.0 months in the FET-PET group and 4.9 months in the MRI group; the difference was not significant. Late serious side effects were less frequent in the FET-PET group (10% vs. 19%), but this was a secondary finding (radiotherapy and radiosurgery [in Turkish]).

The result of GLIAA is not directly applicable to the first radiotherapy in newly diagnosed glioblastoma, because the trial was conducted only in recurrent disease and with short-course re-irradiation. But it has an important lesson: an imaging method showing the tumor better does not by itself mean that it will benefit the patient. This benefit must be demonstrated separately in randomized trials.

After treatment: recurrence or treatment effect?

One of the best-established uses of FET-PET today is telling whether a lesion that grows on MRI after treatment is true recurrence or a change caused by radiotherapy (pseudoprogression or radiation necrosis) (radiation necrosis [in Turkish]). This distinction can prevent unnecessary surgery or the premature abandonment of an effective treatment. The same question is often asked in brain metastases after radiosurgery (brain metastasis [in Turkish]). Still, no PET method is perfect; inflammation and some benign conditions can also show uptake (false-positive results on PET [in Turkish]). Because cortisone (dexamethasone) treatment can reduce contrast uptake on MRI, it is important to interpret the images together with this information (dexamethasone [in Turkish]).

The Situation in Türkiye

Questions you can ask your physician

• Is contrast-enhanced MRI enough to assess the borders of my tumor, or would amino acid PET or advanced MRI techniques provide additional information?
• If a biopsy is planned, which imaging will be used to choose the most active area?
• How is the preservation of my functions being assessed when the extent of surgery is planned?
• If growth is seen on MRI after treatment, how will it be determined whether it is recurrence or treatment effect?
• Has my case been discussed at a multidisciplinary brain tumor board?

Frequently Asked Questions

What is FET-PET?

FET-PET is a PET scan that uses an amino acid called FET, labeled with fluorine-18. Because glioma cells take up this amino acid far more than normal brain tissue, tumor areas become visible even when the blood–brain barrier is intact.

Is FET-PET better than MRI in glioblastoma?

At capturing tumor tissue, yes: in a biopsy-validated study, FET-PET showed 91.2% of tumor-containing samples and contrast-enhanced MRI 52.6%. But it does not replace MRI; the two methods are used together.

Does FET-PET prolong survival in glioblastoma?

This has not yet been shown. The new study measured only diagnostic accuracy. The randomized GLIAA trial, which planned radiotherapy in recurrent glioblastoma with FET-PET, did not prolong progression-free survival compared with MRI.

Is FET-PET performed in Türkiye?

FET-PET is not a widely performed test in Türkiye, and the centers where it can be done and its reimbursement status could not be verified. Other amino acid PET tracers or advanced MRI techniques can be used for a similar purpose; discuss the options with your treatment team.

Glossary

Glioblastoma

The most common primary brain tumor in adults; it progresses rapidly and grows by infiltrating the surrounding brain tissue.

IDH-wildtype

Without a mutation in the IDH gene; one of the key criteria for the diagnosis of glioblastoma in the current classification.

FET

An amino acid tracer labeled with fluorine-18 that glioma cells take up in excess.

Blood–brain barrier

The tight structure surrounding the brain's blood vessels that limits the passage of many substances into brain tissue.

Contrast-enhanced MRI

MRI performed after a gadolinium-containing agent is given intravenously, showing areas where the barrier is disrupted as bright.

FLAIR

An MRI sequence that shows the tumor and the surrounding edema together as bright, but cannot tell the two apart.

Sensitivity

How many of the samples that truly have disease are correctly shown by the test.

Positive predictive value

The probability that disease is truly present when the test is positive.

Stereotactic biopsy

A tissue sample taken by reaching a point defined on imaging with a needle through a small hole in the skull.

Pseudoprogression

A temporary, treatment-related change that makes the tumor appear to grow on MRI after treatment but is not actually tumor growth.