FET PET for Low Grade Glioma

FET PET for Low Grade Glioma

Positron emission tomography (PET) imaging using amino acid tracers has in recent years become widely used in the diagnosis and prediction of disease course in diffuse low grade gliomas (LGG). However, implications of preoperative PET for treatment and prognosis in this patient group have not been systematically studied.

The aim of a systematic review was to evaluate the preoperative diagnostic and prognostic value of amino acid PET in suspected diffuse LGG. Medline, Cochrane Library, and Embase databases were systematically searched using keywords “PET,” “low grade glioma,” and “amino acids tracers” with their respective synonyms. Out of 2137 eligible studies, 28 met the inclusion criteria. Increased amino acid uptake (lesion/brain) was consistently reported among included studies; in 25-92% of subsequently histopathology-verified LGG, in 83-100% of histopathology-verified HGG, and also in some non-neoplastic lesions. No consistent results were found in studies reporting hot spot areas on PET in MRI-suspected LGG. Thus, the diagnostic value of amino acid PET imaging in suspected LGG has proven difficult to interpret, showing clear overlap and inconsistencies among reported results. Similarly, the results regarding the prognostic value of PET in suspected LGG and the correlation between uptake ratios and the molecular tumor status of LGG were conflicting. This systematic review illustrates the difficulties with prognostic studies presenting data on group-level without adjustment for established clinical prognostic factors, leading to a loss of additional prognostic information.

Näslund et al., conclude that the prognostic value of PET is limited to analysis of histological subgroups of LGG and is probably strongest when using kinetic analysis of dynamic FET uptake parameters 1).

For Chan et al., FET PET demonstrated a high positive predictive value for glioma in patients with indeterminate brain lesions on MRI. The combination of negative FET and negative FDG PET scans may predict an indolent clinical course. Confirmatory trials are needed to establish the potential value of FET PET in guiding surgical management in this cohort 2).

Sixty-one patients harboring Gd-negative WHO grade II or III glioma receiving alkylating agents (temozolomide or CCNU/procarbacine) were included. All patients underwent MRI and 18F-FET-PET before chemotherapy and 6 months later. They calculated T2-volume, 18F-FET-PET based biological tumour volume (BTV) and maximal tumour-to-brain ratio (TBRmax). Moreover, dynamic PET acquisition was performed using time-activity-curves (TACs) analysis. For MRI-based response assessment, RANO criteria for low-grade glioma were used. For 18F-FET-PET, following classification scheme was tested: responsive disease (RD) when a decrease in either BTV ≥ 25% and/or TBRmax ≥ 10% occurred, an increase in BTV ≥ 25% and/or TBRmax increase > 10% characterized progressive disease (PD), minor changes ± 25% for BTV and ± 10% for TBRmax were regarded as stable disease (SD). Post-chemotherapy survival (PCS) and time-to-treatment failure (TTF) were calculated using the Kaplan-Meier method.

18F-FET-PET based response has shown patients with RD to have the longest TTF time (78.5 vs 24.6 vs 24.1 months, p = 0.001), while there was no significant difference between patients with a SD and PD. A comparable pattern was observed for PCS (p < 0.001). T2-volume based assessment was not associated with outcome.

18F-FET-PET is a promising biomarker for early response assessment in Gd-negative gliomas undergoing chemotherapy. It might be helpful for a timely adjustment of potentially ineffective treatment concepts and overcomes limitations of conventional structural imaging 3).

A single FET PET scan obtained at the time of radiological and/or clinical progression seems to be of limited value in distinguishing transformed from nontransformed low grade gliomas (LGGs), especially if knowledge of the primary tumor histopathology is not known. Therefore, FET PET imaging alone is not adequate to replace histological confirmation, but it may provide valuable information on the location and delineation of active tumor tissue, as well as an assessment of tumor biology in a subgroup of LGGs 4).

Both Magnetic resonance perfusion imaging and FET PET provide grading information in cerebral gliomas.

Seventy-two patients with untreated gliomas [22 low-grade gliomas (LGG), and 50 high-grade gliomas (HGG)] were investigated with 18F-FET PET and Magnetic resonance perfusion imaging using a hybrid PET/MR scanner. After visual inspection of PET and Magnetic resonance perfusion imaging maps (rCBV, rCBF, MTT), volumes of interest (VOIs) with a diameter of 16 mm were centered upon the maximum of abnormality in the tumor area in each modality and the contralateral unaffected hemisphere. Mean and maximum tumor-to-brain ratios (TBRmean, TBRmax) were calculated. In addition, Time-to-Peak (TTP) and slopes of time-activity curves were calculated for 18F-FET PET. Diagnostic accuracies of 18F-FET PET and Magnetic resonance perfusion imaging for differentiating low-grade glioma (LGG) from high-grade glioma (HGG) were evaluated by receiver operating characteristic analyses (area under the curve; AUC).

The diagnostic accuracy of 18F-FET PET and Magnetic resonance perfusion imaging to discriminate LGG from HGG was similar with highest AUC values for TBRmean and TBRmax of 18F-FET PET uptake (0.80, 0.83) and for TBRmean and TBRmax of rCBV (0.80, 0.81). In case of increased signal in the tumor area with both methods (n = 32), local hot-spots were incongruent in 25 patients (78%) with a mean distance of 10.6 ± 9.5 mm. Dynamic FET PET and combination of different parameters did not further improve diagnostic accuracy.

Both 18F-FET PET and Magnetic resonance perfusion imaging discriminate LGG from HGG with similar diagnostic performance. Regional abnormalities in the tumor area are usually not congruent indicating that tumor grading by 18F-FET PET and Magnetic resonance perfusion imaging is based on different pathophysiological phenomena 5).

Fifty-nine patients with newly diagnosed low-grade glioma and dynamic (18)F-FET PET before histopathologic assessment were retrospectively investigated. (18)F-FET PET analysis comprised a qualitative visual classification of lesions; assessment of the semiquantitative parameters maximal, mean, and total standardized uptake value as ratio to background and biologic tumor volume; and dynamic analysis of intratumoral (18)F-FET uptake over time (increasing vs. decreasing time-activity curves). The correlation between PET parameters and progression-free survival, overall survival, and time to malignant transformation was investigated.

(18)F-FET uptake greater than the background level was found in 34 of 59 tumors. Dynamic (18)F-FET uptake analysis was available for 30 of these 34 patients. Increasing and decreasing time-activity curves were found in 18 and 12 patients, respectively. Neither the qualitative factor presence or absence of (18)F-FET uptake nor any of the semiquantitative uptake parameters significantly influenced clinical outcome. In contrast, decreasing time-activity curves in the kinetic analysis were highly prognostic for shorter progression-free survival and time to malignant transformation (P < 0.001).

Absence of (18)F-FET uptake in newly diagnosed astrocytic low-grade glioma does not generally indicate an indolent disease course. Among the (18)F-FET-positive gliomas, decreasing time-activity curves in dynamic (18)F-FET PET constitute an unfavorable prognostic factor in astrocytic low-grade glioma and, by identifying high-risk patients, may ease treatment decisions 6).



Näslund O, Smits A, Förander P, Laesser M, Bartek J Jr, Gempt J, Liljegren A, Daxberg EL, Jakola AS. Amino acid tracers in PET imaging of diffuse low-grade gliomas: a systematic review of preoperative applications. Acta Neurochir (Wien). 2018 Jul;160(7):1451-1460. doi: 10.1007/s00701-018-3563-3. Epub 2018 May 24. Review. PubMed PMID: 29797098; PubMed Central PMCID: PMC5995993.

Chan DL, Hsiao E, Schembri G, Bailey DL, Roach PJ, Lee A, Jayamanne D, Ghasemzadeh M, Hayes A, Cook R, Parkinson J, Drummond JP, Ibbett I, Wheeler HR, Back M. FET PET in the evaluation of indeterminate brain lesions on MRI: Differentiating glioma from other non-neoplastic causes – A pilot study. J Clin Neurosci. 2018 Dec;58:130-135. doi: 10.1016/j.jocn.2018.09.009. Epub 2018 Sep 19. PubMed PMID: 30243602.

Suchorska B, Unterrainer M, Biczok A, Sosnova M, Forbrig R, Bartenstein P, Tonn JC, Albert NL, Kreth FW. (18)F-FET-PET as a biomarker for therapy response in non-contrast enhancing glioma following chemotherapy. J Neurooncol. 2018 Sep;139(3):721-730. doi: 10.1007/s11060-018-2919-0. Epub 2018 Jun 8. PubMed PMID: 29948765.

Bashir A, Brennum J, Broholm H, Law I. The diagnostic accuracy of detecting malignant transformation of low-grade glioma using O-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography: a retrospective study. J Neurosurg. 2018 Apr 1:1-14. doi: 10.3171/2017.8.JNS171577. [Epub ahead of print] PubMed PMID: 29624154.

Verger A, Filss CP, Lohmann P, Stoffels G, Sabel M, Wittsack HJ, Kops ER, Galldiks N, Fink GR, Shah NJ, Langen KJ. Comparison of (18)F-FET PET and perfusion-weighted MRI for glioma grading: a hybrid PET/MR study. Eur J Nucl Med Mol Imaging. 2017 Dec;44(13):2257-2265. doi: 10.1007/s00259-017-3812-3. Epub 2017 Aug 22. PubMed PMID: 28831534.

Jansen NL, Suchorska B, Wenter V, Eigenbrod S, Schmid-Tannwald C, Zwergal A, Niyazi M, Drexler M, Bartenstein P, Schnell O, Tonn JC, Thon N, Kreth FW, la Fougère C. Dynamic 18F-FET PET in newly diagnosed astrocytic low-grade glioma identifies high-risk patients. J Nucl Med. 2014 Feb;55(2):198-203. doi: 10.2967/jnumed.113.122333. Epub 2013 Dec 30. PubMed PMID: 24379223.

Insular glioma surgery

Shawn Hervey-Jumper and Berger from the UCSF Medical Center reviewed the literature for published reports focused on insular region anatomyneurophysiology, surgical approaches, and outcomes for adults with who grade II-IV gliomas.

While originally considered to pose too great a riskinsular glioma surgery can be performed safely due to the collective efforts of many individuals. Similar to resection of gliomas located within other cortical regions, maximal resection of gliomas within the insula offers patients greater survival time and superior seizure control for both newly diagnosed and recurrent tumors in this region. The identification and the preservation of M2 perforating and lateral lenticulostriate artery are critical steps to preventing internal capsulestroke and hemiparesis. The transcortical approach and intraoperative mapping are useful tools to maximize safety.

The insula’s proximity to middle cerebral and lenticulostriate arteries, primary motor areas, and perisylvian language areas makes accessing and resecting gliomas in this region challenging. Maximal safe resection of insular gliomas not only is possible but also is associated with excellent outcomes and should be considered for all patients with low- and high-grade gliomas in this area 1).

Advances in microsurgical anatomy and brain mapping techniques have allowed an increase in the extent of resection with acceptable morbidity rates. Transsylvian and transcortical approaches constitute the main surgical corridors, the latter providing considerable advantages and a high degree of reliability. Nevertheless, both surgical corridors yield remarkable difficulties in reaching the most posterior insular region.

see Insular tumor surgery.

Small deep infarcts constitute a well-known risk of motor and speech deficit in insulo-opercular glioma surgery. However, the risk of cognitive deterioration in relation to stroke occurrence in so-called silent areas is poorly known.

In a paper, Loit et al. propose to build a distribution map of small deep infarcts in glioma surgery, and to analyze patients’ cognitive outcome in relation to stroke occurrence.

They retrospectively studied a consecutive series of patients operated on for a diffuse glioma between June 2011and June 2017. Patients with lower-grade glioma were cognitively assessed, both before and 4 months after surgery. Areas of decreased apparent diffusion coefficient (ADC) on the immediate postoperative MRI were segmented. All images were registered in the MNI reference by ANTS algorithm, allowing to build a distribution map of the strokes. Stroke occurrence was correlated with the postoperative changes in semantic fluency score in the lower-grade glioma cohort.

One hundred fifteen patients were included. Areas of reduced ADC were observed in 27 out of 54 (50%) patients with a lower-grade glioma, and 25 out of 61 (41%) patients with a glioblastoma. Median volume was 1.6 cc. The distribution map revealed five clusters of deep strokes, corresponding respectively to callosal, prefrontal, insulo-opercular, parietal, and temporal tumor locations. No motor nor speech long-term deficits were caused by these strokes. Cognitive evaluations at 4 months showed that the presence of small infarcts correlated with a slight decrease of semantic fluency scores.

Deep small infarcts are commonly found after glioma surgery, but their actual impact in terms of patients’ quality of life remains to be demonstrated. Further studies are needed to better evaluate the cognitive consequences-if any-for each of the described hotspots and to identify risk factors other than the surgery-induced damage of microvessels 2).


Awake Brain Mapping in Dominant Side Insular Glioma Surgery: 2-Dimensional Operative Video 3).



Hervey-Jumper SL, Berger MS. Insular glioma surgery: an evolution of thought and practice. J Neurosurg. 2019 Jan 1;130(1):9-16. doi: 10.3171/2018.10.JNS181519. Review. PubMed PMID: 30611160.

Loit MP, Rheault F, Gayat E, Poisson I, Froelich S, Zhi N, Velut S, Mandonnet E. Hotspots of small strokes in glioma surgery: an overlooked risk? Acta Neurochir (Wien). 2018 Nov 10. doi: 10.1007/s00701-018-3717-3. [Epub ahead of print] PubMed PMID: 30415385.

Hameed NUF, Zhu Y, Qiu T, Wu J. Awake Brain Mapping in Dominant Side Insular Glioma Surgery: 2-Dimensional Operative Video. Oper Neurosurg (Hagerstown). 2018 Feb 16. doi: 10.1093/ons/opx299. [Epub ahead of print] PubMed PMID: 29471530

Hemorrhagic low grade glioma

Intracerebral hematoma is an unusual clinical presentation for low grade gliomas and it has been described in a small number of cases in adults 1) 2) 3).

Hemorrhagic low grade glioma (LGG) without malignant transformation is rare, accounting for less than 1% of cases.

It is now generally accepted that the main cause of mortality in these tumors is their dedifferentiation to a higher degree of malignancy 4) 5) 6).

Case reports

Hemorrhagic LGG with an arteriovenous(AV)shunt has not been reported.

Matsuura et al., from the Toho University Medical Center Omori Hospital, report the case of a 17-year-old man with low grade glioma (LGG) with an arteriovenous fistula. He presented to the hospital with seizureComputed tomography(CT) demonstrated a hypodense lesion with mass effect in the right frontal lobeT1-weighted images(WI)and T2WI on magnetic resonance imaging(MRI) revealed acute-onset hemorrhage in the right frontal lobe. Furthermore, a ring enhancing lesion was noted on gadolinium (Gd)-DTPA T1WI, and an AV shunt was found in the same region on angiographyGross total tumor resection was performed. The pathological diagnosis was diffuse astrocytoma with pilomyxoid features (WHO grade II). Without adjuvant therapy, no residual tumor was found on MRI at the 6-year follow-up examination. They treated a case of hemorrhagic LGG with an AV shunt. Intratumoral hemorrhage in LGG may occur and should be considered for the differential diagnosis 7).

A 53-year old woman presenting to the hospital with a hemorrhagic low-grade glioma (LGG). She was admitted to a nearby general hospital where she had presented with aphasia, right hemiplegia and change of mental status. Computer tomography (CT) images showed a left temporo-parietal hemorrhage with mass effect. She was transferred to the neuro-intensive care unit where emergency craniotomy was performed. A tumor with hematoma was removed and further histopathology analysis revealed tumor progression. They reviewed the literature reporting cases of central nervous system tumors hemorrhage and found that these types of events are exquisitely rare in adults with LGG. However these events are possible, suggesting that it should be included in the differential diagnosis of any patient presenting with intracranial hemorrhage. This case raises questions regarding the benefit of early versus late intervention for patients known to have LGG 8).

Della Puppa et al., reviewed the literature of such cases and reported another case of a haemorrhagic low-grade glioma in a 54-year-old woman presenting with a left hemiparesis. Computer tomography (CT) images showed a right basal ganglia haemorrhage with no mass effect. Vascular malformations were ruled out by angiography. Eighteen fluoro-fluoro deossiglucosio (18F-FDG) positron emission tomography (PET/CT) showed a large hypometabolic area corresponding to the lesion. We waited for patient’s improvement. Late magnetic resonance images revealed a low-grade glioma at the bleeding site. Tumour was removed and histopathologic examination revealed a WHO grade II mixed glioma. The authors emphasize that this evidence has to be kept in mind since it has important therapeutic implications 9).

Memon et al., treated three cases of brain tumor that presented with intracranial hemorrhage. Two of the three tumors were metastatic. They presented with hemorrhage into the tumor, but no blood in the cerebrospinal fluid. One tumor was a low grade astrocytoma that presented as subarachnoid and intraventricular hemorrhage in a 15-year-old child. It was removed with no neurological sequelae 10).



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Kondziolka D, Bernstein M, Resch L, Tator CH, Fleming JF, Vanderlinden RG, Schutz H: Significance of hemorrhage into brain tumor: clinicopathological study. J Neurosurg 67:852–857, 1987

Licata B, Turazzi S: Bleeding cerebral neoplasm’s with symptomatic hematoma. J Neurosurg Sci 47:201–210, 2003

Mineo JF, Bordron A, Baroncini M, Maurage CA, Ramirez C, Siminski RM, Berthou C, Dam Hieu P: Low HER2-expressing glioblastomas are more often secondary to anaplastic transformation of low-grade glioma. J Neurooncol 85:281-287, 2007

Radulović D: Natural history of supratentorial low-grade astrocytoma: Case report. Srp Arh Celok Lek 134:537-540, 2006

Tungaria A, Sahu RN, Kumar R, Srivastava A: Intratumoral hemorrhage in brainstem low-grade glioma. Neurol India 60: 243-245, 2012

Matsuura C, Sakaeyama Y, Node Y, Ueda K, Ando S, Masuda H, Kondo K, Harada N, Nemoto M, Sugo N. [Diffuse Astrocytoma with Pilomyxoid Features Presenting as Intratumoral Hemorrhage:A Case Report]. No Shinkei Geka. 2018 Dec;46(12):1073-1079. doi: 10.11477/mf.1436203870. Japanese. PubMed PMID: 30572304.

Joković M, Bogosavljević V, Nikolić I, Jovanović N. Spontaneous Intracerebral Hematoma in Low-Grade Glioma After 14 Years of Follow-Up. Turk Neurosurg. 2016;26(3):452-5. doi: 10.5137/1019-5149.JTN.11004-14.1. PubMed PMID: 27161476.

Della Puppa A, Zustovich F, Gardiman M, Manara R, Cecchin D, Scienza R. Haemorrhagic presentation of low-grade glioma in adults. Acta Neurochir (Wien). 2007 Nov;149(11):1151-5; discussion 1155. Epub 2007 Aug 6. Review. PubMed PMID: 17676407.

Memon MY, Neal A, Imami R, Villareal N. Low grade glioma presenting as subarachnoid hemorrhage. Neurosurgery. 1984 May;14(5):574-7. PubMed PMID: 6728165.
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