Challenges, limitations, and pitfalls of PET and advanced MRI in patients with brain tumors: A report of the PET/RANO group

Abstract

Brain tumor diagnostics have significantly evolved with the use of positron emission tomography (PET) and advanced magnetic resonance imaging (MRI) techniques. In addition to anatomical MRI, these modalities may provide valuable information for several clinical applications such as differential diagnosis, delineation of tumor extent, prognostication, differentiation between tumor relapse and treatment-related changes, and the evaluation of response to anticancer therapy. In particular, joint recommendations of the Response Assessment in Neuro-Oncology (RANO) Group, the European Association of Neuro-oncology, and major European and American Nuclear Medicine societies highlighted that the additional clinical value of radiolabeled amino acids compared to anatomical MRI alone is outstanding and that its widespread clinical use should be supported. For advanced MRI and its steadily increasing use in clinical practice, the Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition provided more recently an updated acquisition protocol for the widely used dynamic susceptibility contrast perfusion MRI. Besides amino acid PET and perfusion MRI, other PET tracers and advanced MRI techniques (e.g. MR spectroscopy) are of considerable clinical interest and are increasingly integrated into everyday clinical practice. Nevertheless, these modalities have shortcomings which should be considered in clinical routine. This comprehensive review provides an overview of potential challenges, limitations, and pitfalls associated with PET imaging and advanced MRI techniques in patients with gliomas or brain metastases. Despite these issues, PET imaging and advanced MRI techniques continue to play an indispensable role in brain tumor management. Acknowledging and mitigating these challenges through interdisciplinary collaboration, standardized protocols, and continuous innovation will further enhance the utility of these modalities in guiding optimal patient care.

Keywords: CEST; MR spectroscopy; amino acid PET; diffusion-weighted imaging; perfusion-weighted imaging.

Figure 1.

Fifty-year-old female patient with a neuropathologically confirmed IDH wild-type glioblastoma. The lesion is hyperintense on T2-weighted imaging (T2w) and shows rim enhancement on the post-contrast T1-weighed image (CE-T1w). On the diffusion-weighted image (DWI), the lesion appears predominantly hyperintense suggesting diffusion restriction (arrowheads). However, on the apparent diffusion coefficient (ADC) map the lesion is also predominantly hyperintense which is consistent with T2-shine-through rather than diffusion restriction (arrowheads). There are also some small areas where high signal on DWI corresponds with low signal on ADC (arrows) indicating true diffusion restriction.

Figure 2.

A left temporal chemoradiation-treated glioblastoma on post-contrast T1-weighted imaging (arrows in A and B). Relative cerebral blood volume (rCBV) maps through this lesion from dynamic susceptibility contrast (DSC) perfusion-weighted imaging are shown in C and registered with and superimposed on post-contrast T1-weighted imaging in D. However, susceptibility-related signal loss in proximity to the petrous and mastoid temporal bones artifactually makes rCBV in the inferior temporal lobes appear to be zero (arrows in C and D). Since the treated glioblastoma is within this area of artifactual signal loss, it could falsely appear to be hypoperfusing and so it is unable to be evaluated with DSC.

Figure 3.

Fifty-two-year-old patient with a history of an acute lymphoblastic leukemia was diagnosed more than 35 years ago and treated with methotrexate-based chemotherapy and whole-brain radiotherapy. Subsequently, a secondary and atypical parasagittal meningioma was diagnosed in the right frontal lobe. After resection, the patient had undergone adjuvant proton radiotherapy (radiation dose, 60 Gy). Thirty months after radiotherapy, anatomical MR imaging showed a nodular contrast enhancement at the rim of the resection cavity (sagittal view) with an increased blood volume on 3 T dynamic susceptibility contrast perfusion MRI (relative cerebral blood volume after contrast agent leakage correction, 3.0). At this time, the patient had a Karnofsky performance status of 90% and a mild but worsening left-sided hemiparesis, which required dexamethasone (maximal dose, 8 mg). After resection of the nodular lesion, histology revealed widespread necrotic areas without tumor cells (hematoxylin and eosin staining).

Figure 4.

A 41-year-old male with a newly diagnosed brain lesion suspicious of a glioma without contrast enhancement and widespread FLAIR signal abnormalities in the right frontal lobe. In contrast to the hypometabolic FDG PET in this region, FET PET revealed a pathologically increased tracer uptake. Histological tissue evaluation obtained from biopsy confirmed an anaplastic astrocytoma.

Figure 5.

Early postoperative MRI of a glioblastoma patient after 48 hours, and MR and FET PET imaging 3 and 9 weeks after surgery showing the temporal evolution of a perioperative ischemic stroke involving the left middle cerebral artery territory. Neuroimaging 3 weeks after surgery shows a gyral pattern of parenchymal contrast enhancement in the left insula and temporoparietal region (laterally placed arrows) consistent with postischemic hyperperfusion following vessel recanalization with vasodilation, inflammation, and blood-brain barrier injury leading to leakage of contrast material and FET (maximum tumor-to-brain ratio, 2.5) into the extravascular space obscuring any binding to glioma tissue. The left striatocapsular infarct with a low apparent diffusion coefficient (ADC) does not show increased FET uptake (arrows in the midline) as tracer delivery is perfusion-dependent. Follow-up MRI and FET PET at 9 weeks show fading of gyral contrast enhancement and associated FET uptake (maximum tumor-to-brain ratio, 1.8).

Figure 6.

Forty-eight-year-old patient with a CNS WHO grade 2 astrocytoma who was heavily pretreated by several radiotherapies with a cumulative dose of more than 160 Gy. At suspected relapse, the corresponding FET PET showed pathologically increased metabolic activity (ie, maximum tumor-to-brain ratio, 3.1) and was consistent with tumor progression. In contrast, histological evaluation revealed a coagulation necrosis (right) accompanied by necrosis of blood vessels with hyalinization of the vessel wall remnants, and reactive astrogliosis at the margin of the necrosis (left; hematoxylin and eosin staining; courtesy of Prof. Joachim Weis, Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany).