Pseudoprogression versus true progression in glioblastoma: what neurosurgeons need to know

Abstract

Management of patients with glioblastoma (GBM) is complex and involves implementing standard therapies including resection, radiation therapy, and chemotherapy, as well as novel immunotherapies and targeted small-molecule inhibitors through clinical trials and precision medicine approaches. As treatments have advanced, the radiological and clinical assessment of patients with GBM has become even more challenging and nuanced. Advances in spatial resolution and both anatomical and physiological information that can be derived from MRI have greatly improved the noninvasive assessment of GBM before, during, and after therapy. Identification of pseudoprogression (PsP), defined as changes concerning for tumor progression that are, in fact, transient and related to treatment response, is critical for successful patient management. These temporary changes can produce new clinical symptoms due to mass effect and edema. Differentiating this entity from true tumor progression is a major decision point in the patient's management and prognosis. Providers may choose to start an alternative therapy, transition to a clinical trial, consider repeat resection, or continue with the current therapy in hopes of resolution. In this review, the authors describe the invasive and noninvasive techniques neurosurgeons need to be aware of to identify PsP and facilitate surgical decision-making.

Keywords: glioblastoma; glioma; oncology; radiation necrosis; treatment-related effects; true progression; tumor; pseudoprogression.

FIG. 1.

Example case of PsP. Axial T1-weighted postcontrast MR images of a left frontoparietal GBM. A: Postbiopsy and preradiation therapy image showing left posterior frontal periventricular GBM. B: Image obtained 1 week after completion of external beam radiation therapy demonstrating marked worsening of the mass and mass effect on the adjacent ventricle. C: Image obtained 3 months after completion of radiation therapy showing a marked decrease in the size of the mass and mass effect.

FIG. 2.

DSC perfusion images help distinguish PsP. A–C: Axial T1-weighted postcontrast MR images of a left frontoparietal GBM immediately after radiation therapy demonstrating a large rim-enhancing necrotic mass with surrounding edema and mass effect (same patient as shown in Fig. 1). D–F: Axial DSC perfusion images showing minimal increase in blood volume (arrows) along the posterior margin of the enhancing lesion. G: Axial T2-weighted MR image shows marked edema surrounding the left frontal rimenhancing necrotic mass after radiation therapy with suspected recurrent tumor. Reoperation showed treatment-related changes and no viable tumor. H: Axial T1-weighted postcontrast MR image demonstrates a nodular rim-enhancing mass with necrosis. I: Axial DSC perfusion image shows no elevated blood volume, consistent with the pathological diagnosis of PsP.

FIG. 3.

ASL perfusion image helps distinguish TP in a right insular GBM 1 year after completing radiation therapy. A: Axial T1-weighted postcontrast MR image demonstrates faint, spotty enhancement at the anterior border of the resection cavity in the right basal ganglia. B: Axial FLAIR image shows nonspecific hyperintense signal abnormality surrounding the resection cavity. C: Axial ASL perfusion image demonstrates marked increase in blood flow. Repeat resection targeted to this region showed extensive tumor recurrence.

FIG. 4.

MRS used to aid in determining PsP in a right frontal GBM 12 months after radiation therapy with suspected recurrent tumor. A: Axial T1-weighted postcontrast MR image demonstrates a nodular rim-enhancing mass with necrosis. B: Three-dimensional proton MRS of the lesion shows marked decrease in NAA and choline (yellow outline), suggestive of treatment-related changes rather than recurrent tumor. C: Four consecutive axial T1-weighted postcontrast MR images over 8 months show a progressive decrease in the size of the enhancing lesion without a change in therapy.

FIG. 5.

PET used to confirm progression in a right temporal GBM 6 months after completing the radiation therapy (A–C) and in a recurrent left frontal GBM 2 months after completing re-irradiation and immunotherapy (D–G). A: Axial T1-weighted postcontrast MR image demonstrates an enhancing mass in the right medial temporal lobe. B: Axial FDOPA PET image shows increased metabolic uptake in the right temporal region. C: Axial FDOPA PET-MR image shows precise localization of the metabolic activity to the right medial temporal lobe mass. D: Axial T1-weighted postcontrast MR image demonstrates a mass-like enhancing lesion (short arrows) deep to the surgical margin (long arrow). The patient underwent re-resection based on this imaging, although FDOPA PET imaging did not show high uptake and pathology showed extensive treatment effect without a viable tumor. E: Axial FDOPA image shows no increase in uptake within the enhancing lesion. F: Axial FDOPA color map image shows no increase in uptake within the enhancing lesion. G: Axial T1-weighted postcontrast MR image 1 month after repeat resection shows no residual enhancement.

FIG. 6.

Schematic showing proposed decision algorithm for managing patients with imaging findings concerning for treatment effect versus TP. Cho = choline; Cho_N = choline in normal brain tissue; Cr = creatine; XRT = radiation therapy. Brain Section by Servier Medical Art (smart.servier.com), used under a CC BY 3.0 Unported license (https://creativecommons.org/licenses/by/3.0/). Different stages of cancer in brain (i.e., glioma) by blueringmedia/stock.adobe.com.