Glioblastoma Pseudoprogression Differential diagnosis

Glioblastoma Pseudoprogression Differential diagnosis

The suspicious lesion may represent post-treatment radiation effects (PTRE) such as pseudoprogression, radiation necrosis or Glioblastoma recurrence 1).

A study aimed to investigate whether perioperative markers could distinguish and predict PsP from TeP in de novo isocitrate dehydrogenase (IDH) wild-type GBM patients. Methods: New or progressive gadolinium-enhancing lesions that emerged within 12 weeks after CCRT were defined as early progression. Lesions that remained stable or spontaneously regressed were classified as PsP, otherwise persistently enlarged as TeP. Clinical, radiological, and molecular information were collected for further analysis. Patients in the early progression subgroup were divided into derivation and validation sets (7:3, according to operation date). Results: Among 234 consecutive cases enrolled in this retrospective study, the incidences of PsP, TeP, and neither patterns of progression (nP) were 26.1% (61/234), 37.6% (88/234), and 36.3% (85/234), respectively. In the early progression subgroup, univariate analysis demonstrated female (OR: 2.161, P = 0.026), gross total removal (GTR) of the tumor (OR: 6.571, P < 001), located in the frontal lobe (OR: 2.561, P = 0.008), non-subventricular zone (SVZ) infringement (OR: 10.937, P < 0.001), and methylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter (mMGMTp) (OR: 9.737, P < 0.001) were correlated with PsP, while GTR, non-SVZ infringement, and mMGMTp were further validated in multivariate analysis. Integrating quantitative MGMTp methylation levels from pyrosequencing, GTR, and non-SVZ infringement showed the best discriminative ability in the random forest model for derivation and validation set (AUC: 0.937, 0.911, respectively). Furthermore, a nomogram could effectively evaluate the importance of those markers in developing PsP (C-index: 0.916) and had a well-fitted calibration curve. Conclusion: Integrating those clinical, radiological, and molecular features provided a novel and robust method to distinguish PsP from TeP, which was crucial for subsequent clinical decision making, clinical trial enrollment, and prognostic assessment. By in-depth interrogation of perioperative markers, clinicians could distinguish PsP from TeP independent from advanced imaging 2).

Conventional structural MRI is insufficient for distinguishing pseudoprogression from true progressive disease, and advanced imaging is needed to obtain higher levels of diagnostic certainty. Perfusion MRI is the most widely used imaging technique to diagnose pseudoprogression and has high reported diagnostic accuracy. Diagnostic performance of MR spectroscopy (MRS) appears to be somewhat higher, but MRS is less suitable for the routine and universal application in brain tumor follow-up. The combination of MRS and diffusion-weighted imaging and/or perfusion MRI seems to be particularly powerful, with diagnostic accuracy reaching up to or even greater than 90%. While diagnostic performance can be high with appropriate implementation and interpretation, even a combination of techniques, however, does not provide 100% accuracy. It should also be noted that most studies to date are small, heterogeneous, and retrospective in nature. Future improvements in diagnostic accuracy can be expected with harmonization of acquisition and postprocessing, quantitative MRI and computer-aided diagnostic technology, and meticulous evaluation with clinical and pathological data 3).

The key features pseudoprogression will demonstrate include:

Magnetic resonance perfusion imaging: reduced cerebral blood volume (viable tumor will usually have increased rCBV)

Proton magnetic resonance spectroscopic imaging

low choline

ratio Cho/NAA ratio ≤1.4

increased lactate peak

increased lipid peak

the trace may also be generally flat (hypometabolic)

Apparent diffusion coefficient

tumors that respond to treatment and result in pseudoprogression will have elevated ADC values due to cell death ADC mean values ≥1300 x 10-6 mm2/s 8

Moassefi et al. reported the development of a deep learning model that distinguishes PsP from TP in GBM patients treated per the Stupp protocol. Further refinement and external validation are required prior to widespread adoption in clinical practice 4).

Incorporating all available MRI sequences into a sequence input for a CNN-LSTM model improved diagnostic performance for discriminating between pseudoprogression and true tumor progression 5).

see Glioblastoma progression.


Parvez K, Parvez A, Zadeh G. The diagnosis and treatment of pseudoprogression, radiation necrosis and brain tumor recurrence. Int J Mol Sci. 2014 Jul 3;15(7):11832-46. doi: 10.3390/ijms150711832. PMID: 24995696; PMCID: PMC4139817.

Li M, Ren X, Dong G, Wang J, Jiang H, Yang C, Zhao X, Zhu Q, Cui Y, Yu K, Lin S. Distinguishing Pseudoprogression From True Early Progression in Isocitrate Dehydrogenase Wild-Type Glioblastoma by Interrogating Clinical, Radiological, and Molecular Features. Front Oncol. 2021 Apr 20;11:627325. doi: 10.3389/fonc.2021.627325. Erratum in: Front Oncol. 2021 May 19;11:700599. PMID: 33959496; PMCID: PMC8093388.

Thust SC, van den Bent MJ, Smits M. Pseudoprogression of brain tumors. J Magn Reson Imaging. 2018 May 7;48(3):571–89. doi: 10.1002/jmri.26171. Epub ahead of print. PMID: 29734497; PMCID: PMC6175399.

Moassefi M, Faghani S, Conte GM, Kowalchuk RO, Vahdati S, Crompton DJ, Perez-Vega C, Cabreja RAD, Vora SA, Quiñones-Hinojosa A, Parney IF, Trifiletti DM, Erickson BJ. A deep learning model for discriminating true progression from pseudoprogression in glioblastoma patients. J Neurooncol. 2022 Jul 19. doi: 10.1007/s11060-022-04080-x. Epub ahead of print. PMID: 35852738.

Lee J, Wang N, Turk S, Mohammed S, Lobo R, Kim J, Liao E, Camelo-Piragua S, Kim M, Junck L, Bapuraj J, Srinivasan A, Rao A. Discriminating pseudoprogression and true progression in diffuse infiltrating glioma using multi-parametric MRI data through deep learning. Sci Rep. 2020 Nov 23;10(1):20331. doi: 10.1038/s41598-020-77389-0. PMID: 33230285; PMCID: PMC7683728.

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