Tumor pseudoprogression (brain tumors)

Last revised by Dr Joshua Yap on 13 Oct 2022

Tumor pseudoprogression, also known just as pseudoprogression, corresponds to an increase in lesion size related to treatment, which simulates progressive disease. The term is largely used in brain tumor imaging follow-up, especially for high-grade gliomas (e.g. glioblastoma), and is observed after combined chemotherapy and radiotherapy (Stupp protocol) in about 30% of patients. Radiotherapy alone is less likely to result in pseudoprogression, only observed in about 15% of patients. 

Brain post-radiation treatment effects can be divided into pseudoprogression and radiation necrosis 4.

Due to an overlap between the definitions of pseudoprogression and radiation necrosis, it is not incorrect to say that pseudoprogression represents a mild and self-limiting variant of treatment-related necrosis 1,2.

In almost 60% of cases, pseudoprogression occurs within the first 3 months after completing treatment, but it may occur from the first few weeks to 6 months after treatment 1-3.

Patients with methylated MGMT show pseudoprogression more frequently, particularly when treated with temozolomide 1,5,8.

Generally patients remain clinically stable without the clinical deterioration usually seen with rapid tumor progression 1.

It is related to endothelial damage and consequent tissue hypoxia observed after treatment and it has an early occurrence (~60%), usually in the first 3 months after the treatment, but it may occur from the first few weeks to 6 months after treatment.

The hallmark of pseudoprogression is increased size of the enhancing component of a glioblastoma, and this has proven challenging in the trial setting as the most widely used criteria (Macdonald criteria and RANO criteria) struggle to distinguish between pseudoprogression and true disease progression as they largely rely on only the size of the enhancing component 6. As such conventional CT and MRI are insensitive to the distinction. However, advanced sequences (MR spectroscopy, perfusion, ADC values) are of significant help. 

A good quality MRI including advanced sequences is essential (see MRI protocol: brain tumor). The key features pseudoprogression will demonstrate include: 

  • perfusion: reduced cerebral blood volume (viable tumor will usually have increased rCBV) 6

  • spectroscopy 7

    • low choline

    • choline/NAA ratio ≤1.4 8

    • increased lactate peak 

    • increased lipid peak

    • the trace may also be generally flat (hypometabolic)

  • ADC

    • 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

Not only does pseudoprogression not represent disease progression, it often is a marker of longer survival, presumably because it represents a robust response to treatment 8

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Cases and figures

  • Case 1: glioblastoma 6 months after treatment
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  • Case 1: 5 years after treatment
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  • Case 2: at end of Stupp protocol
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  • Case 2: 2 months later
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  • Case 3: 6 months after treatment
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  • Case 3: 11 months after treatment
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  • Case 4: 1 month post Stupp protocol
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  • Case 4: 6 months post Stupp protocol
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  • Case 5: MR spectroscopy
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  • Case 5: hematoxylin and eosin
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  • Case 6
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  • Case 7
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