Tumor pseudoprogression (brain tumors)

Last revised by Henry Knipe on 26 Aug 2024

Tumor pseudoprogression, also known simply as pseudoprogression, is a relatively common finding in brain tumor imaging follow-up, especially for high-grade gliomas (e.g. glioblastoma).

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.

It is observed in ~30% of patients after combined chemotherapy and radiotherapy (Stupp protocol). Radiotherapy alone is less likely to result in pseudoprogression, only observed in ~15% of patients. 

Tumors with methylated MGMT show pseudoprogression more frequently, mainly when treated with temozolomide 1,5,8.

In almost 60% of cases, pseudoprogression occurs within the first three months after completing treatment, but it may occur from the first few weeks to 6 months after treatment 1-3. Generally patients remain clinically stable without the clinical deterioration usually seen with rapid tumor progression 1.

Pseudoprogression 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 ref.

Brain post-radiation treatment effects can be divided into pseudoprogression and radiation necrosis 4. Importantly, the likelihood of developing pseudoprogression is strongly influenced by the radiation dose. It is unlikely to occur in brain that has received <60 Gy 9-11.

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) along with access to prior imaging and radiation field maps. Key features of pseudoprogression 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

The primary differential diagnosis is that of true tumor progression. Unfortunately, no single feature is pathognomonic of tumor versus pseudoprogression, however, the following features generally favor tumor:

  • location: outside the 60 Gy field

  • timing: late occurrence e.g. >12 months after Stupp protocol

  • perfusion: elevated cerebral blood volume

  • diffusion: lower ADC values

  • spectroscopy: high choline, low lipid and lactate

  • clinical: patient doing poorly

  • histology: MGMT unmethylated

Cases and figures

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