Glioblastoma, IDH- wildtype (pseudoprogression)

Case contributed by Frank Gaillard
Diagnosis certain

Presentation

Focal seizure.

Patient Data

Age: 65 years
Gender: Female

FLAIR hyperintensity in the right frontal parietal temporal region, with mild FLAIR hyperintensity extending to the ependymal surface of the right lateral ventricle posteriorly is noted, with areas of enhancement embedded within it. Although there is T2 shine through, there are also regions of true diffusion restriction, including at the areas of enhancement but also within the nonenhancing FLAIR hyperintensity. MRS demonstrates moderate choline elevation and small to moderate lactate peaks with reduced NAA. Elevation of cerebral blood volume (CBV) is prominent. Incidental left anterior temporal arachnoid cyst. 

Conclusion

Features are those of a diffuse primary brain tumor. Increased cellularity and perfusion suggest a higher grade (III or IV). 

The patient went on to have a biopsy. 

Histology

The sections show features of a moderately cellular astrocytic tumor. The astrocytes are of the fibrillary type. They have elongated, angulated and hyperchromatic nuclei. In one area, 3 mitoses are seen. No microvascular proliferation or necrosis is present.

There is no oligodendroglial component.

The tumor cells are focally p53 positive. The topoisomerase index is about 10%. They are IDH-1 negative (wild-type) and MGMT negative (likely methylated).

FINAL DIAGNOSIS: Glioblastoma, IDH-wildtype (WHO CNS grade 4)

Note: Although this tumor is entirely consistent with IDH wild-type molecular subtype, strictly speaking, to conclusively establish this, IDH would need to be sequenced to ensure that a non-IDH1 R132H mutation was present. In practice, an IDH1 R132H negative tumor in an individual over 55-years-of-age renders the possibility of this being IDH-mutant remote (<1%), and sequencing is not felt to be necessary by many institutions and is not recommended by the WHO classification of CNS tumors

15 weeks post-surgery

mri

MRI obtained 15 weeks post surgery; Stupp protocol, finished 5 weeks earlier (first post treatment MRI). 

Right frontal craniotomy. The residual tumor in the right temporal frontal and parietal lobes has increased slightly in extent on T2-weighted images with some increase in mass-effect with sulcal effacement and minor distortion of the right lateral ventricle.

The tumor infiltrates the insula, posterior putamen, lateral thalmus, temporal lobes and extends superiorly into the right frontal and parietal lobes.

A new area of peripheral contrast enhancement lies within the inferior frontal gyrus. Increased intensity of the regions of per contrast enhancement within the temporal lobe as well as around the region of necrosis are noted. However, cerebral blood volume (rCBV) shows less marked increase than on the prior study and diffusion shows less extensive regions of decreased ADC.

MR spectroscopy is dominated by elevated lipid and lactate consistent with necrosis, as well as persisting areas of elevated choline suggesting a residual tumor

Conclusion:

Although many of the imaging features are in keeping with residual with or without progressive disease, the reduction in rCBV as well as less extensive regions of decreased ADC suggest that least some of the changes are due to response to therapy (pseudoprogression). 

28 weeks post-surgery

mri

MRI study obtained 3 months after the prior study (28 weeks post op, ~4 months post end of Stupp protocol) demonstrates increasing volume of adjacent high FLAIR signal, extending further anteriorly into the frontal lobe and further superiorly to the frontoparietal white matter at the vertex. There is also mild increase in FLAIR hyperintensity into the right cerebral peduncle. There is increasing adjacent peripheral enhancement. The region of contrast enhancement shows significant elevation in choline, reduction in NAA and increase in lactate. 

There is increasing susceptibility within the area of contrast enhancement in keeping with hemorrhage.

48 weeks post-surgery

mri

MRI obtained 11 months post op (3.5 months after last scan).

Previous right parietal craniotomy and frontoparietal resection cavity again noted. The degree of FLAIR signal abnormality has reduced superiorly within the frontal and parietal lobes. Signal abnormality more inferiorly extending into the temporal lobe, insular and the right cerebral peduncle is similar to previous. The peripherally enhancing lobulated lesion is similar in extent to previous. The margins are less distinct, however no discrete new nodular enhancement is identified.

There is persisting persisting reduced ADC values at the margins of the enhancement, progressed since previous with increased CBV within this region.

New FLAIR signal abnormality involving the ipsilateral medial cerebral hemispheric cortex (precuneus and posterior cingulate) and contralateral (left) caudate head, anterior limb of internal capsule and the anterior putamen. This region does not demonstrate abnormal diffusion restriction or definite elevated CBV.

Spectroscopy demonstrates elevated choline and reduced NAA within the FLAIR signal abnormality consistent with residual tumor.

There is stable mass effect on the right cerebral hemisphere with stable ventricular size.

Conclusion:

While the extent of FLAIR signal abnormality within the superior frontal and parietal lobes has reduced, as has contrast enhancement, there is evidence of disease progression at the posteromedial margin of the resection cavity within the periventricular white matter as well as parietal and cingulate cortex.

New mass like FLAIR abnormality involving left caudate head is also concerning for new tumor.

Case Discussion

The diagnosis of pseudoprogression can be difficult and knowledge of timing of the scan relative to chemoradiotherapy is crucial (typically ~3 months post end of chemoradiotherapy, but commonly seen within 0 - 6 months). 

This patient was also more likely to demonstrate pseudoprogression as their tumor is MGMTmethylated (and thus alkylating agents e.g. temozolomide used in the Stupp protocol will have greater efficacy). 

It is also crucial to realize that it is not a question of pseudoprogression OR persistence presence of tumor (or even probably tumor growth); both can be occurring simultaneously. It is really a question of determining which process is dominant and accounts for the imaging features. 

In this case at least part of the initially progressive enhancement, which abates, was due to pseudoprogression, however by the time we see the last study we clearly also have disease progression. 

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