Challenge Case Report: Subacute Cognitive Decline

Discussion

Diagnosis and Differential Diagnosis

Glioblastoma (GBM) are often centered in the subcortical white matter. High-grade gliomas, such as GBM, are typically hypointense on T1 MRI and enhance heterogeneously postcontrast. Vasogenic edema is common and often appears as hyperintense signal abnormalities on T2/FLAIR imaging. Hyperintense areas may harbor tumor cells; however, the extent of tumor is not limited to the area of enhancement.

Oligodendrogliomas less frequently enhance and sometimes have calcifications suggestive, but not pathognomonic for oligodendroglioma. Bacterial/fungal abscesses can appear as ring-enhancing lesions but usually present with concurrent or preceding systemic symptoms. Further, the histopathologic findings of Mr. D’s tumor do not occur with bacterial abscess. On diffusion-weighted sequences, restricted diffusion is typically seen within the lesion. Mr. D is older than is commonly seen with newly diagnosed multiple sclerosis (MS), and tumefactive MS often demonstrates an “open-ring” pattern of enhancement, which is not seen in Mr. D’s imaging studies.

On histopathology, astrocytic tumors characteristically have elongated/irregular nuclei with dark, clumped chromatin, whereas oligodendrogliomas typically show rounded nuclei and speckled chromatin. All glial tumors, including astrocytomas, oligodendrogliomas and ependymomas can be positive for GFAP. Characterized by microvascular proliferation and/or necrosis, GBM are more common than oligodendrogliomas, especially in patients over age 50. By definition, oligodendrogliomas must contain an IDH mutation and a 1p/19q codeletion.^1,2

In 2016, the World Health Organization (WHO) classification of CNS tumors incorporated molecular parameters such as IDH mutation status that is now a part of the official categorization of infiltrating gliomas, with implications for prognosis.² Infiltrating gliomas with IDH mutations have a more favorable prognosis than tumors without IDH mutations.³

The unbalanced translocation 1p/19q codeletion is a defining feature of oligodendrogliomas, detected through fluorescence in situ hybridization (FISH). The H3K27M mutations can be detected via immunochemistry for a mutation-specific antibody or next generation sequencing and are present in diffuse gliomas of midline structures (eg, pons, thalamus, and spinal cord). These tumors have poor prognosis.⁴ The TERT promoter mutations are found in the majority of GBM from adults without IDH mutations.^2,5

Treatment

Treatment is demonstrated to have a survival benefit and, most frequently, is comprised of surgery followed by fractionated radiation therapy with concomitant and adjuvant temozolomide most frequently used.^6-8 Tumor treating fields (TTFields) are directly applied to the scalp via electrodes, creating electrical fields with antimitotic effects. The side effects are usually cutaneous, with some skin irritation. In conjunction with adjuvant temozolomide after radiation, TTFields treatment is approved by the Food and Drug Administration (FDA) to treat GBM.⁹ For progressive GBM, TTFields treatment is also approved as a monotherapy. Addition of TTFields to maintenance temozolomide chemotherapy resulted in statistically improved outcomes (progression free survival and overall survival) compared to treatment with maintenance temozolomide alone or standard radiochemotherapy.¹⁰ Quality of life did not differ between groups treated with TTFields plus chemotherapy, maintenance temozolomide alone, or standard radiochemotherapy.¹¹ Bevacizumab can help decrease edema associated with brain tumors and is a steroid sparing agent that is frequently used in recurrent GBM; however, clinical trials adding it to chemoradiotherapy for people with newly diagnosed GBM have not demonstrated improved survival.^7,8

Recurrence

After treatment and clinical improvement, Mr. D had clinical symptoms of aphasia and apraxia return and also developed new-onset seizures. Worsening mass effect and edema were seen on his repeat brain MRI. There is no evidence of hemorrhage in the tumor bed. Treatment effect, seen with radiation with temozolomide, termed pseudoprogression, can be mistaken radiographically for disease progression. This is most often seen in the first 3 months after completion of radiation. Although there is some tumor pushing against the left lateral ventricle in Figure 3, there is no significant midline shift, nor is there any evidence of overt hydrocephalus. Together this makes it clear that Mr. D has a recurrence of GBM.

The role of reoperation in recurrent GBM is not quite clear. It is often utilized when removal of tumor bulk will lead to symptomatic improvement.^12,13 The benefit with respect to survival is less defined. Several retrospective studies support a survival benefit with extensive resection. As an example, secondary analysis of a trial of 2 dose-intensified temozolomide regimens upon GBM recurrence demonstrated that surgery at first recurrence improves both survival and quality of life if there is complete resection of the contrast-enhancing tumor. This effect is more pronounced in patients who are younger, and those who have good performance status.¹⁴ Although intraoperative imaging, including intraoperative MRI and fluorescence guided surgery with 5-aminolevulinic acid (ALA), may be beneficial to maximize extent of resection, these are not standard of care.^15,16