Glioblastoma with Gliomatosis Cerebri Growth Pattern Presenting as Rapidly Progressive Dementia

Abstract

The differential diagnosis of rapidly progressive dementia includes neurodegenerative, toxic/metabolic, infectious, inflammatory, vascular, and malignant etiologies. This case highlights a patient with rapidly progressive cognitive decline that remained a diagnostic dilemma due to nonspecific symptoms of disorientation that progressed to persistent alteration in mental status over the span of three months. Routine laboratory testing did not help clarify the diagnosis and initial brain imaging showed only subtle abnormalities that were not commensurate with the patient’s neurologic examination. As imaging findings evolved over time to reveal a multifocal process, a biopsy was pursued, with histology consistent with infiltrating glioma and molecular testing consistent with glioblastoma. Glioblastoma with gliomatosis cerebri growth pattern should be considered on the differential diagnosis of rapidly progressive dementia in patients with multifocal imaging findings.

Introduction

The differential diagnosis of rapidly progressive dementia (RPD) encompasses multiple different etiologies. Although most RPD cases are eventually diagnosed as prion disease or atypical presentations of neurodegenerative disorders,^1,2 other diagnostic possibilities should be considered. Here, we report a patient presenting with rapidly progressive cognitive decline of initial undetermined etiology given nonspecific symptoms and only subtle abnormalities on brain imaging that were not commensurate with the patient’s neurologic exam. The patient was eventually diagnosed with glioblastoma, highlighting the importance of considering neoplastic etiologies early in the diagnostic process. This case reviews the differential diagnosis of rapidly progressive dementia, with a focus on neoplastic etiologies such as infiltrating gliomas and central nervous system lymphomas. We also highlight the importance of investigating molecular alterations on biopsy specimens to obtain an accurate diagnosis based on the recently updated 2021 World Health Organization classification of CNS tumors ³ given the considerations for treatment and management. ⁴

Case Description

A 72-year-old right-handed man with a past medical history of hypertension, hyperlipidemia, and coronary artery disease, as well as a prior history of alcohol use disorder, and without any relevant family history, presented with 3 months of progressive cognitive decline. Three months prior, the patient was completely independent with all activities of daily life and in his usual state of health, until experiencing an episode of confusion and disorientation while playing golf described as suddenly not recalling where he was. The confusion was intermittent, lasting only a few minutes and was described as situational, that is, related to golfing but otherwise was able to continue and finish golfing. He was evaluated at a local hospital, where he was found to have a systolic blood pressure of 190 mmHg. MRI brain without contrast showed subtle areas of T2 prolongation in the left medial parietal lobe (Figure 1A). Given concern that the clinical presentation and imaging findings could be consistent with posterior reversible encephalopathy syndrome (PRES), hospital admission was recommended for monitoring, but the patient left the hospital due to concern for SARS-CoV-2 infection. After leaving the hospital, the patient’s wife thought he had returned to his baseline. In the subsequent weeks, he continued to have similar episodes of disorientation such as saying things like “we have not seen my parents in a while” even though his parents had been deceased for many years, but in between episodes, appeared to return to his baseline. He was aware that he was getting confused during these episodes. Approximately a month after the initial episode, the patient’s wife felt that he was more consistently off his cognitive baseline. He used to do crossword puzzles daily, but stopped doing them, and started making mistakes with his finances, which was unusual for him. He was still able to watch television and follow the plot of shows and movies.

Figure 1.

MRI brain at presentation demonstrated T2/FLAIR hyperintensities in the left parieto-occipital area. (A) Post-contrast T1 MRI brain images 6 weeks later demonstrating right temporal, (B) left parieto-occipital, and (C) right frontal areas of enhancement. MRI brain prior to the biopsy demonstrated progression of T2/FLAIR (D) and post-contrast T1 (E, F) findings.

However, he subsequently developed visual hallucinations, where he would describe seeing Native American tribesmen. He would also ask about visiting his mother who passed away many years ago. He re-presented to his local hospital 6 weeks after his initial episode, where a repeated brain MRI re-demonstrated the previously noted findings, patchy enhancement in the right temporal lobe and a small focus on enhancement in the right superior frontal gyrus after gadolinium administration. In light of his extensive alcohol use history (at least six beers a day for 50 years), he was diagnosed with Wernicke’s encephalopathy despite absence of oculomotor dysfunction or gait ataxia, and treatment was started with IV thiamine. After his hospital discharge, he continued to decline, with new difficulties ambulating, requiring a cane within a week, though he was still able to dress himself, shave, shower, and get up at night to urinate.

Given this continued decline, he was readmitted again. At readmission, he was noted to be abulic, unable get out of bed and recognize family members. A repeat brain MRI demonstrated stable findings except for an additional subtle area of enhancement in the left putamen. MRI spine was only notable for multilevel degenerative disease in the cervical, thoracic, and lumbar spine but no cord abnormalities. He was empirically treated for autoimmune encephalitis with high-dose corticosteroids and IV immunoglobulin G (IVIg), but given no improvement, he was transferred to a tertiary center for further evaluation and treatment.

On admission, he was alert but disoriented. He was able to follow some simple axial commands (open eyes, stick out tongue) but perseverated and could not perform complex commands. In addition to paucity of speech, spontaneous speech was nonsensical. He was unable to name, repeat, or read. His cranial nerve exam did not reveal any deficits. His motor exam showed no tremor or myoclonus. Tone was normal. He had a mild R pronator drift. Confrontational strength testing was limited but overall, he appeared to have full power throughout except in his right arm extension where he was 4/5. His sensation was intact to noxious stimulation in all four extremities. His reflexes were noted to be symmetric 2+ in the triceps, biceps, and brachioradialis; his bilateral patellar reflexes had contralateral spread R > L, with absent ankle jerks. The Babinski sign was noted on the R. The patient was unable to participate in coordination or gait testing. Cerebrospinal fluid (CSF) studies showed a WBC of 2/uL (lymphocytic predominance), RBC of 1920/uL, and glucose of 41mg/dL. Total CSF protein quantity was not able to be ascertained due to insufficient CSF. Serum studies revealed mild transaminitis (ALT/AST 111/62 U/L) and normal levels of thyroid-stimulating hormone, inflammatory markers (ESR/CRP), Vit B12, and methylmalonic acid. HIV Ab and TB IFN-gamma release assays were negative. RPR, anti-thyroperoxidase Ab, ANA, anti-ds DNA, anti-Ro/La, and anti-Smith Ab were negative. Anti-thyroglobulin antibodies and syphilis antibodies were positive, but it was felt that they were false positives and difficult to interpret given recent treatment with IVIg.

EEG showed generalized theta > delta slowing consistent with mild-to-moderate bilateral cerebral dysfunction. A brain MRI with and without contrast was obtained and demonstrated interval enlargement of the multiple enhancing lesions since prior, especially of the medial frontal lobes and left parieto-occipital lobe (Figures 1B1C). A brain biopsy of the right temporal lesion was obtained. Histology (Figure 2A) revealed atypical astrocytes and increased cellularity, findings consistent with a diffuse astrocytoma. Immunohistochemistry was negative for an isocitrate dehydrogenase (IDH)-1 R132H mutation (2B), negative for mutation in tumor protein 53 (TP53) (2C), and demonstrates positive staining for α-thalassemia mental retardation X-linked protein (ATRX) consistent with absence of mutation. Next-generation sequencing (NGS) revealed gain of chromosome (Chr) 7, loss of Chr 10, telomerase reverse transcriptase (TERT) promoter mutation, and homozygous cyclin-dependent kinase inhibitors 2A and 2B (CDKN2A/B) deletion. Based on Chr 7 gain, Chr 10 loss, and TERT promoter mutation, the patient was diagnosed with glioblastoma, IDH-wildtype.^3,5 Given his limited functional status and poor prognosis, the family decided to transition the patient to hospice care, dying shortly after. The patient, therefore, died four months after initial symptoms and approximately 1 month after the brain biopsy.

Figure 2.

Histological and immunohistochemical findings on biopsy. (A) Hematoxylin and eosin (H&E) stain demonstrating atypia and increased cellularity. Immunohistochemsitry was negative for an isocitrate dehydrogenase (IDH1) R132H mutation (B), negative for mutation in TP53 (C), and demonstrates staining for ATRX consistent with absence of mutation (D).

Discussion

Although all diffuse gliomas are infiltrating in nature, at diagnosis, there is usually a single focus of disease that can be identified on imaging. Gliomatosis cerebri is a diffuse glioma growth pattern characterized by extensive CNS involvement, ranging from most of one cerebral hemisphere (at least three lobes) to both cerebral hemispheres with additional involvement of the deep grey matter nuclei, brainstem, cerebellum, and spinal cord. ³ Gliomas with a gliomatosis cerebri growth pattern can be of grade 2, 3, or 4 and this characterization can be difficult, even after brain biopsy, as the histology might not represent the full extent of the tumor’s malignant potential. This case highlights the importance of next-generation sequencing in helping identify molecular features that can help determine the tumor’s grade (Table 1).^3,5

Table 1.

Histological and Molecular Features that Determine Tumor Grade in Infiltrating Gliomas. ³

WHO Grade	Astrocytomas		Oligodendrogliomas
	IDH-wildtype	IDH-mutant
2	Diffuse astrocytoma, IDH-wildtype Diffuse infiltrating glioma with no high-grade features AND No EGFR amplification or TERT promoter mutation or gain of Chr 7/loss of Chr 10	Astrocytoma, IDH-mutant, grade 2 Diffuse infiltrating astrocytoma without high-grade histological features and no CDKN2A/B homozygous deletion	1p/19q codeletion
3	Anaplastic astrocytoma, IDH-wildtype Diffuse infiltrating glioma with atypia, vascular proliferation, or necrosis (but not all 3) AND No EGFR amplification or TERT promoter mutation or gain of Chr 7/loss of Chr 10	Astrocytoma, IDH-mutant, grade 3 Diffuse infiltrating glioma with atypia, vascular proliferation, or necrosis and without CDKN2A/B homozygous deletion	1p/19q codeletion + brisk mitotic activity or vascular proliferation
4	Glioblastoma, IDH-wildtype Diffuse infiltrating glioma with atypia, vascular proliferation, necrosis OR Diffuse infiltrating glioma with EGFR amplification or TERT promoter mutation or gain of Chr 7/loss of Chr 10	Astrocytoma, IDH-mutant, grade 4 Diffuse infiltrating glioma with atypia, vascular proliferation, necrosis OR Diffuse infiltrating glioma with CDKN2A/B homozygous deletion	N/A

Given extensive brain infiltration, patients with a gliomatosis cerebri growth pattern generally have a worse prognosis compared to patients with diffuse glioma of corresponding grades with more localized disease at presentation. ³ Gliomatosis cerebri has a variable but typically insidious clinical presentation, therefore delaying diagnosis. Presenting symptoms may be location dependent and can range from focal weakness, sensory loss, seizure, progressive headache, but often include deficits in memory, language, and other higher cortical functions. Therefore, patients initially may undergo evaluation for a rapidly progressive dementia. However, the differential diagnosis for rapidly progressive dementias is extensive and includes neurodegenerative diseases, prion encephalopathies, and antibody-mediated encephalopathies, as well as vascular, infectious, toxic-metabolic, malignancy, iatrogenic, neurodegenerative, and systemic etiologies (Figure 3). This may contribute to delays in diagnosis, as evidenced in our patient, where he was initially diagnosed with PRES, then Wernicke’s encephalopathy, followed by an extensive evaluation for other etiologies. However, when evaluation did not lead to the correct diagnosis, biopsy was pursued, revealing a malignancy-related rapidly progressive dementia.

Figure 3.

Differential diagnosis of rapidly progressive dementia.

Among neoplastic processes, primary central nervous system lymphoma (PCNSL) should also be considered as it can have both multifocal, patchy imaging findings, and an initial clinical presentation of behavioral changes. ⁶ Imaging in gliomatosis cerebri often shows diffuse white matter lesion, infiltration of the cortex, poor grey-white matter delineation, enlargement of affected cerebral structures, and thickened gyri. Although the findings can be nonspecific, they can help exclude diagnoses in the differential as, for example, PCNSL usually presents with periventricular areas of homogenous contrast enhancement that can regress after treatment with corticosteroids.

Conclusion

In patients presenting with rapid cognitive decline and multifocal brain lesions on brain imaging, the differential diagnosis includes infectious, inflammatory/autoimmune, vascular, neurodegenerative, and neoplastic processes. Within neoplastic processes, glioma with gliomatosis cerebri growth pattern should be suspected in patients with progressive evolution of imaging findings and minimal or absent symptomatic improvement after corticosteroids.

Key Points

In a patient presenting with a rapidly progressive cognitive decline and demonstrating multifocal brain lesions on MRI, consider glioma with gliomatosis cerebri growth pattern as a possible etiology. Imaging should be conducted with contrast, and abnormal findings should prompt moving malignancy higher on the differential and a neurodegenerative process lower on the differential. Lesional biopsy is necessary to establish the diagnosis. If corticosteroids are given prior to the biopsy, though there are exceptions, there usually will be minimal response in gliomatosis cerebri as compared to demyelinating diseases or PCNSL. Since the 2016 WHO classification of CNS tumors, gliomatosis cerebri has been refined as a pattern of widespread tumor growth that can be displayed by any of the infiltrating gliomas, though it is most commonly seen with anaplastic astrocytoma. Given the not uncommon inability of a biopsy to establish a definitive diagnosis based on histology alone, next-generation sequencing of the tumor sample is of major utility.

ORCID iDs

John Rhee https://orcid.org/0000-0002-2081-5667

L. Nicolas Gonzalez Castro https://orcid.org/0000-0001-7699-5188