Glioblastoma in Patients With Multiple Sclerosis

Abstract

Background

Although rare, the co-occurrence of multiple sclerosis (MS) and glioma poses unique challenges in terms of diagnosis and management for both neurologists and neuro-oncologists.

Methods

Here we report on a single-center cohort of four patients with a diagnosis of multiple sclerosis who developed gliomas.

Results

Our cohort reflects the epidemiology of glioma in terms of the relative frequency of IDH-wildtype and IDH-mutant cases. The patients in 3 out of the 4 cases presented did not develop their tumors in areas of pre-existing demyelinating lesions.

Conclusions

We did not find evidence to support the hypothesis that chronic gliosis from demyelinating plaques may serve as a substrate for secondary induction of a glial neoplasm. In our Discussion, we provide recommendations for distinguishing neoplastic from demyelinating lesions, review the evidence for demyelination as a risk factor for gliomagenesis, and highlight important considerations for the concurrent management of glioma and MS.

Report of Cases

Case 1

A 63 year-old right-handed man with a 20-year history of relapsing-remitting multiple sclerosis presented with 2 weeks of progressive right arm and right leg weakness as well as word finding difficulties. His multiple sclerosis (MS) was being treated with Interferon beta 1-α as a disease-modifying therapy. He was also receiving dalfampridine to improve gait. His baseline deficits were mild short-term forgetfulness, unsteadiness, right hand fine motor impairment, and diffuse spasticity. On presentation, his neurologic exam was notable for mild non-fluent aphasia, right arm and right leg weakness. MRI brain showed a bi-lobed, left frontal, peripherally enhancing lesion with increased surrounding vasogenic edema (Figure 1A-C). He was started on dexamethasone 4 mg daily with improvement of symptoms. He underwent near-total lesion resection, complicated by intra-operative seizure. Pathology was consistent with glioblastoma (GBM), IDH-wildtype, MGMT promoter unmethylated, with mutations in TP53, TERTp and RB1, as well as PTEN loss. He was treated with concurrent radiation and temozolomide, followed by six cycles of adjuvant temozolomide. Twelve months after his initial presentation and five months after completion of treatment, he was noted to have radiographic and clinical evidence of tumor progression and was started on palliative bevacizumab for symptom management. His MS treatments were continued throughout his treatment for GBM. He passed away two months later.

Figure 1.

Case 1 MRI Brain at time of tumor diagnosis. (A) Axial T2-FLAIR sequences showing left frontal lobe mass lesion with surrounding diffuse T2-FLAIR signal indicating vasogenic edema, with associated mass effect. Additionally, multifocal periventricular and juxtacortical hyperintensities are noted (white arrows indicate examples), consistent with the patient’s known MS. (B) Sagittal T2-FLAIR sequences demonstrate ovoid periventricular white matter hyperintensities (white arrows indicate examples) consistent with the patient’s known MS. (C) Axial T1 post-contrast sequence showing left frontal lesion with heterogeneous contrast enhancement and areas of central necrosis.

Case 2

A 61-year-old right-handed woman with a 21-year history of secondary progressive multiple sclerosis (SPMS), presented with one week of right sided headache, right facial numbness, left facial weakness with drooling, and incoordination. She was receiving treatment for her SPMS with rituximab every six months as well as monthly IV methylprednisolone. Previously, she had been treated with interferon beta-1-α, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, and ocrelizumab. Her baseline deficits had been 4/5 right arm and right leg weakness with hemiparetic gait. On presentation, her exam was notable for left facial weakness in upper motor neuron pattern, mild dysarthria, extinction in the left arm and leg, mild ataxia on finger-to-nose testing on left, and baseline right hemiparesis. MRI brain showed a multi-lobed, right fronto-parietal, heterogeneously enhancing lesion with extensive surrounding vasogenic edema leading to midline shift (Figures 2A and B). She was started on dexamethasone 2 mg daily and underwent maximal safe (subtotal) resection of the lesion 5 days later. Pathology findings were consistent with GBM, IDH-wildtype, MGMT promoter unmethylated. Additional molecular profiling also revealed mutations in STAG2, TERT promoter and TP53.

Figure 2.

Case 2 MRI Brain and C-spine at time of tumor diagnosis. (A) Axial and sagittal T2-FLAIR sequences showing mass lesion in the right inferior frontal lobe with surrounding T2-FLAIR hyperintensity and associated mass effect. Additionally, examples of white matter hyperintense lesions (indicated by white arrows) consistent with known MS. (B) Axial T1 post-contrast sequence showing heterogenous enhancement of the right frontal mass. (C) MRI C-spine STIR sequence few months before MRI Brain in A and B, showing known T2-hyperintense spinal cord lesions at the C2 and C8 levels (indicated by white arrows), consistent with known MS.

She underwent initial glioblastoma treatment with 6 weeks of concurrent radiation and temozolomide, at which time she was also started on bevacizumab due to concern for evolving vasogenic edema from chemoradiation vs progression. Three months after completion of radiation, with evidence of clinical and radiographic progression, lomustine was added. At this point, she also stopped rituximab infusions after discussion with her MS provider. Unfortunately, she continued to decline and had further disease progression. She opted to pursue hospice care and passed away shortly thereafter, eleven months after her initial presentation.

Case 3

A 39 year-old right-handed man with no prior medical diagnoses presented for evaluation of greater than 10 years of gait imbalance and left leg weakness. Exam revealed diffuse spasticity and hyperreflexia, bilateral ankle clonus and extensor plantar responses, left arm and leg weakness (4/5), asymmetrically diminished leg sensation. He underwent an MRI brain that was notable for a non-enhancing T1 hypointense T2-FLAIR hyperintense lesion in the left medial frontal lobe as well as multiple ovoid, periventricular T2-FLAIR hyperintense lesions (Figures 3A and B). MRI of the cervical and thoracic spine did not reveal any additional lesions. Although the left frontal lesion was atypical for MS, the rest of the lesions and clinical presentation were consistent with this diagnosis. He started disease-modifying therapy with glatiramer acetate and subsequently transitioned to fingolimod. He unfortunately developed Herpes zoster on fingolimod and MS treatment was stopped. He was briefly on glatiramer acetate, but this was also stopped due to adverse reactions of muscle stiffness and rigidity. A follow-up MRI brain one year later showed stability of the left frontal lesion. He was subsequently lost to follow up and re-presented three years later after a first generalized seizure. He had no new neurologic deficits. He had sought MS care elsewhere and had declined to start further disease modifying agents. Repeat MRI brain now showed moderate interval growth of the left frontal lesion, mostly non-enhancing but with some nodular enhancement, associated with an increase in surrounding vasogenic edema (Figures 3C and D). MR Spectroscopy showed marked elevation of choline/NAA ratio within the left frontal lesion as well as elevated 2-hydroxyglutarate peak, suggestive of IDH-mutant high grade glioma. He underwent resection of the lesion, and pathology was consistent with GBM, IDH1-mutant, MGMT promoter methylated. Next-generation sequencing of the tumor revealed mutations in TP53, ATRX and PIK3CA. It is worth noting that, according to the recently updated 2021 World Health Organization (WHO) Classification of the Tumors of the Central Nervous System, this patient’s tumor would be reclassified as an astrocytoma, IDH-mutant, WHO grade 4, as the designation of glioblastoma was removed from IDH-mutant astrocytic tumors regardless of histologic grade due to the improved prognosis conferred by IDH mutations.^1,2 He was started on radiation and concurrent temozolomide followed by 6 cycles of adjuvant temozolomide and went into observation. A year and half later, MRI brain showed evidence of disease progression and he was treated with additional cycles or adjuvant temozolomide. Repeat MRI brain three months after adjuvant temozolamide showed disease progression. He is currently receiving bevacizumab with consideration for lomustine as salvage therapy.

Figure 3.

Case 3 MRI Brain at time of initial MS diagnosis, and repeat MRI Brain four years later upon presentation with seizure. (A) Axial and sagittal T2-FLAIR sequences show left frontal lobe lesion (white star) as well as multiple bilateral T2 hyperintense lesions with perpendicular pericallosal orientation (examples indicated by white arrows). (B) Axial T1 post-contrast sequence (left) demonstrating T1 hypointense non-enhancing left frontal lobe lesion, and axial T2 sequence (right) demonstrating hyperintense signal within the left frontal lesion that appears more attenuated on the T2-FLAIR sequence in A except for a peripheral rim, indicating T2/FLAIR mismatch. (C) Axial T2-FLAIR sequence from MRI Brain obtained 4 years after image in A and B, 3 years after radiographic stability (image not shown) of left frontal lesion, now showing interval enlargement in T2-FLAIR hyperintense left frontal lesion (white star). (D) Axial T1 post-contrast sequence from interval scan as in C, showing interval enlargement of mostly non-enhancing left frontal lesion.

Case 4

A 57 year-old right handed female with a 25 year history of SPMS presented with 3 weeks of headaches and left hemifield dysmorphopsia. For her MS, she was on dalfampridine and biotin, but not on any disease modifying therapy. She had previously been treated with interferon beta-1α, mycophenolate mofetil, fingolimod, and ocrelizumab. On presentation, exam was unchanged from her baseline and was notable for diffuse hyperreflexia, bilateral extensor plantar responses, mild right leg weakness, and wide-based gait. MRI brain showed a cluster of ring-enhancing lesions in the right occipital lobe with surrounding vasogenic edema (Figures 4A and B) as well as a small nodular area of enhancement in the right corpus callosum. She underwent maximal safe resection of the enhancing occipital lesion with pathology consistent with GBM, IDH-wildtype, MGMT promoter unmethylated. Additional molecular profiling revealed mutations in PTEN, PTPN11 and STAG2. She transferred her care to an outside institution and underwent chemoradiation, though the exact oncologic treatment regimen is unknown. She continued on dalfampridine. She unfortunately passed away eight months after her GBM diagnosis.

Figure 4.

Case 4 MRI Brain at time of tumor diagnosis. (A) Axial T2-FLAIR sequence showing right occipital T2-FLAIR hyperintense lesion. There are additional areas of hyperintensity seen in the left temporal lobe and right hippocampus. (B) Axial T1 post-contrast sequence showing a cluster of ring-enhancing lesions in the right occipital lobe. (C) Axial T2-FLAIR sequence showing periventricular white matter hyperintensities consistent with known MS (examples indicated by white arrows).

Results

A summary of the clinical characteristics in our patient cohort is presented in Table 1. The limited number of patients in our cohort limits our ability to establish any associations between the type of MS that our patients had, or the treatments they received prior to their diagnosis of glioblastoma, and the clinical or molecular features of the tumors they developed. We however note that with the exception of the patient in Case 3, whose glioma and demyelinating lesions were found concurrently, none of the other patients developed their tumors in areas overlaying prior demyelinating lesions. In addition, despite the small sample size, our cohort reflects the significantly higher prevalence of IDH-wildtype relative to IDH-mutant high grade gliomas. ³

Table 1.

Disease characteristics of patients in our cohort.

Age at GBM diagnosis	Type of MS	Location of MS lesions	Treatment of MS	Duration of MS diagnosis	Presenting symptoms at time of tumor diagnosis	Location of GBM	Pathological diagnosis	Molecular tumor profiling
63	RRMS	Periventricular, juxtacortical, cervical cord	Interferon-beta 1-α	20+ years	RUE/RLE progressive weakness and word finding difficulty	Left frontal	Glioblastoma, IDH-wildtype	Unmethylated MGMT promoter
								PTEN, TERT promoter, TP53 and RB1 mutations.
61	SPMS	Periventricular, juxtacortical (mild); cervical and thoracic cord	Natalizumab, Interferon- beta-1-α, Glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, ocrelizumab, rituximab	23 years	numbness on face, lower lips, trouble managing her own secretions, generalized weakness, worsened bladder control	Right frontal	Glioblastoma, IDH-wildtype	Unmethylated MGMT promoter
								STAG2, TERT promoter and TP53 mutations
39	RRMS	Periventricular, juxtacortical, pontomedullary junction, cerebellum,	Glatiramer acetate, Fingolimod	0 (concurrent diagnosis)	Left leg weakness	Left frontal	Glioblastoma, IDH-mutant (Astrocytoma, IDH-mutant, WHO grade 4)	Methylated MGMT promoter; IDH1 R132H
								IDH1, TP53, ATRX and PIK3CA mutations
57	SPMS	Periventricular, juxtacortical, cerebellum, cervical and thoracic cord	Interferon-beta-1-α, Mycophenolate mofetil, Fingolimod	25 years	Vision changes	Right occipital	Glioblastoma, IDH-wildtype	Unmethylated MGMT promoter; TERT promoter, PTEN, PTPN11 and STAG2 mutations.

GBM = glioblastoma; MS = multiple sclerosis; RRMS = relapsing remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; RUE = right upper extremity; RLE = right lower extremity; IDH = isocitrate dehydrogenase

Discussion

Distinguishing Demyelinating Disease from Glioma based on Clinical and Diagnostic Information

Epidemiology

Demyelinating disease is more common than primary brain tumors. The prevalence of MS in the United States (US) is estimated to be 149 per 100 000, though its prevalence varies by geography and is highest in US, Europe and Australia. ⁴ Age of onset for MS peaks between 25 to 35 years, and in most populations women are more affected than men by 2 to 3-fold. ⁵ Though gliomas can appear at any age, on average peak age is 20-30 years for grade 2 lesions, 40 years for grade 3, and 55-65 years for glioblastoma (WHO grade 4). Glioblastoma is the most common glioma seen in adults, with an annual incidence of approximately 3 in 100 000 people. ⁶ For all grades of glioma, men are more affected than women. ⁷

Clinical Presentation

Multiple sclerosis may present with a range of clinical symptoms and syndromes that arise over hours to days and vary in severity, reflecting one or more foci of active demyelination in the central nervous system. Often the initial presentation involves limb weakness, numbness or paresthesias. Additionally, specific syndromes typical of MS manifestations include optic neuritis, transverse myelitis, brainstem syndromes, cerebellar ataxia, or internuclear ophthalmoplegia. ⁸  In the most common presenting clinical phenotype of MS (relapsing remitting), symptoms occur in discrete episodes and may improve over the course of weeks to months (their recovery hastened by treatment like IV corticosteroids), but often do not fully resolve to prior baseline. ⁹

Gliomas may present with symptoms caused by the tumor itself and by surrounding vasogenic edema. Headache is present in over 50% of patients diagnosed with high grade gliomas, with non-specific pain characteristics though typically unilateral and progressive. Seizures lead to the initial presentation of 20-40% of patients with glioma (more common in IDH-mutant gliomas).^10,11 On the other hand, seizures are rare in MS; a pooled analysis of 39 studies found the prevalence of seizures and epilepsy in MS patients to be 2% and 3%, respectively. ¹²  As with MS, gliomas may cause focal neurologic deficits depending on the size and location of the tumor and on the amount of vasogenic edema. Focal deficits in gliomas are typically initially subtle, subacute to chronic and progressive, though they may present more acutely in rapidly growing tumors. The acuity of glioma presentation is often affected by tumor grade, as slower growing tumors may present with slowly progressive symptoms while higher grade tumors may present with more acute symptoms. ⁷  Finally, tumors may cause more generalized symptoms due to increased intracranial pressure, leading to positional headache, papilledema, or depressed level of consciousness. ⁷  As in MS, symptoms related to gliomas may improve with initial corticosteroid administration, but this is likely a result of decreased vasogenic edema associated with the tumor. A history of episodic neurologic deficits disseminated in space and time, as is typical for MS, is unlikely in gliomas.

Imaging

MRI enhanced with gadolinium contrast is the imaging modality of choice in the diagnosis of both MS and gliomas. There are some types of MS lesions that can resemble gliomas and conversely, early stage gliomas that may resemble MS lesions. Demyelinating MS lesions are hyperintense on T2-FLAIR, may be hypointense on T1 (if chronic) or contrast-enhancing (signifying active demyelination). They are typically ovoid in shape, ranging from 3 mm to 1-2 cm in diameter across their long axis, and found in characteristic locations (periventricular, cortical/juxtacortical, infratentorial, spinal cord) ¹³ (Figures 1A and B, Figures 2A and C, Figure 3A and Figure 4C). Periventricular lesions abut and are oriented perpendicularly to the ventricles (Figure 1A, Figure 3A and Figure 4C). Given the diagnosis of MS involves dissemination of lesions in space and time, lesions may involve at least two of the characteristic locations noted above.

Gliomas tend to have more of an expansile appearance and almost never occur concurrently in the brain and the spine. IDH-mutant gliomas, including low grade and often grade 3, are typically T1 hypointense, T2-FLAIR hyperintense, and non-contrast enhancing on initial presentation (Figure 3A and B). Grade 4 IDH mutant gliomas may demonstrate contrast enhancement. Glioblastomas, IDH-wildtype (as in Cases 1,2,4) are also T1 hypointense and T2-FLAIR hyperintense, but display heterogeneous contrast enhancement, and are more expansile with greater associated vasogenic edema (Figures 1A and B, Figures 2A and B and Figure 4A AND B). Cystic or hemorrhagic changes may be seen in high-grade gliomas but are rarely seen in MS. ¹⁴  One particular radiographic sign worth noting is MRI T2/FLAIR mismatch, an insensitive but highly specific sign that identifies IDH-mutant, 1p/19q non-codeleted gliomas.^15,16 The sign is present if a mass lesion displays near-homogeneous hyperintense signal on T2-weighted sequence, but on T2-weighted FLAIR sequence displays relative hypointense signal except for a hyperintense peripheral rim. The sign, if identified correctly, can help distinguish IDH-mutant astrocytoma from other gliomas as well as from non-malignant etiologies like demyelination, as it does in Case 3 (Figure 3A and B).

If these imaging characteristics inadequately characterize the lesion, advanced imaging techniques can be helpful if available. MR spectroscopy offers metabolic information about a lesion, and tumors have a characteristic spectrographic appearance including increased choline peak, decreased N-acetyl-aspartate (NAA) peak, and increased choline to creatinine ratio.^17,18 While this is helpful in distinguishing tumors from most demyelinating lesions, tumefactive MS can present a unique challenge. Tumefactive MS refers to a demyelinating lesion that may resemble a tumor due to its atypical imaging features, including large solitary lesion greater than 2cm in diameter, associated mass effect and edema, and/or peripheral contrast enhancement. ¹⁹  Tumefactive MS may also share MR Spectroscopy features with gliomas including increased choline to creatinine ratios; however, recent inquiry has suggested that elevated choline to NAA ratios (as in Case 3) can effectively distinguish high-grade (but not necessarily low-grade) glioma from tumefactive MS. ²⁰

Additional potentially useful advanced imaging modalities include dynamic-susceptibility contrast (DSC) MR perfusion imaging and diffusion tensor imaging (DTI). DSC MR perfusion imaging can evaluate for relative cerebral blood volume (rCBV), a marker of angiogenesis, which can aid in differentiating low grade from high grade gliomas. Notably, tumefactive demyelinating lesions usually have decreased rCBV values due to absent neovascular proliferation, which can in many cases distinguish tumefactive MS from high grade (but not low grade) glioma. ²¹ However, tumefactive demyelination has also been shown to at times exhibit elevated rCBV values, mimicking high grade glioma and making this insufficiently reliable as a distinguishing feature. ²² Recent inquiry has suggested that combining DSC MR perfusion imaging with DTI imaging, which evaluates integrity and orientation of axons, may allow for more reliable distinction of high grade gliomas from tumefactive demyelination. ²³

On the other hand, MS lesions on high field strength MRI (7.0T, and less commonly 3.0T) may reveal a “central vein sign” indicating a cerebral vein or venule around which a demyelinating MS lesion has formed. ¹³ In syndromes of multifocal white matter lesions, the presence of central vein sign in a high proportion of lesions (>40-50%) may help distinguish MS from other disorders.^24,25 However, the utility of this finding in individual or in a small number of lesions is unclear, and thus it may not be helpful in convincingly distinguishing a given lesion as demyelinating rather than a glioma. future inquiry in this regard will be helpful.

If ambiguity remains, short interval follow-up MRI scans to assess the evolution of the lesion over months to years can be helpful. Gliomas, unlike MS lesions, will progress over time in size and enhancement pattern as in Case 3 (Figure 3C and D), often in intervals as short as one to three months.

Cerebrospinal Fluid Studies

Cerebrospinal fluid studies alone are insufficient to establish or exclude the diagnosis of MS. However, the presence of oligoclonal bands (two or more) in CSF is an independent predictor of the risk of a second attack in MS, and can be used together with other findings to establish a diagnosis of MS. ²⁶  CSF in MS patients is otherwise typically clear, with normal opening pressure and generally normal cell counts, though mild lymphocytic pleocytosis may be seen in 15-20% of patients. ²⁷  Atypical findings, such as pleocytosis greater than 50 cells per mm³, protein greater than 100 mg/dL, or atypical cells should raise suspicion for alternative diagnoses.^26,27

Lumbar punctures are not performed as frequently in patients with suspected gliomas. If performed, CSF is typically bland, clear, colorless, without any cells. Depending on the grade of the glioma, opening pressure could be elevated, and as is general practice lumbar puncture should be deferred in patients with large lesions with significant vasogenic edema leading to midline shift, or with posterior fossa masses, given the potential risk of brain herniation during the procedure. The diagnostic utility of next-generation sequencing for glioma cell-free DNA in CSF is currently under investigation.^28,29

Finally, it is possible that despite thorough clinical, radiographic and CSF analysis over time, the diagnosis of a given lesion could remain elusive. In these cases, if surgically amenable, a biopsy of the lesion may lead to definitively distinguishing glioma from demyelination or other etiologies. If suspicion for glioma is high or if progression of deficits is rapid, resection or biopsy of the lesion can help arrive at a definitive diagnosis and enable the formulation of a treatment plan.

Demyelinating Disease as a Potential Risk Factor for Developing Glioma

There are over 50 literature reports of co-occurrence of gliomas and MS since 1980. ³⁰ In most of these cases, gliomas are diagnosed in the setting of a pre-existing MS diagnosis (as in cases 1, 2 and 4), and most of the gliomas are glioblastomas or anaplastic astrocytomas. However, in studies of cancer incidence in large cohorts of MS patients, there is no clear evidence for increased risk of glioma in patients with MS. For instance, Bahmanyar et al found an overall reduction in cancer risk among MS patients but an increased risk for brain and genitourinary tumors; notably, there was no clear increase in malignant brain tumors in the MS patients relative to controls, suggesting that surveillance bias due to increased neuroimaging and increased detection of benign tumors may have driven the results. ³¹ Additionally, a recent large cohort study by Marrie et al found an increased incidence of central nervous system (CNS) tumors in MS patients compared to controls, but no increased risk of mortality in these patients with CNS tumors, again suggesting that increased detection of benign tumors may be at play. ³² Finally, a systematic analysis found neither an increased nor decreased risk of glioma in patients with MS, but did find an increased risk of meningioma. ³³

Whether any causal relationships may underlie the co-occurrence of MS and gliomas has been a subject of interest. ³⁴ Based on early observations, including the contiguity of glioma and MS plaques and the temporal sequence of MS followed by glioma in most cases of co-occurrence, it has been hypothesized that chronic gliosis from demyelinating plaques may serve as a substrate for transformation to a low grade glioma and ultimately to GBM.^30,35,36 However, evidence in support of this hypothesis is scant. Khalil et al conducted pathologic and genetic analyses of tumor specimen in patients with MS and glioma. They found that the genetic profile of glioblastomas in this cohort (n = 4) was consistent with primary rather than secondary glioblastoma (n = 4 were IDH-wildtype, and n = 3 had PTEN loss and EGFR expression). If chronic gliosis with transformation to low and then high grade glioma were the underlying pathology, features of secondary gliomas would have been expected. ³⁰ In our cohort, 3 out of 4 patients did not develop their tumors in areas of pre-existing demyelinating lesions and developed IDH-wildtype tumors, corroborating Khalil et al’s findings and providing additional evidence against this hypothesis. Interestingly, our patient in case 3, who presented with MS and glioma concurrently rather than sequentially, had an IDH-mutant secondary glioblastoma (by 2021 WHO classification, a high grade IDH-mutant astrocytoma), and the existence of an antecedent MS plaque at the site of the tumor is unknown.

The role that immunosuppressive disease-modifying therapy (DMT) for MS might play in gliomagenesis has also been a subject of interest. Based on our cohort and prior reports in the literature, it does not appear that one particular DMT is associated with development of glioma. We found three published reports of MS and glioma co-occurrence in patients on fingolimod,^37-39 one on dimethyl fumarate, ⁴⁰ and two on natalizumab. ⁴¹ There were also twelve cases of co-occurrence on fingolimod reported to the Belgium center for pharmacovigilance. ³⁷ Fingolimod has been found to have strong in vitro anti-tumor activity; on the other hand, fingolimod causes downstream activation of p21-activated kinase 1 (Pak1), the increased activation of which in neoplastic glial cells has been correlated with shorter survival time in GBM patients. ³⁹ Alping et al, in a large cohort study, examined the risk of invasive cancer in MS patients on fingolimod, natalizumab and rituximab. ⁴² Overall, there was similar risk of invasive cancer when compared to the general population in patients using rituximab or natalizumab, and a borderline increased risk in patients using fingolimod. Notably in their cohort of over 6000 MS patients on one of these therapies, only two patients with brain cancer were found ⁴² . While these reports raise interesting questions about the relationships between DMT and gliomagenesis that warrant further study, they do not thus far suggest a clear causal relationship therein.

Considerations for the Concurrent Management of Gliomas and Demyelinating Disease

There are no randomized trials that address the concurrent management of MS and gliomas, likely given the rarity of their co-occurrence, though some practical considerations bear mention. With regards to surveillance, suspicion for glioma in a patient with MS warrants more frequent interval neuroimaging to assess for any growth or evolution in the suspect lesion. For instance, if a new white matter lesion is suspicious for glioma, 2-3 month interval imaging may help clarify the diagnosis.

Regarding MS DMT, there are no formal guidelines on the continuation of DMT if glioma co-occurs. In Cases 1 and 2, DMT was continued during glioma treatment to minimize the risk of MS relapse, which is a reasonable approach. However, the decision to continue DMT would ideally be individualized to each patient based on the severity of their MS and on adverse effects or drug interactions associated with their specific DMT agent.

It would be unsurprising if temozolamide and other chemotherapies used in glioma also reduce MS disease activity, just as cytotoxic agents like mitoxantrone or cyclophosphamide are known to do. ⁴³ However, given that the extent or nature of this effect has not been well characterized, it is advisable to consider MS treatment independently of glioma chemotherapy. With regards to radiation, a review of case reports suggests that high dose cranial radiation may promote demyelination, progression of MS symptoms, and potentially relapse, though further studies are needed to establish any causality and it is likely inadvisable to curtail necessary radiation therapy based on these reports. ⁴⁴

There is active and growing interest in the use of immunotherapy to treat GBM, which may have special implications for patients with concurrent MS. Studies of immune checkpoint inhibitors (ICI) and tumor neoantigen-targeted vaccines have not thus far demonstrated clear therapeutic benefit in GBM, but a number of trials are ongoing. ⁴⁵ Furthermore, several CAR T-cell therapy candidates for GBM are in clinical trials. ⁴⁶ If these immunotherapies are used to treat gliomas in the future, two main concerns arise for patients with concurrent MS. First, treatment of MS with corticosteroids (as during exacerbations) or DMTs may decrease the efficacy of immunotherapy for glioma. Immunotherapies rely on cell-mediated and humoral immune responses that, if blunted by corticosteroids or DMTs, may render the therapies less efficacious.^47,48 Second, immunotherapy for glioma may exacerbate underlying MS. Studies of patients with multiple (non-CNS) cancers and pre-existing autoimmune disease who have received ICI therapy have suggested modest increases in the risk of immune-related adverse events (irAEs) and of flares of the underlying autoimmune disease.^49-52 Although not strictly contraindicated, all things considered, the management of glioma with immunotherapy in patients with concurrent MS would pose additional challenges.

Finally, it is vital that providers discuss the change in prognosis with patients with MS who are subsequently diagnosed with glioma, particularly glioblastoma. Transparent discussions on an individual patient’s prognosis and goals of care may ultimately guide how this unique disease co-occurrence is practically managed.

ORCID iDs

Vihang Nakhate https://orcid.org/0000-0002-2941-9740

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