A challenging case of concurrent multiple sclerosis and anaplastic astrocytoma.

BACKGROUND: Cases of gliomas coexisting with multiple sclerosis (MS) have been described over the past few decades. However, due to the complex clinical and radiological traits inherent to both entities, this concurrent phenomenon remains difficult to diagnose. Much has been debated about whether this coexistence is incidental or mirrors a poorly understood neoplastic phenomenon engaging glial cells in the regions of demyelination. CASE DESCRIPTION: We present the case of a 41-year-old patient diagnosed with a left-sided frontal contrast enhancing lesion initially assessed as a tumefactive MS. Despite systemic treatment, the patient gradually developed signs of mass effect, which led to decompressive surgery. The initial microscopic evaluation demonstrated the presence of MS and oligodendroglioma; the postoperative evolution proved complex due to a series of MS-relapses and tumor recurrence. An ulterior revaluation of the samples for the purpose of this report showed an MS-concurrent anaplastic astrocytoma. We describe all relevant clinical aspects of this case and review the medical literature for possible causal mechanisms.
CONCLUSION: Although cases of concurrent glioma and MS remain rare, we present a case illustrating this phenomenon and explore a number of theories behind a potential causal relationship. Copyright:

INTRODUCTION

Multiple sclerosis (MS) is a demyelinating disease with complex clinical and radiological features. Although 85% of MS-cases develop a clinically isolated syndrome involving the optic nerves, brainstem, or spinal cord,[10] MS lesions are also able to mimic a number of cerebral malignancies, particularly in the presence of gradual mass growth (tumefactive MS). Surgical intervention and microscopic evaluation are often necessary to ensure diagnosis;[1] in this specific context, cases of concurrent MS and gliomas have been described.[1,2,5,12,18,23,25,29,31] The origins of this type of coexistence (incidental or causal) remain a matter of debate; indeed, some of the reported theories include neoplastic changes taking place in areas of demyelination.[29] As illustrated by this case, access to modern radiology and reliable microscopic assessment at the time of diagnosis and follow-up remain crucial in terms of treatment optimization and prolonged survival.

CASE DESCRIPTION

A 41-year-old female patient developed epileptic seizures in 2008. Further investigation with magnetic resonance imaging (MRI) revealed a glioma-suspect tumor within the boundaries of the left frontal lobe as well as multiple supratentorial MS-like lesions scattered in both hemispheres. The routine cerebrospinal fluid (CSF)-analysis showed evidence of MS-activity, while the complementary MR spectroscopy (MRS) study suggested the presence of a concurrent oligodendroglioma. The ensuing needle biopsy on the left frontal lobe lesion showed solely inflammatory signs of demyelination, suggesting an evolving tumefactive MS-plaque [Figures 1 and 2]. Despite anti-MS therapy (Natalizumab), the patient gradually developed clinical signs of mass-effect during the course of 2010; the subsequent radiology further strengthened the suspicion of a concurrent low-grade glioma. The patient underwent microsurgery twice followed by prophylactic radiation therapy to the surgical cavity shortly after [Figures 3 and 4]; the corresponding histopathologic evaluation suggested the presence of an oligodendroglioma, WHO Grade 2–3. During the next 5 years, the patient underwent systemic treatment due to a series of tumor-/MS- [Table 1] relapses. A follow-up MRI in April 2017 showed a tumor regrowth next to the surgical site deemed not suitable for microsurgery. The contrast enhancing part of the recurrence was treated in October 2017 using gamma knife radiosurgery (GKRS), applying 18Gy at the 50% isodose line [Figure 5]. A histopathologic revaluation of the previously collected samples pre-GKRS demonstrated the presence of an anaplastic astrocytoma (AA) [Figure 2, Tables 2 and 3]. MRI-examinations post-GKRS (up to the last follow-up) showed gradual regression of the treated lesion without evidence of adverse radiation effects. At the time of paper submission, the patient was suffering from right foot palsy from her second surgical resection as well as fatigue due to chemotherapy. Her general condition and neurological status remained otherwise stable up to this stage (Karnofsky Performance Status 70). Table 1 illustrates the post-biopsy timeline relevant to this case (2010–2018).

Figure 1:

Re-evaluation (2017) of available samples from needle biopsy performed in 2008 (2 samples of <4 mm). (a) Hematoxylin and Eosin glial biopsy with a mild increase in astrocytes. (b) Inflammatory process dominated by foamy macrophages (confirmed by immunohistochemistry). (c+d) CD68 immunohistochemistry: presence of a large number of macrophages.

Figure 2:

T1-weighted magnetic resonance imaging, axial (top), and coronal (bottom) cross sections before biopsy (2008).

Figure 3:

First microsurgery (August 2010): T1-weighted magnetic resonance imaging, axial (top), and coronal (bottom) cross sections. Left column: preoperative images. Right column: postoperative images.

Figure 4:

T1-weighted magnetic resonance imaging (October 2010) before second resection (November 2010). Axial (left), coronal (center), sagittal (right) cross sections: tumor regrowth.

Table 1:

Evolution post-biopsy relevant to this case (2010–2018).

Figure 5:

Gamma knife treatment plan on stereotactic T1-weighted magnetic resonance imaging: Axial (left), coronal (Top, right), and sagittal cross sections (Bottom, right). Yellow line: prescription isodose at the margin (18Gy–50%). Green line: 10Gy-isodose.

Table 2:

Immunohistochemical reassessment (2017) from the second resection (November 2010): Anaplastic astrocytoma (WHO Grade 3). Samples from the first resection were not made available.

Table 3:

Molecular markers and FISH analysis (2017) from second resection (November 2010): Anaplastic astrocytoma (WHO grade 3). Samples from the first resection are currently not available.

DISCUSSION

General aspects

MS is a chronic inflammatory demyelinating disease with contentious evolution. MS-plaques are not uncommonly misdiagnosed as malignant processes, a phenomenon known as tumefactive MS; in fact, some groups have reported that up to 6% of all MS-cases are confused with other diseases, including primary brain neoplasms.[5] To make matters more complicated, brain malignancies may themselves mimic tumefactive MS-lesions. Although seldom reported, gradual deterioration during the course of MS might be due not only to an incomplete recovery after a period of relapse and/or aggregation of neurological damage but also to an underlying neoplastic process.[25] In this context, variables such as lesion size >20 mm, extensive perifocal edema, evolving mass effect, and “abnormal” contrast enhancement patterns are “alarming” signs indicating the presence of a glioma.[6,18,23] Although gliomas (astrocytomas, oligodendrogliomas, and glioblastomas) and central nervous system (CNS)-lymphomas remain the predominant type of MS-concurrent malignancies, other tumors such as meningiomas, ependymomas, gangliogliomas, and metastatic lesions have also been reported.[1,2,11,14,20,23,25] The concurrent presence of more “indolent” tumors (such as low- grade gliomas) may further complicate matters in terms of diagnostics, treatment, and evolution. Clinical experience, access to modern radiology, and reliable microscopic analysis are often deemed necessary (if not mandatory) to distinguish between these tumor groups.

Radiology

Glioma: In the context of glial tumors (including astrocytomas), preoperative MRI-examinations may provide key data as to the plausible grade of malignancy.[32] Distinct variables such as (i) the degree of heterogeneity of contrast enhancement (T1-weighted series), (ii) extension of underlying edema (T2- weighted studies), (iii) development of mass effect, and (iv) presence of necrosis, and cyst formation (T1/T2- weighted studies) are strongly associated to WHO III-IV tumors. As in the case of our patient, complementary MRS and positron emitting tomography may also provide valuable data to identify the presence of glial tumors; further details on their application can be found elsewhere.[4,8]

MS: Lesions are commonly found within the confinements of the posterior fossa, periventricular areas, spinal cord, and optic nerves. Dual-echo and fluid-attenuated inversion recovery (FLAIR) imaging reveal focal areas of hyperintensity while T1-weighted MRI (with Gd) help discerns between active and inactive MS-lesions, as enhancement results from an increase in blood-brain barrier permeability in areas of “active” inflammation.[10] Furthermore, the presence of persistent “black-hole” areas in pre- and post-Gd T1- weighted series mirrors the severity of MS-evolution in terms of axonal loss and demyelination.[10] However, as in the case of gliomas, MR-signal specificity remains an issue, particularly in the face of edema, inflammatory processes, de- and remyelinating activity, gliosis, and axonal loss, as all of these features share complex patterns of hyperintensity on FLAIR and dual-echo studies.[10] Further details on the use of MRI in the field of MS can be found elsewhere (www. magnims.eu).[28,34,35]

Microscopic assessment

CSF-analysis and MS

From a general perspective, the presence of demyelinating activity can be confirmed through CSF-analyses; common traits of MS-disease in CSF-analysis can be found in Table 4. In this case, our review of medical notes suggests that the evaluation of CSF-samples at initial diagnosis and follow- up proved difficult. Unfortunately, more accurate data concerning these samples have not been made available.

Table 4:

Common traits of MS-disease in CSF-analysis.[26,30]

Histopathologic assessment

MS: Histological characteristics of chronic MS lesions are well known to neuropathologists; however, diagnosing MS at early stages may prove complex, particularly in the context of needle biopsy where meager samples frequently represent small areas of a larger lesion. Although larger samples collected from “wider” surgical margins increase diagnostic accuracy, a complete microscopic interpretation of this type of lesion may prove difficult. In this aspect, key microscopic features of early MS lesions are described in Table 5.

Table 5:

Key microscopic features of early MS disease.[17]

Glial tumors: The revaluation made for the purpose of this article exposed the presence of a diffuse, infiltrating isocitrate dehydrogenase (IDH) 1-mutant AA [Figures 1 and 6, Tables 2 and 3]. AAs are more commonly diagnosed without the presence of a less-malignant precursor neoplasm. The presence of morphological components resembling an oligodendroglioma is compatible with AA, particularly in the absence of the 1p/19q codeletion. IDH- mutant AA is not rare and corresponds histologically to the WHO Grade III; these tumors have an intrinsic tendency for malignant progression to IDH-mutant glioblastoma. The principal histopathological features of AA are those of a diffusely infiltrating tumor with increased mitotic activity, distinct nuclear atypia, and high cellularity. Further signs may include multinucleated tumor cells and abnormal mitoses.[36] With progressive anaplasia, nuclear morphology becomes more atypical with increasing variation in nuclear size, shape, and coarseness; in this context, dispersion of chromatin and increasing nucleolar prominence and quantity are also features of evolving anaplasia. Necrosis and microvascular proliferation (multi-layered vessels) are not expected by normal standard.[36]

Figure 6:

Re-evaluation (2017) of 25 mm sample collected from the second resection (November 2010). (a) Hematoxylin and Eosin glial biopsy with moderately increased atypical astrocytes with gemistocytic features and with few mitoses. (b) Smear from the same biopsy: moderate increase in astrocytes with variation in size and shape. (c) Glial fibrillary acidic protein immunohistochemistry: positive in glial cells with astrocytic features. (d) KI-67 proliferation index about 25%. Samples from the first resection were not made available.

Causal relation?

Reports of concurrent MS and glial cell tumors can be traced back as early as 1912; however, despite significant advances in the field of neuro-diagnostics, the number of reported cases of coexistent MS and gliomas remains limited (<100 cases). This is probably due to the condition’s rareness and entangled histopathological characteristics, the repertoire of diagnostic tools used during disease evolution, and the degree of multidisciplinary experience. Despite the latter, our case has a striking resemblance to a number of reports.[2,5,29] In this context, a few questions arise: Is there a causal relation between MS and malignant processes? If so, are there any explanatory onco-immunological mechanisms behind it? Has neoplastic activity a more “indolent” repercussion on MS-evolution, and if so, why? Despite the restricted number of studies on the latter subjects, some data might cautiously suggest that all latter questions seem to share a set of interactive explanatory mechanisms. New foundations for a causal relation between MS and CNS-tumors were laid by Acqui et al. when the group reported the transformation of a MS-plaque into an ependymoma;[3,23] since then, different groups have worked to lay further foundations on a causal- effect issue.[2,12,15,23,29] A retrospective analysis involving 11 patients with concurrent MS and oligodendroglioma by Green et al. reported a more benign course of MS, possibly due to mitotically active oligodendrocyte precursors able to promote focal neoplastic changes while enhancing remyelination;[12] in a theoretical context, the proliferation and overrepresentation of these oligodendrocytes might promote a number of immunosuppressive regulatory factors such as nerve growth factor and cytokines (interleukin-10) that are able to suppress further MS-mediated injury while increasing the risk of tumor transformation.[12,21] In contrast, Podbielska et al. suggested that the combined cytotoxic effects of the pro-inflammatory cytokines tumor necrosis factor-α and interferon-γ (common in MS-brain and oncogenic mechanisms) can instead “enhance” MS- injury by increasing ceramide-enriched exosome activity and cell death signaling in oligodendrocyte cells;[24] whether these mechanisms enhance or “delay” MS-evolution, the above data seem to point to possible causal pathways.[12,21,24] Furthermore, knowing that most MS risk genes belong to the immune system and that particular region in the genetic repertoire related to the innate immune system seem to be associated with an increased risk of gliomas, the theoretical idea of a causal “immuno-genetic” mechanism appears possible.[23] In the context of our case, the potential role of DNA methylation in this concurrent condition is also worth considering due to the fact that MS-brain tissue is able to harbor regions of increased or decreased methylation, while the promotion of DNA hypermethylation in gliomas is a proven predictive factor of drug response and clinical impact.[23] However, despite the latter epigenetic traits, further studies are warranted to elucidate a plausible cause- effect scenario in this particular context. Therapeutic MS- immunomodulators such as Fingolimod have also been suggested to have the potential to develop glioblastomas through the activation of P21-activated kinase-1;[31] despite its proven clinical safety, one case of glioma was reported using azathioprine in a renal transplant recipient.[21] Cases of gliomas evolving from pharmacologic immunomodulators remain rare but suggest a possible environmental relationship between immunosuppression and malignant transformation.

John Cunningham (JC)-virus

As previously described in this paper, different groups seem to share common thoughts concerning plausible environmental- modulated mechanisms and malignant transformation of glial cells during the process of remyelination; the role of the human polyoma JCV remains interesting in this context.[9,23,27] JCV was initially isolated from a patient attained with progressive multifocal leukoencephalopathy (PML) in 1971. Since then, studies have suggested a possible association between the agent and the development of PML and malignancies in the CNS. JCV is present in the majority of the human population; infection occurs by childhood and adolescence. Yet, seroconversion is bound to occur in 50–80% of those reaching adulthood.[3] The initial stages of the infection remain largely subclinical in immunocompetent patients; kidney (and possibly the bone marrow) remain the selective site(s) of long-life, persistent infection.[3] However, cases of JCV-modulated cytolytic activity in the CNS have been widely reported, primarily in immunosuppressed patients. Oligodendrocyte and astrocyte cell lines are mainly affected; PML-evolvement through oligodendrocyte nuclei disruption is bound to happen at this stage.[3] HIV- and MS-patients undergoing immunomodulatory treatment (such as natalizumab and rituximab) are at particularly high risk for PML.[9] Furthermore, studies in animals have suggested a strong carcinogenic association to JCV-tumor (T) antigen expression, including glial tumors, primitive neuroectodermal tumors, neuroblastomas, and malignant peripheral nerve sheath tumors.[9] Although Rencic et al. reported a case of oligoastrocytoma with nuclear staining of tumor cells with antibodies against the JCV T-antigen,[27] more studies in human tissues are warranted to provide further evidence of a possible relationship between JC- virus and the evolvement of glial tumors in human tissue, particularly in immunosuppressive conditions. Unfortunately, this type of staining is currently not available at our institution; hence, not included in our re-evaluation.

CONCLUSION

Although cases of concurrent glioma and MS remain rare, their entangled evolution might pose a challenge in terms of diagnosis and treatment. Modern MRI-protocols are crucial in the diagnosis of MS and gliomas; however, further studies are warranted to overcome issues concerning MR-signal specificity, particularly in the face of a concurrent condition. In this context, microscopic evaluation remains largely dependent on reliable diagnostic markers and multidisciplinary expertise. At least, in theory, MS and CNS malignancies might synergistically concur through a set of shared micro-environmental and immune-modulated mechanisms. From that perspective, a casual origin cannot be fully ruled out. More studies on the subject are warranted and encouraged.