Introduction
Multiple sclerosis (MS) is a chronic demyelinating inflammatory disease of the central
nervous system (CNS) with multi-factorial pathogenesis that includes genetic and environmental
factors. A primary brain tumor is a neoplasm developing from the cells of the brain.
There is high heterogeneity of primary brain tumors (about 100 different types); however,
most of them develop from the glial cells.
Although several types of brain tumors have been widely described in association with
MS (1–20), including astrocytoma (5, 9), oligodendroglioma (12, 17), and glioblastoma
(3, 11, 14, 18), it is not clear whether their occurrence is accidental or consequent
to causal events. Moreover, it is not completely defined if MS and brain tumors, when
associated, have a different course. The true incidence of brain tumors in MS patients
is difficult to define because the diagnosis of a brain tumor in MS patients may seem
more frequent than in the general population due to frequent neuroimaging scans performed
in these patients (21). At the same time, pseudo-tumoral MS lesions may resemble gliomas,
and conversely, early stage gliomas may resemble MS. Brain tumors in MS patients may
be diagnosed later or even post-mortem (22), especially in patients with progressive
MS, since the new symptoms may be attributed to the gradual clinical progression of
MS rather than to the slow growing of tumor itself (23). A recent study reported that
MS patients have a decreased overall cancer risk, but an increased risk for brain
tumor (24). If immunosuppressive treatment for MS might promote cancerogenesis is
still matter of debate, it is difficult to explain on this basis why MS patients have
a decreased overall cancer risk and an increased risk only for brain and genitourinary
tract tumors (24). A successive systematic analysis showed no increased or decreased
risks for glioma in MS patients, while an increased risk was found for meningioma,
as a result of incidental findings (25). Moreover, several autoimmune diseases influence
negatively the survival in glioma and meningioma, likely due to pre-existent disability
or treatment limitations (25).
Differential Diagnosis between MS and Brain Tumors
A first issue emerging in case of concurrence of MS and brain tumors is the differential
diagnosis since MS plaques may resemble gliomas and vice-versa (26). Although brain
tumors associated with MS have their usual distribution at frontal and temporal lobes
(27), the localization criteria are not helpful for the differential diagnosis. Therefore,
the appearance of uncommon neurological symptoms in MS patients should suggest the
need for more extensive investigations in order to exclude overlapping pathologies
(28). In addition to brain tumors, the differential diagnosis of pseudo-tumoral brain
lesions includes infectious, neoplastic (in particular primary CNS lymphomas and metastatic
cancers), congenital, metabolic or vascular diseases, and non-MS idiopathic inflammatory
demyelinating diseases as well (for instance, neuromyelitis optica, opticospinal MS
in Asian populations, acute disseminated encephalomyelitis) (29). They differ from
MS in course, pathophysiology, treatment, and prognosis. In 2008, the Task Force on
Differential Diagnosis in MS has defined major, intermediate, and minor red flags
consisted in informative symptoms, signs, and assays indicative, respectively, of
non-MS diagnosis, uncertainty or possibility that an MS diagnosis is not excluded
(29). The major red flags, for example, for lymphoma, are represented by persistent
Gd-enhancement, continued enlargement of lesions, simultaneous enhancement of all
lesions, marked asymmetry of white matter lesions, headache, or meningismus.
Among the diagnostic tools that have been proposed to differentiate MS from tumors,
there are also some blood indicators such as inflammatory transcription factors of
the peripheral blood mononuclear cells (18). However, they are more useful in expressing
patients’ immunological status than in making a proper differential diagnosis between
MS and brain tumors. To date, the non-conventional MRI techniques such as spectroscopy,
positron emission tomography, and CNS biopsy remain the most useful tools for the
differential diagnosis.
Possible Causal Relationship between Brain Tumors and MS
Whether the concurrence of MS and glioma may be explained by causal relationship or
by coincidence is still matter of debate (17, 25). In 1973, it was observed that despite
the rare concurrence of such relatively common conditions some pathological features,
especially the frequent contiguous relationship between tumor and plaque, suggested
a closer association between these pathologies (30). It was hypothesized that in some
MS patients an unknown factor, hereditary or acquired, may stimulate the neoplastic
transformation of reactive astrocytes. Moreover, it was supposed a causative role
for a bipotential cytolytic-oncogenic agent such as Papova virus (30). Almost 20 years
later, another study, based on the most extensive literature, came to similar conclusions
(31). A transformation of a mega-plaque into an ependymoma added new evidence in favor
to a cause–effect relationship between MS and brain tumors (32). It can be hypothesized
that MS lesions may transform into a tumor likely due to circumscribed increased proliferation
ratio induced by MS remyelinating processes since the neurotropic growth factors promoting
the proliferation and survival of oligodendrocytes have the beneficial effect on the
clinical, pathological, and molecular manifestations of autoimmune demyelination in
experimental models (33, 34). It was also found a re-expression of a developmental
gene in chronic lesions with the highest levels of their products correlating with
remyelination (35). The recapitulation of ontogenetic events during myelin repair
has been supposed as normal adult CNS and non-MS material showed very low levels of
such gene products, while fetal human CNS tissue showed high levels. Therefore, the
possibility of common rare underlying genetic factors in both tumors and MS is possible,
but so far there are no sufficient data to definitely confirm it. Furthermore, owing
to high heterogeneity of primary brain tumors, the research on their genetic alterations
is not simple. Interestingly, the recently identified MS risk genes mainly belong
to the immune system (36), and alterations in innate immunity-related genetic regions
have been associated with an increased risk of adult glioma (37). It may be also hypothesized
that aberrant epigenetic mechanisms, such as DNA methylation and histone protein modifications,
could be involved in both MS and tumor pathogenesis (38). Methylated gene promoters
are silenced, while unmethylated ones can be active reflecting, albeit imprecisely,
gene expression. Certain regions of the brain in MS patients show abnormally methylated
genes with a specific profile or decreased methylation, for example, of cytosine of
the gene encoding the myelin enzyme peptidylarginine deiminase-2 promoter in MS normal-appearing
white matter (39). Still more, DNA methylation is altered in tumors and may represent
a predictive factor of response to specific drugs. In particular, the O6-methylguanine-DNA
methyltransferase promoter hypermethylation was found to be strongly associated with
partial or complete clinical response (40–42). However, no possible causal epigenetic
mechanisms between brain tumors and MS could be inferred by these limited data.
Finally, it is possible to speculate that a common viral agent is involved in the
pathogenesis of these diseases. After 30 years from the first supposition of a possible
Papova virus role in both disorders (30), the post-mortem examination of an immunocompetent
patient with MS plaques and a glioblastoma multiforme provided molecular evidence
of the association of human polyomavirus JC virus (JCV) of Papova virus family with
these concurrent pathologies (14). PCR analysis revealed the presence of viral DNA
in demyelinated plaques and within the tumor, while immunohistochemistry showed the
detection of the viral early protein, T-antigen, and the cellular tumor suppressor
protein, p53, only in the nuclei of neoplastic cells. Conversely, the expression of
T-antigen, but not of p53, was observed in astrocytes and neuronal cells of the cortex
juxtaposed to the MS plaque. No productive replication of JCV was identified in both
tumor and MS lesions since the examination of viral late gene expression by immunohistochemistry
showed no evidence for viral capsid proteins. Furthermore, some authors detected the
presence of JCV in samples derived from several types of neural and non-neural human
tumors (43–50), and several studies highlighted its potential role in a broad range
of animal models and human carcinogenesis (51–54).
JC virus was identified as the etiologic agent of progressive multifocal leukoencephalopathy,
first diagnosed only in immunocompromised patients or those suffering from leukemia,
but now representing a serious complication of Natalizumab treatment in MS (55, 56).
JCV is very common in the general population infecting 70–90% of humans (57), and
a higher rate of JCV seroconversion compared to than expected has been observed in
MS patients treated with Natalizumab (58). JC viral genome has been detected in normal
brain tissue (59), therefore, the latent JCV-DNA antigens expressed at low levels
in the CNS have been proposed as possible targets of pathogenetic immune response
in MS (60). Initially, the JCV-DNA was found neither in the urine (61) nor in the
brain tissue (62) of MS patients. However, more recent studies showed the presence
of JCV-DNA in both CSF (63, 64) and blood (65) in MS patients (although in a low percentage)
and not in controls.
Moreover, novel clinical entities without typical PML lesions caused by JCV variants
infecting cerebellar granule cell neurons and cortical pyramidal neurons as well as
JCV meningitis have been recently discovered (66).
Therefore, JCV might be a feasible etiological candidate for both MS and brain tumors
due to its ability to persist in the latent state mainly in myelin-producing oligodendrocytes
and to its oncogenic capacity. However, JCV presence might still simply reflect the
subclinical immunodeficiency of cancer patients or MS patients treated with immunosuppressive
drugs.
Therapy of Associated MS and Brain Tumors
There are no trials on the treatment of associated cases of MS and brain tumors owing
to their rarity. The data here reported represent case reports and experimental observations.
It should not seem strange that the immunosuppressive treatments given for neoplasms
may reduce disease activity in MS. In a patient of ours with MS and oligodendroglioma,
MS activity significantly reduced both clinically and at MRI during the 2-year treatment
with temozolomide (personal unpublished data).
Although the safety of radiotherapy for MS course was described in one case report
(67), the negative effects of surgery and radiotherapy on MS, due to the liberation
of brain-specific antigens triggering disimmune reactions, have also been reported
(68). A vast review on MS relapses considered cranial radiation as their promoting
factor (69).
Furthermore, a sphingosine analog FTY720, which downregulates the expression of sphingosine-1-phosphate
receptors, is not only effective in MS (70) but also causes in vitro apoptosis of
brain tumor stem cells derived from human glioblastoma tissue (71). Also dimethyl-fumarate,
demonstrated to be effective in treatment of MS (72), appears to act on malignant
brain neoplasms in vitro by reducing the proliferation rate, generating cell lysis,
decreasing the expression of NF-κB, and restricting the growth of CD133 cells in gliomas
(73).
Conclusion
Although the co-existence of MS and brain tumors has been long described, many doubts
regarding their possible causal association persist. JCV is of significant interest
in this issue due to its ability to latent persist in the CNS and to its experimental
neurooncogenic potential. Since MS is caused by putative CNS autoimmune mechanisms
whereas brain neoplasms may be dependent on a subclinical immunosuppressive state,
these pathologies can coexist only in particular situations. It can be hypothesized
that these conditions may occur during the remyelinating processes coinciding with
a decline of the CNS immune reaction and with the production of growth factors in
the effort to repair the damage, thus favoring a hypothetical JCV-related cell neoplastic
transformation in genetically or environmentally induced susceptible individuals.
Studying with special care, the patients affected by both diseases, which apparently
locate at the opposite ends of immunosurveillance, could allow to find the key to
their pathogenesis.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.