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ARTICLES: S. Bahmanyar, S. M. Montgomery, J. Hillert, A. Ekbom, and T. Olsson Cancer risk among patients with multiple sclerosis and their parents Neurology 2009; 72: 1170-1177 [Abstract] [Full text] [PDF]

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Glial brain tumors in patients with multiple sclerosis

Silvia Hofer, Michael Linnebank, Michael Weller   (20 August 2009)

Reply from the authors

Shahram Bahmanyar, S. M. Montgomery, J. Hillert, A. Ekbom, and T. Olsson   (20 August 2009)

Glial brain tumors in patients with multiple sclerosis 20 August 2009
Silvia Hofer, Dept. of Neurology, University Hospital Zurich Frauenklinikstrasse 26, 8091 Zurich, Switzerland, Michael Linnebank, Michael Weller Send Correspondence to journal: Re: Glial brain tumors in patients with multiple sclerosis silvia.hofer{at}usz.ch Silvia Hofer, et al.	Bahmanyar et al. report that multiple sclerosis (MS) patients have a decreased overall cancer risk but an increased risk for brain cancer. No altered risk was detected in first-degree relatives of MS patients. [1] This is unexpected because the incidence of gliomas has been considered inversely correlated with altered immune responsiveness and specifically allergies. [2] The distribution of histological diagnoses of the 131 patients with brain tumors was not provided. [1] We treated six patients with MS and glial brain tumors in the last 6 years (Table). Patients 1 and 4 had a family history of MS. Bahmanyar et al. argue that the chronic inflammation in the brain associated with MS may promote tumorigenesis. [1] They also propose that the neuroimaging monitoring of MS patients renders the early diagnosis of brain tumors more likely, as illustrated by our patient four. While the authors acknowledge that immunosuppressive treatment might promote cancerogenesis, they also contend that this would not explain the differential risk alterations with a decreased overall cancer risk and enhanced risks only for cancers of brain and genitourinary tract. [1] However, states of immunosuppression are strongly related to the development of brain lymphomas, and there is also controversial evidence for an increased incidence of gliomas in patients with human immunodeficiency virus infection. [3] Furthermore, one of our patients was diagnosed with a glioblastoma 5 months after the initiation of natalizumab. Natalizumab therapy is also associated with the development of progressive multifocal leukencephalopathy, a typical complication of AIDS and associated with deficient immune surveillance in the brain. [4] Lastly, the impact of glioma-specific treatments such as brain surgery, radiotherapy, and chemotherapy on the course of MS is interesting. For instance, surgery and radiotherapy are likely to promote the liberation of brain-specific antigens which might promote autoimmunity, (i.e., relapses) in MS. We noted that MS was diagnosed 4 months after the completion of RT in patient 6, which may indicate a temporal relationship. Conversely, chemotherapy (e.g., using temozolomide) would be expected to reduce disease activity similar to other cytotoxic agents such as mitoxantron or cyclophosphamide. Given the extensive series of brain tumor patients included in Bahmanyar et al.’s data [1] we wonder if they could address some of the controversial issues regarding an association of MS with tumorigenesis in the brain. Table References 1. Bahmanyar S, Montgomery SM, Hillert J, Ekbom A, Olsson T. Cancer risk among patients with multiple sclerosis and their parents. Neurology 2009;72:1170-1177. 2. Wiemels J, Wilson D, Patil C, et al. IgE, allergy, and risk of glioma: update from the San Francisco bay area adult glioma study in the temozolomide era. Int J Cancer (in press). 3. Blumenthal DT, Raizer JJ, Rosenblum MK, Bilsky MH, Hariharan S. Abrey LE. Primary intracranial neoplasms in patients with HIV. Neurology 1999;52:1648-1651. 4. Epker LJ, van Biezen P, van Daele PLA, van Gelder T, Vossen A, van Saase JLCM. Progressive multifocal leukoencephalopathy, a review and an extended report of five patients with different immune compromised states. Eur J Intern Med 2009;20:261-267. Disclosures: Dr. Hofer received research support from Roche Pharma Schweiz. Dr. Linnebank served on a scientific advisary board for Biogen Idec; received honoraria for an meeting from Merck Serono; received research support from Bayer, Biogen and Merck; receives funding from private foundations in Germany. Dr. Weller served on scientific advisory boards for Roche, Merck Serono, Shering Plough, Exelixis and Micromet; received honoraria for lectures from Merck Serono, Roche and Shering Plough and received research support from Merck Serono. He is supported by the German Research Foundation.
Reply from the authors 20 August 2009
Shahram Bahmanyar, Karolinska Institutet Clinical Epidemiology Unit, Dept. of Medicine, Karolinska Institutet, Karolinska Hospital, Sweden, S. M. Montgomery, J. Hillert, A. Ekbom, and T. Olsson Send Correspondence to journal: Re: Reply from the authors shahram.bahmanyar{at}ki.se Shahram Bahmanyar, et al.	We agree with Hofer et al. that there are several factors that may potentially increase the risk of brain tumors in patients with MS. We stated that surveillance bias could account for at least some of the increase in brain tumor incidence we identified and now we have extended the analysis to examine this issue. The table shows the distribution of brain tumor histology among patients and the matched comparison population used in our study. The distribution is consistent with a significant role for surveillance bias, where benign tumors are detected more frequently due to the use of neuroimaging to monitor MS patients. However, the distribution of histology among those with tumors is insufficient to produce a definitive conclusion, as those without tumors must also be included in the calculation with more sophisticated handling of differences in follow-up time. We used Cox regression to assess if MS is associated with benign meningioma and found a significant positive association, with a hazard ratio (and 95% confidence interval) of 1.76 (1.31–2.37). In contrast, there was not a marked increased risk for malignant astrocytoma associated with MS, as the hazard ratio is 1.02 (0.70–2.37). This post-hoc analysis lends further support to the assertion that the increase in brain tumor diagnosis among MS patients is largely due to surveillance bias. Despite the various risks outlined by Hofer et al. that could potentially increase the brain tumor risk among patients with MS, the fact that we did not find an increased risk of malignant tumors may reflect the apparent MS-associated protection against various cancer types indicated by our study. The case series reported by Hofer et al. found that a diagnosis of a glioblastoma in one patient was preceded by initiation of natalizumab treatment some months earlier. While such isolated reports from case series are poor evidence of causation, they can suggest potential risks that deserve further investigation. Natalizumab treatment is probably not relevant to cancer risk in our study because it only became available in Sweden during August of 2006, while the follow-up period for our analysis ended in 2005. Table Disclosures: Dr. Bahmanyar reports no disclosures. Dr. Mongomery reports no disclosures. Dr Hillert received honoraria for serving on advisory boards for BiogenIdec and for speaker’s fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis. He has served as P.I. for projects supported by BiogenIdec, Merck-Serono, and Bayer-Schering. His MS research is funded by the Swedish Research Council. Dr. Ekbom reports no disclosures. Dr. Olsson received honoraria for serving on scientific advisory boards from Eli-Lilly, BioMS, BiogenIdec, Sanofi Aventis, AstraZeneca and MerckSerono; has also received honorarias for lectures from Novartis and BiogenIdec; has received unrestricted research grant support from The Swedish Research Council, Söderbergs Foundation, Montel Williams Foundation, Bibbi and Niels Jernsens foundation, and the EU Fp6 program (Neuropromise –LSHM-CT-2005-018637).