Iranian Journal of Neurology 2018. 17(2):64-70.

Evaluation of the risk of cervical cancer in patients with Multiple Sclerosis treated with cytotoxic agents: A cohort study
Rozita Doosti, Mansoureh Togha, Abdorreza Naser Moghadasi, Aida Aghsaei, Amir Reza Azimi, Saeideh Khorramnia, Zahra Moinfar, Fereshteh Ensani, Mohammad Hossein Harirchian, Alireza Minagar, Mohammad Ali Sahraian


Background: Since most patients with relapsing-remitting multiple sclerosis (RRMS) are women, the present study aimed to determine whether treatment of patients with MS by cytotoxic agents is associated with an increased risk of cervical dysplasia. Cancer screening is often neglected in the chronic diseases such as MS, so more attention in this field was needed. Decreasing morbidity and mortality due to cervical cancer is the most important goal of screening in female MS patients especially in child bearing age. Thus, it can be said that this is the first study which investigated this important issue.

Methods: A total of 129 individuals participated in this cohort study. They were assigned into 3 groups including 43 patients with MS who were treated with cytotoxic drugs, 43 patients with MS on immunomodulators, and 43 normal healthy controls. Pap smears were performed following standard methods and the results obtained from the three groups were compared by statistical analysis. Demographic data, Expanded Disability Status Scale (EDSS), and Pap smear changes were analyzed by SPSS software.

Results: The most commonly detected abnormality in all examined patients and healthy controls was inflammation. Five patients with MS who were treated with cytotoxic agents revealed benign cellular changes (BCC) in their Pap smear that were statistically significant in comparison with other groups (P = 0.03). Patients who took Mitoxantrone presented BCC more than other groups [Odds ratio (OR) = 9.44, 95% confidence interval (CI): 1.46-60.70]. There was no significant difference between mean duration of MS diagnosis (P = 0.12), mean duration of previous MS treatments (P = 0.25), and mean duration of current MS treatments (P = 0.21) in patients with BCC compared to normal healthy controls or inflammatory change.

Conclusion: According to the results of present study, BCC is more frequently observed in patients with MS who were treated with cytotoxic agents with immunosuppressive effect. Since BCC is a ‘premalignant condition’, the authors suggest that mandatory annual Pap smear should be performed for patients with MS who are treated with cytotoxic agents irrespective of their age in order to detect early signs of malignancy.


Pap Smear; Multiple Sclerosis; Cytotoxic Agents

Full Text:



Le Page E, Leray E, Taurin G, Coustans M, Chaperon J, Morrissey SP, et al. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: Treatment response factors in a 5 year follow-up observational study of 100 consecutive patients. J Neurol Neurosurg Psychiatry 2008; 79(1): 52-6.

Fox EJ. Management of worsening multiple sclerosis with mitoxantrone: A review. Clin Ther 2006; 28(4): 461-74.

Scott LJ, Figgitt DP. Mitoxantrone: A review of its use in multiple sclerosis. CNS Drugs 2004; 18(6): 379-96.

Ticha V, Kalincik T, Havrdova E. Interferon-beta or azathioprine as add-on therapies in patients with active multiple sclerosis. Neurol Res 2012; 34(10): 923-30.

Burns SA, Lee Archer R, Chavis JA, Tull CA, Hensley LL, Drew PD. Mitoxantrone repression of astrocyte activation: Relevance to multiple sclerosis. Brain Res 2012; 1473: 236-41.

Arruda WO, Montu MB, de Oliveira MS, Ramina R. Acute myeloid leukaemia induced by mitoxantrone: Case report. Arq Neuropsiquiatr 2005; 63(2A): 327-9.

Portaccio E, Zipoli V, Siracusa G, Piacentini S, Sorbi S, Amato MP. Safety and tolerability of cyclophosphamide 'pulses' in multiple sclerosis: A prospective study in a clinical cohort. Mult Scler 2003; 9(5): 446-50.

Lhermitte F, Marteau R, Roullet E. Not so benign long-term immunosuppression in multiple sclerosis? Lancet 1984; 323(8371): 276-7.

Solomon D, Nayar R. The bethesda system for reporting cervical cytology: Definitions, criteria, and explanatory notes. Berlin, Germany: Springer Science & Business Media; 2004.

Malik SN, Wilkinson EJ, Drew PA, Hardt NS. Benign cellular changes in Pap smears. Causes and significance. Acta Cytol 2001; 45(1): 5-8.

Barr Soofer S, Sidawy MK. Reactive cellular change: Is there an increased risk for squamous intraepithelial lesions? Cancer 1997; 81(3): 144-7.

Bernatsky S, Ramsey-Goldman R, Clarke AE. Malignancy in systemic lupus erythematosus: What have we learned? Best Pract Res Clin Rheumatol 2009; 23(4): 539-47.

Bernatsky S, Ramsey-Goldman R, Gordon C, Joseph L, Boivin JF, Rajan R, et al. Factors associated with abnormal Pap results in systemic lupus erythematosus. Rheumatology (Oxford) 2004; 43(11): 1386-9.

Dreyer L, Faurschou M, Mogensen M, Jacobsen S. High incidence of potentially virus-induced malignancies in systemic lupus erythematosus: A long-term followup study in a Danish cohort. Arthritis Rheum 2011; 63(10): 3032-7.

Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain J, et al. American cancer society, American society for colposcopy and cervical pathology, and american society for clinical pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin 2012; 62(3): 147-72.

Klumb EM, Araujo ML Jr, Jesus GR, Santos DB, Oliveira AV, Albuquerque EM, et al. Is higher prevalence of cervical intraepithelial neoplasia in women with lupus due to immunosuppression? J Clin Rheumatol 2010; 16(4): 153-7.

Nath R, Mant C, Luxton J, Hughes G, Raju KS, Shepherd P, et al. High risk of human papillomavirus type 16 infections and of development of cervical squamous intraepithelial lesions in systemic lupus erythematosus patients. Arthritis Rheum 2007; 57(4): 619-25.

Kiss E, Kovacs L, Szodoray P. Malignancies in systemic lupus erythematosus. Autoimmun Rev 2010; 9(4): 195-9.

Tam LS, Chan PK, Ho SC, Yu MY, Yim SF, Cheung TH, et al. Risk factors for squamous intraepithelial lesions in systemic lupus erythematosus: A prospective cohort study. Arthritis Care Res (Hoboken) 2011; 63(2): 269-76.

Klumb EM, Pinto AC, Jesus GR, Araujo M Jr, Jascone L, Gayer CR, et al. Are women with lupus at higher risk of HPV infection? Lupus 2010; 19(13): 1485-91.

Nguyen ML, Flowers L. Cervical cancer screening in immunocompromised women. Obstet Gynecol Clin North Am 2013; 40(2): 339-57.

Vetrano G, Lombardi G, Di Leone G, Parisi A, Scardamaglia P, Pate G, et al. Cervical intraepithelial neoplasia: Risk factors for persistence and recurrence in adolescents. Eur J Gynaecol Oncol 2007; 28(3): 189-92.

Szarewski A, Sasieni P. Cervical screening in adolescents-at least do no harm. The Lancet 2004; 364(9446): 1642-4.

Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla Palma P, Del Mistro A, et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: A randomised controlled trial. Lancet Oncol 2010; 11(3): 249-57.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.