Volume 25, Issue 2, Pages 139-148
Authors: Joaquim J. Ferreira, MD, PhD¹*, Dulce Neutel, MD¹, Tiago Mestre, MD¹, Miguel Coelho, MD¹, Mário M. Rosa, MD¹, Olivier Rascol, MD, PhD², Cristina Sampaio, MD, PhD¹
¹Neurological Clinic Research Unit, Institute of Molecular Medicine, Lisbon School of Medicine, Lisbon, Portugal
²Departments of Clinical Pharmacology and Neurosciences, INSERM CIC-9302 and UMR-825, University Hospital, Toulouse, France
E-mail: Joaquim J. Ferreira (firstname.lastname@example.org)
*Correspondence to Joaquim J. Ferreira, Centro de Estudos Egas Moniz, Faculdade de Medicina de Lisboa, 1649-028 Lisboa, Portugal
Potential conflict of interest: None reported.
The report of an increased frequency of melanoma during the clinical development of rasagiline prompted a renewed interest in a possible association between skin cancer and Parkinson's disease (PD). The evaluation of this risk ended in a recommendation to perform a periodic dermatological examination as a follow-up measure of their treatment. The recognition of this safety concern lead to the need to clarify if the risk of skin cancer is indeed associated with PD and if levodopa or other anti-parkinsonian drugs might contribute to increase such risk. To answer these questions, we critically reviewed all clinical studies available concerning the association between skin cancer and PD. We found 26 studies on cancer occurrence in PD. The best data available suggest the risk of cancer is reduced in PD patients. However, specific cancers like thyroid and the female breast were reported at higher-than-expected rates. Additionally, it was suggested that PD patients have a higher frequency of melanoma and non-melanoma skin cancers than the general population. The data on non-melanoma skin cancer are less robust than the data on melanoma. Causal factors remain unknown. Due to the weak association between skin cancer and PD, no robust recommendation can be made regarding the need for periodic dermatological screening.
© 2010 Movement Disorder Society
Received: 7 April 2008; Revised: 28 September 2009; Accepted: 29 September 2009
Summary and Review by Dr. William Ondo, MD, Professor of Neurology, Baylor College of Medicine, Houston, Texas
Ferreira et al recently published a thorough meta-analysis of the relationship between Parkinson's disease (PD) and melanoma.1 Consistently, studies have found a greater number of cases of melanoma in patients with PD compared to active or historic controls. Most studies suggest a 1.5 to 3.0 fold increase in the incidence of melanoma in PD. This translates into a melanoma prevalence of 1.1-1.4% cases of PD.
As with all associational epidemiologic studies, the question is why. Does PD cause melanoma, does melanoma cause PD, do they share a common genetic predisposition that is culpable for both, do they share related environmental risk factors that are culpable for both, do they coincidentally share environmental risk factors that independently are associated with both (the classic true, true, unrelated) or does the treatment of one cause the other?
The last question is the most practically important. L-dopa has been hypothesized to cause melanoma because it can be converted to melanin in five enzymatic steps.2 That said, there is no clinical evidence that this happens in vivo in PD patients, which should be a relatively easy study, and no evidence that increased melanoma would cause melanoma. Most studies suggest that melanoma occurs before the onset of treatment for PD, and even PD onset, and no study has specifically associated melanoma and L-dopa. Therefore it appears unlikely that L-dopa causes melanoma in epidemiological studies, but there is no systematic data to answer the question of whether L-dopa is problematic in subjects already diagnosed with melanoma, although case reports are numerous.3 Therefore caution must be advised in this setting.
No specific PD gene is associated with melanoma and specific genes that may confer susceptibility to melanoma have not been linked to PD. That said, skin and hair pigmentation is largely genetic, in a more complicated manner than once thought, and fair complexion is the main risk factor for melanoma. Although less overt, studies have shown that Caucasians have higher rates of PD than people of Asian or African descent.4 Therefore the diseases share at least one largely genetically determined trait. Surprisingly, very few studies evaluating PD and melanoma have examined this. Recently, Bertoni et al. did report that fair skin and hair were the main risk factors for melanoma in PD just as in the population at large.5 Environmentally, sun exposure is the greatest risk factor for melanoma. There is relatively little data evaluating sun exposure in PD but many studies suggest PD is greater in men, and more common in rural environments and agrarian professions, all demographics that likely have greater sun exposure. Therefore there are plausible explanations to explain the consistent association between PD and melanoma. Current recommendations suggest special surveillance for melanoma in PD populations. Although never bad advice, I suspect this is most germane to those with the standard risk factors for melanoma.
Ferreira JJ, Neutel D, Mestre T, et al. Skin cancer and Parkinson's disease. Mov Disord;25(2):139-148.
Weiner WJ, Singer C, Sanchez-Ramos JR, Goldenberg JN. Levodopa, melanoma, and Parkinson's disease. Neurology 1993;43(4):674-677.
Charles J, Templier I, Leroux D, et al. Twenty-two cutaneous primary melanomas in a patient with high genetic predisposition to melanoma receiving levodopa therapy for Parkinson's disease. Pigment Cell Melanoma Res 2009;22(6):851-853.
Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 2003;157(11):1015-1022.
Bertoni JM, Arlette JP, Fernandez HH, et al. Increased melanoma risk in Parkinson disease: a prospective clinicopathological study. Arch Neurol;67(3):347-352.
About Dr. William George Ondo
William George Ondo, MD, is a professor of Neurology at Baylor College of Medicine, as well as associate director at the Parkinson's Disease Center and Movement Disorders Clinic in Houston, Texas. His medical degree was awarded by the Medical College of Virginia (Richmond, Virginia), and he completed an internship at the University of North Carolina Hospital (Chapel Hill, North Carolina), and a neurology residency at Duke University (Durham, North Carolina). In 1995, Dr. Ondo undertook a Movement Disorders fellowship with Dr. Jankovic and joined the Baylor faculty the following year.
Dr. Ondo maintains membership in multiple professional associations and research groups, which include the American Neurological Association, the American Academy of Neurology, and numerous study groups. He is also a diplomat of the American Board of Psychiatry and Neurology.
As Dr. Ondo is interested in all areas of adult and pediatric movement disorder research and has served as primary, treating, and sub-investigator for many research projects involving those disease states. He has authored more than 200 original articles, review articles, and book chapters, and has edited two test books on Movement Disorders. He has also served on numerous editorial boards, speaker bureaus, study groups, and has lectured widely. His current research interests include Parkinson's disease, restless legs syndrome, tremor, and the use of botulinum toxins.