In this meta-analysis of published studies, we confirmed an association between PD and a higher occurrence of melanoma. The association was similar in both men and women and appears to be bidirectional. We did not find a significant association between nonmelanoma skin cancers and PD.
Despite the small sample size and exploratory nature of the previous studies, all but one observed a higher occurrence of melanoma among patients with PD or vice versa. The discordant study13
contributed a substantial amount of the observed heterogeneity to the meta-analyses. This study evaluated multiple cancer sites simultaneously in relation to multiple neurologic outcomes (motor neuron disease, multiple sclerosis, and PD). In addition to the low occurrence of melanoma, the authors also reported lower occurrences of nearly all cancers among patients with PD, including breast cancer. Unlike most of the other studies, patients with PD in this study were compared to a reference cohort of hospital patients with selected minor illness. However, the information provided in the study was not sufficient to deduce the reasons for its inconsistency with other studies. Excluding this study from the meta-analyses enhanced the consistency of the association between melanoma and PD.
Our study aimed to explore the potential etiologic links between PD and melanoma. We did not include 2 studies26,27
that examined PD mortality among people previously diagnosed with melanoma. Our reasoning was that mortality was determined by both incidence and survival, which in addition to the inaccuracy of using death certificates in identifying patients with PD would have made our results less interpretable. Nonetheless, the higher PD mortality among patients with melanoma as reported in these 2 studies strengthens the evidence that melanoma and PD are likely to co-occur. Further, a subsequent analysis of the mortality data28
suggests that melanoma chemotherapy cannot explain the higher PD mortality among patients with melanoma.
Most previous studies attempted to examine the temporal relationship between melanoma and PD in both directions. While such analysis may provide insights on how these 2 conditions are connected, these studies often estimated the date of diagnoses based on hospitalization registries or electronic medical records and therefore might be inherently inaccurate. Further, the insidious onset and presumed long latency period of both conditions make it difficult to tease out the temporal sequence. The current meta-analyses based on available literature suggest that these 2 conditions tended to co-occur without a clear temporal order.
A number of past observations from case reports have implicated levodopa use in PD treatment as a risk factor for melanoma. Biologically, such an association is plausible as exogenous levodopa may stimulate melanogenesis, leading to an accumulation of melanin and hence melanoma growth.4
However, recent epidemiologic studies have refuted a causal association.1,4
Opponents have argued that given the relative long latency between initiation and clinical manifestation of melanoma, generally thought to be greater than 10 years and in some cases as long as 40 years,29
it is unlikely that levodopa stimulated the growth of melanoma in a short period of a few months or years, as was often described in earlier case reports. The possibility of higher occurrence of melanoma before a diagnosis of PD, as suggested in our subgroup analysis, further weakens the hypothesis that levodopa use may explain the observed association between melanoma and PD. In addition, preliminary data also suggested higher occurrence of melanoma among patients with PD treated with other medicines, such as rasagiline.3,30
Some researchers have raised the concern that the increased melanoma occurrence may be explained by increased medical surveillance of patients with PD.1,18,21
However, this suggestion is inconsistent with the fact that Parkinsonian patients are often at lower risk for most of the other types of cancers.1
Several lines of evidence point to a possible biological link between melanoma and PD. One important piece of evidence is the common embryonic origin of melanocytes and neurons from neural crest cells.31
Further, levodopa serves as a substrate for the synthesis of dopamine and melanin,4
although the catalytic enzymes are different. In addition, α-synuclein was detected in most malignant and benign melanocytic lesions but not in nonmelanocytic cutaneous carcinoma and normal skin.32
Adding to these lines of evidence are results from a large prospective study33
indicating that people with a family history of melanoma had an approximately twofold higher risk of developing PD than those without. These observations lead to the hypothesis that melanoma and PD are biologically linked,34
although the exact mechanisms are yet to be identified.
One potential explanation is that melanoma and PD have shared environmental or genetic risk factors or common pathogenic pathways. For example, smokers have lower risk for PD35
and may also be at lower risk for melanoma36
; on the other hand, pesticide exposures have been linked to higher risk for both PD37
Results of a recent epidemiologic study linked a known genetic variation of melanoma to higher PD risk.39
The authors of this study reported that lighter hair color was associated with a greater risk of PD. In particular, individuals with red hair or carrying the homozygous recessive melanocortin 1-receptor (MC1R) Arg151Cys variant allele had approximately twofold to threefold higher risk of developing PD compared to those without such traits. Given the important role of pigmentation gene polymorphisms in the development of melanomas, the authors suggested a potential role of pigmentation in explaining, at least partially, the co-occurrence of melanoma and PD.39
Accordingly, a hypothesis was proposed linking pigmentation gene variations, as well as the gene encoding for tyrosinase, to the co-occurrence of PD with melanoma.34
These preliminary genetic links should be further explored in future investigations. Based on available genetic and biochemical evidence, a recent hypothesis posits that the link between melanoma and PD may involve altered activities in the key enzymes of tyrosine metabolism and potential interactions with α-synuclein.40
Given the consistent epidemiologic finding on PD and melanoma, the relevance of these hypotheses should be evaluated in future studies.
Several limitations should be considered when interpreting our results. The majority of these studies were not originally designed to evaluate the relationship between melanoma and PD; melanoma was mostly assessed along with other cancers or medical conditions. Further, these analyses were often based on very small numbers of cases with both melanoma and PD. This is particularly true for the gender-specific analyses. In most of the studies, PD and melanoma cases were identified from hospitalization registers, record linkage, and self-report; misdiagnosis and underdiagnosis were therefore likely, particularly for PD. Moreover, as discussed earlier, the ascertainment of the date of diagnoses in these studies were inherently imprecise. Finally, most of these studies collected limited data on risk factors that made it difficult to explore potential explanations.
Despite these limitations, the results from our meta-analysis support a moderate association of PD with a higher occurrence of melanoma. Further research is needed to examine the nature and mechanisms of this relationship in order to advance our understanding about the etiology of both diseases.