Clinicopathologic Characteristics of Melanoma in Patients with Parkinson Disease

Melanoma is an increasingly common cancer in the United States, with an estimated 106,110 new diagnoses and 7,180 deaths from invasive cutaneous melanoma in 2021 (). Although the overall incidence of melanoma has increased in recent years, certain populations are disproportionately affected, specifically fair-skinned individuals, those living in geographic locations closer to the equator, and patients living with Parkinson disease (PD) (; ). Melanoma mortality is fortunately trending downward, with melanoma death rates between 2014 and 2018 falling by approximately 7% per year in adults aged ≤50 years and approximately 5% per year in older adults; furthermore, the 5-year relative survival rate (2010‒2016) is 93% among all stages at diagnosis and 99% for local disease ().

The enigmatic association between cancer and PD has been explored by numerous studies. Patients with PD have an overall lower risk of developing cancer at any primary site than those in the general population but paradoxically face a significantly higher risk for melanoma (). One study noted that the risk of developing melanoma in patients with PD is increased two-fold (). A multicenter study reported that patients with PD had a 2.24-fold higher risk of developing malignant melanoma than age- and sex-matched controls, recommending that patients newly diagnosed with PD undergo preventative screening for melanoma ().

Multiple theories for the pathophysiological link between melanoma and PD exist, including genetic alterations related to melanin biosynthesis, cellular detoxification mechanisms, the oxidative stress response, cellular trafficking, and disease of the substantia nigra (; ). Additional factors that modulate the risk of developing melanoma in patients with PD have been explored, specifically medication therapy with levodopa and carbidopa-levodopa. The DATATOP (deprenyl and tocopherol antioxidative therapy of parkinsonism) trial suggested that the relationship between levodopa and melanoma was of coincidental rather than causal nature, although the authors admitted that the study was underpowered to assess causality; in addition, there is a paucity of studies including analysis of other medications commonly used in PD as well as studies examining the pathologic characteristics of melanoma in patients with PD ().

We identified 70 adult patients with concurrent diagnoses of PD and melanoma between the dates of January 1, 2007 and January 1, 2020 treated in the Duke University Health System as well as 102 age- (within 2 years), sex-, and race-matched control patients with melanoma but without a diagnosis of PD. Our primary aim was to characterize the clinicopathologic characteristics of melanoma in patients with PD. Secondarily, we sought to identify patient characteristics that may be associated with the development of melanoma in patients with PD such as dopaminergic drug therapy, previous personal or family history of melanoma, personal history of other skin cancers (squamous cell carcinoma [SCC] and basal cell carcinoma [BCC]), or dysplastic nevi. This study is a systematic collation of data and a description of melanoma characteristics in patients with PD that provides an essential update to existing literature regarding this enigmatic diagnostic association. We hope that our study will guide future, prospective research addressing the prevention, surveillance, and treatment of melanoma in patients with PD because previous studies have heralded the need for early detection and screening in this population (; ).

Our case group comprised 70 patients with both melanoma and PD. Ten of these patients had more than one melanoma, including one patient with two primary melanomas diagnosed on the same day. The remaining nine patients had an initial primary melanoma followed by a later diagnosis of a subsequent primary melanoma. Our control group contained 102 patients and 102 primary melanomas with sufficiently detailed pathology reports for inclusion. Case-group patients were matched to controls for age (within 2 years), sex, and race with a similar distribution in variables after matching.

In our single-center retrospective case-control study, most case-group patients had a diagnosis of melanoma that preceded a PD diagnosis, the predominant site of primary melanoma was the head/neck region, and the most common melanoma subtype was melanoma in situ. Using logistic regression analysis, we found that patients with PD had 2.09 times higher odds of having a head/neck melanoma than the control group. Of the 43 invasive tumors in our case group, most originated on the head/neck (n = 17, 39.5%). Although metastasis was uncommon, 50% of metastatic melanomas in patients with PD originated on the head/neck compared with the 42.9% of metastatic melanomas with a primary head/neck site in the control group.

Although our study is limited by a small case-group sample size, we recommend increased surveillance for melanoma in patients with newly diagnosed PD because early detection may result in a more favorable prognosis, including detection of melanoma in situ or early invasive disease and reducing the need for sentinel lymph node biopsy, systemic treatment, and imaging surveillance. Heightened suspicion of and increased screening for concerning pigmented lesions in patients with PD in the primary care setting with a focus on surveilling the head and neck regions may provide an appropriate first intervention and access point to skin screening for this population, with referral to dermatology being warranted if lesions suspicious for malignancy are identified. Dermatology consultation may be considered for full-body skin examinations for patients newly diagnosed with PD to also include surveillance for nonmelanoma skin cancer. Given the effects of PD on motor function, including tremors, rigidity, bradykinesia, freezing gait, and disordered balance, patients with PD are at high risk for falling, with approximately 60% of patients with PD experiencing at least one fall each year; therefore, care must be taken to support these patients as they don gowns or ambulate to the examination table (). Strategies for mitigating fall risk include employing assistance from healthcare staff or patient family members during the removal of clothing; performing skin examinations of one body segment at a time; and examining the head and neck, upper extremities, and trunk while patients are seated upright on the ground level. Examination of the lower extremities, groin, and buttocks can be performed while patients with PD support themselves using assistive devices (i.e., walkers) or use countertops or the examination table to support their upper body. Dermatologists should perform a full-body skin examination when possible for patients with PD, but our results support emphasized screening of the head and neck for melanoma surveillance.

Existing literature emphasizes the pathophysiological link between melanoma and PD as well as discussions on the PD medications hypothesized to increase the risk for melanoma. However, the literature lacks studies reporting the clinicopathologic characteristics of primary melanomas in patients with PD. found an association with the expression of alpha-synuclein in melanocytic lesions, including benign nevi, primary melanoma, and metastatic melanoma, indicating that the link between PD and melanoma warrants further clinicopathologic and genetic studies. The authors were unable to find other clinicopathologic studies to contextualize the results of this study, which further highlights the need for future larger studies of melanoma characteristics in patients with PD to better inform skin cancer screening recommendations.

This study reported the pharmacotherapy for patients with PD with melanoma, including carbidopa-levodopa, dopamine receptor agonists (i.e., ropinirole and pramipexole), catechol-o-methyltransferase inhibitors (i.e., entacapone), and monoamine oxidase inhibitors (i.e., selegiline and rasagiline). It is worth noting that some patients had initially been treated with dopamine receptor agonists before transitioning to carbidopa-levodopa therapy, although only 11.4% of patients (n = 8) were still taking these medications. Interestingly, there was a recent case of palmar eruptive melanocytic nevi in a male aged 86 years diagnosed with PD and treated with carbidopa-levodopa, in which his new-onset eruptive melanocytic nevi increased in both number and pigmentation after doubling his dose of carbidopa-levodopa (). Dopaminergic drugs are the mainstay of PD treatment, and levodopa has been well-characterized as an important intermediate in melanogenesis; furthermore, increased melanogenesis in melanoma, particularly invasive subtypes, is a poor prognostic factor (; ).

Our study found that a diagnosis of melanoma predominantly preceded the diagnosis or treatment of PD, suggesting the possibility of an alternative pathophysiological link between the disease processes beyond the previously reported association with levodopa. Supporting our results, a 2017 retrospective cohort study examining the association between melanoma and PD concluded that patients with PD had a 3.8-fold increased probability of having pre-existing melanoma and that patients with melanoma had a 4.2-fold increased risk of developing PD compared with the controls (). These results may weaken the hypothesis that melanoma may be induced by medications used in the treatment of PD; in contrast, a 2015 meta-analysis examining the temporal relationship of melanoma in 292,275 patients with PD found that there was a significant risk for melanoma after PD diagnosis but no significant risk before the PD diagnosis (). An analysis of data from the DATATOP clinical trial examined the incidence of malignant melanoma in a PD cohort before and after levodopa therapy, reporting an increased risk of melanoma in patients with PD compared with that in the general population; however, it failed to support an association between levodopa and development of melanoma because the study was limited by a small number of definite malignant melanomas (n = 5) (). Finally, it is important to recognize that PD and melanoma may develop independently with advancing age, that older non-Hispanic white males are a demographic group at high risk for head and neck and thick melanomas independent of PD diagnosis, and that the results of our study are insufficient to confirm a definite link.

This study and previous work show the need for deeper exploration of the mechanisms linking PD and melanoma because there is a lack of high-powered cohort studies along with conflicting reports on the temporality of the association (). Our study was limited by a small sample of patients with PD with pathology-confirmed melanoma (n = 70), and validation of the reported trends in tumor site could contribute to the development of more robust guidance for detecting melanoma early in patients with PD. We propose increased screening for melanoma in patients with PD with a particular focus on the head and neck because most noninvasive, invasive, and metastatic melanomas originated from these anatomic locations. Our case cohort lacked diversity in terms of race, ethnicity, and sex, although it is possible that this is reflective of the demographics of patients living with PD and melanoma. We recognize the importance of ensuring that our data can be applied to a wide range of patients across multiple clinical settings. Future studies with larger sample sizes could provide more power to validate the findings of this study.

Michael Seth Flynn: https://orcid.org/0000-0002-7941-1069

Camille Robinson: https://orcid.org/0000-0001-6479-3036

Surya Patel: https://orcid.org/0000-0003-3635-695X

Beiyu Liu: https://orcid.org/0000-0003-1455-0233

Cynthia Green: https://orcid.org/0000-0002-0186-5191

Michelle Pavlis: https://orcid.org/0000-0001-5491-6653

The authors state no conflict of interest.

We wish to acknowledge support from the Biostatistics, Epidemiology and Research Design (BERD) Methods Core funded through Grant Award Number UL1TR002553 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Conceptualization: MP; Data Curation: MSF, CR, SP; Formal Analysis: BL, CG; Funding Acquisition: MP, BL; Investigation: MP, MSF, CR, SP; Methodology: MP, SP, MSF, CR; Project Administration: MP; Supervision: MP, CG; Validation: MSF, CR, SP; Visualization: MSF, CR, SP, BL; Writing - Original Draft Preparation: MSF, CR, SP; Writing - Review and Editing: MSF, CR, SP, MP, BL, CG

The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.