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Parkinson disease appears linked to melanoma

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July 5, 2017

Patients with Parkinson disease or melanoma each had increased risk for the other disease, according to results of a retrospective cohort study.

These results suggest a prevalent association between the two diseases, according to the researchers.

Lauren A. Dalvin

“If we can pinpoint the cause of the association between Parkinson disease and melanoma, we will be better able to counsel patients and families about their risk [for] developing one disease in the setting of the other,” Lauren A. Dalvin, MD, Mayo Foundation scholar in ocular oncology at Mayo Clinic in Rochester, Minnesota, said in a press release.

Previous studies have demonstrated a range from two-fold to seven-fold increased risk for melanoma among patients with Parkinson disease.

However, whether a link exists between Parkinson disease and melanoma remains controversial.

To determine any association between melanoma and Parkinson disease, the researchers used records from the Rochester Epidemiology Project to identify 974 patients (58% men) with Parkinson disease in Olmsted County, Minnesota between January 1976 and December 2013.

The patients had an average age at diagnosis of 75 ± 10 years (range, 42-98). All patients received treatment with carbidopa/levodopa in the index year and continued through study follow-up or death.

In the first study phase, researchers matched each patient with Parkinson disease by age and sex to three referent individuals without Parkinson disease also living in Olmsted County (n = 2,922).

“We hypothesized that there would be a higher incidence of melanoma diagnosed in patients with Parkinson disease compared with an age- and sex-matched cohort with similar environmental exposures,” the researchers wrote.

Overall, patients with Parkinson disease had a 3.8-fold (95% CI, 2.1-6.8) increased risk for preexisting melanoma than controls.

These results led researchers to hypothesize that patients with a history of melanoma are more likely to develop Parkinson disease after melanoma diagnosis than controls with similar environmental exposures.

In these second phase of the study, researchers reviewed cases of melanoma from the same database (n = 1,544; 52% men) and matched them by sex and age to one referent individual without melanoma. Average age at melanoma diagnosis was 57 ± 18 years.

Results indicated patients with melanoma had a 4.2-fold (95% CI, 2-8.8) increased risk for Parkinson disease. Patients with melanoma had an increased 35-year cumulative risk for Parkinson disease (11.8% vs. 2.6%; P < .001).

Patients with melanoma without Parkinson disease experienced a 10.5-fold (95% CI, 1.5-72.2) increased relative risk for mortality of metastatic melanoma than patients with both diseases.

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“This suggests that somehow Parkinson disease may be a protective factor when considering

the risk of metastatic melanoma, but it is also possible that there is an underlying immune reaction that both suppresses development of metastatic melanoma and causes Parkinson disease,” the researchers wrote. It is known that patients with Parkinson disease have inadequate innate immune responses, increased markers of adaptive immunity and disruption of the blood–brain barrier. This makes a common underlying immunologic association between Parkinson disease and melanoma plausible.”

Future research should focus on identifying common genes, immune responses and environmental exposures that may link these melanoma and Parkinson disease, Dalvin said in the press release. – by Melinda Stevens

Disclosure: Dalvin reports grants from VitreoRetinal Surgery Foundation during the study. Another researcher reports grants from Deshong Family, Paul Family, Research to Prevent Blindness and VitreoRetinal Surgery Foundation during the study.

itj+ Perspective

Asim Amin, MD, PhD
Perspective

Dalvin and colleagues reported their findings from a study designed to evaluate the association between melanoma and Parkinson’s disease from the Rochester Epidemiology Project. In the first phase of the study, researchers identified 974 patients with a diagnosis of Parkinson’s disease between 1976 and 2013 who received treatment with carbidopa/levodopa. Investigators compared them with 2,922 age- and sex-matched controls who lived in the same county to minimize environmental variation. In the second phase, researchers interrogated the same database and identified 1,544 patients with a melanoma diagnosis and compared them with age- and sex-matched controls who did not have a melanoma diagnosis.
Based on prior data and the theoretically increased risk for melanoma among patients being treated with levodopa, also called L-DOPA, the researchers hypothesized an increased rate of melanoma in this patient population.
Data showed patients diagnosed with Parkinson’s disease had a statistically significant increase in risk for developing melanoma (11.8% vs. 2.6%; P < .001), and patients with melanoma had a 4.2 fold increase risk for being diagnosed with Parkinson’s disease.
Interestingly, patients who did not have a diagnosis of Parkinson’s disease had a 10.5-fold higher relative risk for dying of metastatic melanoma, suggesting a protective effect.
Several studies have previously examined the link between Parkinson’s disease and higher incidence of malignant melanoma. Biochemical basis for this concern resides in the fact that levodopa has been the standard of care for patients with Parkinson’s disease and is also a precursor for melanin. However, increased risk for melanoma secondary to treatment with levodopa has not been conclusively shown.
Loss of pigmented neurons in the substantia nigra is one of the characteristic histologic features of Parkinson’s disease and is thought to be secondary to immune-mediated cell death. Neuromelanin present in the substantial nigra and the locus coeruleus confers pigmentation to these areas. It differs from the melanin pigment found in melanocytes in its mode of formation. L-Tyrosine — the initial substrate for melanin — is oxidized by the enzyme tyrosinase to 3, 4-dihydroxyphenyl (L-DOPA) and then dehydrogenized to DOPA-quinone, a precursor for melanin found in melanocytes, whereas neuromelanin is a result of auto-oxidation. Although generated from biochemically distinct mechanisms, melanin and neuromelanin may share antigenic determinants.
Vitiligo has been observed in patients treated with high-dose interleukin-2 and correlated with improved cancer outcomes. The depigmentation is attributed to sharing of normal tissue antigens that can become targets for cancer immunotherapy. Several studies have corroborated the above observations in patients with advanced melanoma who received immune checkpoint inhibitors. The vitiligo-like changes in the skin have been clearly associated with improved clinical outcomes.
Based on the improved outcomes for metastatic melanoma noted in patients with diagnosis of Parkinson’s disease, it is tempting to conjecture that processes akin to developing vitiligo-like lesions after immunotherapy may have been triggered by cross-reactive immune mechanisms between neuromelanin in the substantia nigra and melanin in melanocytes.

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Asim Amin, MD, PhD

Levine Cancer Institute
Carolinas HealthCare System

Disclosure: Amin reports no relevant financial disclosures.