Narcolepsy and skin cancer risk: Inverse comorbidity and the protective role of orexin deficiency.

Abstract

e21575 Background: Narcolepsy is a disorder characterized by daytime sleepiness, potential cataplexy, and hallucinations. The condition is subdivided into narcolepsy type 1 (NT1), involving orexin (or hypocretin) deficiency; and narcolepsy type 2 (NT2), which does not. Malignancy risk has had limited investigation with narcolepsy; limited to retrospective analysis of a Taiwanese database that found an increased cancer risk in 2833 narcoleptic patients with increased incidence in females. Orexin is a neuropeptide with an emerging role in cancer development, with pro-apoptotic evidence in colon, pancreatic, prostate, and neuroblastomas, but anti-apoptotic evidence in gastric cancers. Hence, we aimed to conduct a large retrospective cohort study of narcolepsy and melanoma and non-melanoma skin cancer (NMSC) risk, with the first subtype analysis of NT1 and NT2. Methods: The TriNetX US database was utilized, providing real-world, de-identified data of 124 million patients. Exposed patients were defined as having at least 2 instances of the ICD-10 code, G47.41, for narcolepsy. The control cohort was defined by having no history of narcolepsy and at least 2 general outpatient annual physical examinations (Z00.0). For subgroup analysis, NT1 and NT2 cohorts were defined using at least two instances of ICD-10 coding G47.411 or G47.419. Patients were propensity score matched 1:1 by age at index, sex, Hispanic ethnicity, and Black and White race. Results: 43,463 patients with narcolepsy were included to matched unexposed. Narcoleptic patients had a significant decrease in risk of basal cell carcinoma (BCC) (RR 0.615, p<0.0001) and squamous cell carcinoma (SCC) (RR 0.686, p<0.0001). In subgroup analysis by sex, females with narcolepsy had a significantly decreased risk of BCC (RR 0.656, p=0.0001) and SCC (RR 0.532, p<0.0001) compared to males. Additionally, patients with NT1 had significantly decreased risk of melanoma (RR 0.575, p=0.0200) and BCC (RR 0.752, p=0.0415) compared to patients with NT2. Conclusions: In prior studies of narcolepsy, it was suggested that patients have a higher risk of malignancy; however, our findings support potential for inverse comorbidity in the context of cutaneous malignancies. Our findings suggest that patients with narcolepsy may have a decreased risk of NMSC, with decreased risk in females compared to males. Additionally, NT1, orexin deficient patients, may have significantly decreased risk of melanoma and NMSC compared to NT2 patients.