Abstract
IMPORTANCE: Chronic lymphocytic leukemia (CLL) and its immunosuppressive treatment has been suggested to be associated with increased risk of skin cancer. However, detailed long-term evidence of this association is lacking, including whether an increased skin cancer incidence translates into increased risk of skin cancer-specific metastasis and death in patients with CLL. OBJECTIVE: To assess the overall risk of skin cancer, skin cancer subtypes, and skin cancer-specific metastasis and death among patients with CLL compared with individuals without CLL (controls). DESIGN, SETTING, AND PARTICIPANTS: This nationwide population-based matched cohort study analyzed Danish registry data from January 1990 to December 2020. Follow-up began at CLL diagnosis and continued until an event of interest, death, emigration, or study end. Patients with prior skin cancer or immunosuppression were excluded. Patients with CLL were matched 1:5 with controls based on birth year, sex, geographic region, educational level, income, marital status, and Charlson Comorbidity Index score. Data were analyzed from June to September 2025. MAIN OUTCOMES AND MEASURES: Absolute risks and risk differences for overall skin cancer, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma, cutaneous lymphoma, and skin cancer-specific metastasis and death. All risks were estimated using multivariable cause-specific Cox proportional hazards regression models with death from other causes as a competing risk. RESULTS: Among the 8352 patients with CLL included in the study (median age, 70.7 years [IQR, 62.2-78.3 years]; 4902 [58.7%] male), the absolute 10-year risk of skin cancer was 13.5% (95% CI, 12.7%-14.3%) compared with 6.9% (95% CI, 6.6%-7.2%) among 41 760 controls (median age, 70.7 years [IQR, 62.2-78.2 years]; 24 510 [58.7%] male), resulting in an absolute risk difference (ARD) of 6.6 percentage points (pp) (95% CI, 5.7-7.4 pp; P < .001). Patients with CLL had an increased risk of most skin cancer subtypes compared with controls, with the most common being basal cell carcinoma (8.6% [95% CI, 7.9%-9.2%] vs 5.4% [95% CI, 5.2%-5.7%]; ARD, 3.2 pp [95% CI, 2.4-3.8 pp]; P < .001) and squamous cell carcinoma (4.7% [95% CI, 4.2%-5.2%] vs 1.4% [95% CI, 1.3%-1.6%]; ARD, 3.3 pp [95% CI, 2.8-3.8 pp]; P < .001). Patients with CLL, compared with controls, had a higher risk of both skin cancer metastasis (0.7% [95% CI, 0.4%-0.9%] vs 0.1% [95% CI, 0.1%-0.2%]; ARD, 0.6 pp [95% CI, 0.3-0.7 pp]; P < .001) and skin cancer-specific death (0.3% [95% CI, 0.2%-0.4%] vs 0.1% [95% CI, 0.1%-0.1%]; ARD, 0.2 pp [95% CI, 0.1-0.3 pp]; P = .004). All-cause mortality among patients with CLL was 56.3% (95% CI, 55.3%-57.2%) compared with 39.3% (95% CI, 38.8%-39.8%) among controls (ARD, 17.0 pp; 95% CI, 16.0-18.0 pp; P < .001). CONCLUSIONS AND RELEVANCE: This cohort study found that patients with CLL had an increased risk of developing skin cancer, mainly basal cell carcinoma and squamous cell carcinoma. Skin cancer-specific metastasis and death were also more frequent among patients with CLL, although the absolute risk remained low given markedly higher all-cause mortality.