Abstract
BACKGROUND: Hypospadias is a common genital malformation among boys. Studies indicate that hypospadias is associated with a higher risk of testicular cancer. Other forms of urological cancer may be linked to hypospadias via a mutual aetiology, hormonal dysfunction, or hypospadias complications, but this has not yet been studied. OBJECTIVE: To investigate the association between hypospadias and testicular cancer and the risk of other urological cancers among individuals born with hypospadias. DESIGN SETTING AND PARTICIPANTS: The study used a population-based male cohort born in Sweden in 1964-2018. Exposure was hypospadias diagnosis in national registers. Outcomes were defined using the Swedish Cancer Register. An extended cohort born from 1940 was used to study cancers among older men. Biological brothers and fathers were linked to investigate familial coaggregation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Associations were assessed using Cox proportional-hazards regression analysis, with results presented as hazard ratios. RESULTS AND LIMITATIONS: We found that hypospadias was associated with a higher risk of testicular cancer (hazard ratio 2.04, 95% confidence interval 1.42-2.92), especially for proximal hypospadias, but did not observe any clear familial coaggregation of hypospadias and testicular cancer. Hypospadias was associated with Wilms' tumour in childhood. We also found an association between hypospadias and bladder and urethral cancers, but not prostate cancer. The number of cases with hypospadias was small and the results for cancers among older men may be impacted by limitations in register coverage. CONCLUSIONS: Our study supports the hypothesis of a higher risk of testicular cancer for men with hypospadias, especially with proximal phenotypes. Hypospadias may also be associated with a higher risk of lower urinary tract cancers, although this requires further investigation in older cohorts. PATIENT SUMMARY: Boys and men in whom the opening of the urethra is not at the end of the penis (called hypospadias) at birth are at higher risk of developing testicular cancer, although their overall risk is still low. They may also have a higher risk of developing other forms of cancer in the urinary tract.