Incidence of Gonadal and Extragonadal Germ Cell Tumours in Patients With Klinefelter Syndrome

Klinefelter's syndrome (KS; 47, XXY) is associated with an altered risk profile for malignancies compared with non-KS males. In particular, several reports have noted a striking association between KS and extragonadal germ cell tumours (EGCTs), especially in the mediastinum, whereas the risk of testicular germ cell tumours (TGCTs) in KS remains unclear. KS patients also have a higher prevalence of cryptorchidism (undescended testes)-a known risk factor for TGCT in the general population-yet it is uncertain if cryptorchidism confers the same cancer risk in the KS population. This study aims to compare the incidence of TGCTs and EGCTs in KS against the general population, and to evaluate the impact of cryptorchidism on TGCT risk in KS.

We conducted a retrospective cohort study of 233 KS patients (age range 2-83, mean 35.1 years) managed at a dedicated KS clinic between 2019 and 2025. Clinical histories, ultrasound findings and histopathology reports were reviewed to identify cases of TGCT, EGCT and cryptorchidism. Incidence rates per 100,000 patient-years were calculated based on 8311 total person-years of follow-up (from birth until age of diagnosis or until end of study period-30th June 2025) and compared with population data from cancer registries. A one-sided Poisson test was used to assess differences in observed tumour incidence versus the general population, with 95% confidence intervals (CIs) derived by exact Poisson methods.

In 233 KS patients, we identified two cases of TGCTs (both testicular tumours in adult men) and one case of mediastinal EGCT. The incidence of TGCT in the KS cohort was 24.1 per 100,000 patient-years (95% CI, 3.0-88.6), which was higher than that in the general male population (∼4.8 per 100,000) but did not reach statistical significance (p = 0.060). In contrast, the incidence of mediastinal EGCT in KS was 12.0 per 100,000 patient-years, exceeding the general population rate (∼0.04 per 100,000). The age-standardised incidence ratios for TGCT was 2.24 (95% CI, 0.27-8.10) compared with the UK population. For EGCT, the crude age-standardised incidence ratio was 83.0 (95% CI, 2.1-460.5). Cryptorchidism was documented in 10 of the 233 KS patients (4.3%). Notably, none of the KS patients with a history of cryptorchidism developed TGCT, and neither of the two KS-TGCT patients had cryptorchidism or other typical risk factors for testicular cancer other than markedly atrophic testes.

KS confers a markedly increased risk of mediastinal EGCT but not a clear increase in TGCT. The pathogenesis of germ cell tumours in KS is multifactorial: aberrant primordial germ cell migration/survival and an altered hormonal milieu are central hypotheses for the predilection towards midline extragonadal tumours, whereas intrinsic testicular degeneration in KS might protect against TGCT despite risk factors like cryptorchidism and atrophy. Genetic factors (e.g., extra X chromosome effects, KIT mutations) and environmental influences (e.g., hypergonadotropic state) may also play roles in these observations.

For clinicians managing Klinefelter patients, these findings emphasise the importance of vigilance for EGCTs, particularly in the mediastinum, even though routine testicular cancer surveillance beyond standard care may not be necessary in the absence of other risk factors. Our data do not support a need for intensive TGCT screening in KS at present, given the lack of a statistically significant increase in testicular cancer incidence. Conversely, the significantly elevated incidence of mediastinal GCT in KS raises the question of screening such as periodic chest imaging in adolescent KS patients. While universal screening is debatable due to the rarity of these tumours, a thorough physical exam (looking for mediastinal mass effects) and a low threshold for chest imaging if symptoms arise (e.g., chest pain, dyspnoea) are advisable in KS. In future, larger multi-centre cohort studies and cancer registry linkages (ideally capturing genotype-confirmed KS cases) will be needed to definitively quantify TGCT risk in KS and to explore the molecular underpinnings of the KS-GCT connection.