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117 INCIDENCE OF TESTICULAR CANCER IN TRANS WOMEN USING GENDER-AFFIRMING HORMONAL TREATMENT 7 DISCUSSION The aim of this study was to assess testicular cancer incidence in trans women using GAHT. A total of three testicular cancer cases were observed in our cohort, of which two were discovered due to symptoms and the third was encountered during routine histopathological analysis of the bilateral orchiectomy specimen. Our observations suggest that there is no difference in testicular cancer risk between trans women using GAHT and cis men. In addition, no testicular cancer cases were observed in trans women with a follow-up time of more than 5 years. To the best of our knowledge, there is only one other epidemiological study that, in addition to other types of cancer, also assessed testicular cancer incidence in trans women, reporting an incidence ratio of 0.3 (95% CI 0.1-0.6) compared to cis men. 127 However, in contrast to our study this proportional incidence study lacked data on GAHT and GAS. Since trans women are no longer at risk for testicular cancer after bilateral orchiectomy, we feel that with our longitudinal data we were able to accurately calculate follow-up time, and hereby, adequately assess the effect of GAHT on testicular cancer risk. In total, five case reports have been published on testicular cancer cases in trans women. Histopathological analyses showed seminoma in three cases, non-seminoma (mature teratoma) in one case, and mixed germ cell tumor (embryonal carcinoma (75%), immature teratoma (15%), seminoma (9%), and yolk sac tumor ( < 1%)) in the last case. Similar to the cases observed in our cohort, two trans women were referred to urologists because they felt a painless scrotal mass which was, in one case, already present since several months. 43,45 In the other three cases, testicular pathology was only discovered after extensive examination, initiated when antiandrogenic treatment failed to suppress serum testosterone concentrations. 41,42,44 This illustrates how diagnosis of testicular cancer in trans women may be delayed when people experience severe genital dysphoria, and may ignore or be unaware of abnormalities such as a testicular mass. Besides, physicians might not be aware of the presence of testicles during a consultation with a phenotypical woman, which can also lead to a delayed diagnosis. Improving awareness on this topic is important to provide proper care for the increasing number of trans women who may not undergo genital gender-affirming surgery. In addition, it is imperative that health care providers are counseled on working in a trans sensitive manner. 128,129 Furthermore, in line with recommendations for cis men, trans women with clinical risk factors such as a family history of testicular cancer, should be encouraged to regularly perform testicular self- examination. 16,130 Several studies addressed the influence of GAHT on testicular tissue and mainly showed severe spermatogenic involution, reduced numbers of Leydig cells, seminiferous tubules with a decreased diameter or an absent lumen, heavy peritubular hyalinization, and fibrosis. 29 Because of depletion of germ cells, testicular volumes have shown to generally decrease by 25% within the first year of hormonal treatment. 131 However, in previous studies, no malignant changes were observed in the orchiectomy specimens of trans