Prognostic factors for relapse in patients with clinical stage I testicular seminoma: A nationwide, population-based cohort study.

person Thomas Wagner Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark info_outline Thomas Wagner, Birgitte Grønkær Toft, Jakob Lauritsen, Mikkel Bandak, Ib Jarle Christensen, Birte Engvad, Michael Kreiberg Jessen, Mads Agerbaek, Lars Dysager, Josephine Rosenvilde, Daniel Berney, Gedske Daugaard

Authors person Thomas Wagner Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark info_outline Thomas Wagner, Birgitte Grønkær Toft, Jakob Lauritsen, Mikkel Bandak, Ib Jarle Christensen, Birte Engvad, Michael Kreiberg Jessen, Mads Agerbaek, Lars Dysager, Josephine Rosenvilde, Daniel Berney, Gedske Daugaard Organizations Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, Department of Pathology, Copenhagen University Hospital, Herlev Gentofte Hospital, Herlev, Denmark, Department of Pathology, Odense University Hospital, Odense, Denmark, Aarhus University Hospital, Aarhus, Denmark, Department of Oncology, Odense University Hospital, Odense, Denmark, Centre of Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, London, United Kingdom Abstract Disclosures Research Funding Other Foundation The Danish Cancer Society, The Danish Cancer Research Foundation, The Preben and Anna Simonsen’s Foundation, and The Valdemar Beck’s Foundation Background: Approximately 20% of patients with clinical stage I testicular seminoma will relapse after orchiectomy. No robust prognostic factors for relapse exist which challenges risk assessment and counselling for patients. Previous studies have been hampered by selection bias and variable pathology reporting that limit interpretation and generalization of results. We therefore assessed prognostic factors for relapse in a large unselected nationwide population-based setting with centralized pathology review. Methods: Patients with clinical stage I seminoma diagnosed in Denmark between 2013 and 2018 were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, microscopic slides from the orchiectomy specimens were retrieved and reviewed blinded to the clinical outcome. Clinical data were obtained from medical records with follow-up until July 2022. The association between prespecified clinical and histopathological prognostic factors and relapse were assessed by use of Cox regression analysis. Potential prognostic factors included age, pre-orchiectomy values of β-human chorionic gonadotropin (β-hCG) and lactate dehydrogenase (LDH), tumor size, tumor multifocality, tumor necrosis, lymphovascular invasion, pagetoid rete involvement, and invasion of rete testis, hilar soft tissue, epididymis, spermatic cord, tunica albuginea, and tunica vaginalis. Results: In total, 924 patients were included. During a median follow-up of 6.3 years, 148 (16%) patients relapsed. Invasion of the testicular hilum (rete testis and hilar soft tissue), lymphovascular invasion, and elevated pre-orchiectomy levels of β-hCG and LDH were independent predictors of relapse. The estimated 5-year risk of relapse ranged from 6% in patients with no risk factors, to 64% in patients with all four risk factors with tumor extension into the hilar soft tissue of the testicular hilum. After internal model validation, the model had an overall concordance statistic of 0.70. Conclusions: The provided prognostic factors allow a long-awaited opportunity to make more informed treatment decisions about post-orchiectomy management in patients with clinical stage I seminoma. These should replace current risk factors in guidelines and be used in future studies investigating risk-adapted follow-up and treatment strategies. Results of the final multivariable Cox model. Hazard ratio, 95% CI p-value Testicular hilum invasion Rete testis invasion - 1 (Reference) -- Rete testis invasion + Hilar soft tissue invasion - 1.80 (1.18-2.74) 0.0061 Rete testis invasion + Hilar soft tissue invasion + 2.90 (1.87-4.49) <0.0001 Lymphovascular invasion (present vs absent) 1.85 (1.24-2.75) 0.0024 β-hCG (elevated vs normal) 1.91 (1.36-2.67) 0.0002 LDH (elevated vs normal) 1.66 (1.18-2.33) 0.0034