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A large Danish cohort study provides the best evidence to date on which prognostic factors predict relapse in patients with stage I testicular seminoma, researchers reported.

Thomas Wagner, MD, of Copenhagen University Hospital in Denmark, and colleagues analyzed histologic slides from orchiectomy specimens of 924 patients with stage I testicular cancer. During a median follow-up of 6 years, 148 of these patients (16%) relapsed.

The investigators used Cox regression to look for associations between clinical and histopathologic prognostic factors and relapse, and identified the following independent predictors of relapse: tumor invasion into the testicular hilum, lymphovascular invasion, and elevated preorchiectomy values of lactate dehydrogenase (LDH) and β-human chorionic gonadotropin (β-hCG).

"Different combinations of these risk factors categorized patients into six risk groups with the estimated 5-year risk of relapse increasing from 6% in patients with no risk factors to 62% in patients with all four factors with tumor extension into the hilar soft tissue of the testicular hilum," the team wrote in the

Wagner elaborated on the study findings in the following interview.

Why did the management of stage I seminoma in Denmark offer a unique opportunity to assess risk factors for relapse?

Wagner: Previous studies on prognostic factors have been challenged by selection bias as many "high-risk" patients have been treated upfront with adjuvant therapy. In Denmark, all patients with stage I seminoma have been managed with surveillance for the last decades regardless of the pathologic features in the primary tumor. Thus, none have been treated with adjuvant therapy.

By use of the Danish nationwide registries, we could identify all patients with a testicular cancer diagnosis in Denmark, and very few were lost to follow-up as we had access to a nationwide electronic healthcare system. Uniquely, we therefore could assess prognostic factors in a truly unselected population-based cohort with adequate follow-up.

You mentioned several ways the risk factors you identified can be useful. What are they?

Wagner: First, the identified prognostic factors enable providers and patients to make more informed decisions about post-orchiectomy management. Second, our findings provide evidence-based recommendation on risk stratification and could be incorporated into clinical guidelines.

Finally, our findings can be used in future studies investigating risk-adapted follow-up and treatment strategies, which potentially could lead to a less intense follow-up of patients with low risk of relapse, reducing morbidity and cost for the patients and healthcare system.

What did your study find about the strength of hilar soft tissue invasion as a predictor of relapse?

Wagner: The testicular hilum consists of rete testis and hilar soft tissue and has been shown to be the predominant pathway of extra-testicular tumor spread. Yet, its significance as a predictor of relapse has not been properly addressed, since previous studies uniformly lacked data on hilar soft tissue invasion.

In line with other studies, we found rete testis invasion prognostic for relapse, but our findings show that hilar soft tissue invasion is a much stronger predictor, reflecting the more advanced tumor spread into the testicular hilum.

What did you find about the prognostic significance of tumor size?

Wagner: In line with numerous studies, we found tumor size to be significantly associated with increased risk of relapse in the univariable analyses. However, the prognostic significance of tumor size was superseded by including information on pre-orchiectomy levels of LDH and β-hCG in the multivariable analyses.

Accurate assessment of tumor size in seminomas is challenged by multifocality, intertubular growth, and fibrotic areas not visible on macroscopic examination, potentially leading to under- and overestimation of tumor size. To the contrary, analysis of serum tumor markers is objective and seems to be a more reliable measurement of tumor burden and risk of relapse.

Potential novel serum tumor markers are being evaluated to further improve relapse prediction. Can you tell us about one of these potential markers?

Wagner: Increasing evidence shows that novel microRNAs have prognostic relevance in testicular cancer. However, use of microRNAs is currently not robustly validated for routine clinical application.

Furthermore, current data indicate that these biomarkers are most promising in early detection of relapse rather than improving relapse prediction. In future studies, we will try to clarify whether microRNAs can be an important supplement to our prognostic model.

Read the study here.