Ki67 and LSD1 Expression in Testicular Germ Cell Tumors Is Not Associated with Patient Outcome: Investigation Using a Digital Pathology Algorithm.

Beatriz Chaves Lourenço,Joaquina Maurício,Vera Miranda-Gonçalves,Mariana Cantante,João Lobo,Carmen Jerónimo,Isaac Braga,Rita Guimarães,Catarina Guimarães-Teixeira,Paula Lopes,Bianca C T Flores,Rui Henrique

doi:10.3390/life12020264

Beatriz Chaves Lourenço, Joaquina Maurício + Show 10 more

Open Access

https://doi.org/10.3390/life12020264

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Abstract

TGCTs represent a model of curable disease afflicting especially young men. Defining tumor biological characteristics is crucial to increase current knowledge and tailor the best clinical management. Ki67, a potential prognostic marker, still exhibits heterogenous associations with patient outcomes, thus bringing the need of corroboration with larger cohorts in clinical practice. LSD1, an epigenetic enzyme, represents a future target for epigenetic drugs that may lower treatment-associated morbidity. This study aimed to assess Ki67/LSD1 immunoexpression across all TGCT histological subtypes and correlate it with clinicopathological features. Results were compared with an in silico analysis of the TCGA database. Immunohistochemistry for Ki67 and LSD1 was carried out in a cohort of 157 TGCT tumor samples and assessed using a digital pathology algorithm. LSD1 protein expression was explored in TGCT cell lines, including ATRA-differentiated clones. There was a significant positive correlation between Ki67 and LSD1 H-scores (rs = 0.182, p = 0.037). Ki67 positivity percentage and H-score were significantly higher in non-seminomas (p = 0.0316 and 0.0113, respectively). Expression was not significantly different according to clinicopathological features, including stage, IGCCCG prognosis-based system, or relapse/progression-free survival, which was corroborated by in silico analysis. Our study, making use of digital image analysis, does not confirm the utility of these biomarkers in a daily practice cohort. Although not affecting patient outcome in our cohort, LSD1 is expressed overall in TGCTs, suggesting sensitivity to LSD1 inhibitors.

Highlights

Rare, representing only 1% of male malignancies worldwide, testicular germ cell tumors (TGCTs) are the most common solid testicular neoplasms (95%) in men between the ages of 20 and 34 years, presenting a rising global incidence over the past decades [1,2].In particular, type II TGCTs, the most frequent testicular neoplasms, exhibit a striking complex and heterogenous histology
TGCTs represent a model of curable disease, with most patients presenting with stage I disease, but approximately 75% of these are cured with orchiectomy alone, without the need for subsequent adjuvant treatments [4,8,9]
We used a digital imaging analysis system for IHC analysis in TGCTs, increasing the robustness of data acquired regarding the clinical impact of such biomarkers compared to previous investigations

Summary

Introduction

Type II TGCTs, the most frequent testicular neoplasms, exhibit a striking complex and heterogenous histology Their common precursor is germ cell neoplasia in situ (GCNIS), and they are divided into seminomas (SE) and non-seminomas (NS). TGCTs represent a model of curable disease, with most patients presenting with stage I disease (around 70%), but approximately 75% of these are cured with orchiectomy alone, without the need for subsequent adjuvant treatments [4,8,9]. For those who require systemic therapy, TGCTs present extreme sensitivity to cisplatin-based chemotherapy, due to their unique molecular background [3,10]. Inguinal orchiectomy followed by close surveillance may not be enough, implying the need for further treatments, which leads to higher morbidity [9]

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