Digital pathology does not improve the prognostic performance of Ki-67 in a large cohort of penile cancer.

Authors

Jan Hrudka, Radoslav Matěj, Michal Grus, Anežka Marková, Zuzana Prouzová, Jan Hojný, Michaela Kendall Bártů, David Čapka, Nicolette Zavillová, Květoslava Michalová, Jiří Soukup, Miroslav Záleský, Petr Waldauf

Published in

The journal of pathology. Clinical research. Volume 12. Issue 6.

Abstract

Penile squamous cell carcinoma (pSCC) is a rare but prognostically unfavourable genitourinary malignancy in which the search for reliable prognostic biomarkers has intensified in recent years. The prognostic role of Ki-67 in pSCC remains uncertain. This study aimed to assess the prognostic value of Ki-67 in pSCC using digital image analysis (HALO) and assessment by two pathologists, to compare their prognostic performance and interobserver agreement, and to explore associations with clinicopathological, immune and molecular features. In a large retrospective cohort of 224 invasive pSCCs, Ki-67 was quantified by digital image analysis and independently estimated by two senior pathologists. Optimal cut-points (67%, 25%, and 75%) were derived using maximally selected rank statistics. Ki-67-high status was significantly associated with 5-year overall survival with HALO in univariate analysis [hazard ratio (HR) = 1.62, 95% CI 1.03-2.55, p = 0.037], and for HALO (HR 1.63, 95% CI 1.03-2.56, p = 0.035) and Pathologist 2 (HR 1.63, 95% CI 1.02-2.58, p = 0.04) after adjustment for age. When assessed by Pathologist 1, high Ki-67 expression (≥25%) was significantly associated with shorter cancer-specific survival. Further covariate-adjusted analyses showed variable results across assessment methods, with the most consistent prognostic associations observed for Pathologist 2. Penalized spline analysis demonstrated a gradual, approximately linear increase in mortality risk with increasing Ki-67 values across all three raters, without identifying a clear prognostic threshold. Interobserver agreement was moderate to substantial (Cohen's kappa 0.42-0.61). High Ki-67 was associated with high grade, p16, and HPV positivity by quantitative PCR (qPCR) in all three raters. Exploratory analyses suggested an inverse association between Ki-67 and B-cell/plasma-cell infiltration. The prognostic value of Ki-67 in pSCC was non-robust and depended on the assessment method and chosen cut-off. Digital image analysis did not significantly outperform manual scoring or improve interobserver agreement. Finally, the inverse association between Ki-67 and B-cell/plasma-cell infiltration represents a potentially novel observation warranting further validation.

PMID:
43006143
Bibliographic data and abstract were imported from PubMed on 10 Nov 2026.

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