The prognostic value of tumor-stroma ratio and a newly developed computer-aided quantitative analysis of routine H&E slides in high-grade serous ovarian cancer

Abstract

Abstract Introduction: Tumor-stroma ratio (TSR) is prognostic in multiple cancers, while its role in high-grade serous ovarian cancer (HGSOC) remains unclear. Despite the prognostic insight gained from genetic profiles and tumor-infiltrating lymphocytes (TILs), the prognostic use of histology slides remains limited, while it enables the identification of tumor characteristics via computational pathology reducing scoring time and costs. To address this, this study aimed to assess TSR's prognostic role in HGSOC and its association with TILs. We additionally developed an algorithm, Ovarian-TSR (OTSR), using deep learning for TSR scoring, comparing it to manual scoring. Methods: 340 patients with advanced-stage who underwent primary debulking surgery (PDS) or neo-adjuvant chemotherapy (NACT) with interval debulking (IDS). TSR was assessed in both the most invasive (MI) and whole tumor (WT) regions through manual scoring by pathologists and quantification using OTSR. Patients were categorized as stroma-rich (≥ 50% stroma) or stroma-poor (< 50%). TILs were evaluated via immunohistochemical staining. Results: In PDS, stroma-rich tumors were significantly associated with a more frequent papillary growth pattern (60% vs 34%), while In NACT stroma-rich tumors had a lower Tumor Regression Grading (TRG 4&5, 21% vs 57%) and increased pleural metastasis (25% vs 16%). Stroma-rich patients had significantly shorter overall and progression-free survival compared to stroma-poor (31 versus 45 months; P < 0.0001, and 15 versus 17 months; P = 0.0008, respectively). Combining stromal percentage and TILs led to three distinct survival groups with good (stroma-poor, high TIL), medium (stroma-rich, high TIL, or; stroma-poor, Low TIL), and poor(stroma-rich, low TIL) survival. These survival groups remained significant in CD8 and CD103 in multivariable analysis (Hazard ratio (HR) = 1.42, 95% Confidence-interval (CI) = 1.02–1.99; HR = 1.49, 95% CI = 1.01–2.18, and HR = 1.48, 95% CI = 1.05–2.08; HR = 2.24, 95% CI = 1.55–3.23, respectively). OTSR was able to recapitulate these results and demonstrated high concordance with expert pathologists (correlation = 0.83). Conclusions: TSR is an independent prognostic factor for survival assessment in HGSOC. Stroma-rich tumors have a worse prognosis and, in the case of NACT, a higher likelihood of pleural metastasis. OTSR provides a cost and time-efficient way of determining TSR with high reproducibility and reduced inter-observer variability.