Clinical and molecular characterization of ovarian carcinoma displaying isolated lymph node relapse

Abstract Background Disease relapse is the primary cause death from ovarian carcinoma (OC). Isolated lymph node relapse (ILNR) is a rare pattern of OC recurrence, with a reported median post-relapse survival (PRS) of 2.5-4 years. To date, investigations have not compared ILNR OC directly to a matched extra-nodal relapse (ENR) cohort or performed molecular characterization of cases that subsequently experience ILNR. Objective(s) Here we seek to compare the clinical outcome, tumour-infiltrating lymphocyte burden and frequency of known prognostic genomic events in ILNR OC versus ENR OC. Study design 49 ILNR OC patients were identified and matched to 49 ENR cases using the Edinburgh Ovarian Cancer Database, from which the clinical data for identified patients were retrieved. Matching criteria were disease stage, histological subtype and grade, extent of residual disease following surgical debulking and age at diagnosis. Clinicopathological factors and survival data were compared between the ILNR and ENR cohorts. Genomic characterization of tumor material from diagnosis was performed using panel-based high throughput sequencing and tumor-infiltrating T-cell burden was assessed using immunohistochemistry for CD3+ and CD8+ cells. Results ILNR cases demonstrated significantly prolonged PRS and overall survival (OS) versus ENR upon multivariable analysis (HR multi =0.52[0.33-0.84] and 0.51[0.31-0.84]). Diagnostic specimens from high grade serous (HGS) OCs that subsequently displayed ILNR harboured significantly greater CD3+ and CD8+ cell infiltration compared to ENR cases (P=0.001 and P=0.009, Bonferroni-adjusted P=0.003 and 0.019). ILNR HGS OC cases did not show marked enrichment or depletion of cases with BRCA1/2 mutation or CCNE1 copy number gain when compared to their ENR counterparts (24.4% vs 19.4% and 18.2% vs 22.6%, P=0.865 and P=0.900). Conclusion(s) ILNR OC represents a distinct clinical entity with favorable outcome compared to ENR. There was no clear enrichment or depletion of BRCA1/2 mutation or CCNE1 gain in the ILNR OC cohort compared with ENR cases, suggesting that these known prognostic genomically-defined subtypes of disease do not display markedly altered propensity for ILNR. Diagnostic tumor material from ILNR patients demonstrated greater CD3+ and CD8+ cell infiltration, indicating stronger tumor engagement by T-cell populations, which may contribute to the more indolent disease course of ILNR.