Computational pathology identifies a low B-cell content in the tumour microenvironment as a predictor of adverse outcome in patients with classic Hodgkin lymphoma treated with ABVD.
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AIMS: The prognostic impact of B lymphocytes surrounding Hodgkin and Reed Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL) and pathogenic variants in genes associated with apoptosis regulation remains undefined. METHODS: We have quantified the proportion of B lymphocytes in tumour microenvironment (TME) in 220 diagnostic slides from 110 cHL patients applying computational pathology (CP) and sequenced cases using a targeted panel including 47 genes recurrently mutated in mature B-cell neoplasms. Kaplan-Meier estimators and multivariate Cox regression on overall survival (OS) and progression-free survival (PFS) were assessed following the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines. RESULTS: The mean percentage of B lymphocytes was 45.1 (SD: 24.8). Genes recurrently affected by nonsynonymous somatic mutations in 25% or more of patients included EP300, NOTCH and ABL1. A lower number of mutations were discovered in Epstein-Barr virus-positive cHL (21.1% vs 78.8%) reinforcing the notion that viral infection could functionally replace the need for genomic aberrations. Classic Hodgkin lymphoma (cHL) patients that jointly presented a reduction in the number of B lymphocytes in TME (<8%) and the absence of mutations in apoptosis-associated genes (ABL1, BIRC3, CASP8 and FAS) presented a lower OS (mean OS: 31.5 months, 95% CI: 0 to 69.7 months) in comparison with patients without this event (mean OS: 84.7 months, 95% CI: 61.9 to 107.5 months) (p=0.01). This high-risk cHL subgroup also presented a significantly lower PFS (mean PFS: 8.5 months, 95% CI: 7.5 to 9.5 months) in comparison with B-cell-enriched or apoptosis-mutated cHL (mean PFS: 55.2 months; 95% CI: 42.4 to 68 months) (p<0.001). CONCLUSIONS: This study expands previous data on the value of CP in cHL, and specifically, the distribution of B cells, identifying patients with an increased risk of treatment failure and progression. Furthermore, immune escape by apoptosis dysregulation during clonal selection occurring in germinal centres constitutes a landmark of cHL. These results could be the basis for further development of targeted therapies directed against apoptosis modulators in cHL.