Sex-Specific Differences in Primary CNS Lymphoma

Abstract

Sex-specific differences have been increasingly recognized in many human diseases including brain cancer, namely glioblastoma. Primary CNS lymphoma (PCNSL) is an exceedingly rare type of brain cancer that tends to have a higher incidence and worse outcomes in male patients. Yet, relatively little is known about the reasons that contribute to these observed sex-specific differences. Using a population-representative cohort of patients with PCNSL with dense magnetic resonance (MR) imaging and digital pathology annotation (n = 74), we performed sex-specific cluster and survival analyses to explore possible associations. We found three prognostically relevant clusters for females and two for males, characterized by differences in (i) patient demographics, (ii) tumor-associated immune response, and (iii) MR imaging phenotypes. Upon a multivariable analysis, an enhanced FoxP3+ lymphocyte-driven immune response was associated with a shorter overall survival particularly in female patients (HR 1.65, p = 0.035), while an increased extent of contrast enhancement emerged as an adverse predictor of outcomes in male patients (HR 1.05, p < 0.01). In conclusion, we found divergent prognostic constellations between female and male patients with PCNSL that suggest differential roles of tumor-associated immune response and MR imaging phenotypes. Our results further underline the importance of continued sex-specific analyses in the field of brain cancer.

Keywords: DLBCL; PCNSL; microenvironment; multimodal data; sex-specific analyses.

Figure 1

Population-representative cohort with dense phenotypic annotation. (A) Starting from a population-based cohort (n = 189), we retrieved dense phenotypic annotation for a sub-cohort of patients (n = 74) representative of the underlying population in terms of outcome. The dataset was split into female (n = 41) and male (n = 33) patients for a further sex-specific analysis. (B) The latter was based on clinical and therapeutic data; magnetic resonance imaging data, including tumor segmentations; and digital pathology data, including immune scores. magnification: ×20. (C) The data were integrated using cluster and survival analyses in a sex-specific manner.

Figure 2

Cluster analysis (Euclidean distance, Ward-linked) based on numerical and ordinal variables. (A–D) Female patients. (E–H) Male patients. (A) Cluster analysis of the female dataset results in three clusters that significantly differ in the combination of features, three of which are depicted in (B), such as immune response (CD3+ TILs), age, and contrast enhancement (all p < 0.01, ANOVA). (C) Comparison of the CD45ro+ immune response of two representative female patients. (D) Comparison of the MR imaging features of two representative female patients. (E) Cluster analysis of male patients yields two main clusters. (F) Examples of cluster-defining features include immune response (CD3+ TILs), age, and contrast enhancement (all p < 0.01, ANOVA). (G) Comparison of the CD45ro+ immune response of two representative male patients. (H) Comparison of the MR imaging features of two representative male patients.

Figure 3

Selected Kaplan–Meier survival plots for variables with differential prognostic associations in female (upper row) and male patients (lower row). (A) In female patients, CD45ro+ TIL were associated with a worse survival (mOS 5.3 vs. 18.2 months, p = 0.027). (B) In contrast, there is no significant association in male patients (mOS 37.7 vs. 9.95 months, p = 0.25). (C) In female patients, FoxP3+ TILs are associated with worse survival (mOS 9.6 months vs. mOS not reached, p = 0.049), whereas in males (D) there is no association (mOS 49.6 vs. 11.8 months, p = 0.16). (E) While increased enhancing tumor volume does not affect survival in females (mOS 16.8 vs. 7.1 months, p = 0.23), male patients (F) with an increased contrast enhancement show a non-significant tendency towards worse outcomes (6.92 vs. 37.7 months, p = 0.09). (G) Cluster membership was associated with survival in female patients (mOS 3.9 vs. 18.2 vs. 82.9 months, p = 0.005, (H) but not in male patients (37.7 vs. 11.8 months, p = 0.17).

Figure 4

Spatially heterogeneous immune response in Primary CNS lymphoma (PCNSL). (A) Correlation of intratumoral TIL/TAM counts across multi-sector regions (n = 26). (B) CD3 TIL staining of a large PCNSL specimen. (C) Virtual tissue cores randomly sampled from four sectors annotated in (B) demonstrate significant heterogeneity between immune hot and cold spots. (D) Heatmap of the CD3+ cell density with immune hot and cold spots across the whole slide scan.