Morphologic intratumoral heterogeneity from routine whole-slide histopathology is prognostic for survival in primary central nervous system lymphoma: development in the LOC Network and international external validation

Rincon de la Rosa, L.; Barillot, N.; Hernandez-Verdin, I.; Velasco, R.; Mathon, B.; Eimer, S.; Vignes, J. R.; Rousseau, A.; Paillassa, J.; Ahle, G.; Lerintiu, F.; Uro-Coste, E.; Oberic, L.; Tabouret, E.; Appay, R.; Gauchotte, G.; Taillandier, L.; Marolleau, J.-P.; Adam, C.; Ursu, R.; Cuzzubbo, S.; Schmitt, A.; Nichelli, L.; Pons-Escoda, A.; Charlotte, F.; Davi, F.; Le Garff-Tavernier, M.; Choquet, S.; Soussain, C.; Vidal, N.; Gonzalez-Barca, E.; Climent, F.; Lopez, P.; Drieux, F.; Veresezan, E.-L.; Heming, M.; Meyer zu Hörste, G.; Grauer, O.; Jardin, F.; Mokhtari, K.; Houillier, C.; Hoang-Xua

doi:10.64898/2026.08.31.748241

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bioRxiv · 10.64898/2026.08.31.748241

Morphologic intratumoral heterogeneity from routine whole-slide histopathology is prognostic for survival in primary central nervous system lymphoma: development in the LOC Network and international external validation

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Abstract

Background: Clinical scores incompletely capture outcomes in primary central nervous system lymphoma (PCNSL). We quantified morphologic heterogeneity in pretreatment hematoxylin and eosin (H\&E) whole slides. Patients and methods: Three independent cohorts of immunocompetent, HIV- and EBV-negative patients treated recently were analyzed: LOC 2023 (122 slides), phase III BLOCAGE-01 (245 slides; NCT02313389), and external Barcelona (BCN; 41 slides). UNI embeddings, prototype learning, spatial metrics, and elastic-net Cox regression defined ITH-C. Results: Models achieved bootstrap-corrected concordance of 0.797--0.834. Age-, sex-, and KPS-adjusted ITH-C HRs were 1.29 (95\% CI 1.01--1.64), 1.27 (1.07--1.51), and 2.13 (1.35--3.37), respectively. Adding ITH-C increased MSKCC C-index from 0.671 to 0.717, 0.560 to 0.593, and 0.588 to 0.706. Spatial transcriptomics linked ITH-C to immune programs. Conclusions: Routine H\&E encodes prognostic spatial heterogeneity in PCNSL. ITH-C complements clinical scores, supporting prospective risk stratification.

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Rincon de la Rosa, L., Barillot, N., Hernandez-Verdin, I., Velasco, R., Mathon, B., Eimer, S., Vignes, J. R., Rousseau, A., Paillassa, J., Ahle, G., Lerintiu, F., Uro-Coste, E., Oberic, L., Tabouret, E., Appay, R., Gauchotte, G., Taillandier, L., Marolleau, J.-P., Adam, C., Ursu, R., Cuzzubbo, S., Schmitt, A., Nichelli, L., Pons-Escoda, A., Charlotte, F., Davi, F., Le Garff-Tavernier, M., Choquet, S., Soussain, C., Vidal, N., Gonzalez-Barca, E., Climent, F., Lopez, P., Drieux, F., Veresezan, E.-L., Heming, M., Meyer zu Hörste, G., Grauer, O., Jardin, F., Mokhtari, K., Houillier, C., Hoang-Xua. 2026-09-03. Morphologic intratumoral heterogeneity from routine whole-slide histopathology is prognostic for survival in primary central nervous system lymphoma: development in the LOC Network and international external validation. https://doi.org/10.64898/2026.08.31.748241

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