PreprintCC BY-NC-NDbioRxiv
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
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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BibTeX
@misc{rosa2026morphologic,
title = {{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}},
author = {L. Rincon de la Rosa and N. Barillot and I. Hernandez-Verdin and R. Velasco and B. Mathon and S. Eimer and J. R. Vignes and A. Rousseau and J. Paillassa and G. Ahle and F. Lerintiu and E. Uro-Coste and L. Oberic and E. Tabouret and R. Appay and G. Gauchotte and L. Taillandier and J.-P. Marolleau and C. Adam and R. Ursu and S. Cuzzubbo and A. Schmitt and L. Nichelli and A. Pons-Escoda and F. Charlotte and F. Davi and M. Le Garff-Tavernier and S. Choquet and C. Soussain and N. Vidal and E. Gonzalez-Barca and F. Climent and P. Lopez and F. Drieux and E.-L. Veresezan and M. Heming and G. Meyer zu Hörste and O. Grauer and F. Jardin and K. Mokhtari and C. Houillier and Hoang-Xua},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.31.748241},
url = {https://www.biorxiv.org/content/10.64898/2026.08.31.748241v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - 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
AU - L. Rincon de la Rosa
AU - N. Barillot
AU - I. Hernandez-Verdin
AU - R. Velasco
AU - B. Mathon
AU - S. Eimer
AU - J. R. Vignes
AU - A. Rousseau
AU - J. Paillassa
AU - G. Ahle
AU - F. Lerintiu
AU - E. Uro-Coste
AU - L. Oberic
AU - E. Tabouret
AU - R. Appay
AU - G. Gauchotte
AU - L. Taillandier
AU - J.-P. Marolleau
AU - C. Adam
AU - R. Ursu
AU - S. Cuzzubbo
AU - A. Schmitt
AU - L. Nichelli
AU - A. Pons-Escoda
AU - F. Charlotte
AU - F. Davi
AU - M. Le Garff-Tavernier
AU - S. Choquet
AU - C. Soussain
AU - N. Vidal
AU - E. Gonzalez-Barca
AU - F. Climent
AU - P. Lopez
AU - F. Drieux
AU - E.-L. Veresezan
AU - M. Heming
AU - G. Meyer zu Hörste
AU - O. Grauer
AU - F. Jardin
AU - K. Mokhtari
AU - C. Houillier
AU - Hoang-Xua
PY - 2026
DA - 2026/08/31
PB - bioRxiv
DO - 10.64898/2026.08.31.748241
UR - https://www.biorxiv.org/content/10.64898/2026.08.31.748241v1
AB - 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.
ER -