Precision Immunopathology in Classic Hodgkin Lymphoma: From Conventional Pathology to Integrated Biologic Profiling

Classic Hodgkin lymphoma (cHL) is histologically defined by rare Hodgkin and Reed–Sternberg (HRS) cells embedded within an extensive, biologically active immune microenvironment that HRS cells actively recruit and reprogram to sustain their own survival. For decades, diagnosis has relied on morphology and a limited immunohistochemical panel (CD30, CD15, PAX5, CD20, EBER), an approach that confirms disease identity but provides little insight into the immune ecosystem that governs prognosis and treatment response. Over the past fifteen years, discovery of near-universal 9p24.1/CD274-PDCD1LG2-JAK2 copy-number alterations, CIITA gene fusions, B2M mutations, and NF-κB/JAK-STAT pathway activation has progressively reframed cHL—conceptually rather than through a formal reclassification—as a genetically driven disorder of immune evasion. In parallel, multiplex immunohistochemistry, imaging mass cytometry, digital spatial profiling, spatial transcriptomics, single-cell sequencing, whole-slide digital pathology, and machine-learning algorithms now allow the tumor-immune ecosystem to be mapped at unprecedented resolution. This convergence is giving rise to what we term “precision immunopathology”: an overarching conceptual framework, rather than a formal diagnostic category, that combines morphology with immune, molecular, spatial, and computational data and that, once prospectively validated, may refine prognostic stratification, prediction of benefit from PD-1 blockade and other immunotherapies, and non-invasive disease monitoring through circulating tumor DNA. At present, beyond the standard diagnostic panel, no tissue biomarker is required to select patients for PD-1 blockade or CD30-directed therapy. This review summarizes the evolution from conventional to precision immunopathology in cHL, discusses the technologies enabling this transition, grades each candidate biomarker and assay by level of evidence and clinical readiness (routine, clinically validated but non-routine, or investigational), incorporates the move of PD-1 blockade into first-line therapy (SWOG S1826) and the BrECADD regimen (HD21), proposes a minimum dataset for an integrated precision immunopathology report, and discusses the practical barriers—tissue availability, cost, turnaround time, standardization, and regulatory validation—that must be overcome before an ecosystem-centered diagnostic model can be translated into routine hematopathology practice.