Hodgkin Reed-Sternberg Cells of Classic Hodgkin Lymphoma: Morphology, Phenotype, Genotype, and Cell of Origin

Classic Hodgkin lymphoma (cHL) is a distinctive B-cell malignancy defined by the presence of scarce but pathobiologically dominant Hodgkin Reed-Sternberg (HRS) cells within an inflammatory tumor microenvironment (TME). Although representing less than 10% of total tumor cellularity, HRS cells shape the TME by recruiting and functionally polarizing immune and stromal elements through cytokine- and chemokine-mediated signaling. Morphologically, HRS cells are large, atypical, often binucleated or multinucleated cells with prominent eosinophilic nucleoli and abundant cytoplasm, giving rise to the classic “owl’s eye” appearance. Distinct morphological variants—including lacunar, mummified, mononuclear, and anaplastic forms—contribute to the histopathologic diversity across cHL subtypes such as nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted disease. The immunophenotype of HRS cells is equally characteristic, with strong and uniform CD30 expression, frequent CD15 positivity, reduced expression of B-cell markers (CD20, CD79A/B), and partial retention of PAX5, reflecting profound lineage dysregulation. Aberrant expression of activation markers and immune-evasion molecules, including PD-L1 driven by recurrent 9p24.1 amplification, underscores their capacity for immune escape. Genetically, HRS cells display alterations affecting NF-κB, JAK/STAT, and PI3K/AKT pathways, facilitated by somatic mutations, chromosomal gains, and epigenetic remodeling that silence B-cell-defining genes. Despite reprogramming, clonality and somatic hypermutation patterns confirm their origin from germinal center B-cells, even in EBV-associated cases. Collectively, the morphology, phenotype, and genotype of HRS cells reveal a complex pathogenic network in which intrinsic oncogenic pathways and extrinsic TME interactions co-operate to sustain malignant transformation. Understanding these integrated mechanisms provides a biological foundation for current therapeutic strategies.