Reed-Sternberg cell

**Morphology:** Large cell with abundant cytoplasm, a bilobed or two-nucleus appearance (mirror-image), and large, inclusion-like eosinophilic nucleoli surrounded by a clear halo ("owl's eyes"). Rare in the background of a mostly reactive infiltrate (lymphocytes, eosinophils, plasma cells, histiocytes, fibroblasts), so only ~1% of the tumor mass is neoplastic.

**Origin:** Derived from germinal center (or post-germinal center) B cells. They have often lost much of the B-cell program (usually CD20−, CD45−, with weak or absent Ig expression) despite clonal Ig gene rearrangement.

**Immunophenotype (classic HL):** CD15+, CD30+, PAX5 weak+ (dim), MUM1+, CD45−, usually CD20−/weak, EBV LMP1 in a subset. Nodular lymphocyte-predominant HL instead has "popcorn" (LP) cells: CD20+, CD15−, CD30−, BCL6+, OCT2+.

**Pathophysiology:** Constitutive NF-κB activation (e.g., REL amplification, mutations in NFKBIA/TNFAIP3, or EBV LMP1 signaling), JAK-STAT activation (9p24 amplification with PD-L1/PD-L2 overexpression). The cells secrete cytokines (IL-5 → eosinophilia; IL-13/IL-6; TGF-β → fibrosis; IL-1/TNF/IL-6 → B symptoms). A neoplastic cell recruits and depends on the reactive microenvironment.

**Clinical associations:** - Bimodal age distribution (young adults and >55 years); contiguous spread; typically presents with painless cervical/supraclavicular/mediastinal lymphadenopathy. - B symptoms (fever, night sweats, weight loss), pruritus, Pel-Ebstein fever, alcohol-induced lymph node pain. - EBV association (especially mixed cellularity); HIV. - Subtypes: Nodular sclerosis (most common; lacunar cells, collagen bands; young women; mediastinal mass), mixed cellularity (classic RS cells, EBV+), lymphocyte-rich (good prognosis), lymphocyte-depleted (worst prognosis, older/HIV). - Dx: excisional lymph node biopsy; staging with PET/CT (Ann Arbor/Lugano). - Treatment: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) ± radiation; brentuximab vedotin (anti-CD30) and PD-1 inhibitors (nivolumab, pembrolizumab) for advanced or relapsed disease. Know toxicities: doxorubicin → dilated cardiomyopathy; bleomycin → pulmonary fibrosis; vinblastine → myelosuppression; late effects include secondary malignancies (AML, breast, lung) and hypothyroidism after neck/chest radiation. - Prognosis: Excellent overall (>85–90% cure in early stage).

**Pearls/Distractors:** RS-like cells can be seen in infectious mononucleosis (EBV), non-Hodgkin lymphomas (e.g., ALCL, diffuse large B-cell), and some solid tumors, so they are characteristic but not absolutely specific; the appropriate background and immunophenotype are required for diagnosis.