This lymph node from a 77-year-old woman with suspected metastatic tonsil cancer showed a diffuse proliferation (panel A: hematoxylin and eosin [H&E] stain, original magnification ×100) of small- to medium-sized mature lymphoid cells with scant cytoplasm (panel B: Giemsa stain, original magnification ×400), intermixed with prolymphocytes and paraimmunoblasts (panel B inset: Giemsa stain, original magnification ×640) in proliferation centers. Areas of coagulation necrosis (panel C: H&E stain, original magnification ×100) contained cells with eosinophilic nuclear inclusions intermixed with debris and granulocytes (panel D: H&E stain, original magnification ×800). The lymphoid cells expressed CD20, CD5, LEF1, and, focally, CD23, consistent with a diagnosis of small lymphocytic leukemia (SLL); showed increased proliferation (panel E: MIB1 stain, original magnification ×200); showed strong positivity for p53 (panel F: P53 stain, original magnification ×200) with confirmed TP53 mutation; and interspersed Epstein-Barr virus (EBV)⁺ and LMP1⁺ cells (panel G: EBV-encoded small RNAs in situ hybridization, original magnification ×100). The nuclear inclusions in the necrosis were positive for herpes simplex virus (HSV) (panel H: HSV I and II stain, original magnification ×200).

This case highlights the propensity for local reactivation of latent viral infections in the background of chronic lymphocytic leukemia (CLL)/SLL, due to immune dysregulation even in untreated patients. Neoplastic B cells in CLL act as HSV antigen-presenting cells and are readily infected. HSV lymphadenitis is an exceedingly rare finding, but characteristically shows rapid lymph node enlargement and is an important differential diagnosis for Richter transformation, recommending a low threshold for HSV staining in the setting of necrosis.