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Short note on RS Cells

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Here is a short note on Reed-Sternberg (RS) cells, based on Robbins' Pathologic Basis of Disease:

Reed-Sternberg (RS) Cells

Definition

RS cells are the pathognomonic neoplastic cells of Hodgkin Lymphoma (HL). Their identification is essential for diagnosis, but they must be seen in an appropriate reactive cellular background to confirm HL.

Morphology

Classic (Diagnostic) RS Cell:
  • Large cell (~45 µm in diameter)
  • Bilobed or multinucleated nucleus
  • Each lobe contains a large, prominent, inclusion-like "owl-eye" nucleolus (5-7 µm - roughly the size of a small lymphocyte)
  • Abundant pale cytoplasm
  • Surrounded by reactive cells: lymphocytes, eosinophils, plasma cells, macrophages
RS cells and variants - A: Classic diagnostic RS cell (owl-eye nucleoli), B: Mononuclear variant, C: Lacunar variant, D: Lymphohistiocytic (popcorn) variant

RS Cell Variants

VariantFeaturesAssociated Subtype
Mononuclear (Hodgkin cell)Single nucleus with large inclusion-like nucleolusMixed cellularity, lymphocyte-rich
Lacunar cellFolded/multilobate nucleus, pale cytoplasm, sits in an empty space (artifact of formalin fixation)Nodular sclerosis
Lymphohistiocytic (L&H / "Popcorn" cell)Multiple in-folded nuclear membranes, small nucleoli, fine chromatin, abundant pale cytoplasmNodular lymphocyte predominant HL

Cell of Origin

RS cells originate from germinal center or post-germinal center B cells, established by clonal IGH gene rearrangements and somatic hypermutation patterns in single isolated RS cells. Despite this B-cell origin, classic RS cells paradoxically fail to express most B-cell genes including immunoglobulin.

Pathogenesis

  • NF-κB activation is the central oncogenic event; it rescues "crippled" germinal center B cells from apoptosis
  • EBV (Epstein-Barr Virus): Present in ~30-70% of cases depending on subtype. EBV-encoded LMP-1 directly activates NF-κB
  • In EBV-negative cases, loss-of-function mutations in IκB or TNFAIP3 activate NF-κB
  • RS cells are aneuploid with frequent gains at chromosome 2p (REL oncogene) and chromosome 9p (PD-L1/PD-L2), the latter helping immune evasion

Immunophenotype

FeatureClassic HL RS cellsNodular LP (Popcorn cells)
CD15+-
CD30+-
CD20-+
CD45-+
EBVVariable (subtype-dependent)-
PAX5Weak +Strong +

Reactive Microenvironment

RS cells secrete cytokines (IL-5, IL-10, M-CSF) and chemokines (eotaxin) that attract a polymorphic reactive infiltrate. The recruited cells (eosinophils, T cells) in turn feed back to activate CD30 and CD40 on RS cells, further upregulating NF-κB. RS cells also express PD-L1 and PD-L2, which suppress cytotoxic T-cell responses and enable immune escape.

Conditions with RS-Like Cells (Must Exclude)

Cells resembling RS cells can be seen in:
  • Infectious mononucleosis
  • Solid tissue cancers (metastatic)
  • Certain non-Hodgkin lymphomas
RS cells are therefore diagnostic of HL only when identified in the correct morphological and immunophenotypic context.
Source: Robbins, Cotran & Kumar - Pathologic Basis of Disease (Robbins Pathology), Chapter 13 - Lymphoid Neoplasms
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