Hodgkin Lymphoma: Pathogenesis and the Role of Reed-Sternberg Cells
What is Hodgkin Lymphoma?
Hodgkin lymphoma is a type of lymphoid neoplasm. That means it’s a cancer that starts in cells of the lymphatic system—a part of the immune system. It typically begins in a single lymph node or a group of lymph nodes and then spreads to nearby (contiguous) lymphoid tissues.
There are two main types:
Classical Hodgkin Lymphoma (CHL) – makes up about 95% of cases.
Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) – accounts for the remaining 5%.
It was first described in 1832 by British physician Thomas Hodgkin. That’s why the disease carries his name.
Hodgkin lymphoma is slightly more common in men. CHL shows a bimodal age distribution: one peak between 15–35 years and another in older adults. NLPHL generally affects people between 30–50 years.
What are the risk factors for developing Hodgkin Lymphoma?
Prior infection with Epstein-Barr virus (EBV), especially those who had infectious mononucleosis.
Specific HLA subtypes, particularly HLA-B18.
Conditions with altered immunity or autoimmune diseases like rheumatoid arthritis.
It also accounts for around 7% of cancers seen in people with ataxia-telangiectasia.
The tumor cell is known as the Reed-Sternberg (RS) cell, named after Dorothy Reed and Carl Sternberg, who described this unusual cell in the early 1900s.
Describe a Reed-Sternberg cell ?
Very large, over 50 microns in diameter.
Has abundant eosinophilic cytoplasm.
Typically binucleated with mirror-image nuclei.
Prominent, eosinophilic nucleoli that give it the classic “owl’s eye” appearance.
What is the origin of the Reed-Sternberg cell?
RS cells are derived from germinal center B cells. These are the same B cells responsible for antibody production. However, in Hodgkin lymphoma, only a few of these neoplastic cells are found within a lymph node, and they are surrounded by a prominent background of mixed inflammatory cells.
What triggers the transformation into a Reed-Sternberg cell?
It begins with:
Clonal immunoglobulin (Ig) heavy chain gene rearrangement, and
Somatic hypermutation in germinal center B cells.
Although they originate from B cells, RS cells lose the expression of typical B-cell markers due to extensive epigenetic reprogramming. Instead, they express CD15 and CD30.
What is the key molecular event in Hodgkin Lymphoma pathogenesis?
The activation of the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) plays a central role.
This can happen through:
EBV-positive cases: EBV expresses LMP1 (latent membrane protein 1), which activates NF-κB.
EBV-negative cases: Mutations in inhibitors of NF-κB (like A20) lead to its activation.
What happens after NF-κB activation in RS cells?
NF-κB moves into the nucleus and triggers:
Inflammatory gene expression (cytokines, chemokines),
Upregulation of anti-apoptotic proteins, helping RS cells survive,
Recruitment of immune cells, leading to inflammation.
Why is there such a strong inflammatory background in Hodgkin Lymphoma?
RS cells produce various cytokines and chemokines, including:
M-CSF: Activates macrophages.
IL-13: Works via autocrine and paracrine signaling to promote RS cell survival.
IL-5 and eotaxin: Attract eosinophils, causing tissue eosinophilia.
TNF and basic FGF: Promote fibrosis.
Also, RS cells express CD30, which binds to its ligand on eosinophils—further enhancing RS cell survival.
How do RS cells suppress the immune system?
They secrete IL-10, which suppresses the Th1 response and promotes Th2 response.
They promote T-regulatory cells via Galectin-1, helping the tumor escape immune detection.
RS cells express CD40, which interacts with CD40 ligand on Th2 cells, triggering survival signals.
Importantly, RS cells express PD-L1 (programmed death ligand-1), which binds to PD-1 on cytotoxic T cells, leading to immune evasion.
summary of Hodgkin Lymphoma pathogenesis
Ig gene rearrangement and somatic hypermutation in germinal center B cells.
Transformation into Reed-Sternberg cells, with loss of B-cell identity and expression of CD15/CD30.
NF-κB activation leads to survival, inflammation, and immune evasion.
Intense crosstalk between RS cells and the reactive inflammatory cells shapes the disease environment.
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