What You Need to Know About Hodgkin Lymphoma: Types, Symptoms, and Key Insights
Understanding Hodgkin Lymphoma: A Unique Form of Blood Cancer
Hodgkin lymphoma (HL) stands out as a distinct subtype of lymphatic system cancer, accounting for approximately 10% to 20% of all diagnosed lymphomas worldwide. Unlike other blood cancers, HL is characterized by the presence of only a small number of malignant cells within affected lymph nodes—specifically, Reed-Sternberg (R-S) cells and their variants. These abnormal cells are surrounded by a dense microenvironment of non-cancerous inflammatory and immune cells, which play a crucial role in disease progression and clinical presentation.
The Two Main Categories of Hodgkin Lymphoma
There are two primary forms of HL: Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL) and Classical Hodgkin Lymphoma (CHL). While both share certain histological features—such as the presence of large atypical cells and reactive background infiltrates—they differ significantly in terms of clinical behavior, cellular morphology, immunophenotype, genetic markers, and patient outcomes. These differences guide diagnosis, treatment strategies, and long-term monitoring.
Classical Hodgkin Lymphoma: Subtypes and Clinical Features
CHL makes up about 95% of all Hodgkin lymphoma cases and is further divided into four distinct subtypes based on tissue architecture, cell composition, and disease progression patterns:
1. Nodular Sclerosis Hodgkin Lymphoma (NSHL)
This is the most common subtype, particularly prevalent among young adults—especially females. It frequently affects cervical, supraclavicular, and mediastinal lymph nodes. In many patients, an enlarged mediastinum detected on imaging may be the first sign of disease. Microscopically, NSHL is defined by broad bands of collagen fibrosis that divide the lymph node into nodules. Characteristic "lacunar cells"—a variant of Reed-Sternberg cells—are commonly observed. As the disease advances, involvement of the spleen, liver, or bone marrow can occur, often preserving the nodular growth pattern. Importantly, this subtype does not transform into other CHL variants over time.
2. Mixed Cellularity Hodgkin Lymphoma (MCHL)
MCHL is more frequently diagnosed in males and tends to present with advanced-stage disease and systemic symptoms such as fever, night sweats, and weight loss. The lymph node architecture is partially or completely destroyed, with tumor cells scattered among a diverse mix of inflammatory cells including eosinophils, plasma cells, and histiocytes. Notably, Epstein-Barr virus (EBV) plays a significant role here—around 70% of R-S cells in MCHL test positive for EBV DNA. This subtype has the potential to evolve into the more aggressive lymphocyte-depleted form if left untreated or poorly managed.
3. Lymphocyte-Rich Classical Hodgkin Lymphoma (LRCHL)
A rarer form, LRCHL typically presents with early-stage disease and carries a favorable prognosis. The pathological hallmark is a high proportion of normal-appearing lymphocytes with relatively few Reed-Sternberg cells. Approximately 40% of cases show evidence of prior EBV infection. Due to its indolent nature, patients often experience fewer systemic symptoms and respond well to standard therapies.
4. Lymphocyte-Depleted Hodgkin Lymphoma (LDHL)
Representing less than 5% of all CHL diagnoses, LDHL is the rarest and most aggressive subtype. It predominantly affects older individuals and is usually diagnosed at an advanced stage. Patients often suffer from pronounced B-symptoms and have poor outcomes due to limited treatment responsiveness. Histologically, there's a marked scarcity of lymphocytes alongside numerous pleomorphic R-S cells or their bizarre variants. This subtype is strongly associated with immunocompromised states, including HIV infection.
Immunophenotypic Profile of Classical Hodgkin Lymphoma Cells
The malignant Reed-Sternberg cells in CHL exhibit a consistent immunophenotype across all subtypes, despite their morphological diversity. These cells are uniformly negative for CD45 (a leukocyte common antigen), but strongly positive for CD30—present in nearly 100% of cases—and CD15, expressed in about 75%. Their staining pattern typically shows dot-like positivity in the perinuclear region, with or without membranous expression. Non-neoplastic histiocytes and granulocytes serve as useful internal controls during immunohistochemical analysis.
Additional Markers and Molecular Signatures
R-S cells also commonly express HLA-DR, CD25 (IL-2 receptor), CD40, CD138, peanut agglutinin, and fascin—molecules involved in immune activation and cell adhesion. However, they lack expression of germinal center markers like BCL6, immunoglobulin J-chain, and epithelial membrane antigen (EMA). Latent Membrane Protein 1 (LMP1) from EBV may be detected in some subtypes, particularly in mixed cellularity and immunodeficient-related cases, though its presence varies depending on geographic region and patient demographics.
Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Distinct Entity
Comprising roughly 5% of all HL cases, NLPHL primarily affects middle-aged and younger men. It commonly manifests as painless swelling in neck or axillary lymph nodes, with minimal risk of mediastinal or bone marrow involvement—making it clinically distinct from classical forms. Although relapses are possible, the overall prognosis remains excellent, with high survival rates even after recurrence.
Pathological and Immunological Characteristics
Under the microscope, NLPHL reveals nodular patterns filled with small B-cells and histiocytes, creating a "fuzzy" appearance. The defining malignant cells—known as "popcorn cells" or lymphocytic and histiocytic (L&H) cells—are large and highly irregular. Unlike R-S cells, these tumor cells retain typical B-cell markers: they are positive for CD20, CD79a, CD45, and BCL6, indicating origin from germinal center B cells. Most cases also express J-chain and CD75, while EMA is positive in around half of the patients. Immunoglobulin light and heavy chains are often strongly expressed, confirming clonal B-cell derivation.
Key Differences from Classical HL
Crucially, L&H cells in NLPHL do not express CD15 and rarely react with CD30 antibodies. Additionally, there is no association with Epstein-Barr virus—setting it apart from many CHL subtypes. This unique profile influences therapeutic decisions, as CD20-targeted treatments like rituximab can be effectively used in NLPHL, unlike in classical HL where such therapies are generally ineffective.