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PubMed This is a summary of 26 peer-reviewed journal articles Updated
Oncology

The Biology and Subtypes of Your Lymphoma

At a Glance

Classic Hodgkin lymphoma (cHL) is a unique cancer where rare Reed-Sternberg cells recruit healthy immune cells to protect them. There are four main subtypes—nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted—which all respond to similar, highly effective treatments.

While most cancers are a solid mass of malignant cells, classic Hodgkin Lymphoma (cHL) is unique. In this disease, the actual cancer cells—known as Hodgkin and Reed-Sternberg (HRS) cells—usually make up less than 5% of the total tumor [1][2]. The remaining 95% is a complex “neighborhood” of normal immune cells that have been recruited by the cancer to help it grow and hide [3][4].

The Role of HRS Cells and the Microenvironment

The HRS cells are the “brains” of the operation. They are derived from B cells (a type of white blood cell), but they have lost their original identity [5][6]. These cells cannot survive on their own; they are strictly dependent on the tumor microenvironment (TME)—the surrounding crowd of healthy T cells, macrophages, and other immune cells [5][7].

The HRS cells send out chemical signals to “trick” these healthy cells into providing growth nutrients and creating a shield that prevents the immune system from attacking the tumor [2][8]. One way they do this is by displaying a protein called PD-L1, which acts like a “stop sign” to keep the immune system’s T cells from attacking [9][10].

The Connection to Epstein-Barr Virus (EBV)

In many cases of cHL, the Epstein-Barr Virus (EBV)—the virus that causes mononucleosis—plays a role in the biology of the cancer [11]. EBV can infect the B cells and provide them with survival signals that mimic the body’s natural growth instructions, helping them turn into cancerous HRS cells [11][12]. While having had “mono” does not mean you will get lymphoma, doctors often check for EBV because it can influence how the immune system reacts to the tumor [13][14].

The Four Subtypes of Classic Hodgkin Lymphoma

Doctors categorize cHL into four subtypes based on what the “neighborhood” (the TME) looks like under a microscope. While these subtypes help doctors understand the disease, they are all treated with similar, highly effective therapies [15][16].

  1. Nodular Sclerosis (NSCHL): The most common subtype, often seen in young adults. It is characterized by bands of scar tissue (fibrosis) that divide the lymph node into “nodules” [17][18].
  2. Mixed Cellularity (MCCHL): This subtype features a diverse mix of many different types of immune cells and is more frequently associated with the EBV virus [19][20].
  3. Lymphocyte-Rich (LRCHL): A less common, usually slow-growing (indolent) form where the tumor is filled with many healthy-looking lymphocytes [21][22].
  4. Lymphocyte-Depleted (LDCHL): The rarest form, where there are many cancer cells but very few healthy lymphocytes. It is more common in older adults or those with weakened immune systems [21][19].

How cHL Differs from Other Lymphomas

It is important to distinguish cHL from other similar-sounding conditions:

  • Non-Hodgkin Lymphoma (NHL): Unlike cHL, where cancer cells are rare and surrounded by healthy cells, NHL tumors are usually composed entirely of malignant cells [6][23].
  • Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL): Although it has “Hodgkin” in the name, NLPHL is biologically different. It features “popcorn cells” (LP cells) that carry different markers—specifically CD20—which often allows it to be treated with different targeted therapies than classic Hodgkin lymphoma [24][25].

Understanding these biological details helps your care team choose the most effective “key” to unlock and destroy the cancer’s defenses [26].

Common questions in this guide

What are the four subtypes of classic Hodgkin lymphoma?
The four subtypes are nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted. While they appear differently under a microscope based on the surrounding immune cells, they are all generally treated with similar, highly effective therapies.
What are Reed-Sternberg cells?
Hodgkin and Reed-Sternberg (HRS) cells are the actual cancer cells in classic Hodgkin lymphoma. They make up a very small percentage of the tumor, but they act as the 'brains' by recruiting healthy immune cells to protect and feed them.
How does the Epstein-Barr virus (EBV) affect classic Hodgkin lymphoma?
In many cases, EBV (the virus that causes mononucleosis) plays a role in the cancer's biology by infecting B cells and providing survival signals that help them become cancerous. Doctors often test for EBV because it can influence how your immune system reacts to the tumor.
What is the difference between classic Hodgkin lymphoma and non-Hodgkin lymphoma?
In classic Hodgkin lymphoma, the actual cancer cells are rare and are surrounded by a large neighborhood of healthy immune cells. In contrast, non-Hodgkin lymphoma tumors are usually composed almost entirely of malignant cancer cells.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which of the four subtypes of classic Hodgkin lymphoma was identified in my biopsy?
  2. 2.Did my pathology report show any evidence of the Epstein-Barr virus (EBV)?
  3. 3.How does the 'environment' of my tumor—the other immune cells around the cancer—affect my prognosis or treatment choice?
  4. 4.Since my cancer is 'classic' Hodgkin, does that mean treatments like PD-1 inhibitors might be an option for me later if needed?
  5. 5.What specific markers (like CD30 or CD15) were found on my Reed-Sternberg cells?

Questions For You

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References

References (26)
  1. 1

    Checkpoint inhibition enhances cell contacts between CD4+ T cells and Hodgkin-Reed-Sternberg cells of classic Hodgkin lymphoma.

    Yadigaroglu K, Scharf S, Gretser S, et al.

    Haematologica 2024; (109(10)):3295-3304 doi:10.3324/haematol.2023.284512.

    PMID: 38779721
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    Significance of trogocytosis and exosome-mediated transport in establishing and maintaining the tumor microenvironment in lymphoid malignancies.

    Kawashima M, Higuchi H, Kotani A

    Journal of clinical and experimental hematopathology : JCEH 2021; (61(4)):192-201 doi:10.3960/jslrt.21005.

    PMID: 34193756
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    Microenvironment-related biomarkers and novel targets in classical Hodgkin's lymphoma.

    Carlo-Stella C, Santoro A

    Biomarkers in medicine 2015; (9(8)):807-17 doi:10.2217/BMM.15.30.

    PMID: 26223461
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    Current and Emerging Approaches to Study Microenvironmental Interactions and Drug Activity in Classical Hodgkin Lymphoma.

    Casagrande N, Borghese C, Aldinucci D

    Cancers 2022; (14(10)) doi:10.3390/cancers14102427.

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    The circuitry of the tumor microenvironment in adult and pediatric Hodgkin lymphoma: cellular composition, cytokine profile, EBV, and exosomes.

    Nagpal P, Descalzi-Montoya DB, Lodhi N

    Cancer reports (Hoboken, N.J.) 2021; (4(2)):e1311 doi:10.1002/cnr2.1311.

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    Hodgkin lymphoma: Pathology and biology.

    Mathas S, Hartmann S, Küppers R

    Seminars in hematology 2016; (53(3)):139-47.

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    Genome-scale spatial mapping of the Hodgkin lymphoma microenvironment identifies tumor cell survival factors.

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    bioRxiv : the preprint server for biology 2025; doi:10.1101/2025.01.24.631210.

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    Transcriptome sequencing of Hodgkin lymphoma Hodgkin and Reed-Sternberg cells reveals escape from NK cell recognition and an unfolded protein response.

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    bioRxiv : the preprint server for biology 2025; doi:10.1101/2025.08.05.667241.

    PMID: 40799573
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    9p24.1 alterations and programmed cell death 1 ligand 1 expression in early stage unfavourable classical Hodgkin lymphoma: an analysis from the German Hodgkin Study Group NIVAHL trial.

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    High PD-L1 Expression in HRS Cells and Macrophages in Tumor Immune Microenvironment Is Associated with Adverse Outcome and EBV Positivity in Classical Hodgkin Lymphoma.

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    Contribution of Epstein⁻Barr Virus Latent Proteins to the Pathogenesis of Classical Hodgkin Lymphoma.

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    Pathogens (Basel, Switzerland) 2018; (7(3)) doi:10.3390/pathogens7030059.

    PMID: 29954084
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    NF-κB deregulation in Hodgkin lymphoma.

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    Seminars in cancer biology 2016; (39()):32-9.

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    Classical Hodgkin Lymphoma with Positive Epstein-Barr Virus Status is Associated with More FOXP3 Regulatory T Cells.

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    Mechanisms of Epstein-Barr virus nuclear antigen 1 favor Tregs accumulation in nasopharyngeal carcinoma.

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    Cancer medicine 2020; (9(15)):5598-5608 doi:10.1002/cam4.3213.

    PMID: 32573058
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    Impact of cluster of differentiation 20 expression and rituximab therapy in classical Hodgkin lymphoma: Real world experience.

    Abuelgasim KA, Shammari RA, Alshieban S, et al.

    Leukemia research reports 2021; (15()):100240 doi:10.1016/j.lrr.2021.100240.

    PMID: 33936943
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    Modification of initial therapy in early and advanced Hodgkin lymphoma, based on interim PET/CT is beneficial: a prospective multicentre trial of 355 patients.

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    British journal of haematology 2017; (178(5)):709-718 doi:10.1111/bjh.14734.

    PMID: 28589704
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    American Registry of Pathology Expert Opinions: Immunohistochemical evaluation of classic Hodgkin lymphoma.

    O'Malley DP, Dogan A, Fedoriw Y, et al.

    Annals of diagnostic pathology 2019; (39()):105-110 doi:10.1016/j.anndiagpath.2019.02.001.

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    Classic Hodgkin lymphoma: An illustrative review of select diagnostic limitations and immunomorphological challenges.

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    Clinicopathologic Insights and Molecular Oncogenesis: Understanding Epstein-Barr Virus-Induced B-cell Lymphoproliferations.

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    CD20+ T Cells in Primary Mediastinal Large B Cell Lymphoma Microenvironment.

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This page provides educational information about the biology and subtypes of classic Hodgkin lymphoma. Always consult your oncologist or hematologist for specific information regarding your pathology report and treatment plan.

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