Subtitle: Classical Hodgkin lymphoma and NLPHL side by side: the four CHL subtypes, Reed-Sternberg cells and their variants, the LP (popcorn) cell, the CD30/CD15/CD20/PAX5 panel, RS-like cells in other lymphomas and how to tell them apart, with virtual-slide-style image guidance and 10 MCQs.
Author: PathologyMCQ Editorial Board
Category: Haematopathology
Last Updated: October 2026
Read Time: 9 minutes
At-a-Glance
- HRS cell (CHL): CD30 strong and uniform, CD15 +/-, PAX5 weak, CD20 and CD45 usually negative, OCT2/BOB1 lost.
- LP cell (NLPHL): CD20+, CD45+, CD79a+, PAX5 strong, OCT2 and BOB1 co-expressed, CD30 and CD15 negative.
- CHL background is polymorphous: eosinophils, plasma cells, small lymphocytes, fibrosis. A true RS cell needs that background.
- NLPHL: nodular, CD21+ follicular dendritic meshworks, LP cells rosetted by CD3+/CD57+/PD-1+ T cells.
- RS-like cells occur in DLBCL, ALCL, EBV-positive mucocutaneous ulcer, infectious mononucleosis and some low-grade lymphomas.
- Separator: RS-like cells express B-cell markers homogeneously; HRS cells do not.
- NLPHL is EBV negative, indolent, may transform to T-cell/histiocyte-rich large B-cell lymphoma, and is CD20-targetable.
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Classification
Hodgkin lymphoma splits into two biologically distinct diseases that happen to share a name: classical Hodgkin lymphoma (CHL), which accounts for about 95% of cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), about 5%. Both are germinal centre B-cell derived, but they differ in the phenotype of the tumour cell, the architecture, the EBV association, the behaviour and the treatment.
CHL has four subtypes: nodular sclerosis, mixed cellularity, lymphocyte rich and lymphocyte depleted. In the WHO 5th edition NLPHL is also recognised under the alternative designation nodular lymphocyte predominant B-cell lymphoma, reflecting how closely it behaves like an indolent B-cell lymphoma.
Classical Hodgkin Lymphoma
The tumour cell is the Hodgkin and Reed-Sternberg (HRS) cell, and it is vastly outnumbered by reactive cells. The diagnostic trap is that the malignant population may be under 1% of the tissue, so the inflammatory background is what first catches the eye.
The HRS cell has crippled its B-cell programme. Despite a germinal centre B-cell origin it loses CD20, CD45, CD79a, OCT2 and BOB1, and retains only weak PAX5. That loss is diagnostically useful, because it is exactly what the mimics fail to do.
| Marker | HRS cell (CHL) | LP cell (NLPHL) |
|---|---|---|
| CD30 | Strong, uniform (membrane + Golgi) | Negative |
| CD15 | Positive in ~75% | Negative |
| CD20 | Negative or weak, variable | Strong, uniform |
| CD45 (LCA) | Negative | Positive |
| PAX5 | Weak | Strong |
| OCT2 / BOB1 | Lost (one or both) | Both expressed |
| EMA | Negative | Often positive |
| EBV (EBER/LMP1) | Positive in a proportion | Negative |
| Background rosettes | CD4+ T cells | CD3+/CD57+/PD-1+ T cells |
The Four CHL Subtypes
- Nodular sclerosis: commonest, young adults, mediastinal, birefringent collagen bands and lacunar cells; EBV positive in a minority.
- Mixed cellularity: classic HRS cells in a richly polymorphous background; highest EBV association (~75%); commonest subtype in HIV infection and in older patients.
- Lymphocyte rich: nodular or diffuse small lymphocyte background with few HRS cells; the main morphological mimic of NLPHL, separated by immunophenotype.
- Lymphocyte depleted: rarest; sheets of HRS cells or diffuse fibrosis with few lymphocytes; associated with HIV and advanced stage.
Nodular Lymphocyte Predominant Hodgkin Lymphoma
The tumour cell is the LP cell, historically the popcorn or L&H cell: a large cell with a folded, multilobated nucleus, vesicular chromatin and small basophilic nucleoli, far less conspicuous than the eosinophilic nucleolus of an HRS cell.
Architecture matters as much as cytology. LP cells sit within nodules of small B cells supported by CD21-positive follicular dendritic meshworks, and are rosetted by CD3+, CD57+, PD-1 positive T cells. Eosinophils, plasma cells and fibrosis, which define the CHL background, are typically absent.
Clinically it is indolent, presents in peripheral nodes, relapses late, and is EBV negative. Because LP cells retain CD20, rituximab is an option, which is the practical reason the distinction from CHL cannot be fudged. A minority transform to T-cell/histiocyte-rich large B-cell lymphoma.
Reed-Sternberg Cells and Their Variants
The diagnostic (classic) RS cell is binucleate or bilobed with two mirror-image nuclei, each carrying a large inclusion-like eosinophilic nucleolus with perinucleolar clearing: the owl-eye appearance. Several variants are recognised.
- Mononuclear (Hodgkin) cell: single nucleus, same large eosinophilic nucleolus.
- Lacunar cell: retraction of cytoplasm in formalin leaves the cell sitting in a space; characteristic of nodular sclerosis.
- Mummified cell: apoptotic, shrunken, intensely eosinophilic with pyknotic nuclei.
- Pleomorphic / anaplastic forms: bizarre and multinucleate, seen in lymphocyte depleted disease.
- LP (popcorn) cell: the NLPHL tumour cell, with basophilic rather than eosinophilic nucleoli.
RS-Like Cells and Their Mimics
RS-like cells appear in conditions that have nothing to do with Hodgkin lymphoma, and calling one a Reed-Sternberg cell on morphology alone is a well-recognised way to get the diagnosis wrong. They turn up in:
- Diffuse large B-cell lymphoma, including T-cell/histiocyte-rich large B-cell lymphoma.
- Anaplastic large cell lymphoma: horseshoe-shaped hallmark cells, strong CD30, EMA+, ALK+ in a subset, CD15 negative.
- EBV-positive mucocutaneous ulcer: immunosuppression or old age, circumscribed ulcer, EBER-positive HRS-like cells with basophilic nucleoli, often self-limiting.
- Infectious mononucleosis and other viral lymphadenitis.
- Peripheral T-cell lymphoma, including angioimmunoblastic T-cell lymphoma with EBV-positive B blasts.
- Rarely, low-grade B- and T-cell non-Hodgkin lymphomas.
Separating RS from RS-Like Cells
Four questions settle most cases: what is the background, how strong and uniform is CD30, are B-cell markers retained homogeneously, and does the clinical context fit.
| Feature | RS cells | RS-like cells |
|---|---|---|
| Associated conditions | Hodgkin lymphoma and composite lymphomas | High-grade lymphomas; rarely low-grade B- or T-cell NHL |
| Background | Characteristic polymorphous background (fibrosis, eosinophils, plasma cells) | No characteristic background |
| CD30 | Strong and homogeneous | Variable, often weak or patchy |
| B-cell markers | Negative or variably weak | Homogeneously expressed (CD20, CD79a, PAX5) |
| PAX5 | Weak | Strong |
| CD15 | Positive in about 75% | Usually negative |
| CD45 | Negative | Usually positive |
RS cells can be recognised on routine haematoxylin and eosin, but CD15, CD30, CD20 and CD45 remain the practical panel for separating them from their mimics. Add PAX5, OCT2 and BOB1 when the distinction is CHL versus NLPHL or DLBCL, and EBER where an EBV-driven mimic is in play.
Identify the True RS Cell
A useful self-test. Of the four images below, only one shows a true Reed-Sternberg cell.
The answer is B. The RS cell has a characteristic eosinophilic nucleolus and a polymorphous background. A shows horseshoe-shaped hallmark cells of anaplastic large cell lymphoma. C shows EBV-positive cells with basophilic nucleoli from an EBV-positive mucocutaneous ulcer. D is diffuse large B-cell lymphoma.
Test Yourself: 10 MCQs
Hodgkin lymphoma: 10 MCQs
CHL subtypes, NLPHL, RS cells and their mimics, with instant explanations.
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Exam Pearls
- CHL: CD30 strong, CD15 often +, PAX5 weak, CD20/CD45 negative, OCT2/BOB1 lost.
- NLPHL: the mirror image. CD20+, CD45+, PAX5 strong, OCT2 and BOB1 both present, CD30/CD15 negative.
- CD57+/PD-1+ rosettes and CD21+ meshworks support NLPHL.
- Mixed cellularity has the strongest EBV link; NLPHL is EBV negative.
- No polymorphous background means think RS-like, not RS.
- Homogeneous CD20/CD79a/PAX5 in the large cells points away from CHL.
- ALCL: hallmark cells, CD30 strong, EMA+, ALK+/-, CD15 negative.
- Elderly or immunosuppressed with a circumscribed ulcer: consider EBV-positive mucocutaneous ulcer before diagnosing CHL.
For more concise notes, see the Concise Hematopathology Notes →
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References
- Alaggio R, et al. The 5th edition of the WHO Classification of Haematolymphoid Tumours: lymphoid neoplasms. Leukemia. 2022;36:1720–48.
- Campo E, et al. The International Consensus Classification of mature lymphoid neoplasms. Blood. 2022;140:1229–53.
- Eberle FC, Mani H, Jaffe ES. Histopathology of Hodgkin lymphoma. Cancer J. 2009;15:129–37.
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