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PA19.1-6 | Lymphomas — Hodgkin vs Non-Hodgkin — Part 1

CLINICAL SCENARIO

A 22-year-old woman notices a painless lump above her right collarbone for six weeks. She has lost 4 kg without trying, sweats through her sheets at night, and has had intermittent fever. Her GP feels a firm, rubbery node in the right supraclavicular fossa. CBC is near-normal. The GP books an excision biopsy.

Before you read further: what kind of malignancy are you thinking of, and why would a blood test alone not be sufficient to diagnose it?

WHY THIS MATTERS

Lymphomas account for roughly 5–6% of all cancers worldwide, yet they are disproportionately common in young adults — making them a high-yield diagnosis for a clinician just entering practice. Hodgkin lymphoma (HL) has one of the best cure rates of any cancer when caught early; non-Hodgkin lymphoma (NHL) encompasses dozens of subtypes, some indolent and watchable, others aggressive and immediately life-threatening. Knowing the pathological basis of the distinction lets you interpret a histopathology report, counsel a patient, and select the right referral pathway.

RECALL

Before you continue, briefly recall:

From Module H7: What is the difference between reactive and neoplastic lymphadenopathy? Why is excision biopsy preferred over fine-needle aspiration for suspected lymphoma?
From Year-1 Haematology: Where do B cells and T cells mature? What is the role of BCL2 in programmed cell death?
From Biochemistry: What is a chromosomal translocation, and why might placing a proto-oncogene next to an immunoglobulin gene locus be harmful?

These three anchors will carry you through the pathogenesis section.

What Is a Lymphoma?

A multi-panel pathology diagram explains lymphoma as a malignant solid lymphoid tumour, contrasts it with leukaemia, summarizes WHO classification criteria, pathogenetic themes, and the Reed-Sternberg cell. — **Panel A:** Lymph node capsule, solid tumour mass, malignant lymphoid clone, B cell, T cell, NK cell, extranodal lymphoid tissue. **Panel B:** Lymphoma: nodal solid mass; leukaemia: peripheral blood and bone marrow involvement; leukaemia-lymphoma overlap. **Panel C:** WHO classification framework showing cell of origin, immunophenotype, molecular genetics, and clinical behaviour. **Panel D:** Oncogenic translocation, EBV viral oncogenesis, immunodeficiency, lymphoma development. **Panel E:** Reed-Sternberg cell, binucleate cell, prominent eosinophilic nucleoli, owl-eye appearance, reactive lymphocytes.

A lymphoma is a malignant neoplasm arising from lymphoid cells — predominantly B cells, T cells, or NK cells — that proliferates as a solid tumour mass, typically in a lymph node or extranodal lymphoid tissue. This distinguishes it from leukaemia, where the neoplastic clone circulates primarily in peripheral blood and bone marrow.

The distinction is partly conceptual: leukaemia–lymphoma overlap exists in several entities (e.g., small lymphocytic lymphoma and chronic lymphocytic leukaemia are the same B-cell clone, differing only in whether it predominates in nodes or blood). The classification that underpins modern management is the WHO Classification of Lymphoid Neoplasms, which groups lymphomas by cell of origin, immunophenotype, molecular genetics, and clinical behaviour.

All lymphomas share three pathogenetic themes:
1. Oncogenic translocations that place proto-oncogenes under constitutive promoters
2. Viral oncogenesis, most importantly by Epstein-Barr virus (EBV)
3. Immunodeficiency — both congenital and acquired (HIV, post-transplant) — that removes normal immune surveillance

Hodgkin Lymphoma — The Reed-Sternberg Cell

A three-panel medical diagram shows Hodgkin lymphoma histology, Reed-Sternberg owl-eye morphology, and the CD15 positive, CD30 positive, CD45 negative, weak PAX5 immunophenotype with diagnostic caution. — **Panel A:** H&E histology at 40x showing a central binucleate Reed-Sternberg cell, owl-eye nucleoli, small lymphocytes, eosinophils, plasma cells, neutrophils, fibroblasts, and rare RS cells forming 1-5% of tumour mass.. **Panel B:** Enlarged classical Reed-Sternberg cell showing binucleation, mirror-image nuclei, prominent eosinophilic nucleoli, perinucleolar clearing, and abundant cytoplasm.. **Panel C:** Immunophenotype panel showing CD15 positive, CD30 positive, CD45 negative, PAX5 weak positive staining, CD30 as brentuximab vedotin target, and caution that RS-like cells can occur outside Hodgkin lymphoma..

Hodgkin lymphoma (HL) is defined by the presence of the Reed-Sternberg (RS) cell — a large binucleate or multinucleate cell with prominent eosinophilic nucleoli that resemble owl's eyes. The RS cell is of B-cell origin (clonal immunoglobulin gene rearrangements are detectable) but has lost most B-cell surface markers.

The canonical immunophenotype is CD15+ and CD30+ (and CD45−, PAX5 weakly+). CD30 is the target of the antibody-drug conjugate brentuximab vedotin, making immunophenotyping therapeutically important.

RS cells constitute only 1–5% of the tumour mass. The bulk is a reactive inflammatory infiltrate — lymphocytes, plasma cells, eosinophils, neutrophils, and fibroblasts — whose composition determines the histological subtype.

IMPORTANT NOTE: RS cells alone are not diagnostic of HL. Cells resembling RS cells (called RS-like or lacunar cells) can occur in infectious mononucleosis, anaplastic large cell lymphoma, and other reactive states. Diagnosis requires the correct cellular background.

Histological diagram showing Reed-Sternberg cells in Hodgkin lymphoma with characteristic binucleate morphology and immunohistochemical markers. — **Panel A:** H&E histology at 40× showing binucleate Reed-Sternberg cell with owl-eye nucleoli, mixed inflammatory background including lymphocytes and eosinophils. **Panel B:** Immunohistochemical profile showing CD15+/CD30+/CD45- staining pattern characteristic of classical Reed-Sternberg cells.

SELF-CHECK

A lymph node biopsy shows large binucleate cells with prominent eosinophilic nucleoli. Immunohistochemistry reveals CD15+, CD30+, CD45− staining. Which of the following BEST describes these cells?

A. Reed-Sternberg cells of B-cell origin confirming Hodgkin lymphoma

B. Germinal-centre centroblasts indicating follicular lymphoma

C. Reed-Sternberg-like cells diagnostic of anaplastic large cell lymphoma

D. Plasma cells indicating multiple myeloma

Reveal Answer

Answer: A. Reed-Sternberg cells of B-cell origin confirming Hodgkin lymphoma

The CD15+/CD30+/CD45− immunophenotype in a binucleate large cell with owl-eye nucleoli is the hallmark of the classical Reed-Sternberg cell in Hodgkin lymphoma. Note: the clinical context and reactive background are also required for a definitive diagnosis — RS-like cells can occur in other settings, but this immunophenotype in the right histological context confirms HL.

Hodgkin Lymphoma — Subtypes

The WHO recognises two broad categories of HL:

1. Classical Hodgkin Lymphoma (cHL) — Four subtypes, all with CD15+/CD30+ RS cells:

Subtype	Key Features	Epidemiology
Nodular Sclerosis (NSHL)	Collagen bands dividing node into nodules; lacunar cells (RS variant); CD15+/CD30+	Commonest (70%); young women; mediastinal mass; EBV ~ 20–40%
Mixed Cellularity (MCHL)	Classic RS cells in rich inflammatory background; no sclerosis	2nd commonest; older males; advanced stage; EBV ~ 70%
Lymphocyte-Rich (LRHL)	Lymphocytic background; rare RS cells	Rarest cHL; best prognosis within cHL
Lymphocyte-Depleted (LDHL)	Abundant RS cells; scant lymphocytes; necrosis	Elderly/HIV; worst prognosis; advanced stage

2. Nodular Lymphocyte-Predominant HL (NLPHL):
- Neoplastic cell is the LP cell ("popcorn cell"), not a classic RS cell
- CD20+, CD45+, CD15−, CD30− — a B-cell phenotype, unlike cHL
- Indolent clinical course; excellent prognosis; risk of transformation to diffuse large B-cell lymphoma

Bimodal age distribution of cHL: peaks at 15–35 years (NSHL) and >55 years (MCHL/LDHL).