Understanding Lymphoma 🧬

 Lymphoma is a malignancy of lymphoid tissue, encompassing a diverse group of blood cancers originating in B cells, T cells, or (rarely) natural killer (NK) cells. Though primarily arising within lymph nodes, lymphomas can also involve the spleen, liver, bone marrow, gastrointestinal tract, or skin.

🩸 Two Broad Categories

Lymphomas are classified into:

• Hodgkin lymphoma (HL)
• Non-Hodgkin lymphoma (NHL)

These groups differ in epidemiology, pathogenesis, clinical behaviour, and response to therapy—HL and NHL are distinct disease families, rather than variations on a spectrum.

Why this classification may seen unusual 

Hodgkin lymphoma is named after Dr. Thomas Hodgkin, an English physician who first described the disease in 1832. His observations identified a distinct pattern of lymph node enlargement and systemic symptoms, which later became the foundation for diagnosing Hodgkin lymphoma. For many years, all lymphoid cancers were grouped under "Hodgkin’s disease." However, as medical research advanced, it became clear that many lymphomas did not share the same characteristics—particularly the presence of Reed–Sternberg cells, which are unique to Hodgkin lymphoma.

Thus, in the mid-20th century, scientists classified all other lymphomas as non-Hodgkin lymphoma (NHL)—essentially, a catch-all term for lymphoid malignancies without Reed–Sternberg cells. NHL encompasses a vast range of subtypes, including B-cell, T-cell, and NK-cell lymphomas, each with distinct molecular and clinical behaviours. 

To give you an analogy, it’s like identifying the distinct features of a Great Dane first, before understanding there is any other dog breed .... and then calling every other dog a "non-Great Dane" from then on —a broad category that lumps together vastly different breeds under one umbrella. 

🔬 Pathophysiology: What Goes Wrong?

🧪 Hodgkin Lymphoma (HL)

Hodgkin lymphoma originates from germinal centre B cells, yet paradoxically, these cells often lose key B-cell markers, such as CD20, which would typically be expressed.

Why Does This Happen?

• The malignant transformation likely involves genetic mutations and Epstein–Barr virus (EBV) interactions, leading to aberrant signalling.
• Instead of functioning as normal B cells, these transformed cells become Reed–Sternberg cells, characterised by their binucleate structure and "owl’s eye" nucleoli.
• The loss of B-cell identity may result from altered expression of transcription factors, such as NF-κB, driving uncontrolled survival mechanisms while shutting down normal antibody production.

"Owls eye" appearance of a Reed Sternberg cell

Inflammatory Microenvironment & Tumour Mass Formation

• Reed–Sternberg cells secrete pro-inflammatory cytokines like IL-6, TNF-α, and IL-10, attracting a dense infiltrate of non-malignant immune cells (T cells, eosinophils, plasma cells).
• Unlike most cancers, where malignant cells make up most of the tumour, Hodgkin lymphoma's tumour mass consists largely of recruited immune cells, while Reed–Sternberg cells remain relatively scarce (~1% of total tumour volume).
• This cytokine-driven environment suppresses the anti-tumour immune response, allowing Hodgkin lymphoma to persist despite an active immune system.
• Reed–Sternberg cells are the ultimate "puppet masters"—they manipulate surrounding immune cells to fuel tumour growth rather than fight it.

Why Does It Spread Predictably?

• Hodgkin lymphoma tends to spread contiguously through adjacent lymph node groups, rather than via the bloodstream.
• This unique stepwise progression reflects the lymphatic drainage pattern, differentiating it from non-Hodgkin lymphomas, which often appear widely disseminated at diagnosis.

Subtypes:

• Classical HL (95%) – CD15+, CD30+, CD45−, often Epstein–Barr virus (EBV)-associated.
• Nodular lymphocyte-predominant HL – CD20+, CD45+, lacks CD15/30; more indolent course.

🧪 Non-Hodgkin Lymphoma (NHL)

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies that arise from B cells (90%), T cells, or NK cells, depending on the subtype. Unlike Hodgkin lymphoma, NHL lacks Reed–Sternberg cells and often presents with widespread, non-contiguous lymphadenopathy at diagnosis.

🔬 Pathophysiology: What Goes Wrong?

1️⃣ Genetic Mutations & Oncogene Dysregulation

• NHL arises from various stages of lymphocyte development, meaning different subtypes originate from immature or mature B/T/NK cells.
• Key oncogene mutations drive uncontrolled proliferation:
• MYC (Burkitt lymphoma) → promotes rapid cell division.
• BCL2 (Follicular lymphoma) → inhibits apoptosis, allowing cells to survive abnormally.
• BCL6 (Diffuse large B-cell lymphoma, DLBCL) → disrupts normal germinal centre function.

2️⃣ Loss of Growth Regulation & Survival Signals

• Normal lymphocytes undergo controlled activation and apoptosis, but NHL cells evade these checkpoints.
• Dysregulated signalling pathways (e.g. NF-κB, PI3K/AKT) allow malignant cells to resist apoptosis and proliferate unchecked.
• Some NHL subtypes (e.g. Mantle cell lymphoma) involve cyclin D1 overexpression, leading to uncontrolled cell cycle progression.

3️⃣ Microenvironment & Immune Evasion

• NHL cells manipulate the tumour microenvironment, suppressing immune surveillance:
• Follicular lymphoma creates an immunosuppressive niche, preventing T-cell attack.
• DLBCL can recruit stromal cells to support tumour growth.
• Some NHLs, like MALT lymphoma, arise due to chronic antigen stimulation (e.g. Helicobacter pylori infection).

4️⃣ Patterns of Spread & Extranodal Involvement

• NHL often disseminates early, affecting bone marrow, spleen, liver, CNS, or GI tract.
• Extranodal disease is common, unlike Hodgkin lymphoma, which typically remains lymph node-centric.

📊 Epidemiology

🧬 Clinical Presentation

Both HL and NHL can present similarly, but key patterns help distinguish them.

🔍 Common Features

• Painless lymphadenopathy (often cervical, supraclavicular, or axillary).
• B symptoms: fever >38°C, drenching night sweats, unintentional weight loss >10% in 6 months.
• Fatigue, pruritus (from cytokines), and alcohol-induced lymph node pain (classically in HL).
• Extranodal disease (GI tract, skin, CNS, bone marrow) is much more common in NHL.

While HL and NHL share some core features, their progression and clinical behaviour differ significantly:

• HL often spreads predictably from one lymph node group to the next, making staging straightforward.
• NHL frequently presents in multiple locations, sometimes with extranodal disease as the initial finding.

📋 Comparison Table

Lymphoma mimics infection, autoimmune disease, and even drug reactions:

• A young woman with night sweats, weight loss, and elevated ANA? SLE is likely—but lymphoma must be excluded.
• An older patient with "long COVID" symptoms and persistent fatigue? Before attributing everything to post-viral effects, consider lymphoma

🏥 Special Considerations in Diagnosis

Gold-Standard Diagnosis:

• Excisional lymph node biopsy (FNA is inadequate).
• Histological classification (WHO or REAL system).
• Immunophenotyping (flow cytometry and IHC):
• CD20+ → B-cell lineage
• CD3+ → T-cell lineage
• CD15/CD30+ → classical HL

Advanced Molecular Testing:

• Cytogenetics: MYC and BCL2 translocations refine NHL subtyping.
• Minimal Residual Disease (MRD) monitoring: Emerging techniques like circulating tumour DNA improve response assessment.

🔬 Why Molecular Testing Matters

• MYC translocations in aggressive lymphomas signal poor prognosis, influencing the choice between intensive chemotherapy or novel targeted therapies.
• Circulating tumour DNA (ctDNA) may soon replace bone marrow biopsy as a tool to detect relapse earlier, sparing patients unnecessary procedures.

Staging:

• PET-CT (preferred over CT alone).
• Bone marrow biopsy (for some NHL subtypes).
• Ann Arbor Staging:

The Ann Arbor staging system is used to classify the extent of Hodgkin lymphoma and non-Hodgkin lymphoma based on how far the disease has spread. It was developed in 1971 in Ann Arbor, Michigan, and remains a foundational staging system, though it has been refined. The Lugano classification is a modern lymphoma staging system that refined the Ann Arbor staging to better reflect disease extent and treatment decisions. It was introduced in 2014 at the International Conference on Malignant Lymphoma in Lugano, Switzerland.

🩺 Staging Breakdown (including refined Lugarno staging)

** Note: Stage II and III  Bulky Disease Definition (guides radiotherapy decisions)

• Hodgkin lymphoma: A single nodal mass ≥10 cm or ≥⅓ of the transthoracic diameter.
• Follicular lymphoma: Bulky disease defined as ≥6 cm.
• Large B-cell NHL: Bulky disease ranges from 6–10 cm.

🔍 Additional Substaging Variables

• A: No systemic symptoms.
• B: Presence of B symptoms (fever >38°C, night sweats, weight loss >10% in 6 months).
• E: Involvement of a single extranodal site contiguous to a known nodal site (stages I–III only).
• S: Splenic involvement.
• X: Bulky disease (nodal mass >1/3 of intrathoracic diameter or >10 cm in size).

🧠 Why Does Staging Matter?

• Early-stage (I–II) lymphomas often have localized disease, allowing for curative treatment with chemotherapy and/or radiotherapy.
• Advanced-stage (III–IV) lymphomas require systemic therapy, such as R-CHOP for NHL or ABVD for Hodgkin lymphoma.
• The presence of B symptoms often indicates a more aggressive disease course, influencing treatment intensity

💊 Treatment Overview

🩺 Hodgkin Lymphoma

• ABVD chemotherapy (adriamycin, bleomycin, vinblastine, dacarbazine) is the gold standard treatment.
• Why ABVD? It directly targets the highly inflammatory microenvironment of Hodgkin lymphoma, breaking down tumour cells while limiting immune-driven toxicity.
• Analogy: Think of ABVD as a precise demolition crew—it clears out the tumour while limiting collateral damage to surrounding immune cells.

• Radiotherapy is used for bulky or localised disease, especially in early-stage Hodgkin lymphoma.
• Prognosis: Hodgkin lymphoma is highly curable—even Stage IV disease has a 5-year survival exceeding 65%. For Stage I/II, survival is 90%+, meaning most patients never relapse.

🩺 Non-Hodgkin Lymphoma

Unlike Hodgkin lymphoma, NHL encompasses many subtypes, requiring subtype-specific treatment approaches.

🔹 Indolent NHLs:

• Example: Follicular lymphoma.
• Treatment: Often "watchful waiting"—no immediate therapy unless symptoms develop.
• Why? Indolent lymphomas grow slowly, often behaving more like chronic diseases than acute cancers. Treating too early doesn’t improve long-term survival.
• Analogy: Think of follicular lymphoma as a slow-burning candle—it won’t go out, but it rarely flares up aggressively.

🔹 Aggressive NHLs:

• Example: Diffuse large B-cell lymphoma (DLBCL).
• Treatment: R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone).
• Why? R-CHOP targets rapidly dividing cancer cells and includes rituximab, a monoclonal antibody that directly attacks CD20+ B cells.
• Analogy: R-CHOP is a full-force attack strategy—like a military operation designed to eliminate aggressive, fast-growing lymphoma cells.
• Prognosis: Early-stage aggressive NHL is often curable, but late-stage disease depends on subtype and response to therapy.

Emerging Therapies:

• CAR-T cell therapy revolutionises relapsed NHL management, particularly DLBCL.
• BTK inhibitors, immune checkpoint inhibitors expand precision treatment options.
• Modern radiotherapy techniques reduce toxicity.

💊 What Makes CAR-T Therapy Revolutionary?

• Standard chemotherapy targets fast-growing cells indiscriminately, leading to broad toxicities.
• CAR-T genetically reprograms a patient's own immune cells to target cancer, often achieving cures in relapsed/refractory cases.
• Challenge? Cytokine release syndrome—a potentially fatal immune reaction—requires expert management.

 Case Vignettes

🧠 Case 1: The "Infection That Won’t Go Away"

Patient: 22-year-old university student

Presenting Symptoms: Persistent sore throat, cervical lymphadenopathy, intermittent fevers, fatigue

Initial Workup and Misdiagnosis:

• Monospot test: Negative (EBV unlikely, but symptoms suggest viral cause).
• CBC: Mild lymphocytosis and normocytic anaemia (suggests viral infection or inflammatory process).
• Autoimmune screen: Negative (SLE ruled out).

Despite symptomatic treatment, the lymphadenopathy persists. Patient now reports night sweats and weight loss.

Final Diagnosis: Nodular Sclerosing Hodgkin Lymphoma

• Excisional biopsy: Reed–Sternberg cells (CD15+, CD30+).
• PET-CT staging: Localised disease (Stage II).

Lesson: Don't dismiss prolonged viral-like symptoms—persistent lymphadenopathy plus B symptoms should trigger concern for Hodgkin lymphoma.

Things to think about: 

What features in this case suggest lymphoma rather than a prolonged viral illness?

• Why is a Monospot test insufficient to rule out serious causes of lymphadenopathy?
• If this were EBV-associated Hodgkin lymphoma, how might the treatment plan differ

🔬 Case 2: The "Autoimmune" Puzzle

Patient: 39-year-old woman with a history of rheumatoid arthritis

Presenting Symptoms: Fatigue, night sweats, intermittent joint pain, mild weight loss

Initial Workup and Confusion:

• ANA, RF, anti-CCP: Positive (consistent with autoimmune disease).
• CBC: Mild anaemia, leukopenia.
• CT abdomen: Mesenteric lymphadenopathy (attributed to inflammatory process).

Patient is started on corticosteroids, but symptoms persist, and she now develops abdominal discomfort and splenomegaly.

Final Diagnosis: Diffuse Large B-Cell Lymphoma (most common NHL)

• Biopsy of mesenteric nodes: CD20+, Ki67 high (aggressive B-cell NHL).
• Bone marrow biopsy: Involvement confirmed.

Lesson: Lymphoma mimics autoimmune disease, and new systemic symptoms should prompt reconsideration of a cancer workup, especially in an older patient.

Things to think about 

What red flags suggest the patient’s symptoms could be malignancy-related rather than autoimmune?

• Why might initial corticosteroid treatment mask lymphoma progression?
• How does rheumatoid arthritis affect the risk of developing certain NHL subtypes, such as diffuse large B-cell lymphoma

💊 Case 3: The "Heartburn That’s Not Just Reflux"

Patient: 58-year-old man

Presenting Symptoms: Chronic epigastric pain, weight loss, occasional nausea

Initial Workup Suggests Peptic Ulcer Disease:

• H. pylori serology: Positive
• Endoscopy: Gastric ulcer with mild inflammation
• Trial of PPI and antibiotics: No improvement

But Something Is Off…

• Endoscopic biopsy: Lymphocytic infiltration, CD20+ cells.
• CT abdomen: Gastric wall thickening, mild mesenteric lymphadenopathy.

Final Diagnosis: Gastric MALT Lymphoma

• Pathology confirms low-grade lymphoma associated with H. pylori infection.

Lesson: Not all peptic ulcers are benign—persistent GI symptoms should raise suspicion for MALT lymphoma, which may be curable with antibiotics alone if caught early.

Things to think about 

Why is it critical to biopsy gastric ulcers that don’t heal with proton pump inhibitors (PPIs) and antibiotics?

• How does Helicobacter pylori contribute to lymphoma pathogenesis, and why can eradication therapy be curative?
• If MALT lymphoma progresses beyond early disease, what treatment escalation would be required?

💡 Key Takeaways

• Lymphoma = cancer of lymphoid cells, with diverse subtypes requiring specific diagnosis and management.
• Reed–Sternberg cells = Hodgkin; all others fall under the NHL umbrella.
• Biopsy and immunophenotyping are essential—never rely on imaging or FNA alone.
• Treatments are increasingly tailored, with immunotherapy and precision approaches leading the way.
• Remember B symptoms, extranodal involvement, and age distribution to help distinguish subtypes.

Want to keep learning?

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