Non-Hodgkin & Hodgkin Lymphoma
Learning objectives
- LO 1Classify lymphoid neoplasms and name the ones that behave as both leukemia and lymphoma.
- LO 2Explain how immunophenotyping and other ancillary tests diagnose lymphoid neoplasms.
- LO 3Contrast low-grade (indolent) and high-grade (aggressive) lymphoid neoplasms.
- LO 4Define each major B- and T-cell lymphoma by cell of origin, markers, genetics and morphology.
- LO 5Describe the presentation, course and complications of each of those lymphomas.
- LO 6Outline the classification of Hodgkin lymphoma.
- LO 7Describe the Reed-Sternberg cell and its variants, including markers.
- LO 8Explain how Hodgkin lymphoma develops and the role of EBV.
- LO 9Compare the pathology and clinical features of the five Hodgkin subtypes.
- LO 10Distinguish Hodgkin from non-Hodgkin lymphoma by clinical features, grade and stage.
MAPThe lymphoid neoplasm map: sort by speed, then match the marker
LO 1Classifying lymphoid neoplasms
Q1. What is the difference between a leukemia and a lymphoma?
Leukemia
- Mainly bone marrow + circulating tumor cells
- Acute = immature precursors; chronic = mature cells
Lymphoma
- Clonal lymphocytes forming masses in nodes or extranodal sites
- Marrow involvement = higher stage
- Both forms of one disease: CLL = SLL (blood vs node); mycosis fungoides → Sézary when cells circulate; ATLL
- Location, not biology, decides the name
In-house exam
Disorders that are both leukemia and lymphoma: CLL/SLL, mycosis fungoides/Sézary, ATLL (and lymphoblastic ALL/LBL).
Q2. How is the WHO classification organized?
- B ≫ T: most lymphoid neoplasms are B-cell
- Each tumor mimics a normal stage of B- or T-cell development
- Hodgkin = few Reed-Sternberg cells in an inflammatory background; NHL = everything else
- Precursor (lymphoblastic) neoplasms = ALL, covered with the acute leukemias
Normal node
- Follicles with germinal centers and mantles
Lymphoma vs carcinoma
- Fish-flesh, soft (lymphoma) vs hard, white (carcinoma)
High yield — risk factors
- Immunodeficiency: HIV, transplant, Wiskott-Aldrich
- Autoimmune disease (chronic stimulation): Sjögren, Hashimoto
- Infection: H. pylori, EBV, HHV-8, HTLV-1, HCV
Memory tool
Lymphoma nodes are soft, rubbery, painless; metastatic carcinoma is hard and fixed; infection is tender and localized.
LO 2Immunophenotyping and ancillary tests
Q1. How is a lymphoid neoplasm diagnosed?
- Biopsy: node, marrow or tissue (B and T cells look alike, so morphology alone isn't enough)
- Immunophenotype: flow cytometry or IHC for CD markers
- Clonality: one light chain only (κ or λ), or clonal Ig/TCR gene rearrangement
- Cytogenetics / molecular: FISH or PCR for translocations
High yield — monoclonality
All κ (or all λ) = monoclonal → neoplasm. Mixed κ + λ = polyclonal → reactive.
Q2. Which markers matter?
| Neoplasm | Markers |
|---|---|
| All B cells | CD19, CD20 (pan-B); CD10 = germinal center |
| CLL/SLL | CD19, CD20, CD23, CD5 |
| Mantle cell | CD5, CD19, CD20, cyclin D1; CD23− |
| Follicular | CD10, CD19, CD20, BCL2, BCL6 |
| Marginal zone | CD20, BCL2, CD43 weak; CD5−, CD10− |
| Hairy cell | CD11c, CD25, CD103, CD22, CD19, CD20 |
| DLBCL | CD19, CD20, BCL6 ± CD10 |
| Burkitt | CD10, CD19, CD20, IgM; BCL2− |
| Mycosis fungoides | CD2, CD3, CD4, CD5; CD8− |
| Anaplastic large cell | CD30; ALK |
| Classic Hodgkin | CD15, CD30; B markers lost |
| Nodular LP Hodgkin | CD20+; CD15−, CD30− |
| Myeloid (contrast) | CD13, CD33 |
Step 1
CD5+ B cell? Only two: CLL (CD23+) and mantle cell (CD23−, cyclin D1+). CD10+ B cell: follicular, Burkitt (± DLBCL).
Q3. Which translocations should I know?
Most non-random translocations put a partner gene next to the immunoglobulin heavy chain (IGH) on chromosome 14 and its strong promoter.
| Translocation | Gene | Effect | Lymphoma |
|---|---|---|---|
| t(8;14) | MYC | Oncogene → rapid growth | Burkitt |
| t(14;18) | BCL2 | Blocks apoptosis | Follicular |
| t(11;14) | Cyclin D1 | Loss of cell-cycle control | Mantle cell |
| t(11;18) | API2-MALT1 | NF-κB activation | MALT |
| t(2;5) | NPM-ALK | Tyrosine kinase | Anaplastic large cell |
| Point mutation | BRAF V600E | Kinase on | Hairy cell |
| Amplification | PD-L1/PD-L2 | Immune evasion | Hodgkin |
In-house exam
The chromosome involved in most lymphoma translocations = 14 (IGH).
Memory tool
In order: 8;14 Burkitt → 11;14 Mantle → 11;18 MALT → 14;18 Follicular: "Burkitt Makes More Friends."
ApplyLO 2 application question
A1Flow cytometry shows CD19+, CD20+, CD5+, CD23− cells. What stain confirms the diagnosis?
LO 3Low grade vs high grade
Q1. How do indolent and aggressive lymphomas differ?
| Low grade / indolent | High grade / aggressive | |
|---|---|---|
| Patient | Older (>50) | All ages incl. children; median 60 |
| Nodes | Multiple, painless | Single rapidly growing node or mass |
| Spread | Marrow + blood; extranodal rare | Extranodal common (CNS, testis); blood rare |
| Histology | Non-destructive; small cells, clumped chromatin | Diffuse, destructive; large cells, vesicular nuclei, nucleoli, many mitoses |
| Outcome | Slow, rarely curable; may transform → DLBCL | Fatal untreated, but chemo-sensitive, curable |
Analogy — tortoise and hare
Chemo kills dividing cells. The hare (aggressive) divides constantly, so chemo catches it. The tortoise (indolent) barely divides and has already wandered everywhere, so it escapes.
Step 1 — transformation
Stable indolent disease, then a fast-growing node, B symptoms, ↑ LDH → transformation, usually to DLBCL: CLL (Richter, ~10%), follicular (30–50%, MYC), marginal zone, NLP Hodgkin.
LO 4Defining features of each lymphoma
Q1. What is the master table?
| Neoplasm | Cell | Markers | Genetics | Morphology clue |
|---|---|---|---|---|
| CLL / SLL | Naïve/memory B | CD5, CD23 | +12, del 13q/11q/17p | Smudge cells; marrow nodules |
| Hairy cell | Memory B | CD11c, 25, 103 | BRAF V600E | Hairy projections; "fried-egg" marrow; dry tap |
| Follicular | Germinal center B | CD10, BCL2 | t(14;18) | Back-to-back follicles; paratrabecular marrow aggregates |
| Marginal zone / MALT | Memory B | CD20, BCL2 | t(11;18) | Lymphoepithelial lesions |
| Mantle cell | Naïve B | CD5, cyclin D1 | t(11;14) | Vague nodules; monotonous small cells |
| Lymphoplasmacytic | Post-GC B → plasma | CD20, sIgM | MYD88 L265P | Plasmacytoid cells, Dutcher bodies |
| DLBCL | GC / post-GC B | CD19, 20, BCL6 | BCL6, BCL2, MYC | Sheets of large cells |
| Burkitt | Germinal center B | CD10, IgM; BCL2− | t(8;14) MYC | "Starry sky" |
| Mycosis fungoides | CD4 helper T | CD2, 3, 4, 5 | None specific | Cerebriform nuclei; Pautrier abscess |
| ATLL | CD4 helper T | CD4, CD25 | HTLV-1 (Tax) | Clover-leaf nuclei |
| Anaplastic large cell | T | CD30 | t(2;5) ALK | Horseshoe nuclei |
Q2. What do the chronic leukemias look like under the microscope?
CLL
- Small mature lymphocytes + smudge cells
CLL marrow
- Nodular lymphoid aggregates
Hairy cell marrow
- "Fried-egg" cells; dry tap
Mycosis fungoides
- Pautrier microabscess in epidermis
ATLL
- Clover-leaf (flower) cells
In-house exam
- CLL: smudge cells and marrow nodules
- Hairy cell: CD11c/25/103, BRAF
- Mycosis fungoides: cerebriform nuclei, Pautrier abscess
Step 1
Hairy cell: TRAP+, dry tap (marrow fibrosis), treat with cladribine (purine analog).
Q3. What do the indolent B-cell lymphomas look like?
Follicular
- Back-to-back follicles, thin mantles
BCL2 stain
- Reactive follicle − (left) · follicular lymphoma + (right)
MALT
- Lymphoepithelial lesions (cells invading glands)
Mantle cell
- Monotonous small cells, vague nodules
In-house exam
Paratrabecular lymphoid aggregates in marrow → follicular. Reactive follicles are BCL2−; neoplastic follicles are BCL2+.
Q4. What do the aggressive lymphomas look like?
DLBCL
- Sheets of large cells, prominent nucleoli
Burkitt
- Starry sky: macrophages eating apoptotic debris
Bulky node
- Rapidly growing mass (DLBCL)
In-house exam
Burkitt: starry sky, CD10/CD19/CD20/IgM, t(8;14), endemic = EBV + jaw.
LO 5Presentation, course and complications
Q1. How do the chronic B- and T-cell leukemias present?
| Disease | Presentation | Course / complications |
|---|---|---|
| CLL / SLL | >60; often incidental lymphocytosis; nodes, hepatosplenomegaly | 4–10 y by stage; hypogammaglobulinemia → infections; AIHA/ITP (10–15%); Richter → DLBCL; worse with del 11q/17p (TP53) |
| Hairy cell | Older men; splenomegaly, pancytopenia, no nodes; infections | Indolent; responds to cladribine |
| Mycosis fungoides / Sézary | Pruritic patch → plaque → tumor; Sézary: circulating cells + erythroderma | Variable; systemic disease = poor |
| ATLL | HTLV-1 (Japan, Caribbean); skin lesions, nodes, HSM, hypercalcemia | Aggressive; HTLV-1 also causes myelopathy |
Mycosis fungoides
- Plaques that won't heal → biopsy
Trap
Hypercalcemia + bone lesions isn't always myeloma: with skin lesions and CD4+ T cells, think ATLL (HTLV-1). A small M-spike can occur in CLL.
Q2. How do the indolent B-cell lymphomas present?
| Disease | Presentation | Course |
|---|---|---|
| Follicular | Older adults; painless bilateral cervical + axillary nodes, waxing-waning; fatigue | Incurable, ~7–10 y; low-dose chemo; → DLBCL 30–50% |
| Marginal zone / MALT | Sites of chronic stimulation: stomach (H. pylori), salivary (Sjögren), thyroid (Hashimoto), small bowel (RLQ pain, wall thickening) | Usually localized; gastric MALT regresses with H. pylori eradication (t(11;18) resists) |
| Mantle cell | Older men; diffuse nodes, HSM, GI polyposis | Incurable, 3–5 y |
| Lymphoplasmacytic | IgM spike → hyperviscosity (vision, headache, neuropathy) = Waldenström | Indolent; plasmapheresis; no lytic lesions |
Intestinal lymphoma
- Bowel wall thickening, RLQ pain
In-house exam
Small bowel distention + asymmetric wall thickening → MALT. Stomach = most common GI lymphoma site; H. pylori ulcer → atrophic gastritis, intestinal metaplasia, lymphoid hyperplasia, gastric lymphoma.
Trap — follicular vs mantle
Both: older patient, generalized nodes. CD10+, CD5−, t(14;18) = follicular; CD5+, cyclin D1, t(11;14) = mantle.
Q3. How do the aggressive lymphomas present?
| Disease | Presentation | Course |
|---|---|---|
| DLBCL | Median 60; rapidly growing bulky node or extranodal mass (GI, testis, Waldeyer ring, CNS) | Fatal untreated; CR 60–80%, ~50% cured; MYC/bulky = worse |
| Burkitt | Children/young adults; jaw (endemic, EBV) or ileocecal mass (sporadic) → obstruction, intussusception | Very fast (~40% in S phase) but chemo-sensitive; tumor lysis |
| Anaplastic large cell | Children/young adults; ulcerated skin lesions, nodes, high fever | Aggressive; ALK+ better |
In-house exam
- HIV + HHV-8 + pleural/ascitic lymphoma without a mass → primary effusion lymphoma
- AIDS + brain mass of CD20+ B cells → also EBV+ (primary CNS lymphoma)
Step 1
Tumor lysis: ↑K⁺, ↑PO₄³⁻, ↑uric acid, ↓Ca²⁺ → AKI. Prevent with hydration + allopurinol/rasburicase.
ApplyLO 4–5 application questions
A1A 55-year-old man has abdominal fullness, a huge spleen, no lymphadenopathy, Hb 4, WBC 1.2k and platelets 28k. Marrow aspirate is a dry tap. Diagnosis and mutation?
A2A 69-year-old with CLL stable for 10 years develops rapid splenic growth, anemia and B symptoms. What happened?
A3A 54-year-old woman with early satiety has small CD20+ cells infiltrating gastric glands; she improves after H. pylori therapy. Diagnosis?
LO 6–7Hodgkin classification and the Reed-Sternberg cell
Q1. What is Hodgkin lymphoma, and how is it classified?
- Clonal B-cell lymphoma: few malignant cells (RS cells or variants) in a large background of lymphocytes, eosinophils, plasma cells
- Bimodal age: 15–40 and >50
- Two families:
- Classic (CD15+, CD30+): nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depleted
- Nodular lymphocyte predominant (CD20+; CD15−, CD30−)
Q2. What does the Reed-Sternberg cell look like, and what are its variants?
- Large, binucleate (or bilobed) with huge eosinophilic nucleoli: "owl's eyes"
- From germinal center/post-GC B cells but lose B markers; CD15+, CD30+
- Variants: lacunar (nodular sclerosis), pleomorphic (lymphocyte depleted), popcorn / L&H (NLP)
RS cell and variants
- Binucleate "owl's eyes"
CD30
- Membrane + Golgi dot
CD15
- Positive in classic HL
In-house exam
RS cell = Hodgkin; markers CD15 and CD30. Guaranteed question.
Trap
RS-like cells occur in infectious mononucleosis and some NHLs: the right inflammatory background is required. CD30 alone also fits anaplastic large cell (T, ALK); classic HL adds CD15.
LO 8Pathogenesis and EBV
Q1. How do the RS cell and its background feed each other?
In-house exam
Transcription factor active in RS cells = NF-κB → uncontrolled cytokines.
Analogy — the owl in the crowd
A few owls (RS cells) shout for a crowd (cytokines); the crowd brings them food (growth factors). Most of the tumor is the crowd, not the owls.
Q2. What role does EBV play?
- EBV is frequently found in RS cells, especially mixed cellularity and lymphocyte depleted; lymphocyte rich ~40%; nodular sclerosis uncommon; NLP negative
- Prior infectious mononucleosis ↑ risk; workup includes testing for EBV
| Infection | Lymphoma |
|---|---|
| EBV | Endemic Burkitt, Hodgkin (MC, LD), HIV/transplant DLBCL, primary CNS lymphoma in AIDS |
| HHV-8 | Primary effusion lymphoma (HIV) |
| HTLV-1 | ATLL |
| H. pylori | Gastric MALT |
| HCV | Splenic marginal zone, lymphoplasmacytic |
In-house exam
HIV patient with EBV+ RS cells and few background lymphocytes → lymphocyte depleted.
LO 9The five Hodgkin subtypes
Q1. How do the subtypes compare?
| Subtype | Patient | Sites / stage | Pathology | EBV | Prognosis |
|---|---|---|---|---|---|
| Nodular sclerosis | Most common (65–70%); young adults, women ≈ men | Mediastinal, cervical, supraclavicular; early | Fibrous bands; lacunar cells | Uncommon | Excellent |
| Mixed cellularity | 2nd most common; older men | Abdominal nodes, spleen; B symptoms; often advanced | Classic RS in mixed lymphocytes, eosinophils, plasma cells | Often + | Good |
| Lymphocyte rich | Uncommon; older | Early | Classic RS in a T-cell background | ~40% | Very good |
| Lymphocyte depleted | Rarest; older, HIV | Advanced | Pleomorphic RS; few background cells | + | Worst |
| Nodular LP | <5%; young–middle-aged men | Cervical/axillary; localized | Popcorn cells in B-cell nodules; CD20+, CD15/30− | − | Good (may → DLBCL) |
Nodular sclerosis
- Fibrous bands split the node
Mixed cellularity
- RS cells in a mixed inflammatory background
Lymphocyte rich
- Classic RS cells, T-cell background
Lymphocyte depleted
- Pleomorphic RS, few lymphocytes
Nodular LP
- Popcorn (L&H) cell
Memory tool
Nodular Sclerosis = Sisters, Sternum (mediastinum), Scars (bands). Mixed cellularity = Men with Many symptoms and Mono (EBV). Lymphocyte Depleted = lost Defense (HIV) → worst. Prognosis tracks lymphocytes: more = better.
Step 1
Young woman + anterior mediastinal mass + fibrous bands + lacunar cells → nodular sclerosis.
Trap — lymphocyte rich vs NLP
Both are full of lymphocytes. Lymphocyte rich has classic CD15/30 RS cells in a T-cell background; NLP has CD20+ popcorn cells in a B-cell background.
ApplyLO 9 application question
A1A 74-year-old man has fevers, weight loss, splenomegaly and mesenteric nodes. Biopsy shows lymphocytes, plasma cells, eosinophils and binucleate CD15+/CD30+ cells. Subtype?
LO 10Hodgkin vs non-Hodgkin
Q1. How do HL and NHL differ?
| Hodgkin | Non-Hodgkin | |
|---|---|---|
| Tumor cell | Few RS cells among reactive cells | Tumor cells make up the mass |
| Age | Bimodal: young adults + >50 | Older (Burkitt in children) |
| Nodes | Single group (cervical, mediastinal) | Multiple peripheral |
| Spread | Contiguous, orderly | Non-contiguous |
| Mesenteric / Waldeyer | Rare | Common |
| Extranodal | Rare | Common |
| B symptoms | Common (+ pruritus) | Less common |
| Staging | Critical for prognosis and therapy | Histologic type matters more |
Memory tool
Hodgkin hops to the neighbor node; NHL parachutes anywhere.
Q2. How is lymphoma staged?
| Ann Arbor stage | Extent |
|---|---|
| I | One node region |
| II | ≥2 regions, same side of the diaphragm |
| III | Both sides of the diaphragm (± spleen) |
| IV | Disseminated extranodal (liver, marrow, lung) |
| A / B | B = fever, night sweats, >10% weight loss |
- Imaging stages the disease; most HL is caught early
- HL outcome: radiation + chemo; early stage 75–90% curable
- Adverse factors: stage IV, older age, B symptoms, bulky mediastinum, extensive spleen, multiple extranodal sites
Step 1 — late effects of HL therapy
- Second cancers: AML/MDS (alkylators), NHL, breast cancer after mediastinal radiation, lung, thyroid, sarcoma
- Bleomycin → pulmonary fibrosis; doxorubicin → cardiomyopathy
- Accelerated atherosclerosis, hypothyroidism, infertility
ApplyLO 10 application question
A1A patient has involved cervical and mediastinal nodes plus night sweats; nothing below the diaphragm. Stage?
IDImage ID
Image 1 — blood smear
Image 2 — marrow
Image 3 — node
Image 4 — node
Image 5 — skin
Image 6 — stomach
Image 7 — blood
Image 8 — node
Image 9 — node
Image 10 — cells
MCQExam-style questions
1A 70-year-old man has painless generalized lymphadenopathy and a WBC of 62,000/µL. The smear shows small mature lymphocytes and smudge cells. Flow cytometry will most likely show:
2Most non-random translocations in B-cell lymphomas involve a gene on which chromosome?
3A 61-year-old man has fatigue and painless bilateral cervical and axillary nodes. Biopsy shows crowded back-to-back follicles that stain BCL2+; marrow shows paratrabecular aggregates. The translocation is:
4A 55-year-old man has massive splenomegaly, pancytopenia and no lymphadenopathy. Marrow aspiration yields a dry tap. Which finding is expected?
5A 52-year-old man has a 6-month pruritic, scaly rash on his back that won't heal. Biopsy shows atypical CD4+ T cells with cerebriform nuclei clustered in the epidermis. Diagnosis?
6A 4-year-old boy from equatorial Africa has a rapidly enlarging jaw mass. Biopsy shows sheets of intermediate cells with many mitoses and scattered macrophages containing debris. Which virus is associated?
7A 48-year-old man has right lower quadrant pain. CT shows focal small-bowel distention with asymmetric wall thickening. Biopsy shows small B cells invading glands. Most likely diagnosis?
8A 62-year-old man has an 11-cm ileal mass made of sheets of large CD19+/CD20+ cells with BCL6 rearrangement. Which statement about prognosis is correct?
9A man with AIDS develops a pleural effusion containing large malignant lymphoid cells without a solid mass. Which virus is in the tumor cells?
10A 24-year-old woman has a cough and an anterior mediastinal mass. Biopsy shows broad collagen bands and cells sitting in clear spaces. Diagnosis?
11Which transcription factor is constitutively active in Reed-Sternberg cells and drives cytokine release?
12A 35-year-old man has a localized cervical node. Biopsy shows nodules of small B cells with scattered large cells with folded "popcorn" nuclei. Expected phenotype of the large cells?
13Which feature favors Hodgkin over non-Hodgkin lymphoma?
14A 40-year-old woman treated with chest radiation for Hodgkin lymphoma at age 17 now has a breast mass. Most likely explanation?
!Source notes
| Item | Lecture | Step 1 / standard references |
|---|---|---|
| Most common NHL | Follicular (U.S.) | DLBCL overall; follicular = most common indolent |
| HL share of lymphomas | 20–30% | ~10% |
| PD-L1 gene in HL | "Chromosome 2" | PD-L1/PD-L2 amplification at 9p24.1; know the mechanism (immune escape) |
| t(14;18) | Follicular | Also rare MALT (IGH-MALT1); without a mucosal story, t(14;18) = follicular |
| Cyclin D1 | Mantle cell, t(11;14) | Cyclin D1 = BCL1 (CCND1), not BCL2 |