Non-Hodgkin lymphomas (NHL) are classic USMLE territory because they reward pattern recognition: which B-cell stage is involved, which translocation is driving it, what the node looks like, and what the patient looks like. The Step 1 game is to connect molecular lesion → pathophysiology → clinical presentation → diagnosis → treatment, and to avoid mixing up the “big four” you’ll see again and again: DLBCL, follicular lymphoma, Burkitt lymphoma, and mantle cell lymphoma.
Big-Picture Framework (How to Think About NHL on Step 1)
What is Non-Hodgkin lymphoma?
A heterogeneous group of malignant clonal lymphoid proliferations that primarily involve B cells (most common), but can be T/NK cell derived.
Key Step framing:
- Most NHL are B-cell.
- NHL tends to spread noncontiguously (contrast with Hodgkin’s “orderly” contiguous spread).
- Extranodal involvement is common (GI tract, skin, CNS, etc.).
Pathophysiology in one line
Most NHL are driven by chromosomal translocations that dysregulate oncogenes (e.g., BCL2, BCL6, MYC, Cyclin D1) during normal B-cell processes:
- V(D)J recombination
- Somatic hypermutation
- Class switching
This is why translocations so often involve the Ig heavy chain locus (chromosome 14).
Rapid Comparison Table (High-Yield Differentiators)
| Lymphoma | Typical Pt / Tempo | Core Genetic Lesion | Key Path Finding | Classic Buzzwords | High-Yield Tx Notes |
|---|---|---|---|---|---|
| DLBCL | Older adults; aggressive | Often BCL6 rearrangements; can be “double hit” (MYC + BCL2/BCL6) | Diffuse sheets of large cells | Rapidly enlarging mass (node or extranodal) | Curable; R-CHOP commonly |
| Follicular lymphoma | Middle-aged; indolent | t(14;18) → BCL2↑ | Follicular/nodular pattern | Painless generalized LAD; waxing/waning | Often incurable but slow; anti-CD20 options |
| Burkitt lymphoma | Children/young; very aggressive | t(8;14) → MYC↑ (also 2;8, 8;22) | “Starry sky” | EBV assoc (endemic), jaw mass; sporadic abdominal mass | Needs intensive chemo; tumor lysis risk |
| Mantle cell lymphoma | Older men; aggressive-ish | t(11;14) → Cyclin D1↑ | Mantle zone expansion | Diffuse LAD ± GI polyposis | Often relapses; targeted agents used |
Diffuse Large B-Cell Lymphoma (DLBCL)
Definition & pathogenesis
Most common NHL in adults. An aggressive B-cell lymphoma composed of large transformed B cells, often arising de novo or via transformation (e.g., from follicular lymphoma).
Genetics (Step 1 level):
- Classically associated with BCL6 dysregulation (a germinal center transcription factor).
- High-yield twist: “Double-hit” lymphomas can involve MYC + BCL2 and/or BCL6, which behave more aggressively.
Clinical presentation
- Rapidly enlarging lymph node or mass
- Can present extranodally (GI tract, CNS, bone, skin)
- “B symptoms” (fever, night sweats, weight loss) may occur but aren’t required
Diagnosis
- Excisional lymph node biopsy is preferred for architecture.
- Histology: diffuse growth pattern of large atypical lymphoid cells.
- Immunophenotype: CD20+ (B-cell marker) is common and therapeutically relevant.
Treatment (board-relevant concepts)
- Potentially curable even though aggressive.
- Common regimen: R-CHOP (includes rituximab, anti-CD20).
- Rapid growth → watch for tumor lysis syndrome after therapy (esp. bulky disease).
First Aid cross-reference (where to look)
- First Aid → Hematology/Oncology → Lymphomas (Non-Hodgkin)
- Monoclonal antibody therapy (rituximab, CD20) often appears nearby.
Follicular Lymphoma
Definition & pathogenesis
An indolent B-cell NHL derived from germinal center B cells. Think: “slow, nodular, long course.”
Signature translocation:
- t(14;18) → Ig heavy chain enhancer drives BCL2 overexpression
- BCL2 inhibits apoptosis, so cells accumulate rather than proliferate wildly.
Clinical presentation
- Painless, generalized lymphadenopathy
- Often waxing and waning course
- Many present with advanced-stage disease but feel relatively well
Diagnosis
- Lymph node biopsy shows follicular (nodular) architecture.
- Mechanism-to-histo connection: too much BCL2 → survival of follicles that should undergo apoptosis.
Treatment & prognosis (Step 1 emphasis)
- Indolent; often not curable, but patients can live many years.
- Anti-CD20 therapy (e.g., rituximab) commonly used.
- High-yield progression: can transform into DLBCL (sudden rapid growth, new B symptoms).
First Aid cross-reference
- First Aid → Hematology/Oncology → t(14;18), BCL2 (anti-apoptotic) is a recurring theme (also appears in apoptosis regulation).
Burkitt Lymphoma
Definition & pathogenesis
A high-grade, extremely fast-growing B-cell lymphoma.
Signature genetic lesion:
- t(8;14) → MYC translocated to Ig heavy chain locus → massive proliferation
- Variants: t(2;8), t(8;22) (light chain loci)
Why it looks “starry sky”:
- Tumor has a sky-high proliferation rate → many cells die → macrophages engulf debris, creating pale “stars” on dark “sky” of tumor cells.
Clinical presentation (know the two classic forms)
- Endemic (African): strongly associated with EBV
- Classically jaw/facial bone tumors
- Sporadic (US/Europe): less EBV, often abdominal mass (ileocecal region), can mimic appendicitis/intussusception symptoms
Diagnosis
- Biopsy: “starry sky” pattern
- Very high proliferation index (often described with Ki-67 near 100% in clinical contexts)
Treatment pearls
- Requires intensive chemotherapy; can be highly responsive.
- Tumor lysis syndrome is a major risk because the tumor divides (and dies) so quickly.
- Expect ↑K, ↑Phos, ↑uric acid, ↓Ca, AKI risk.
First Aid cross-reference
- First Aid → Hematology/Oncology → MYC translocation
- First Aid → Metabolic complications of malignancy → Tumor lysis syndrome
Mantle Cell Lymphoma
Definition & pathogenesis
A B-cell lymphoma arising from the mantle zone (naive pregerminal center B cells). Often behaves more aggressively than “indolent” lymphomas and tends to relapse.
Signature translocation:
- t(11;14) → overexpression of Cyclin D1
- Cyclin D1 pushes cells through G1 → S transition (cell cycle acceleration).
Clinical presentation
- Typically older man
- Generalized lymphadenopathy
- Classic association: GI involvement with multiple lymphomatous polyps
- “Multiple lymphomatous polyposis” can show up as a vignette clue.
Diagnosis
- Biopsy with mantle-zone pattern; immunophenotype usually B-cell markers.
- Cyclin D1 overexpression is a key confirmatory clue.
Treatment (Step-level)
- Often treated with immunochemotherapy; relapse is common.
- On exams, the main point is recognizing t(11;14) Cyclin D1 and distinguishing it from the other translocations.
First Aid cross-reference
- First Aid → Hematology/Oncology → t(11;14), Cyclin D1
How They Try to Trick You (Common Step 1 Pitfalls)
1) Mixing up translocations
Memorize as a clean mapping:
- Follicular: t(14;18) → BCL2 (anti-apoptosis)
- Burkitt: t(8;14) → MYC (proliferation)
- Mantle cell: t(11;14) → Cyclin D1 (cell cycle)
- DLBCL: often BCL6 (germinal center TF), can be “double-hit”
2) Confusing “indolent” vs “aggressive”
- Indolent: follicular (slow, nodular, hard to cure)
- Aggressive: DLBCL (fast but often curable), Burkitt (very fast, TLS risk), mantle cell (relapsing)
3) Architecture words matter
- Follicular/nodular → follicular lymphoma
- Diffuse sheets → DLBCL
- Starry sky → Burkitt
Diagnosis Workflow (What the vignette wants you to pick)
Best initial diagnostic concept
- Excisional lymph node biopsy is the go-to for lymphoma because you need architecture, not just cells.
Supporting studies you should recognize
- Flow cytometry / immunohistochemistry to confirm B-cell lineage (e.g., CD20).
- Cytogenetics/FISH to identify hallmark translocations.
Treatment Principles You Should Know (Without Turning Step 1 into Step 2/3)
- Anti-CD20 therapy (rituximab) is relevant because many NHL are CD20+ B-cell tumors.
- Aggressive lymphomas can be curable (DLBCL is the classic example).
- Burkitt → tumor lysis syndrome is a frequent board angle; know the lab pattern and clinical risk.
High-Yield Mini-Table: “One-Liner” Memory Hooks
| Disease | One-liner |
|---|---|
| DLBCL | Most common adult NHL; diffuse large cells, rapidly enlarging mass; often BCL6; treat with R-CHOP |
| Follicular | Indolent, painless LAD; t(14;18) → BCL2 (anti-apoptosis); can transform to DLBCL |
| Burkitt | Fastest; t(8;14) MYC; starry sky; endemic EBV jaw vs sporadic abdominal; TLS risk |
| Mantle cell | Older men; t(11;14) Cyclin D1; mantle zone; multiple lymphomatous polyposis |
Quick Self-Check (USMLE-Style)
-
Painless waxing/waning generalized LAD; biopsy shows nodular pattern; translocation t(14;18).
→ Follicular lymphoma (BCL2↑) -
Child with jaw mass in Africa; “starry sky” histology.
→ Burkitt lymphoma (MYC↑, EBV association) -
Older man, diffuse LAD + GI polyposis; t(11;14).
→ Mantle cell lymphoma (Cyclin D1↑) -
Rapidly enlarging extranodal mass; biopsy shows diffuse sheets of large CD20+ cells.
→ DLBCL (often BCL6; R-CHOP)