Non-Hodgkin's Lymphoma¶
Chapter 113 | Part 4: Oncology and Hematology · Part 4 – Oncology: Hematologic Malignancies · Chapter 113
Key Clinical Points¶
- NHL incidence has nearly doubled over the past 20–40 years and continues to rise by 1.5–2% each year.
- Approximately 90% of all lymphomas are of B-cell origin; ~80–85% of HL patients are cured, whereas NHL prognosis is more variable.
- The International Prognostic Index (IPI) uses 5 risk factors: Age ≥60, elevated LDH, Performance status ≥2 (ECOG) or ≤70 (Karnofsky), Stage III/IV, and >1 extranodal site.
- Burkitt's lymphoma has a doubling time of <24 hours and requires immediate intensive chemotherapy with CNS prophylaxis.
- DLBCL is the most common NHL subtype (30% of cases), with median age at diagnosis of 64.
- Gene expression profiling identifies GCB and ABC subtypes of DLBCL, with GCB-like having a better prognosis.
- Infectious agents like EBV, HTLV-1, HIV, HCV, and H. pylori are associated with specific NHL subtypes.
- FDG-PET is useful for aggressive lymphomas (DLBCL, BL) but PET during therapy is recommended only as part of clinical trials.
- Relapsed DLBCL may be treated with CD79b ADC polatuzumab, tafasitamab, loncastuximab, or bispecific antibodies.
- Approximately 30% of NHLs in immunosuppressed patients arise as polyclonal B-cell proliferation evolving into clonal malignancy.
1. DEFINITION & OVERVIEW¶
• Definition: Non-Hodgkin's lymphomas (NHLs) are cancers of mature B, T, and natural killer (NK) cells. • Distinction from HL: Characterized by the absence of Reed-Sternberg cells and distinct biological features. • Classification Basis: Classification depends on cell lineage: B-cell or T/NK-cell origin. • Clinical Behavior: Aggressive subtypes grow rapidly, while indolent subtypes progress slowly. • Prognosis: Prognosis is more variable in NHL than in Hodgkin's lymphoma (HL), which has an ~80–85% cure rate.
1.1 WHO Classification¶
The WHO-HAEM5 classification categorizes lymphoid neoplasms into B-cell and T-cell mature (peripheral) neoplasms.
2. EPIDEMIOLOGY¶
• Incidence: In 2023, ~80,550 new NHL cases in the US (~4% of all cancers). • Comparison: Incidence is 10x higher than HL, plasma cell disorders, or lymphoid leukemias. • Trends: Rising by 1.5–2%/year since the 1980s. • Demographics: Slight male predominance; higher incidence in Caucasians. Age-related: peaks after 40 but also common in adolescents. • Risk Factors (Immunodeficiency): Immunodeficiency states (HIV, post-transplant) increase risk.
2.1 Risk Factors¶
• Environmental: Agricultural chemicals, prior HL treatment (radiation), immunosuppression (organ transplant, HIV). • Genetic/Inherited: Inherited immunodeficiencies (XLP, Wiskott-Aldrich); ~9% of lymphoma patients have a first-degree relative with NHL/HL/CLL. • Autoimmune Association: Autoimmune diseases (Sjögren's, celiac) associate with MALT lymphoma.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Developmental Origin: Lymphoid cells derive from hematopoietic progenitors. • B-cell Path: Commitment occurs via PAX5 expression and immunoglobulin gene rearrangement. Errors in somatic hypermutation and class switching contribute to oncogenesis. • T-cell Path: Development involves NOTCH-1 and TCR gene rearrangement. • Genetics of DLBCL: Gene expression profiling identifies GCB (better prognosis) vs ABC (worse prognosis). • High-Risk Features: Double-hit lymphoma (MYC+BCL2 rearrangements) has poor outcomes.
3.1 B-cell Differentiation Pathway¶
• Mantle zone B cells: HLA-DR+, CD19+, CD10+/- , CD20+, CD22+, CD21+, CD5+ → correlates with Mantle zone lymphoma. • Intermediate transition (IgM+): Indicates progression toward marginal zone. • Secretory B cells: CD19+, CD20+, CD38+, PCA-1+, IgM+ or IgM+/IgD+ → correlates with SL and LL. • Developmental Progression: Mantle zone B cells → [Transition via IgM expression] → Secretory B cells.
3.2 T-cell Differentiation Pathway¶
• Stage I Prothymocyte: CD: 2, 7, 38, 71. • Stage II Thymocyte: CD: 1, 2, 4, 7, 8, 38. • Stage III Thymocyte: CD: 2, 3, 4/8, 5, 6, 7; TCR (T-cell receptor) → marks transition to mature-capable cell. • Mature T Helper Cell: CD: 2, 3, 4, 5, 6, 7; TCR. • Mature T Cytotoxic/Suppressor Cell: CD: 2, 3, 5, 6, 7, 8; TCR. • Developmental Progression: Prothymocyte → Stage II Thymocyte → Stage III Thymocyte → Mature T cells (Helper or Cytotoxic).
3.3 Genetic Features¶
• B-cell Translocations: → t(8;14) (MYC/IgH) → Burkitt's lymphoma → t(14;18) (BCL2/IgH) → Follicular lymphoma, DLBCL → t(11;14) (CCND1/IgH) → Mantle cell lymphoma, multiple myeloma → t(11;18) (API2/MALT1) → MALT lymphoma → t(9;14) (PAX5/IgH) → Lymphoplasmacytic lymphoma • T-cell Translocations: → inv(14), t(14;14) (TCRα/TCL1) → Peripheral T-cell lymphoma, T-PLL → t(2;5), t(1;2), t(2;3), t(2;17), inv(2) → Various ALK-related lymphomas (e.g., ALCL).
4. CLINICAL FEATURES¶
• General Presentation: Symptoms vary by progression rate (aggressive vs. indolent). • B symptoms: Fever, night sweats, weight loss. • Localizing symptoms: Chest, abdomen, CNS involvement. • Physical Exam: Lymphadenopathy, hepatosplenomegaly, Waldeyer's ring, effusions, masses, cutaneous lesions. • Laboratory Workup: CBC, chemistries, LDH, β-microglobulin, serum protein electrophoresis.
4.1 Specific Subtypes¶
• Burkitt's lymphoma: → Rapid doubling time (<24h) → Requires immediate CNS prophylaxis → 80–90% cure rate with intensive chemotherapy (Magrath, EPOCH-R). • DLBCL: → Most common NHL (~30% of cases) → Median age at diagnosis: 64 → Advanced stage in 60–70% of patients → Prognostic factors: IPI score, LDH, extranodal sites. → Subtypes: GCB (better prognosis) vs ABC (worse prognosis). → Double-hit lymphoma (MYC+BCL2): Poor outcomes.
5. DIFFERENTIAL DIAGNOSIS¶
• Primary Differentials: Hodgkin's lymphoma, reactive lymphadenopathy, infectious mononucleosis, autoimmune disorders (Sjögren's, lupus), other hematologic malignancies (CLL, myeloma). • Distinguishing Features: Absence of Reed-Sternberg cells in NHL, immunophenotype, genetic abnormalities, and PET/CT findings.
6. INVESTIGATIONS & DIAGNOSIS¶
- Initial Laboratory Evaluation: → CBC, chemistries, LDH, β-microglobulin, serum protein electrophoresis.
- Imaging Studies: → CT scan (standard for all) → FDG-PET/CT (preferred for aggressive NHL like DLBCL and Burkitt's).
- Tissue Diagnosis: → Biopsy with immunohistochemistry (CD19, CD20, CD79a for B-cell; TCR expression for T-cell).
- Staging & Site Assessment: → Bone marrow biopsy (standard staging). → Lumbar puncture (required for high-risk cases: Burkitt's, DLBCL with positive marrow, or involvement of testes, breast, paranasal sinuses).
- Ann Arbor Staging (Table 113-6): → Stage I: Single lymph node region or single extranodal site. → Stage III: Involvement of lymph node regions on both sides of the diaphragm (may include spleen, or limited, contiguous, extralymphatic organ/tissue, or both).
7. MANAGEMENT & TREATMENT¶
- General Strategy: Treatment depends on subtype and stage.
- Aggressive NHL (e.g., DLBCL): → First-line: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for 6 cycles. → High-risk/Double-hit: More aggressive approaches required.
- Burkitt's Lymphoma: → Immediate intensive chemotherapy (Magrath, EPOCH-R). → Mandatory CNS prophylaxis.
- Relapsed/Refractory DLBCL: → CD79b ADC (polatuzumab) → Tafasitamab → Loncastuximab → Bispecific antibodies (epcoritamab).
- Indolent NHL: → Early-stage: Watchful waiting. → Advanced disease: Rituximab-based chemotherapy.
7.1 Treatment of DLBCL¶
• Standard First-line: R-CHOP (6 cycles). • Risk Stratification: Based on IPI score, LDH, and extranodal sites. • Relapsed/Refractory Options: CD79b ADC (polatuzumab), bispecific antibodies (epcoritamab), CAR-T therapy.
8. PROGNOSIS & COMPLICATIONS¶
• Prognosis by Subtype: → DLBCL: 5-year survival ~60–70%. → Burkitt's lymphoma: 80–90% cure rate with timely treatment. • Complications: Infection (immunodeficiency), tumor lysis syndrome, CNS relapse (especially in BL or testicular NHL), and secondary malignancies.
International Prognostic Index (IPI)¶
• Risk Factors: Age ≥60; LDH elevated; Performance status ≥2 (ECOG) or ≤70 (Karnofsky); Ann Arbor stage III/IV; >1 extranodal site. • DLBCL Outcomes (Standard): → 0-1 factor: Low risk (35% of cases; 5-year survival 73%). → 2 factors: Low-intermediate risk (27% of cases; 5-year survival 51%). → 3 factors: High-intermediate risk (22% of cases; 5-year survival 43%). → 4-5 factors: High risk (16% of cases; 5-year survival 26%). • DLBCL Outcomes (R-CHOP): → 0 factor: Good (10% of cases; 4-year survival 94%). → 1-2 factors: Intermediate (45% of cases; 4-year survival 80%). → 3-5 factors: Poor (45% of cases; 4-year survival 53%).
9. SPECIAL CONSIDERATIONS¶
• Immunocompromised Patients: → 30% of NHLs arise from polyclonal B-cell proliferation evolving into clonal malignancy. → EBV association is common in these patients. • HIV-related NHL: More aggressive, higher LDH, poorer prognosis. • Post-transplant Lymphoma: High risk for CNS involvement.
9.1 Immunodeficiency¶
• Risk Factors: HIV, post-transplant, genetic disorders (XLP, Wiskott-Aldrich). • Associations: MALT lymphoma in autoimmune diseases (Sjögren's, Hashimoto's).
10. KEY PEARLS & CLINICAL TRAPS¶
• IPI Score: Critical for determining prognosis and treatment intensity in DLBCL. • Imaging Choice: FDG-PET is standard for aggressive NHL (DLBCL, BL); CT is used for indolent types. • DLBCL Subtypes: GCB-like has a better prognosis than ABC-like. • Burkitt's Alert: Requires immediate CNS prophylaxis and intensive chemotherapy due to <24h doubling time. • Clinical Trap: Avoid over-treatment of indolent NHL; recognize 'double-hit' (MYC+BCL2) as high-risk.
Reference Tables¶
TABLE 113-1 WHO-HAEM5 Classification of Lymphoid Malignancies B CELL Mature (peripheral) B-cell neoplasms¶
Harrison's 22e, p.857
| B CELL | T CELL |
|---|---|
| Mature (peripheral) B-cell neoplasms | Mature (peripheral) T-cell neoplasms |
| L ymphoplasmacytic lymphoma (Waldenström’s macroglobulinemia) Hairy cell leukemia S plenic marginal zone B-cell lymphoma E xtranodal marginal zone B-cell lymphoma of MALT type N odal marginal zone B-cell lymphoma Follicular lymphoma Mantle cell lymphoma D iffuse large B-cell lymphoma (including subtypes) H igh-grade B-cell lymphoma with MYC and BCL2 rearrangements High-grade B-cell lymphoma NOS H igh-grade B-cell lymphoma with 11q aberrations B urkitt’s lymphoma/Burkitt’s cell leukemia P rimary mediastinal large B-cell lymphoma Mediastinal grey zone lymphoma P rimary large B-cell lymphoma of immune-privileged sites |
T-cell granular lymphocytic leukemia |
| Adult T-cell leukemia/lymphoma (HTLV-1+) |
|
| Extranodal NK/T-cell lymphoma, nasal type |
|
| Enteropathy-associated T-cell lymphoma |
|
| Hepatosplenic T-cell lymphoma | |
| Subcutaneous panniculitis-like T-cell lymphoma |
|
| Mycosis fungoides | |
| Sezary syndrome | |
| Peripheral T-cell lymphoma NOS | |
| Angioimmunoblastic T-cell lymphoma |
|
| Anaplastic large-cell lymphoma, ALK+ |
|
| Anaplastic large-cell lymphoma, ALK– |
|
| Plasmablastic lymphoma | |
| Primary effusion lymphoma | |
| HHV8+ DLBCL NOS | |
| Intravascular large B-cell lymphoma | |
| ALK+ large B-cell lymphoma |
TABLE 113-2 Infectious Agents Associated with the Development of Lymphoid Malignancies¶
Harrison's 22e, p.858
| INFECTIOUS AGENT | LYMPHOID MALIGNANCY |
|---|---|
| Epstein-Barr virus | Burkitt’s lymphoma |
| Post–organ transplant lymphoma | |
| Primary CNS diffuse large B-cell lymphoma | |
| Hodgkin’s lymphoma | |
| Extranodal NK/T-cell lymphoma, nasal type |
TABLE 113-3 Diseases or Exposures Associated with Increased Risk of Development of Malignant Lymphoma Inherited…¶
Harrison's 22e, p.858
| Inherited immunodeficiency disease Klinefelter’s syndrome Chédiak-Higashi syndrome Ataxia-telangiectasia syndrome Wiskott-Aldrich syndrome Common variable immunodeficiency disease Acquired immunodeficiency diseases Iatrogenic immunosuppression HIV-1 infection Acquired hypogammaglobulinemia |
Autoimmune disease Sjögren’s syndrome Celiac sprue Rheumatoid arthritis and systemic lupus erythematosus Chemical or drug exposures Phenytoin Dioxin, phenoxy herbicides Radiation Prior chemotherapy and radiation therapy Anti-TNF drugs |
|---|---|
| HIV | Diffuse large B-cell lymphoma |
| Burkitt’s lymphoma | |
| Helicobacter pylori | Gastric MALT lymphoma |
TABLE 113-4 Genetic Features of B- and T-Cell Lymphomas¶
Harrison's 22e, p.860
| GENETIC FEATURE | GENES | LYMPHOMA |
|---|---|---|
| t(8;14) t(2;8) t(8;22) |
MYC/IgH MYC/Igκ MYC/Ig λ |
Burkitt’s lymphoma |
| BCL1 (CCND1)/IgH | ||
| t(14;18) t(3;14) |
BCL2/IgH BCL6/IgH |
Follicular lymphoma, diffuse large B-cell lymphoma (DLBCL) |
| API2/MALT1 BCL10/IgH MALT1/IgH FOXP1/IgH |
||
| Trisomy 3 7q21 deletion |
Unknown CDK6 |
Splenic marginal zone lymphoma |
| PAX5/IgH Unknown |
||
| inv(14) t(14;14) |
TCRα/TCL1 | Peripheral T-cell lymphoma, NOS; T-PLL |
| NPM1/ALK TPM3/ALK TFG/ALK CTLC/ALK ATIC/ALK |
||
| Trisomy 3 Trisomy 5 |
Unknown Unknown |
Angioimmunoblastic T-cell lymphoma |
| Unknown | ||
| THYMUS | ||
| CD: 2, 7, 38, 71 | ||
| CD: 1, 2, 4, 7, 8, 38 | ||
| CD: 2, 3, 4/8, 5, 6, 7; TCR | ||
| CD: 2, 7, 38, | ||
| CD: 1, | ||
| 4, 7, 8, 38 | ||
| RAL BLOOD | ||
| 2, 3, 4, 5, 6, |
TABLE 113-6 Ann Arbor Staging for Lymphoma a STAGE I II¶
Harrison's 22e, p.861
| STAGE | DESCRIPTION |
|---|---|
| I | Involvement of a single lymph node region (I) or single extranodal site (IE) |
| III | Involvement of lymph node regions on both sides of the diaphragm (III), which may include the spleen (IIIS), or limited, contiguous, extralymphatic organ or tissue (IIIE), or both (IIIES) |
TABLE 113-7 International Prognostic Index for NHL Five Clinical Risk Factors Age ≥60 years Serum lactate dehydrogenase…¶
Harrison's 22e, p.861
| Five Clinical Risk Factors | |
|---|---|
| Age ≥60 years | |
| Serum lactate dehydrogenase levels elevated | |
| Performance status ≥2 (ECOG) or ≤70 (Karnofsky) | |
| Ann Arbor stage III or IV | |
| >1 site of extranodal involvement | |
| For Diffuse Large B-Cell Lymphoma | |
| 0, 1 factor = low risk | 35% of cases; 5-year survival, 73% |
| 2 factors = low-intermediate risk | 27% of cases; 5-year survival, 51% |
| 3 factors = high-intermediate risk | 22% of cases; 5-year survival, 43% |
| 4, 5 factors = high risk | 16% of cases; 5-year survival, 26% |
| For Diffuse Large B-Cell Lymphoma Treated With R-CHOP | |
| 0 factor = good | 10% of cases; 4-year survival, 94% |
| 1, 2 factors = intermediate | 45% of cases; 4-year survival, 80% |
| 3, 4, 5 factors = poor | 45% of cases; 4-year survival, 53% |
TABLE 113-5 Staging Evaluation for Non-Hodgkin’s Lymphoma Physical examination Documentation of B symptoms Laboratory…¶
Harrison's 22e, p.861
- Physical examination
- Documentation of B symptoms
- Laboratory evaluation
- Complete blood counts
- Liver function tests
- Uric acid
- Calcium
- Serum protein electrophoresis
- Serum β-microglobulin
2 - Chest radiograph
- CT scan of abdomen, pelvis, and usually chest
- Bone marrow biopsy
- Lumbar puncture in lymphoblastic, Burkitt’s, and diffuse large B-cell lymphoma
with positive marrow biopsy - Gallium scan (SPECT) or PET scan in large-cell lymphoma