What is Lymphoma?
Lymphoma is a group of malignant neoplasms arising from clonal proliferation of lymphocytes within the lymphatic system, comprising over 90 distinct subtypes that are broadly classified into two main categories: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). 1, 2
Classification and Subtypes
Lymphoma is traditionally divided into two major categories based on the WHO classification 3:
Hodgkin Lymphoma (HL)
- Classical Hodgkin lymphoma (CHL) accounts for approximately 95% of all HL cases and is characterized by the presence of Reed-Sternberg cells (large malignant cells expressing CD15+/CD30+/CD20-) in an inflammatory background 3
- CHL includes four histologic subtypes: lymphocyte-rich, nodular sclerosis, mixed cellularity, and lymphocyte-depleted 3
- Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) represents approximately 5% of cases, characterized by lymphocyte-predominant cells (L & H cells or "popcorn cells") with a distinct immunophenotype (CD15-/CD30-/CD20+) 3
Non-Hodgkin Lymphoma (NHL)
- Represents approximately 90% of all lymphomas and includes over 30 unique subtypes 1, 2
- B-cell lymphomas account for approximately 90% of NHL cases 4
- T-cell and NK-cell lymphomas comprise the remaining cases 3
Major B-Cell NHL Subtypes 3:
- Diffuse large B-cell lymphoma (DLBCL): accounts for 30-40% of adult NHL, representing the most common aggressive subtype 5
- Follicular lymphoma: second most frequent nodal lymphoid malignancy in Western Europe 3
- Chronic lymphocytic leukemia/small lymphocytic lymphoma
- Mantle cell lymphoma
- Marginal zone lymphomas (MALT type, nodal, splenic)
- Burkitt's lymphoma
T-Cell and NK-Cell NHL Subtypes 3:
- Peripheral T-cell lymphomas
- Extranodal NK/T-cell lymphoma, nasal type
- Mycosis fungoides/Sézary syndrome
- Anaplastic large cell lymphoma
Epidemiology
Incidence
- Hodgkin lymphoma: crude incidence of 2.3 cases per 100,000 population per year in the European Union, with mortality of 0.4 per 100,000 per year 5
- DLBCL: crude incidence of 3.8 cases per 100,000 per year in Europe 5
- Approximately 82,000 new lymphoma cases are diagnosed annually in the United States 1
- NHL incidence has increased worldwide by approximately 30% in the 5 years prior to 2010 5
Age Distribution
- HL demonstrates a bimodal age distribution with peaks in young adults aged 20-40 years and in individuals aged 55 years and older 3, 5
- Most HL patients are diagnosed between 15 and 30 years of age 3
- NHL can affect all age groups but incidence increases with age 1
Gender
- Slightly more men than women are diagnosed with HL 5
Pathophysiology
Cellular Origin
- Hodgkin lymphoma: malignant Reed-Sternberg cells represent only 0.1-1% of the tumor mass, with the remainder consisting of a heterogeneous inflammatory infiltrate including lymphocytes, histiocytes, eosinophils, plasma cells, and fibroblasts 3
- NHL: arises from clonal proliferation of lymphocytes at various stages of differentiation 2
- Most lymphomas are of B-cell origin, though T-cell and NK-cell variants exist 4
Immunophenotyping
Critical for diagnosis and classification 3:
- Classical HL: CD15+, CD30+, CD20- 3
- NLPHL: CD15-, CD30-, CD20+ 3
- B-cell NHL: typically CD20+, CD79a+ with variable expression of other markers 3
- T-cell NHL: variable expression of CD2, CD3, CD4, CD5, CD7, CD8 3
- NK-cell lymphomas: CD2+, surface CD3-, cytoplasmic CD3ε+, CD56+, EBV-EBER+ 3
Clinical Presentation
Common Presenting Features
- Painless lymphadenopathy is the most common presentation, with over 60% of HL patients initially observing enlarged cervical lymph nodes 3, 1
- Lymphoma typically presents as painless adenopathy in accessible lymph node regions 1
B Symptoms
Present in more advanced disease and include 3, 1:
- Fever (>38°C)
- Unexplained weight loss (>10% body weight in 6 months)
- Drenching night sweats
Site-Specific Presentations
- Extranodal NK/T-cell lymphoma: predominantly affects the upper aerodigestive tract (nasal cavity, nasopharynx, paranasal sinuses), but can involve skin, testis, and gastrointestinal tract 3
- Primary cutaneous lymphomas: present with patches, plaques, nodules, or tumors on the skin 3
- Other lymphoid organs that can be involved include spleen, liver, bone marrow, and lung 3
Diagnosis
Tissue Biopsy Requirements
- Excisional lymph node biopsy is the gold standard for diagnosis of lymphoma 3, 1
- Core needle biopsies should only be performed when easily accessible lymph nodes are not available (e.g., retroperitoneal masses) 3
- Fine needle aspiration is inappropriate for reliable diagnosis 3
- For NK/T-cell lymphomas, biopsy specimens should include edges of lesions to increase odds of obtaining viable tissue, as necrosis is very common 3
Pathologic Evaluation
The histological report must include 3:
- Diagnosis according to WHO classification
- Histologic grade (for follicular lymphoma: grade 1-2 with ≤15 blasts/high-power field; grade 3 with >15 blasts) 3
- Specification if more than one histologic type is present (composite lymphoma)
- Statement regarding specimen adequacy
- Results of ancillary studies (immunohistochemistry, molecular diagnostics) 3
Essential Immunophenotyping
Must specify 3:
- All markers investigated (both positive and negative)
- CD nomenclature for antigen identification
- Which cell population expresses each antigen
- Percentage of positive cells when relevant
- Whether expression is focal or diffuse
Molecular Studies
- Molecular analysis to detect clonal T-cell receptor (TCR) gene rearrangements for T-cell lymphomas 3
- EBV viral load by quantitative PCR is important for diagnosis and monitoring of NK/T-cell lymphomas; lack of normalization suggests persistent disease 3
- Clonality assessment may be helpful but cannot definitively distinguish low-grade B-cell lymphomas from reactive processes 3
Staging and Risk Assessment
Staging System
- Ann Arbor staging system (modified by Cotswolds classification) is used for HL 3
- Lugano Classification has modernized staging recommendations for both HL and NHL, formally incorporating FDG-PET/CT 5
Risk Stratification for HL 3:
Early-stage favorable (Stage I-II without risk factors)
Early-stage unfavorable (Stage I-II with any of the following):
- Bulky mediastinal disease (mediastinal mass ratio >0.33) or bulky disease >10 cm
- B symptoms
- ESR >50 (or >30 without B symptoms)
- More than 3 nodal sites of disease
- Extranodal disease
Advanced-stage (Stage III-IV):
- International Prognostic Score (IPS) determines prognosis based on number of adverse factors present at diagnosis 3
Essential Staging Workup for HL 3:
- History and physical examination with attention to all node-bearing areas including Waldeyer's ring
- Assessment for B symptoms
- Performance status
- Complete blood count with differential
- Comprehensive metabolic panel, LDH, uric acid
- Bone marrow biopsy and aspirate
- CT scans of chest, abdomen, and pelvis with contrast or PET/CT scan
- Echocardiogram or MUGA scan if anthracycline-containing regimens planned
Staging for NK/T-Cell Lymphoma 3:
- ENT evaluation of nasopharynx
- Dedicated CT or MRI of nasal cavity, hard palate, anterior fossa, nasopharynx
- Calculation of Prognostic Index of Natural Killer Lymphoma (PINK)
- EBV viral load by quantitative PCR
- Bone marrow biopsy showing EBER-1 positive lymphoid aggregates indicates involvement
Modern Staging Considerations
- FDG-PET/CT has been formally incorporated into standard staging for FDG-avid lymphomas 5
- Bone marrow biopsy is no longer indicated for routine staging of HL and most diffuse large B-cell lymphomas 5
Treatment Principles
Hodgkin Lymphoma
- Chemotherapy or combined modality therapy (chemotherapy plus radiotherapy) is standard initial treatment 3
- Early-stage favorable disease: 2 cycles of ABVD followed by 30 Gy involved field radiotherapy 3
- Advanced-stage disease: ABVD, Stanford V, or BEACOPP chemotherapy regimens with or without radiotherapy 1
- Relapsed/refractory disease: brentuximab vedotin (CD30-directed antibody-drug conjugate) has shown encouraging results 3
- High-dose chemotherapy with autologous stem cell transplantation for recurrent disease 6
Non-Hodgkin Lymphoma
Aggressive NHL (e.g., DLBCL) 7, 1:
- R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is standard first-line therapy
- Treated with curative intent due to chemosensitivity despite aggressive behavior 4
Indolent NHL (e.g., follicular lymphoma) 3:
- Stage I-II: radiotherapy (30-40 Gy involved or extended field) has curative potential
- Stage III-IV: chemotherapy initiated only upon occurrence of symptoms, B symptoms, hematopoietic impairment, bulky disease, or rapid progression
- Rituximab in combination with chemotherapy (CHOP, CVP, or purine analog-based regimens) for complete remission
- Generally incurable, requiring balance between quality of life and treatment toxicity 4
Pediatric mature B-cell NHL and B-cell acute leukemia 7:
- Rituximab in combination with chemotherapy for previously untreated advanced-stage disease
Treatment Considerations
- Long-term toxicities include neuropathy, cardiotoxicity, and secondary cancers (lung, breast) that must be discussed in shared decision-making 1
- Potential long-term treatment effects remain an important consideration requiring long-term follow-up 3
Prognosis
Hodgkin Lymphoma
- HL is now curable in at least 80% of patients 3
- 5-year survival rates have improved dramatically over the past four decades 3
- Mortality rate is 0.4 per 100,000 per year in the European Union 5
Non-Hodgkin Lymphoma
- Prognosis varies widely depending on subtype and stage 2
- Aggressive lymphomas are more dangerous if untreated but more chemosensitive, allowing curative treatment 4
- Indolent lymphomas are largely incurable but have prolonged survival with appropriate management 4
- Smoking, alcohol consumption, and obesity before diagnosis are associated with poorer overall and lymphoma-specific survival 5
Risk Factors
Modifiable Risk Factors 5, 1:
- Tobacco use
- Obesity (particularly high body mass as a young adult)
- Certain occupational exposures
- Environmental factors including pesticide exposure
Non-Modifiable Risk Factors 5:
- Family history of lymphoma
- Autoimmune diseases
- HIV infection
- Hepatitis C virus (HCV) seropositivity
- Infectious diseases (including EBV for certain subtypes)
Surveillance and Follow-Up
Post-Treatment Monitoring
- Routine surveillance is essential to monitor for complications and relapse 1
- PET/CT restaging using Deauville criteria (5-point scale) to assess treatment response 3
- Age-appropriate cancer screenings per U.S. Preventive Services Task Force recommendations 1