Lymphoma

Lymphoma – Comprehensive Study Guide for Medical Students

Definition

Lymphoma is a heterogeneous group of malignant neoplasms arising from lymphoid cells, predominantly B cells, T cells, or NK cells, that originate in lymphoid tissues such as lymph nodes, spleen, thymus, and extranodal mucosa-associated lymphoid tissue. It is broadly divided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), each with distinct biology, clinical behavior, and treatment paradigms.[1](https://europepmc.org/article/MED/41830965)

Epidemiology

Globally, lymphomas represent one of the most common hematologic malignancies, with NHL being more frequent than HL. Incidence increases with age, particularly for most NHL subtypes, although HL shows a bimodal age distribution (young adults and older adults). There is geographic variation in subtype distribution (e.g., higher HTLV-1-associated adult T-cell leukemia/lymphoma in endemic regions such as southwestern Japan, parts of Iran, the Caribbean, and West Africa).[3](https://europepmc.org/article/MED/41737423)

Risk factors include underlying immunodeficiency, chronic antigenic stimulation, oncogenic viral infections, prior chemotherapy/radiation, and certain autoimmune diseases.

Pathophysiology

Lymphomas arise from genetic and epigenetic alterations in lymphoid precursors or mature lymphocytes that drive uncontrolled proliferation, survival advantage, and evasion of apoptosis. These changes often involve translocations affecting oncogenes or anti-apoptotic genes (e.g., BCL2, BCL6, MYC in B-cell NHL), dysregulated signaling pathways (e.g., NF-κB, JAK/STAT), and aberrant somatic hypermutation.

In HL, a minority of neoplastic Reed–Sternberg cells and variants arise from germinal center B cells but exist within a rich inflammatory and immune microenvironment that contributes to disease biology and clinical features. In NHL, malignant cells typically form a larger proportion of the tumor mass and more directly infiltrate nodal and extranodal structures.

Certain viral infections are etiologically linked to specific lymphomas: EBV with some HL, Burkitt lymphoma, and diffuse large B-cell lymphoma; HTLV-1 with adult T-cell leukemia/lymphoma; and chronic immune stimulation by persistent infections or autoimmunity can promote lymphomagenesis.[3](https://europepmc.org/article/MED/41737423)

Classification Overview

The WHO/ICC classification divides lymphomas primarily into:

• Hodgkin lymphoma (HL)
  • Classical HL (cHL): nodular sclerosis, mixed cellularity, lymphocyte-rich, lymphocyte-depleted
  • Nodular lymphocyte-predominant HL (NLPHL)
• Non-Hodgkin lymphoma (NHL)
  • B-cell NHL: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, marginal zone lymphoma, etc.
  • T-cell and NK-cell NHL: peripheral T-cell lymphoma, adult T-cell leukemia/lymphoma, anaplastic large cell lymphoma, extranodal NK/T-cell lymphoma, etc.

Clinically, NHL is also grouped as indolent (e.g., follicular) versus aggressive (e.g., DLBCL, Burkitt) based on natural history and treatment urgency.

Clinical Presentation

General Features

Presentation varies widely by subtype and disease burden, but common features include:

• Lymphadenopathy
  • Non-tender, rubbery, persistent lymph node enlargement
  • Cervical, supraclavicular, axillary, or inguinal involvement; may be generalized
  • Mediastinal mass particularly common in nodular sclerosis HL, often detected on imaging
• B symptoms
  • Unexplained fever >38°C
  • Profuse drenching night sweats
  • Unintentional weight loss >10% of body weight over 6 months
• Constitutional symptoms
  • Fatigue, malaise, anorexia

Extranodal Disease

Extranodal involvement is more common in NHL and may manifest as:

• Gastrointestinal tract: abdominal pain, bleeding, obstruction, or mass
• CNS involvement: headaches, focal neurologic deficits, seizures, altered mental status (as in primary CNS lymphoma or secondary CNS involvement)[1](https://europepmc.org/article/MED/41830965)
• Bone marrow: cytopenias, infections, bleeding
• Skin: nodules, plaques, erythematous lesions (especially in cutaneous T-cell lymphomas)
• Testis, breast, lung, salivary glands: site-specific masses or dysfunction

HL vs NHL Clinical Distinctions (Typical Patterns)

• Hodgkin Lymphoma
  • Often presents with localized, contiguous spread of nodal disease
  • Mediastinal mass especially in young adults with nodular sclerosis subtype
  • B symptoms common in advanced disease
• Non-Hodgkin Lymphoma
  • Often noncontiguous nodal and extranodal disease at presentation
  • Indolent forms may present with advanced-stage but relatively asymptomatic disease
  • Aggressive forms present with rapidly enlarging masses and systemic symptoms

Diagnosis

Definitive diagnosis of lymphoma requires integration of clinical, histopathologic, immunophenotypic, and molecular data.

Initial Evaluation

• History and physical examination
  • Duration and distribution of lymphadenopathy
  • Presence of B symptoms or pruritus
  • Exposure history: infections (HBV, HCV, HIV, EBV, HTLV-1), immunosuppression, autoimmune disease
• Baseline labs
  • CBC with differential: anemia, leukocytosis or leukopenia, thrombocytopenia
  • Liver and renal function tests
  • Lactate dehydrogenase (LDH) and uric acid (tumor burden)
  • ESR: often elevated in HL
  • Serologies as appropriate (HIV, HBV, HCV, HTLV-1)

Pathologic Diagnosis

Excisional lymph node biopsy is the gold standard. Core needle biopsy may be used when excision is not feasible, but fine-needle aspiration alone is insufficient for classification. Pathologic work-up includes:

• Histology: architecture (nodular vs diffuse), cytologic features, fibrosis
• Immunohistochemistry (IHC)
  • HL: Reed–Sternberg cells typically CD30+, CD15+, PAX5 weak+, CD45− in cHL
  • B-cell NHL: CD19, CD20, PAX5, subtype markers (BCL2, BCL6, cyclin D1)
  • T-cell NHL: CD3, CD4/CD8, and other lineage markers
• Flow cytometry: helps determine clonality and lineage (B vs T vs NK)
• Cytogenetics/molecular testing: translocations (e.g., t(14;18), t(8;14)), clonality, and mutation profiles guiding prognosis and targeted therapy

Imaging and Staging

Staging uses the Ann Arbor system (with Cotswolds modifications) for HL and often applied to NHL as well.

• PET-CT (FDG-PET)
  • Preferred for HL and most aggressive NHL to assess metabolic activity, staging, and treatment response
• Contrast-enhanced CT of neck, chest, abdomen, pelvis when PET is unavailable
• Bone marrow biopsy
  • Often performed for staging in many NHL subtypes; may be omitted in some HL when PET is negative

The presence of B symptoms is denoted by “A” (absent) or “B” (present) after the stage (e.g., Stage IIIB). Bulky disease may be designated by “X.”

Management

Management is highly subtype- and stage-specific and must balance curative intent with toxicity and long-term survivorship issues. Treatment is increasingly risk-adapted and often guided by prognostic indices and interim PET response.

Hodgkin Lymphoma

• Early-stage (I–II) favorable risk
  • Short-course combination chemotherapy (e.g., ABVD: doxorubicin, bleomycin, vinblastine, dacarbazine) often followed by involved-site radiotherapy (ISRT)
• Early-stage unfavorable / advanced-stage (III–IV)
  • More cycles of ABVD or escalated BEACOPP in selected high-risk patients
  • Interim PET scanning to adapt therapy intensity
• Relapsed/refractory HL
  • Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation
  • Novel agents: brentuximab vedotin (anti-CD30), PD-1 inhibitors in selected cases

Non-Hodgkin Lymphoma

Regimens depend on histologic subtype, grade, and patient factors.

• Aggressive B-cell NHL (e.g., DLBCL)
  • Standard first-line: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
  • Involved-site radiotherapy may be added for bulky or localized disease
  • High-risk for CNS relapse may warrant CNS prophylaxis (e.g., intrathecal methotrexate)
• Indolent B-cell NHL (e.g., follicular lymphoma)
  • “Watchful waiting” for asymptomatic, low-burden disease
  • Rituximab ± chemotherapy (e.g., bendamustine, CHOP, CVP) for symptomatic or high-tumor burden
  • Consider radiotherapy alone for truly localized stage I/II disease
• Highly aggressive NHL (e.g., Burkitt lymphoma)
  • Urgent intensive multiagent chemotherapy with CNS-directed therapy
  • Meticulous tumor lysis syndrome prophylaxis
• T-cell and NK-cell lymphomas
  • Often managed with anthracycline-based regimens (e.g., CHOEP) but with generally poorer outcomes than B-cell counterparts
  • Adult T-cell leukemia/lymphoma related to HTLV-1 may involve antiviral approaches and allogeneic stem cell transplantation in selected cases.[3](https://europepmc.org/article/MED/41737423)

Primary CNS Lymphoma

Primary CNS lymphoma (PCNSL), often a DLBCL confined to the CNS, eye, or leptomeninges, requires CNS-penetrant therapy. Standard management is based on high-dose methotrexate-based chemotherapy with or without additional agents and consolidation (e.g., reduced-dose whole-brain radiotherapy or high-dose chemotherapy with autologous stem cell rescue). Stereotactic radiosurgery has been explored as a salvage or adjunct option in CNS lymphoma management, particularly for focal lesions or relapsed disease.[1](https://europepmc.org/article/MED/41830965)

Supportive and Psychosocial Care

Comprehensive lymphoma care extends beyond cytotoxic and targeted therapy and should incorporate:

• Management of treatment toxicities: myelosuppression, infections, mucositis, neuropathy, cardiotoxicity
• Fertility preservation discussions in younger patients before gonadotoxic therapy
• Survivorship care: monitoring for secondary malignancies, cardiovascular disease, endocrine disorders, and late neurologic effects
• Psychosocial support: addressing anxiety, depression, financial toxicity, and impact on quality of life, which are increasingly recognized as essential components of lymphoma care policy.[4](https://europepmc.org/article/MED/41677904)

Key Clinical Pearls

• Always obtain an adequate excisional biopsy when possible; subtype classification guides therapy and prognosis.
• B symptoms and bulky disease are important for staging, risk stratification, and treatment planning.
• PET-CT is central in staging and response assessment for HL and many aggressive NHLs.
• Indolent NHL may be advanced at diagnosis but often does not require immediate therapy; symptom burden and clinical risk scores guide initiation of treatment.
• Primary CNS lymphoma and other CNS-involved lymphomas require CNS-penetrant regimens; conventional systemic regimens like R-CHOP alone are inadequate for CNS disease.[1](https://europepmc.org/article/MED/41830965)
• Consider infectious and autoimmune backgrounds such as HTLV-1, HIV, HCV, and Sjögren syndrome when evaluating etiologic context.[3](https://europepmc.org/article/MED/41737423)
• Patients may present with oral manifestations (e.g., gingival or palatal masses, ulcerations), so careful head and neck/oral examination is important, particularly in those with systemic disease.[5](https://europepmc.org/article/MED/41731818)
• Survivorship and psychosocial issues should be addressed early, as long-term physical and mental health burden can be substantial even in curable subtypes.[4](https://europepmc.org/article/MED/41677904)

High-Yield Exam Points for Medical Students

• HL: Reed–Sternberg cells, CD15+/CD30+, bimodal age distribution, contiguous nodal spread, good prognosis with combination chemotherapy.
• NHL: diverse subtypes, often noncontiguous nodal and extranodal involvement, classification and IHC pattern critical for diagnosis.
• B symptoms: fever, night sweats, weight loss >10%/6 months – modify staging and prognosis.
• DLBCL: most common NHL, aggressive but potentially curable with R-CHOP.
• Follicular lymphoma: indolent, often presents with advanced disease; watch-and-wait is appropriate for asymptomatic, low-burden cases.
• Primary CNS lymphoma: treat with high-dose methotrexate-based regimens; radiotherapy and stereotactic radiosurgery may be used as adjuncts or salvage approaches.[1](https://europepmc.org/article/MED/41830965)