Lymphomas ( Hodgkin and Non Hodgkin lymphoma )

Summary

Lymphomas are malignant tumors of lymphocytes that arise primarily in lymph nodes and lymphoid tissue. They are divided into two main groups:

• Hodgkin lymphoma (HL): Characterized by Reed–Sternberg (RS) cells. Usually presents in young adults with painless cervical lymphadenopathy and B symptoms. Highly curable.
• Non-Hodgkin lymphoma (NHL): A heterogeneous group of B-cell (85%) or T-cell lymphomas without RS cells. More common, often disseminated at diagnosis, and includes both indolent and aggressive subtypes.

Both groups share clinical features such as painless lymphadenopathy and B symptoms (fever, night sweats, weight loss >10% in 6 months), but differ in pathology, spread, and prognosis. Diagnosis requires an excisional lymph node biopsy (not FNA). Staging uses the Ann Arbor system, and treatment combines chemotherapy (e.g., ABVD for HL, R-CHOP for B-cell NHL) with or without radiation.

Definition and Classification

Lymphomas are solid tumors of the immune system, arising from clonal proliferation of B or T lymphocytes within lymph nodes, spleen, or extranodal lymphoid tissue.

Hodgkin Lymphoma (HL)

• Defined by Reed–Sternberg cells — large, binucleated "owl-eye" cells (CD15+, CD30+).
• Spreads in a contiguous, orderly fashion from one lymph node group to the next.
• Almost always nodal, rarely extranodal.

Non-Hodgkin Lymphoma (NHL)

• A heterogeneous group of lymphomas without RS cells.
• ~85% are B-cell origin; ~15% T-cell or NK-cell.
• Spreads non-contiguously (skip lesions), often extranodal involvement (GI tract, skin, CNS).
• Classified by cell of origin and behavior:
  • Indolent (slow): follicular, marginal zone, small lymphocytic, CLL.
  • Aggressive (fast): diffuse large B-cell lymphoma (DLBCL), mantle cell.
  • Highly aggressive: Burkitt lymphoma, lymphoblastic lymphoma.

Epidemiology and Risk Factors

Hodgkin Lymphoma

• Bimodal age peaks: young adults (15–35 y) and older adults (>55 y).
• Male predominance (except nodular sclerosing subtype → female).
• Risk factors:
  • EBV infection (history of infectious mononucleosis).
  • HIV and immunosuppression.
  • Family history (sibling with HL).

Non-Hodgkin Lymphoma

• More common than HL (~5× incidence). Median age >60 years.
• Risk factors:
  • Immunosuppression: HIV/AIDS, post-transplant (PTLD), congenital immunodeficiency.
  • Autoimmune disease: Sjögren (MALT), Hashimoto thyroiditis, SLE, RA.
  • Chronic infections:
    • H. pylori → gastric MALT lymphoma.
    • EBV → Burkitt, primary CNS lymphoma.
    • HHV-8 → primary effusion lymphoma.
    • HTLV-1 → adult T-cell leukemia/lymphoma.
    • HCV → marginal zone lymphoma.
  • Pesticides, radiation, prior chemotherapy.

Two diseases worth remembering by association: Burkitt lymphoma (endemic African form linked to EBV and the jaw) and gastric MALT lymphoma (regresses with H. pylori eradication).

Clinical Features

Shared features

• Painless lymphadenopathy — firm, rubbery, non-tender lymph node.
  • HL: usually cervical or supraclavicular.
  • NHL: any nodal region; often multiple sites.
• B symptoms (define stage suffix "B"):
  • Fever >38°C
  • Drenching night sweats
  • Unintentional weight loss >10% over 6 months
• Hepatosplenomegaly, fatigue, pruritus.

Features more specific to HL

• Pel–Ebstein fever — cyclical high fever every 1–2 weeks.
• Alcohol-induced lymph node pain (classic but rare).
• Pruritus without rash.
• Mediastinal mass on CXR (esp. nodular sclerosing subtype in young women) → may cause SVC syndrome.

Features more specific to NHL

• Extranodal involvement is common:
  • GI tract (most common extranodal site) — abdominal pain, obstruction, bleeding.
  • Skin — mycosis fungoides / Sézary syndrome (T-cell).
  • CNS — primary CNS lymphoma (HIV patients).
  • Waldeyer's ring, testis, thyroid.
• Bone marrow involvement → cytopenias.
• Burkitt lymphoma: rapidly enlarging jaw (African) or abdominal mass (sporadic).

Hodgkin Lymphoma Subtypes

All classical HL subtypes share the Reed–Sternberg cell — a large, binucleated lymphocyte with prominent eosinophilic nucleoli giving the classic "owl-eye" appearance. RS cells are CD15+ and CD30+ but CD20− and CD45−.

The 4 classical subtypes (in order of frequency):

• Nodular sclerosing (NS) — most common (~70%). Young women, mediastinal mass. Histology: "lacunar cells" in collagen bands. Excellent prognosis.
• Mixed cellularity (MC) — older adults, often HIV/EBV+. Many RS cells with mixed inflammatory background. Intermediate prognosis.
• Lymphocyte-rich — many lymphocytes, few RS cells → best prognosis.
• Lymphocyte-depleted — few lymphocytes, many RS cells → worst prognosis. Elderly, HIV+.

A separate, non-classical type:

• Nodular lymphocyte-predominant HL — contains "popcorn cells" (L&H cells), CD20+, CD15−, CD30−. Behaves more like an indolent B-cell NHL. Excellent prognosis.

Non-Hodgkin Lymphoma Subtypes

NHL is divided by cell of origin (B vs T) and by behavior (indolent vs aggressive). Below are the highest-yield subtypes for the exam.

B-cell NHL (~85%)

• Diffuse large B-cell lymphoma (DLBCL) — most common NHL in adults. Aggressive but curable. Rapidly enlarging nodal/extranodal mass in older adults. Treated with R-CHOP.
• Follicular lymphoma — most common indolent NHL. Translocation t(14;18) → BCL-2 overexpression (anti-apoptosis). Waxing/waning lymphadenopathy. May transform to DLBCL.
• Burkitt lymphoma — highly aggressive, t(8;14) → c-MYC. "Starry sky" appearance on histology (tingible body macrophages). High Ki-67 (~100%). Endemic (African, jaw, EBV), sporadic (abdominal), HIV-related.
• Mantle cell lymphoma — aggressive, older men. t(11;14) → cyclin D1. CD5+ (like CLL but CD23−).
• Marginal zone / MALT lymphoma — indolent, arises in chronically inflamed tissue (gastric — H. pylori; salivary — Sjögren; thyroid — Hashimoto). t(11;18).
• Primary CNS lymphoma — DLBCL of the brain in HIV/AIDS. EBV-driven. Solitary ring-enhancing lesion (differential: toxoplasmosis).

T-cell NHL (~15%)

• Adult T-cell leukemia/lymphoma (ATLL) — HTLV-1. Skin lesions, hypercalcemia, lytic bone lesions.
• Mycosis fungoides / Sézary syndrome — cutaneous T-cell lymphoma. Patches/plaques on skin. Sézary cells in blood with "cerebriform" nuclei.

Key Translocations and Genetics

Most NHL translocations involve the immunoglobulin heavy chain locus on chromosome 14, placing a partner oncogene under strong constitutive expression.

Diagnosis

Step 1 — Initial workup

• CBC — cytopenias if marrow involvement; sometimes eosinophilia in HL.
• LDH — elevated; marker of tumor burden and prognosis (especially NHL).
• ESR — elevated in HL (prognostic).
• Uric acid, calcium, electrolytes — baseline before treatment (tumor lysis risk).
• HIV, HBV, HCV, EBV serologies.
• Peripheral smear — may show abnormal lymphocytes.

Step 2 — Definitive diagnosis: BIOPSY

• Excisional lymph node biopsy is the gold standard — preserves architecture.
• Fine-needle aspiration (FNA) is NOT adequate — destroys architecture.
• Findings:
  • HL: Reed–Sternberg cells (CD15+, CD30+) in a reactive background of lymphocytes, eosinophils, plasma cells.
  • NHL: monoclonal lymphocyte proliferation; classification by immunophenotype (CD20+ → B-cell) and cytogenetics.

Step 3 — Staging workup

• PET/CT of neck, chest, abdomen, pelvis — standard for staging and response assessment.
• Bone marrow biopsy — for advanced HL and most NHL.
• LP if CNS-risk (Burkitt, lymphoblastic, primary CNS, HIV).
• Echocardiogram / MUGA before doxorubicin (cardiotoxicity).
• PFTs before bleomycin (pulmonary fibrosis).

Staging

Both HL and NHL use the Ann Arbor staging system, modified by the Cotswolds and Lugano updates. Staging determines treatment intensity and prognosis.

Examples:

• Stage IIA = two cervical and one supraclavicular node, no B symptoms.
• Stage IIIB = nodes above and below diaphragm + fever and weight loss.
• Stage IVB = bone marrow involvement + B symptoms (advanced).

Management

Hodgkin Lymphoma

• Early stage (I–II): short-course ABVD chemotherapy + involved-field radiation therapy.
• Advanced stage (III–IV): full 6 cycles of ABVD (± radiation to bulky disease).
• Relapsed/refractory: salvage chemo + autologous stem cell transplant; brentuximab vedotin (anti-CD30) and PD-1 inhibitors (nivolumab, pembrolizumab).

ABVD = Adriamycin (doxorubicin) + Bleomycin + Vinblastine + Dacarbazine.

Non-Hodgkin Lymphoma

• DLBCL and other aggressive B-cell NHL: R-CHOP × 6 cycles → curable in ~60–70%.
  • Rituximab (anti-CD20)
  • Cyclophosphamide
  • Hydroxydaunorubicin (doxorubicin)
  • Oncovin (vincristine)
  • Prednisone
• Burkitt lymphoma: intensive multi-agent chemo + intrathecal therapy (CNS prophylaxis) + tumor lysis prophylaxis (rasburicase, hydration, allopurinol).
• Follicular lymphoma (indolent):
  • Asymptomatic, low burden → "watch and wait."
  • Symptomatic → rituximab ± bendamustine or R-CHOP.
• MALT lymphoma (gastric): H. pylori eradication first — regression in >75%. Radiation if no response.
• CLL/SLL: watch-and-wait if asymptomatic; treat with BTK inhibitors (ibrutinib) or BCL-2 inhibitors (venetoclax) when indicated.

Complications and Prognosis

Disease-related complications

• Bone marrow failure → cytopenias, infections.
• SVC syndrome from large mediastinal mass (HL, lymphoblastic NHL).
• Spinal cord compression from epidural mass.
• Tumor lysis syndrome — especially Burkitt and lymphoblastic; can be spontaneous before chemo.
• Hyperviscosity (Waldenström / lymphoplasmacytic).
• Paraneoplastic: hypercalcemia (ATLL), autoimmune hemolytic anemia (CLL/SLL).

Treatment-related (long-term)

• Secondary malignancies — AML/MDS, solid tumors. After mantle radiation for HL: breast cancer, lung cancer, thyroid cancer.
• Cardiotoxicity (doxorubicin, mediastinal RT).
• Pulmonary fibrosis (bleomycin).
• Infertility, hypothyroidism (after RT to neck).

Prognosis

• HL: overall excellent — 5-yr survival ~85–95% in early stage; ~70–80% in advanced.
• DLBCL: ~60–70% cure with R-CHOP. Use the IPI score (age, LDH, performance status, stage, extranodal sites) for prognosis.
• Follicular: incurable but indolent — median survival >15 years.
• Burkitt: highly aggressive but very chemo-sensitive → curable.

Mnemonics