Hodgkin's & Non-Hodgkin's Lymphoma

NON-HODGKIN'S LYMPHOMA (Chapter 113)

Definition & Classification

Epidemiology & Etiology

• ~80,550 new US cases in 2023; 7th most common cancer; 5-year survival ~74%
• Incidence has nearly doubled over 20–40 years, rising 1.5–2%/year
• Male > female; Caucasians > African Americans; incidence rises with age
• Risk factors: HIV, organ transplantation, inherited/acquired immunodeficiency, autoimmune disease
• Geographic variation: T-cell lymphomas more common in Asia; FL more common in Western countries; nasal NK/T-cell lymphoma peaks in Southeast Asia and Latin America; HTLV-1-associated ATL in southern Japan and Caribbean
• Viral associations: EBV (Burkitt's, CNS lymphoma in immunosuppressed), HTLV-1 (ATL), H. pylori (gastric MALT), HCV (splenic marginal zone)

Pathology & Molecular Biology

• Translocations are hallmarks:
  • t(14;18) → BCL2 overexpression → follicular lymphoma (prevents apoptosis)
  • t(8;14) → MYC overexpression → Burkitt's lymphoma
  • t(11;14) → Cyclin D1 overexpression → mantle cell lymphoma
  • t(2;5) → ALK+ anaplastic large-cell lymphoma
• Double-hit lymphoma: concurrent MYC + BCL2 (or BCL6) rearrangements — aggressive, poor prognosis
• Immunophenotyping essential: CD20+ on B cells (therapeutic target for rituximab), CD30+ on Reed-Sternberg-like cells in some large B-cell lymphomas

Clinical Presentation

• Painless lymphadenopathy is the classic presentation
• Extranodal disease common: GI tract (especially MALT), skin (mycosis fungoides), CNS, bone marrow
• Aggressive lymphomas: rapid onset, bulky disease, systemic "B symptoms" (fever >38°C, drenching night sweats, weight loss >10%)
• Indolent lymphomas: often incidental, waxing-and-waning adenopathy, may transform to aggressive disease

Diagnosis & Staging

• Excisional lymph node biopsy is standard (core needle biopsy acceptable if excision not feasible)
• Workup: CBC, LDH, β2-microglobulin, uric acid, HIV serology, CT chest/abdomen/pelvis, PET/CT (for aggressive lymphomas), bone marrow biopsy if clinically relevant
• Ann Arbor staging:
  • Stage I: single lymph node region
  • Stage II: ≥2 regions, same side of diaphragm
  • Stage III: both sides of diaphragm
  • Stage IV: extranodal involvement (liver, bone marrow)
  • "B" suffix = systemic symptoms

Prognostic Indices

• International Prognostic Index (IPI) for aggressive lymphomas (DLBCL):
  • Age >60, Stage III/IV, LDH elevated, ECOG PS ≥2, >1 extranodal site
  • Low (0–1), Low-intermediate (2), High-intermediate (3), High (4–5)
• FLIPI for follicular lymphoma (age, stage, Hgb, nodes, LDH)

Treatment by Subtype

• 1st line: R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone) × 6 cycles — cures ~60–70% of patients
• Addition of polatuzumab vedotin (CD79b ADC) to R-CHP (pola-R-CHP) approved for high-risk untreated DLBCL
• Relapse/refractory: salvage chemotherapy → autologous SCT (late relapse >12 months); CAR-T cell therapy (axi-cel, liso-cel, tisa-cel) for primary refractory or early relapse
• ZUMA-7 and TRANSFORM trials established CAR-T as superior to salvage chemo + auto-SCT in early relapse

• Often asymptomatic at diagnosis; "watch and wait" acceptable if low tumor burden
• Treatment when indicated: rituximab ± bendamustine, R-CHOP, or R-lenalidomide (R2)
• PI3K inhibitors (idelalisib, copanlisib, umbralisib), EZH2 inhibitor tazemetostat for relapsed disease
• Transformation to DLBCL occurs in ~3%/year — treat as de novo DLBCL

• Aggressive despite indolent appearance; rarely curable with conventional chemotherapy
• Young/fit patients: intensive chemo (R-HyperCVAD or R-CHOP alternating with R-cytarabine) → autologous SCT + rituximab maintenance
• BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) for relapsed/refractory

• Highly aggressive; c-MYC translocation; "starry sky" histology
• Must treat rapidly; intensive regimens (CODOX-M/IVAC, HyperCVAD/MA + rituximab); CNS prophylaxis mandatory; cure rates >70% in adults

• Gastric MALT → H. pylori eradication first-line (curative in H. pylori-positive cases)
• Non-gastric or H. pylori-negative: rituximab ± chemotherapy

• Generally poor prognosis; CHOP-based regimens + brentuximab vedotin (for CD30+ subtypes per ECHELON-2 trial)
• Mycosis fungoides: skin-directed therapy (topical corticosteroids, phototherapy, nitrogen mustard) for early disease; systemic therapy (brentuximab, mogamulizumab) for advanced stages

HODGKIN'S LYMPHOMA (Chapter 114)

Definition & Background

1. Classical HL (cHL) — ~95% of HL cases
2. Nodular Lymphocyte-Predominant HL (NLPHL) — biologically more related to indolent B-NHL

Epidemiology & Etiology

• ~8,830 new US cases in 2023
• More common in whites and males
• Bimodal age distribution: peak in 20s, second peak in 80s
• Risk factors: EBV (present in 20–40% of cHL; nearly 100% in HIV-associated cHL), HIV infection
• cHL subtypes by histology:
  • Nodular sclerosis — most common in young patients in developed nations
  • Mixed cellularity — more common in elderly, HIV+, developing countries
  • Lymphocyte-rich — best prognosis
  • Lymphocyte-depleted — worst prognosis, rare
  • Nodular sclerosis + mixed cellularity = ~95% of all cases

Pathology

• HRS cells are the malignant cells but constitute <1% of the tumor mass
• HRS cells express CD15, CD30 (therapeutic targets); lack CD45 and B-cell markers (CD20−)
• Surrounded by reactive T cells, plasma cells, eosinophils, and neutrophils
• NLPHL: "popcorn cells" (lymphocytic and histiocytic cells); CD20+, CD15−, CD30−

Clinical Presentation

• Painless cervical or supraclavicular lymphadenopathy (most common)
• Mediastinal mass common (especially nodular sclerosis) — can cause cough, SVC syndrome
• B symptoms in ~40%: fever, night sweats, weight loss
• Pel-Ebstein fever (periodic high-grade fever): classic but rare
• Alcohol-induced pain at lymph node sites: pathognomonic but rare

Diagnosis & Staging

• Excisional biopsy; immunohistochemistry: CD15+, CD30+, CD45−
• PET/CT is standard for staging and response assessment
• Ann Arbor staging (same as NHL)
• Risk stratification for early-stage disease:
  • Favorable (low-risk): no bulk, <3 nodal areas, no B symptoms, ESR <50
  • Unfavorable (high-risk): bulk, ≥3 areas, B symptoms, elevated ESR

Treatment

• ABVD × 4–6 cycles alone (doxorubicin, bleomycin, vinblastine, dacarbazine): PFS 88–92%, OS 97–100% at 5–7 years
• Abbreviated ABVD × 2 + involved-field RT 20 Gy for particularly favorable disease (German studies)
• PET-adapted therapy: negative interim PET → de-escalate (omit RT or shorten chemo)

• ABVD × 4 cycles + involved-field RT (30 Gy), or ABVD × 6 cycles alone
• PET negativity after chemo may justify omitting RT even in unfavorable disease

• ABVD × 6 cycles OR BV-AVD (brentuximab vedotin + doxorubicin, vinblastine, dacarbazine)
• BV-AVD: in the ECHELON-1 trial, significantly improved modified PFS vs ABVD in advanced-stage cHL; now preferred in many centers
• Escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone): higher response rate but greater toxicity; not superior in OS to ABVD in most trials

• Brentuximab vedotin (CD30-targeted ADC) → high response rates
• Salvage chemo → autologous SCT (curative in ~40–50%)
• Pembrolizumab and nivolumab (PD-1 inhibitors): high response rates in relapsed cHL (50–70%); exploits PD-L1 overexpression on HRS cells driven by 9p24.1 amplification
• Allogeneic SCT for multiply relapsed disease

• Often low-stage at diagnosis; excellent prognosis
• Stage IA: RT alone or rituximab alone
• Advanced stages: treated similarly to indolent NHL (rituximab-based)
• Does not express CD30; brentuximab not appropriate

Late Effects of HL Therapy

• Secondary malignancies (breast cancer, lung cancer, leukemia) — related to RT and alkylating agents
• Cardiovascular disease — premature atherosclerosis, valvular disease (radiation)
• Pulmonary toxicity — bleomycin-induced pneumonitis/fibrosis
• Hypothyroidism — after neck RT
• Current trials focus on minimizing RT field/dose and substituting brentuximab for bleomycin to reduce toxicity while maintaining efficacy

Key Comparisons at a Glance