Hodgkin Lymphoma

Overview

Epidemiology

• Incidence: ~2.7 per 100,000 in North America; approximately 30,000 new cases annually in North America and Europe
• Bimodal age distribution: early peak at ages 25-30 years, later peak after age 50
• Slightly more common in men; higher rates in Whites and higher socioeconomic groups
• Lifetime risk approximately 1 in 250-300 in North America
• Low incidence in East Asia; in the Indian subcontinent, the age distribution shifts strongly into childhood
• Goldman-Cecil Medicine, p. 1964

Pathogenesis & Etiology

• EBV is identified in RS cells in ~50% of all HL cases (up to 70% in the mixed-cellularity subtype)
• A history of infectious mononucleosis increases HL risk approximately 3-fold
• Integration site is identical in all RS cells per case, confirming infection precedes clonal expansion
• Anti-EBV antibodies appear several years before tumor development
• EBV is likely one of several oncogenic steps, not the sole cause

• Loss of beta-2 microglobulin → failure to express MHC class I molecules (hiding from cytotoxic T cells)
• High-level expression of PD-L1 and PD-L2 (immune checkpoint ligands) - often due to amplification of chromosome 9p region
• This PD-1/PD-L1 axis is clinically exploitable: anti-PD-1 antibodies produce responses even in chemotherapy-resistant disease

• Robbins & Kumar, pp. 417-419

Reed-Sternberg Cell - The Diagnostic Hallmark

• An enormous multilobate nucleus or two mirror-image nuclei/lobes
• Exceptionally prominent nucleoli (inclusion-like, acidophilic), surrounded by a clear halo - the classic "owl-eye" appearance
• Abundant eosinophilic cytoplasm

• Positive: CD15, CD30
• Negative: CD45 (leukocyte common antigen), B-cell markers (CD20), T-cell markers

• Robbins & Kumar, p. 418

Classification - Five Subtypes

Classic Hodgkin Lymphoma (~90% of cases)

Nodular Lymphocyte-Predominant HL (~10% of cases)

• Distinct entity: RS cell variants ("popcorn cells" or LP cells) express germinal center B-cell markers including CD20, CD79a
• CD15 negative, CD30 negative (key distinction from classic HL)
• Indolent course; excellent prognosis; late relapses possible
• Robbins & Kumar, p. 417; Goldman-Cecil Medicine, p. 1963

Clinical Features

• Painless lymphadenopathy - most commonly cervical, supraclavicular, or axillary
• Mediastinal involvement is very common (especially nodular sclerosis subtype) - may cause cough, dyspnea, or superior vena cava syndrome
• Disease spreads in a predictable, contiguous fashion through lymph node groups - unlike non-Hodgkin lymphoma

• Fever (>38°C)
• Drenching night sweats
• Unexplained weight loss >10% body weight in 6 months

• Pruritis (can be severe)
• Pel-Ebstein fever - cyclical fever pattern (classic but uncommon)
• Alcohol-induced pain at nodal sites (characteristic but rare)
• Splenomegaly in advanced disease
• Goldman-Cecil Medicine, p. 1964

Staging - Modified Ann Arbor System

Workup / Staging Evaluation

• Complete history (B symptoms, bone pain, other localizing symptoms)
• Physical examination for lymphadenopathy, organomegaly
• CBC, ESR, serum creatinine, alkaline phosphatase, LDH, bilirubin, albumin, protein electrophoresis
• HIV and hepatitis B/C serology
• Chest X-ray (PA and lateral)
• Contrast-enhanced CT scan of neck, thorax, abdomen, and pelvis
• FDG-PET/CT - now standard; more sensitive and specific than CT alone; has replaced bone marrow biopsy for staging
• Excisional lymph node biopsy for histological diagnosis
• Goldman-Cecil Medicine, p. 1965

Treatment

Early-Stage (I-II, non-bulky) - Favorable

• ABVD x 2-4 cycles followed by involved-site radiation therapy (ISRT) - the standard backbone
• ABVD = Adriamycin (doxorubicin) + Bleomycin + Vinblastine + Dacarbazine
• PET-adapted therapy: if PET is negative after 2 cycles of ABVD, radiation may be omitted in selected patients; if PET positive, escalation to BEACOPP is considered

Early-Stage with Unfavorable Features or Bulky Disease

• ABVD x 4-6 cycles + ISRT, or
• BEACOPP-based regimens

Advanced-Stage (III-IV)

• A+AVD = Brentuximab vedotin + Doxorubicin + Vinblastine + Dacarbazine
  • Brentuximab vedotin is an anti-CD30 antibody-drug conjugate
  • Shown to improve 5-year progression-free and overall survival vs. ABVD in stage III/IV disease
  • Now considered standard of care for previously untreated advanced HL

• ABVD x 6 cycles; if PET negative after 2 cycles, bleomycin can be safely omitted
• Escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) - superior initial disease control but no proven overall survival benefit over ABVD in randomized trials; used for high-risk patients under age 60

• Goldman-Cecil Medicine, p. 1965

Relapsed / Refractory Disease

1. Salvage chemotherapy (e.g., BEAM - carmustine, etoposide, cytarabine, melphalan)
2. High-dose chemoradiation + autologous hematopoietic stem cell transplant (ASCT)
   • Approximately 1/3 of refractory patients and 2/3 of relapsed patients can be cured
3. Consolidative brentuximab vedotin post-ASCT reduces relapse rate by ~1/3

• Nivolumab (anti-PD-1) and pembrolizumab (anti-PD-1) produce high response rates (60-70%) even in multiply relapsed/refractory HL, exploiting the PD-L1/PD-L2 overexpression on RS cells
• Some patients achieve durable remissions; role as bridge to allogeneic transplant is evolving
• Goldman-Cecil Medicine, pp. 1965-1966

Prognosis

• Early-stage disease (I-II): cure rate >90% with combined modality therapy
• Advanced-stage (III-IV): 5-year overall survival ~80-85% with modern regimens
• International Prognostic Score (IPS) for advanced HL - 7 adverse factors: albumin <4 g/dL, hemoglobin <10.5 g/dL, male sex, age ≥45, stage IV, leukocytosis (WBC ≥15,000), lymphopenia (<600/µL or <8% of WBC)
• Long-term complications of treatment (secondary malignancies, cardiotoxicity from anthracyclines, pulmonary toxicity from bleomycin, hypothyroidism from neck radiation) are a major focus of modern treatment design

Key Distinguishing Points vs. Non-Hodgkin Lymphoma

• Robbins & Kumar Basic Pathology, Chapter 10, pp. 417-419
• Goldman-Cecil Medicine, Chapter 172 (Connors JM, Savage KJ)

Hodgkin Lymphoma

What Is It?

Who Gets It?

• Affects roughly 1 in 250-300 people over a lifetime
• Classic bimodal age curve: first peak in young adults (ages 25-30), second peak after age 50
• Slightly more common in men
• Higher rates in developed countries, White populations, and higher socioeconomic groups
• Rare in East Asia; when it does occur in South Asia, it tends to affect children rather than young adults

Why Does It Happen?

• EBV (the virus behind mono/glandular fever) is found inside RS cells in about 50% of cases - up to 70% in the mixed-cellularity subtype
• Having had infectious mononucleosis triples your subsequent risk of HL
• Anti-EBV antibodies appear in the blood years before the tumor, suggesting EBV is an early contributor, not a bystander
• EBV is probably one step on the path to transformation, not the sole cause

• They shed their MHC class I molecules (the flag that lets killer T cells recognize and attack them) by losing beta-2 microglobulin
• They overexpress PD-L1 and PD-L2 - immune checkpoint proteins that put the brakes on T-cell activity, essentially telling the immune system "stand down"
• This PD-L1 overexpression turns out to be their Achilles heel - anti-PD-1 drugs (checkpoint inhibitors) can lift that brake and reawaken the immune response even in heavily treated disease

The Reed-Sternberg Cell - What to Look For

• A huge multilobate nucleus - or two mirror-image nuclei side by side
• Giant, prominent nucleoli surrounded by a clear halo
• The classic look: two nuclei each staring back at you like a pair of eyes - the "owl-eye" appearance

The Five Subtypes

Classic HL (~90% of all HL)

• Thick collagen bands divide the lymph node into nodules
• RS cell variant here is the lacunar cell - looks like it's sitting in an empty space (lacune) because the cytoplasm retracts in formalin fixation
• Loves the mediastinum, lower cervical, and supraclavicular nodes
• Typical patient: adolescent or young adult; equal male-to-female ratio
• Excellent prognosis

• Classic owl-eye RS cells are abundant
• Most strongly linked to EBV (~70% positive)
• Background is a rich mix - eosinophils, plasma cells, macrophages, lymphocytes
• More common in older adults; often presents at a later stage

• RS cells are sparse in a sea of lymphocytes
• Good prognosis

• RS cells are abundant, lymphocytes are few
• Worst prognosis among classic subtypes; often EBV-positive; tends to present at advanced stage

Nodular Lymphocyte-Predominant HL (~10%)

• The neoplastic cells are called LP cells ("popcorn cells") - with a folded, lobulated nucleus
• They retain germinal center B-cell markers: CD20+, CD79a+
• They are CD15 negative, CD30 negative - the opposite of classic HL
• Indolent course; excellent long-term prognosis; can relapse late but usually responds again to treatment

Clinical Presentation

• B symptoms (important for staging and prognosis):
  • Fever >38°C
  • Drenching night sweats
  • Weight loss >10% over 6 months
• Mediastinal mass - cough, breathlessness, or superior vena cava obstruction (facial swelling, dilated neck veins)
• Pruritis - can be severe and is often underappreciated
• Pel-Ebstein fever - a cyclical fever pattern; classic but uncommon
• Alcohol-induced pain at nodal sites - rare but almost pathognomonic for HL

Staging - The Ann Arbor System

Workup

Treatment

Early-Stage (I-II, non-bulky)

• A - Adriamycin (doxorubicin)
• B - Bleomycin
• V - Vinblastine
• D - Dacarbazine

Advanced-Stage (III-IV)

• Brentuximab vedotin (anti-CD30 antibody-drug conjugate) + Adriamycin + Vinblastine + Dacarbazine
• Brentuximab delivers a cytotoxic payload directly to CD30+ RS cells
• Proven to improve both progression-free and overall survival vs. ABVD in stage III/IV HL

• Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin (vincristine), Procarbazine, Prednisone
• Better initial disease control but no proven overall survival advantage over ABVD in randomized trials

Relapsed or Refractory Disease

• Cures ~1/3 of refractory patients and ~2/3 of those who relapse after primary therapy

• Nivolumab or pembrolizumab (anti-PD-1 antibodies) achieve 60-70% response rates by reactivating the T-cell response that RS cells had suppressed via PD-L1/PD-L2
• Some patients achieve durable remissions; can bridge to allogeneic transplant

Prognosis

1. Albumin <4 g/dL
2. Hemoglobin <10.5 g/dL
3. Male sex
4. Age ≥45
5. Stage IV disease
6. Leukocytosis (WBC ≥15,000)
7. Lymphopenia (<600/µL or <8% of WBC)

HL vs. Non-Hodgkin Lymphoma - At a Glance