Hodgkin S Lymphoma

Introduction

  • 1832 —> British physician Thomas Hodgkin
  • Development of kilovoltage equipment in the 1920s
    • Gilbert, a Swiss radiotherapist

Etiology and Epidemiology

  • Relatively uncommon
    • 8000/yr
    • 1% of all cancer diagnoses
  • Age-incidence curve
    • Developed countries
      • Initial peak —> around age 25 yrs
        • Mostly nodular sclerosis
        • Reflection of delayed exposure to infectious agents
        • Higher socioeconomic status
          • Early birth order
          • Small sibship size
          • Growing up in single-family
          • Having few playmates
          • Parents with a high level of education
      • Second peak —> 60-70 yrs
        • Male>Female (in this peak)
    • Developing countries
      • Rare among young adults
      • Mostly mixed cellularity
      • Initial peak —> childhood
        • Boys>girls
      • Late peak —> older patients
  • Epstein-Barr virus (EBV)
    • Infectious mononucleosis —> threefold increased risk
    • Elevated levels of the IgG and IgA against the EBV capsid Ag
      • + months to years prior to clinical Hodgkin's lymphoma development
      • ~ 1/3-1/2 of cases of classical HL (in Western populations)
        • Monoclonal EBV genome can be detected in the Reed-Sternberg cells
      • EBV + —> associated with the Mixed Cellularity
        • (MC): More common among young children and older adults
        • EBV + is less frequent in NS ( and remeber NS is more in young adult
  • Familial
    • First-degree relatives —> x5 risk
    • Siblings —> x7 risk
      • Monozygotic twins —> x100!
  • Certains HLAs

Molecular Biology

  • Reed-Sternberg cells
    • Large
    • Binucleated cells( but malignant cells in HL can be uni or multinucleated as well)
      • 1% of the cells present in the sample
    • Most of the tissue —>
      • Non-neoplastic inflammatory cells & fibrosis
    • Monoclonal immunoglobulin gene rearrangements:
      • No Ig gene expression
      • Resistant to apoptosis
      • Mature B lymphocytes
      • Mutated VH genes
        • Specific markers for germinal center B cells and their descendants
  • Activation of nuclear factor kappa B (NFκB)
    • Constitutive NFκB is required for proliferation and survival of Hodgkin's lymphoma tumor cells
  • What activates (NFκB)?
    • REL gene may be responsible!
    • Mutations in NFκB inhibitors
    • Somatic mutations in the novel tumor suppressor gene TNFAIP3
      • TNFAIP3 encodes A20!
      • EBV inactivates A20!
      • Some common pathogenesis?!!!!
  • CD95 is upregulated
    • Another NFκB-dependent regulator of apoptosis

Cellular Classification of HL

WHO/Revised European-American Lymphoma (REAL) classification:

  • Classical
    • Nodular sclerosis
    • Mixed-cellularity
    • Lymphocyte depletion
    • Lymphocyte-rich
    • Immunophenotype:
      • CD15+, CD20-, CD30+, CD45-
        • CD20+ <40%
        • CD3 -
  • Nodular Lymphocyte–Predominant HL
    • Distinct from classic HL
    • CD15-, CD20+, CD30-, CD45+
      • CD3 -
    • Usually earlier-stage disease, longer survival, and fewer treatment failures than those with classic HL
    • However, there is a tendency for histologic transformation to diffuse large B-cell lymphoma in around 10% of patients by 10 years
    • Present in asymptomatic young males with cervical or inguinal lymph nodes
    • Usually without mediastinal involvement
    • Limited-field radiation therapy is the most common treatment approach for patients with early-stage disease

Few things on staging

  • If there is any involvement of following organs then that's stage IV:
    • Liver
    • Lung
    • Bone Marrow
    • CSF
  • One single LN —> stage I
  • Two LN —> stage II
  • Focal involvement of one extralymphatic ONLY( no LN ) —> stage I
  • Focal involvement of one extralymphatic + LN(if same side of diaohragm) —> stage II
  • Focal involvement of one extralymphatic + LN(if both side of diaohragm) —> stage III

Natural History and general work-up:

History:

  • Ask about B symptoms
    • Fever
    • Drenching sweat
    • Weight loss
  • Other general symptoms:
    • Performance status
      • ALWAYS check as important for tolerance to therapy
    • Fatigue
    • Alcohol intolerance
    • pruritis
    • Lump/bump
  • Ph/E
    • Check for total LN
      • Pre-popliteal
      • trochlear
    • Cachetia?
    • Fever?
    • Skin rash —> scratch for pruritis
    • Splenomegaly
    • Hepatomegaly
      • Remember any liver involvement is stage IV and poor prognostic
  • Investigation:
    • Excisional biopsy
      • FNA to be avoided
    • Blood work:
      • CBC-diff
        • Remember high WBC and low lymph is poor prognostic factor in advance stage
      • ESR
        • If >30 in B and >50 in A is a poor prognostic factor for early stage
      • LDH
        • >4.0 is poor prognostic factor for advance stage
      • Albumin
        • as LFT
      • Biochem and kidney and liver function test
        • Is patienta chemo candidate?
      • Check HIV if high risk
      • Check beta-HCG for pregnancy if young patient
    • Imaging:
      • CT C/A/P
      • PET scan
    • Other:
      • EF test
        • For Adriamycin contatining regimen
      • PFT
        • RT in chest
        • or ABVD or BEACCOPP regimen
      • Pneumococcal, H-flu, Meningococceal vaccination
        • If spleen RT
  • 5% involvement of bone marrow.
    • biopsy is indicated if:
      • Constitutional B symptoms
      • Stage III and IV
        • as per NCCN
      • Anemia
      • Leukopenia
      • Thrombocytopenia
        • as per pdq
    • Staging laparotomy is no longer recommended
    • Considered only if substantial reduction in treatment
      • It should not be done in patients who require chemotherapy. Risks of potential morbidity should be considered

Keys on Management of HL