Non Hodgkin S Lymphoma

Epidemiology

  • Male:Female —> 1.5:1
  • Icrease with age
    • Burkitt Lymphoma and Lymphoblastic Lymphoma —> more common in young age
      • Both highly aggressive
  • white>black
    • 5yr OS in black is 6% less
  • Developed > developing
    • highest in US, lowest in China

Etiology

  • Pectiside
    • Farmers
  • Hair Dye
NHL Type Viral Factor Comment
Adult T-Cell Lymphoma/Leukemia Human t-cell Lymphotropic Virus Endemic Area(southern Japan-Caribbean)
Burkitt's Lymphoma HIV Africa, higher risk for more aggressive lymphoma*
Mucosa-Associated Lymphoma Tissue Helicobacter Pylori eradication of H-Pylori may be beneficial

Classification

Know these types:( in order of frequency)

  • Diffuse Large B Cell Lymphoma (30%)
  • Follicular Lymphoma (20%)
  • Small Lymphocytic Lymphoma/CLL (<10%)
  • Mantle Cell Lymphoma
  • Peripheral T-Cell Lymphoma
  • Marginal Zone B-cell Lymphoma

Molecular Biology

Translocation NHL Type Gene Involved Comment
t(14:18) Follicular Lymphoma bcl-2
t(8:14) Burkitt's Lymphoma c-myc
t(11:14) Mantle Cell Lymphoma bcl-1 encodes cyclin D1; function is cell cycle control: G1 progression
t(11:18) MALT associated w poor response to antibiotic therapy in gastric MALT, found also in lung and eye
DLBCL bcl-6 in 1/3 of patients

IPI for NHL

  • Age>60
  • LDH > 1xN
  • ECOG 2-4
  • >1 extranodal site
  • Stage III-IV
Total IPI points 5yr Survival
0-1 70%
2 50%
3 40%
4-5 25%

FLIPI

  • Age>60
  • Stage III-IV
  • abN LDH
  • >4 nodal areas
  • Hgb<120

Other prognostic factors include

  • Histo type —> DLCL, mantle, T-cell, NK cell
  • Bulk —> >10 cm
  • B symptoms
  • High s-phase fraction
  • Ki-67>80%
  • HLA-DR expression
  • beta2-microglobulin
  • bcl-2 protein
  • bcl-6 rearrangement
  • CD44 expression

Common Lymphoma and the Role of Radiation

Low-Grade Lymphomas

Follicular Lymphoma

  • A lymphoma of follicle center B cells (centrocytes and centroblasts), which has at least a partially follicular pattern.
  • Morphology
    • A mixture of centrocytes (cleaved follicle center cells) and centroblasts (large noncleaved follicle center cells)
    • Follicular pattern
      • Clinical aggressiveness of the tumor increases with increasing numbers of centroblasts
  • GRADES
    • 1: 0–5 centroblasts per high-power field
    • 2: 6–15 centroblasts per high-power field
    • 3: >15 centroblasts per high-power field
      • 3a: >15 centroblasts, but centrocytes are still present
      • 3b: Centroblasts form solid sheets with no residual centrocytes
  • IMMUNOPHENOTYPE
    • Surface immunoglobulin
      • 60% —> IgG
      • 40% —> IgG or, less often, IgA
    • pan-B-cell–associated antigens
      • Most are CD10+
      • CD5−
      • CD23−/+
    • Most cases are bcl-2+
    • Nuclear bcl-6 is expressed by at least some of the neoplastic cells
    • Ki-67+ fraction is lower than that of reactive follicles
  • GENETICS:
    • t(14;18)(q32;q21)
    • BCL-2 gene
    • Abnormalities in 3q27
      • BCL6 (40%)
        • More risk for transformation to DLBCL

Clinical Features

  • The second most common lymphoma
  • 30% of all NHLs
  • Female>Male
    • 1.7:1
  • Predominantly involving lymph nodes
    • But also:
      • Spleen
      • Bone marrow
    • Occasionally:
      • Peripheral blood
      • Extranodal sites
  • Indolent
  • Median survivals: ~10 years
  • Not usually curable
  • Transformation risk to diffuse and large cell: ~30% in 10yr
    • DLBCL evloved from follicular is more resistant to treatment
      • Median Survival after transformation: ~1.2yr

Therapy of Localized Follicular Lymphoma

Stage I and II

  • RT alone is standard treatment
  • Stanford University —> Observation may provide same outcome!
  • 10-year freedom from treatment failure —> 40-50%
  • 10-year OS —> 40-80%
  • Median survival —> 12-15 years
  • Adding CHEMOTHERAPY —> no clear benefit
    • Randomized studies (1970s)
      • non–Adriamycin-containing chemo added to Rt —> no benefit
    • M.D Anderson single arm study
      • COP (cyclophosphamide, vincristine, and prednisone) or CHOP-B (cyclophosphamide, doxorubicin, vincristine, prednisone plus bleomycin)
        • Better Freedom from Recurrence ( compared to historical data
        • No OS benefit

When to consider Chemo?

  • Grade 3
  • Stage II disease with multiple sites of involvement
  • Bulky nodes

Adverse prognostic factors for freedom from treatment failure:

  • Age
  • Garde 3
  • Extensive clinical stage IIA
  • Bulky disease (defined as >2 or 3 cm)
  • Extranodal presentations

Radiation Technique:

  • Intent is curative
  • High Energy Photon
    • 6MV
  • Preparation tests:
    • Hematology Consult
    • If young female patient —> R/O pregnancy
      • If pelvic RT —> Oophoroplexy
    • Baseline endocrinological
    • Pulmunary Function test
    • Renal Function Test
  • CT Simulation
    • Chest versus Abdo versus Neck
  • Position:
    • Supine
    • Arms at sides if Neck or Abdo/Pelvis
    • Arms up if chest
    • Surface lead marker: any Enlarged LN
  • Aides:
    • knee cushion
    • head rest
  • Dose:
    • 30Gy + boost 6Gy to GTV
  • 3D Conventional
  • GTV
  • CTV is Involved Field Nodal Area
  • PTV —> margin ( ~1cm )
  • Organs at risk
  • Dose Constraint
  • Outcome
    • Median Survival : 10yr
    • 10yr Disease Free Survival: 50%

Advance Stage ( III and IV )

  • 80% of cases
  • Treatment primarily is systemiv therapy
    • Chemotherapy +/- immunotherapy
      • Chemo
        • CHOP ( Cyclophosphamide, doxorubicin, vincristine, prednisone)
      • Immunotherapy
        • Rituximab
          • anti-CD20 Ab
  • Low grade and non-symptomatic —> Observation is a choice as well

Role of Radiation in advance stage?

  • NCI prospective randomized trial
  • Chemo + RT versus no initial treatment
    • 4yr DFS better in combined modality group (50% vs 12%)
    • No OS benefit!

Marginal Zone Lymphomas

  • Extranodal
    • MALT ( mucosal associated Lymphoid Tissue ) Lymphoma
  • Nodal
    • =monocytoid B-cell lymphoma
    • older age-group
  • Morphology:
    • Heterogeneous small B cells
    • Marginal zone (centrocytelike) cells
    • Monocytoid cells
    • With plasma cell differentiation in 40% of the cases
    • Infiltration of mucosa, lymphoepithelial lesions, clonal proliferation of centrocyte-like B-cells
  • Immunophenotype:
    • Surface Ig
    • pan-B-antigen
    • BUT CD5 - and CD10 -

Extranodal MZL

  • Most commonly in stomach
  • Salivary glands
  • Waldeyer's ring
  • Large and small intestine
  • Thyroid
  • Orbit & Conjunctivae
  • Lung
  • Breast
  • Skin

Either epithelial mucosa or columnar epithelium

  • Clinical course is indolent
  • Usually present in early stage
  • Usually limited to invloved organ
    • Occasionally adjucant LN +
  • Result of an antigenic simulation
    • Hashimoto's Thyroiditis —> higher risk of MALT in thyroid
    • Sogren's Syn
    • H.pylori —> stomach
Treatment of MALT (Stomach)
  • If H-Pylori +
    • First step —. eradication of H-Pylori
      • 50% of patients eventually will require further treatment
        • 30-50% —> persistent disease
        • 15% of CR will progress
  • If H-pylori - and in case of progression
    • IFRT
      • Rt to stomach and regional LN
      • 30Gy/20fr ( 4 weeks )
      • ~90% CR
      • 4yr Freedom from treatment failure —> 90%
      • 4yr OS —> 80%
      • 4yr DSS —> 100%