Lymphoid Malignancies


    Approach to Lymphoid Malignancies





    Acute Lymphoblastic Leukemia (ALL)

    • Malignant disease of bone marrow - early lymphoid precursors proliferate and replace normal hematopoietic cells of the bone marrow.
    • 75% occur in children < 6yo (most common acute leukemia in children) + second peak at age 40.
    • B or T Lymphoblasts, 
    • Divided into:
      • B cell precursor ("Precursor B lymphoblastic leukemia")
      • T cell precursor ("Precursor T lymphoblastic leukemia")
      • Leukemic variant of Burkitt Lymphoma. (manged identically to Burkitt Lymphoma)
    • Clinical Features:
      • (Almost same as AML)
      • Marrow Failure (days to weeks)
        • Anemia: Fatigue, dyspnea
        • Thrombocytopenia: Bleeding
        • Lymphopenia: Infection
      • Physical Exam:  (Oral infiltration)
        • Lymphadenopathy
        • Hepatosplenomegaly
        • T-cell ALL: Large anterior mediastinal mass, pleural effusions, SVC syndrome.
          • (T=Thymus, think of mass)
      • CNS Involvement is common (Unlike AML!)
        • Headache, lethargy, N/V, Nuchal rigidity, CN palsy, radiculopathy.
    • Labs:
      • WBC is normal or elevated (50%) -  Most have circulating lymphoblasts.
      • Peripheral Smear: circulating lymphoblasts (hard to say if lympho or myeloblasts, but if see Auer Rod = AML)
      • Cytopenias, TLS common.
    • Diagnosis of ALL: ≥25% Lymphoblasts on BM examination.

    • Investigations:
      • Order CBC (50% WBC >10), Uric Acid, K+, PO4, Ca, LDH (TLS), PT, aPTT, fibrinogen, D-Dimers (DIC).
        • Immunophenotyping / pathology - Leukemic lymphoblasts lack morphological or cytochemical features (i.e. no granules). 
        • Cytogenetics (Philadelphia chromosome in 25% of ALL - poor prog. factor)
      • BM biopsy for diagnosis
      • Flow cytometry to identify AML (-TDT, + MPO) vs. ALL (+TDT, - MPO), and B-cell vs. T-cell.
        • (Terminal Deoxynucleotidal Transferase [TDT], and Myeloperoxidase [MPO])
    • ALL vs. AML:
      • Auer Rods = AML
      • If no Auer Rods need to do flow cytometry (proteins on blast surface). [In the ol' days use various stains]
      • Flow cytometry can also distinguish B from T-cell ALL.
      • AML ALL
        Big People (adults) Small People (kids)
        Big Blasts Small Blasts
        Big Mortality Rate Small Mortality Rate (kids)
        Lots of cytoplasm Less cytoplasm
        Lots of nucleoli (3-5) Few nucleoli (1-3)
        Lots of granules + Auer rods No granules
        (Sudan black stain)
        PAS (periodic acid-Schiff)
    • Prognosis (markers of poor prognosis:)
      • Poor: Advanced Age, high-risk cytogenetics (hypodiploidy, MLL translocations, philadelphia chromosome) , B-cell disease, high WBC at diagnosis
      • Good: Hyperdiploidy (in ALL is favourable - normally in cancer is poor marker), 12:21 gene.
    • Treatment:
      • LP prior to chemo to assess CNS involvement?
      • Avoid TLS: IV hydration, allopurinol or rasburicase (convert uric acid to allantoin, rapid lowering).
        • Test for G6PD, b/c rasburicase causes hemolysis in G6PD, and high risk methemoglobinemia.
      • Chemo:
    1. Induction: Anthracycline, vincristine, asparaginase (deprives leukemic cell of asparagine), corticosteroid.
    2. Consolidation
    3. Maintenance (2-3yrs)    [AML = only Induction & Consolidation]
    • Need to prophylax CNS: radiation, intrathecal chemo, or both. 
    • If Philadelphia chromosome positive --> use BCR-Abl inhibitors on top of chemo.
    • Cure: 30-40% with standard therapy.
    • In young patients with an HLA matched donor consider stem cell transplant. 
      • NOTE: (longer, more intense tx than AML; unlike AML also requires maintenance and CNS prophylaxis)


    Chronic Lymphocytic Leukemia


    • Indolent disease - cloncal malignancy of mature B-cells
    • Similarly slow-growing lymphoma, but involves bone marrow.
      • Very indolent
      • Special lymphoma that involves BONE MARROW +/- Blood
    • Epidemiology:
      • Most common leukemia
      • Usually B-cell (rarely T-cell)
      • Older patients: Median 65yo
      • M>F
    • Staged: (different from other lymphomas)
      • Stage 0 - Elevated lymphocytes ONLY
      • Other Stages --> each lymphoid organs (liver, spleen hepatosplenomegaly, BM)
    • Prognosis:
      • Molecular characteristics (certain mutations)
      • B2-microglobulin = prognostic factor
    • Clinical Features:
      • 25% asymptomatic (incidental finding)
      • 5-10% have B-symptoms (unintentional weight loss, fever, night swetas, extreme fatigue)
      • Lymphadenopathy (50-90%)
      • Splenomegaly (25-55%)
      • Hepatomegaly (15-25%)
      • Immune dysregulation
        • AIHA (Coombs positive)
        • ITP
        • Hypogammaglobulinemia ± neutropenia.
      • Bone Marrow Failure (LATE FINDING!)
    • Investigations:
      • CBC (WBC > 5)
      • Peripheral Blood Film
        • Lymphocytes small + mature.
        • Smudge Cells (Damaged lymphocytes from slide preparation)
      • Flow cytometry
      • Cytogenetics - FISH
      • Bone Marrow Aspirate
        • Lymphocytes >30% of all nucleated cells
        • Infiltration of marrow
    • Treatment:
      • Indolent, incurable, slow progression --> Select gentlest treatment to control symptoms.
        (WBC doesn't matter as much)
        • Observation
        • Intermittent fludarabine chemo + rituximab if CD20+  (sometimes chlorambucil)
          • 90% respond, >70% have complete response, but likely relapse later (incurable)
          • Fludarabine: must prophylaxis for PCP and HSV
        • Steroids or IVIG if autoimmune phenomenon.
        • Radiotherapy??
      • Small minority: aggressive disease 2ndary to chromosomal abnormalities (i.e. p53 deletion).
      • 9yr mean survival, but varies greatly.
        • Prognosis based on Rai staging:
          • Risk Features
            LOW Lymphocytosis in blood and bone marrow only.
            INTERMEDIATE Lymphocytosis with enlarged nodes or splenomegaly, hepatomegaly.
            HIGH Lymphocytosis with anemia < 110 (related to malignancy), or thrombocytopenia (< 100)
    • Complications:
      • Bone marrow failure
      • Hypogammaglobulinemia
      • Immune Complications (AIHA, ITP, immune deficiency - hypogamma, impaired T-cells)
      • Polyclonal or monoclonal gammopathy (often IgM)
      • Hyperuricemia with treatment.
      • 5% - Richter's Transformation (Aggressive transformation to Diffuse Large B-Cell Lymphoma [DLBCL])
        • (if transformed, DLBCL is usually not curable.  Primary DLBCL usually curable)


    Small Lymphocytic Lymphoma

    • Disease Involving
      Bone Marrow / Blood CLL
      Lymphoid Tissue Small Lymphocytic Lympoma (SLL)
      Both CLL / SLL (together)




    • Classified as Non-Hodgkin's and Hodgkin's
      • Non-Hodgkin's --> 30 subtypes with different features.
      • Most lymphomas are Non-Hodgkin's
    • 70,000 cases of Lymphoma in US yearly, 20,000 will die of this disease.
    • They are all very different entities with each own disease process (CNS involvement, BM involvement, aggressive/indolent, staging, prognosis, etc..)
    • Epidemiology:
      • Hodgkin's
        • Adolescents and young adults ages 15-45yo
      • Non-Hodgkin's (NH)
    • Risk Factors:
      • ***Immunosuppression***
        • Infection: (HIV, HTLV1, Hepatitis, EBV)
          • HIV ass'd with anaplastic large-cell NH lymphoma and Burkitt's Lymphoma
          • HTLV1: T-cell NH lymphoma [ Human T-cell Lymphotropic Virus Type 1]
          • Hepatitis C: Low-grade B-cell NH lymphoma
          • EBV: Burkitt's Lymphoma, Post-transplant proliferative disorders, and Hodgkin's
          • H.pylori: MALT Lymphoma
        • Anti-Rejection: Tacrolimus, Cyclosporine
        • Genetic Predisposition (Herbicides, chlorinated compounds)
          • Prev. Hodgkin's Lymphoma predisposes to NH Lympoma
    • Diagnosis:
      • Lymph Node Biopsy:
        • Excisional Biopsy is best (if possible)
        • Incisional Biopsy is 2nd best (must preserve architecture)
        • Aspiration is the worst... only see lymphoma cells, but unclear which type (follicular etc..)
      • **Flow Cytometry**
        • Can do on a biopsy specimen, peripheral blood, CSF, bone marrow.
          • (wherever suspect involvement)
        • See antigens on lymphoid cells --> look for clonality.
        • Can see if T-cell or B-cell + other surface makers, which help identify point in B/T cell development.
        • Must have flow cytometry and cytogenetics for diagnosis. (immunophenotyping - FISH)
        • Molecular testing, immunophenotyping, histopathology for dx, tx, prognostic info.
    • Workup:
      • Routine Labs:
        • CBC + Diff (bone marrow involvement? clonal lymphocytosis).
        • LDH, B2-microglobulin (helps with turnover rate + prognostic marker on how aggressive).
        • Viral Testing if suspicion. (HIV, EBV, HTLV1, Hep)
      • PET Scan
        • Staging more aggressive lymphomas.
        • Low grade lymphomas aren't PET-avid, not seen well on PET
        • Hodgkin's: staged well on PET, or if someone with CLL gets worse (biopsy nodes, PET scan)
      • Bone Marrow Biopsy
        • Depends if suspect marrow involvement. (if suspect marrow involvement).
        • If peripheral lymphocytosis, likely don't need marrow (can just flow cytometry on peripheral blood)
      • Lumbar Puncture
        • R/O lymphomatous meningitis / CSF involvements?
        • Can also get intra-thecal methotrexate
        • LP required in NHL with risk factors for CNS involvement:
          • Aggressive NHL involving sinuses, testes, bone marrow, or ocular sites


    • Classification

      • 85% are B-cell Lymphomas
      • Classified usually as:
        • B-cells (85%)
        • T-cells (10-15%)
        • NK-Cells (natural killer) - rare
      • Also classified as:
        • Indolent (slow-growing)
          • Usually disseminated, incurable, but long survivorship... treated with palliative fashion.
        • Aggressive
          • Typically "Diffuse Large B-Cell" Category
          • Usually curable (chemo involving rituximab)
        • Highly Aggressive (High growth fraction, high risk of tumor-lysis syndrome)
          • Burkitt Lymphoma
          • Lymphoblastic Lymphoma


    World Health Organization 2008 Classification of Hodgkin and Non-Hodgkin Lymphomas

    Mature B Cell

    Mature T cell and NK Cell

    Chronic lymphocytic leukemia

    B-cell prolymphocytic leukemia

    Splenic marginal zone lymphoma

    Hairy cell leukemia

    Splenic lymphoma/leukemia, unclassifiable

    Lymphoplasmacytic lymphoma (Waldenström)

    Heavy chain diseases (α, γ, μ)

    Plasma cell myeloma

    Solitary plasmacytoma of bone

    Extraosseous plasmacytoma

    Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)

    Nodal marginal zone B-cell lymphoma

    Follicular lymphoma

    Primary cutaneous follicle center lymphoma

    Mantle cell lymphoma

    DLBCL, not otherwise specified

    DLBCL (EBV+) of the elderly

    Lymphomatoid granulomatosis

    Primary mediastinal (thymic) large B-cell lymphoma

    Intravascular large B-cell lymphoma

    Primary cutaneous DLBCL, leg type

    ALK+ large B-cell lymphoma

    Plasmablastic lymphoma

    Primary effusion lymphoma

    Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease

    Burkitt lymphoma

    B-cell lymphoma, unclassifiable with features intermediate between DLBCL and Burkitt lymphoma

    B-cell lymphoma, unclassifiable, with features intermediate between large B-cell lymphoma and classic Hodgkin lymphoma

    Hodgkin lymphoma

    Nodular lymphocyte-predominant Hodgkin lymphoma

    Classic Hodgkin lymphoma

    Nodular sclerosis

    Lymphocyte rich

    Mixed cellularity

    Lymphocyte depleted

    T-cell prolymphocytic leukemia

    T-cell large granular lymphocytic leukemia

    Chronic lymphoproliferative disorder of NK cellsaAggressive NK-cell leukemia

    Systemic EBV+ T-cell lymphoproliferative disease of childhood

    Hydroa vacciniforme-like lymphoma

    Adult T-cell leukemia/lymphoma

    Extranodal NK/T-cell lymphoma, nasal type

    Enteropathy-associated T-cell lymphoma

    Hepatosplenic T-cell lymphoma

    Subcutaneous panniculitis-like T-cell lymphoma

    Mycosis fungoides

    Sézary syndrome

    Primary cutaneous CD30+ T-cell lymphoproliferative disorder

    Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphomaaPrimary cutaneous γ&delta; T-cell lymphoma

    Primary cutaneous small/medium CD4+ T-cell lymphoma

    Peripheral T-cell lymphoma, not otherwise specified

    Angioimmunoblastic T-cell lymphoma

    Anaplastic large cell lymphoma (ALK+)

    Anaplastic large cell lymphoma (ALK-)

     Swerdlow SH, Campo E, Harris NL, et al. (Eds). World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.



    Staging and Prognosis

    • Ann Arbor Staging System (Stages I-IV)
      • Determines the extent of disease in both HL and NHL
      • Offers extent of disease and organ involvement.
      • Not necessarily a prognostic tool.
    • AnnArbor2.jpg
    • Prognosis:  International Prognostic Index (IPI) (Growing out of favour?)
      • Factors: Age, Stage, Extranodal Involvement 
      • IPI is no longer an important prognostic tool in pts with B-cell NHL --> b/c rituximab made such a huge survival impact and prognostic change.
      • i..e Diffuse Large B-Cell Lymphoma (aggressive) - standard CHOP-R therapy = 50-80% cure rate
    • Prognosis: B2-microglobulin, molecular testing.
      • B-2-microglobulin - used in lymphoproliferative disorders (incl. myeloma), indicative of cell growth/turnover
      • (Usually don't trend to check response)


    Follicular Lymphoma

    • Indolent, survives ~10y with diagnosis.
    • CD20+ (B-cell), CD5 negative (mantle)
    • 2nd most common lymphoma (DLBCL is most common NHL)
    • Graded 1,2,3 (low, int, high).
      • Low Grade (i.e. 1-2): small cells, very indolent, slow.
      • High grade (i.e. 2-3): large cells, aggressive = more like DLBCL.
    • bcl-2 t(14;18) defect present in 90% (cytogenetics)
    • Natural History varies by grade, and FLIPI score.
    • Treatment:
      • Early treatment does not improve survival for Grade 1 & 2!  (possible to cure some of them)
        • Symptomatic tx only: i.e. rituximab monotherapy (or ritux-based chemo)
        • Indicated ONLY when BM involvement, or progressive lymphadenopathy.
      • Localized Disease: Involved-field radiation + rituximab
        • Other chemo agents:
          • bendamustine - old mustard-drug, first line for NHL. (equivalent to CHOP, less S/E)
      • Advanced Disease:
        • Rituximab, R-CVP, R-CHOP, radioimmunoconjugates
        • radioimmunoconjugates (tositumomab, ibritumomab)
      • Recent studies (PRIMA): better progression-free survival with rituximab maintenance x2 years
        • 8 year f/u --> no difference in survival R-maintenance post CVP
      • Autologous and allogeneic HSCT for relapsed patients.

    MALT Lymphoma

    • Mucosa-Associated Lymphoid Tissue Lymphoma
      • MALT cells are throughout GI tract, provide immunosurveillance, respond to foreign antigens.
    • Malignant transformation --> MALT lymphoma.
      • B-cell origin, CD20+ (rituximab responder)
    • 1/2 of all gastric lymphomas, localized, due to chronic infection by H. pylori
    • Presentation:
      • Isolated to single organ
      • Indolent
      • Extranodal Involvement: Orbit, colon, lung, thyroid gland, salivary, bladder.
    • Risk Factors:
      • Autiimmune inflammatory syndrome (Sjogren's, Hashimoto Thyroiditis)
      • H. pylori infection
    • Treatment:
      • Initial: Triple-therapy:Metronidazole + amoxicillin + clarithromycin, + omeprazole
        • If early enough, may not need chemo
      • If no response to triple therapy:
        • Localized radiation, rituximab


    Hairy Cell Leukemia

    • Aggressive, but highly curable
    • Older adults with cytopenias and splenomegaly. (usually w/o LAD)
    • Diagnosis:
      • Blood film: hair cells
      • Must do flow cytometry (CD103?)
    • Treatment:
      • 80-90% have complete remission with one cycle of chemo that lasts 7 days
        • Once that recur, can still cause remission with another cycle
      • Cladribine


    Diffuse Large Cell Lymphoma

    • Most commonly B-cell. (can be T-cell)
    • Most common form of NHL.
    • Highly aggressive
    • Symptoms:
      • Can be localized (single LN) or disseminated
      • Fevers, night sweats, weight loss
    • Staging: same Ann Arbor Classification
    • Treatment:
      • if B-Cell can use rituximab = great prognosis (R-CHOP)
        • 70% response, but 50% cured.
      • if T-Cell  (CHOP), brentuximab (new!)
      • If relapse:  high dose chemo with autologous HSCT.
        • Transplanted stem cells may have lymphoma, but usually don't survive freezing etc.
      • Prognosis: Age, performance status, serum LDH level, number of extranodal disease sites.


    Burkitt Lymphoma

    • Very aggressive lymphoma.
    • High risk of CNS involvement, need CNS prophylaxis (intrathecal chemo).
      • 45% cured, 80% respond
    • Treatment
      • R-Hyper-CVAD

    Mantle Cell Lymphoma

    • Fusion of follicular (indolent) and DLBCL (aggressive), high risk of tumor-lysis syndrome
      • Follicular - respond to therapy, but always relapse (10y med. survival)
      • DBCL - potentially curable half-time.
    • Follicular + DBCL  ==> Mantle Cell Lymphoma
      • (Incurable, highly responsive, but relapses.
        • Avg survival 3-4y.
    • Diagnosis:
      • Overexpression cyclin D1 (immunohistochemical stains) t(11;14) translocation
      • (Also see multiple colonic polyps)
    • Treatment:
      • R-CHOP --> short disease-free period, but median survival 3y.
      • R-HYPERCVAD --> aggressive form of CHOP (now standard, med survival >3y)
      • Allogeneic HSCT only curative options (esp if relapses) (Autologous HSCT being investigated as possible cure)
      • Can use MIPI (Mantle-cell International Prognostic Index) --> response to therapy


    Hodgkin Lymphoma

    • Highly curable regardless of stage and presentation
    • Presentation:
      • Palpable lymphadenopathy or mediastinal mass
    • Diagnosis:
      • Needs tissue biopsy
      • STAGE is important for treatment, but all likely curable.
    • Treatment:
      • ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) - low toxicity
        • If CD20+ --> add Rituximab
      • Challenge: reduce toxicity
      • Stage 1 & 2: Low-dose radiation +/- Short Course ABVD (+/- Rituximab)
      • Stage 3 & 4: Longer ABVD (+/- ritux) x6 cycles
      • Relapsed patients: can be cured with autologous HSCL
    • Can repeat PET (limit therapy if normal PET after 2-3 cycles of ABVD).
    • Risk Factors: age >45, males, leukocytes > 15,000, albumin < 40g/L, Hb < 105 g/L (if NO RF's: 89% 5y-survival, if 5 RF's 56%)


    Cutaneous T-cell Non-Hodgkin Lymphoma

    • Mycosis fungoides ==>  affects the skin
    • Sézary syndrome ==> affects the skin and blood (more advanced)
    • Presentation:
      • Dry, itchy, red skin patches.
      • Usually indolent for years, can get plaques, diffuse erythema, ulcerated lesions
      • Can infiltrate other organs and become leukemic phase
    • Diagnosis:
      • Flow: T-cell expresses CD4 antigens, with "cerebroform" (brain-like) nucleus, clonal
    • Treatment:
      • Usually treated by dermatologists.
      • High risk of infection (skin breakdown).
      • High risk of recurrent sepsis/bacterial infection.
      • Topical corticosteroids and retinoids
      • Psoralen and ultraviolet A light (PUVA) - if early stage, usually combine with interferon alpha.
        • If advanced: electron-beam radiation or extracorporeal photopheresis.
      • If involving other organs: CHOP (Alemtuzumab can be used).  Allogeneic HSCT can be curative (if younger)


    Treatment Principles

    • Typically CHOP Therapy (+/- Rituximab)
    • Rituximab is an anti-CD20 antibody (B-cells), only used for B-cell lymphomas.
    • Types of regimens:
      • R-CHOP
        • R - Rituximab (only for CD20+ B-Cells)
        • C - Cyclophosphamide - Alkylating agent
        • H - Hydroxydaunorubicin (aka Doxorubicin or Adriamycin) - Intercalating DNA agent
          • Replace with Etoposide (adriamycin cardiac s/e)
        • O - Oncovin (Vincristine) - binds tubulin
        • P - Prednisone
      • Bendamustine - often first line for NHL, shown equivalent to CHOP, but much less toxic.
      • R-CVP
        • Cyclophosphamide
        • Vincristine
        • Prednisone
      • ABVD - Less toxic, usually for Hodgkin's Lymphoma
        • A - Doxorubicin
        • B - Bleomycin
        • V - Vinblastine
        • D - Dacarbazine
      • Radioimmunoconjugates (tositumomab, ibritumomab)
    • Autologous + allogeneic HSCT appropriate for young pts
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