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  1. Approach To Medicine
  2. Hematology
  3. Lymphoid Malignancies

Lymphoid Malignancies

Modified 19:47, 16 Apr 2016 by apavel | Page History
    Table of Contents
    1. 1. Approach to Lymphoid Malignancies
    2. 2. Acute Lymphoblastic Leukemia (ALL)
      1. 2.1. Chronic Lymphocytic Leukemia
      2. 2.2. Small Lymphocytic Lymphoma
    3. 3. Lymphoma
      1. 3.1. Introduction
      2. 3.2. Classification
      3. 3.3. Staging and Prognosis
      4. 3.4. Follicular Lymphoma
      5. 3.5. MALT Lymphoma
      6. 3.6. Hairy Cell Leukemia
      7. 3.7. Diffuse Large Cell Lymphoma
      8. 3.8. Burkitt Lymphoma
      9. 3.9. Mantle Cell Lymphoma
      10. 3.10. Hodgkin Lymphoma
      11. 3.11. Cutaneous T-cell Non-Hodgkin Lymphoma
      12. 3.12. Treatment Principles

    .

    Approach to Lymphoid Malignancies

     

     

    LymphoidMalignanciesSmall.jpg

     

    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
        Myeloperoxidase
        (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)

     

    Lymphoma

    Introduction

    • 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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