Table of contents
- 1. Approach to Lymphoid Malignancies
- 2. Acute Lymphoblastic Leukemia (ALL)
- 3. Lymphoma
- 3.1. Introduction
- 3.2. Classification
- 3.3. Staging and Prognosis
- 3.4. Follicular Lymphoma
- 3.5. MALT Lymphoma
- 3.6. Hairy Cell Leukemia
- 3.7. Diffuse Large Cell Lymphoma
- 3.8. Burkitt Lymphoma
- 3.9. Mantle Cell Lymphoma
- 3.10. Hodgkin Lymphoma
- 3.11. Cutaneous T-cell Non-Hodgkin Lymphoma
- 3.12. Treatment Principles
.
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])
- Order CBC (50% WBC >10), Uric Acid, K+, PO4, Ca, LDH (TLS), PT, aPTT, fibrinogen, D-Dimers (DIC).
- 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.
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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:
- Induction: Anthracycline, vincristine, asparaginase (deprives leukemic cell of asparagine), corticosteroid.
- Consolidation
- 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:
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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)
-
- Prognosis based on Rai staging:
- Indolent, incurable, slow progression --> Select gentlest treatment to control symptoms.
- 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
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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)
- Hodgkin's
- 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
- Infection: (HIV, HTLV1, Hepatitis, EBV)
- ***Immunosuppression***
- 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.
- Can do on a biopsy specimen, peripheral blood, CSF, bone marrow.
- Lymph Node Biopsy:
- 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
- Routine Labs:
-
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
- Indolent (slow-growing)
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 γδ 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.
- 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)
- Other chemo agents:
- 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
- Initial: Triple-therapy:Metronidazole + amoxicillin + clarithromycin, + omeprazole
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
- 80-90% have complete remission with one cycle of chemo that lasts 7 days
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.
- if B-Cell can use rituximab = great prognosis (R-CHOP)
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.
- (Incurable, highly responsive, but relapses.
- 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
- ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) - low toxicity
- 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)
- R-CHOP
- Autologous + allogeneic HSCT appropriate for young pts
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