Medicine2 - Myeloproliferative, Lymphoproliferative Workshop

Myeloproliferative and Lymphoproliferative Disorders Section of Hematology & Oncology Department of Medicine

Clonal Bone Marrow Disorders PNH RARS CLL LEUKEMIAS ALL

CML MMM

RAEB, T

RA

MYELODYSPLASTIC SYNDROMES

AML CMML

MYELOPROLIFERATIVE SYNDROMES P.V. E.T.

Kouides PA and Bennett JM. Sem Hematol, April 1

Case 2-01-01 • 46 year old Filipino female • profuse menstrual flow for the past few months • on and off fever, easy bruisability, shortness of breath on exertion for the past 3 weeks • no headache, bone pain, nausea, vomiting, melena, hematochezia, dysuria, nor hematuria • denies any exposure to insecticides or other chemicals • FH: diabetes mellitus • Physical examination: BP: 100/70, pulse rate of 100/min, regular and full; RR of 24/min  pale, not jaundiced, no palpable cervical lymphadenopathy  Cardiovascular and pulmonary examinations are normal  Liver and spleen are not palpable  Neurologic and musculoskeletal examinations are unremarkable

Case 2-01-01 CBC : hgb : 7.2 wbc of 45,000 with blasts of 55%, platelets: 65,000.

Case 2-01-01 1. What are blast cells? Describe them. 2. What laboratory examinations should be requested? Why? 3. What is/are your clinical impression(s)? 4. What is the appropriate management for this patient?

Blast cells • Immature cells characterized morphologically as mononuclear cells with large nuclei relative to the cytoplasm, containing one or more nucleoli • May be of lymphoid or myeloid origin Back to Questions

Examinations • Peripheral smear • Bone marrow examination:  Aspirate  Light microscopic studies  Flow cytometry  Cytogenetics  Biopsy

• Blood chemistries: LFT, Renal function, BUA • Others as indicated by clinical situation

AML, peripheral blood

Myelomonocytic leukemia

Blast cells

Acute promyelocytic leukemia

Acute Myelogenous Leukemia

Undifferentiated

Myelomonocytic

Monoblastic, bone marrow biopsy

Acute Erythroleukemia

Peripheral blood

Bone marrow

ALL, microscopy & cytochemistry

Lymphoblasts, peripheral blood

PAS stain: lymphoblasts positive

Myeloperoxidase stain: lymphoblasts are negative

Alpha naphthyl esterase stain: lymphoblasts are negative

Immunophenotyping: AML CD GrpAntibodies Reactivity CD33

MY9, LeuM9, L4F3

CFU-GEMM to promyelocyte and mature monocytes

CD13

MY7, LeuM7

CD14

MY4, LeuM3, MO2

CFU-GM to mature granulocytes and monocytes Monocytes

CD15

LeuM1, MY1

Promyelocytes to granulocytes, monocytes

Immunophenotyping: AML CD GrpAntibodies

Reactivity

CD34

MY10, HPCA-1, HLA-DR, Ia

Progenitor cells, Blymphocytes, monocytes, activated T-cells

CD41

GPIIbIIIa, PL-273

Platelets and megakaryocytes

CD42

GP1b, FMC-25, Glycophorin A, 10F7

Monocytes

CD56

Leu19, NKH1

Natural killer cells

Cytogenetic Abnormalities: Significance

(Overall Survival in De Novo AML)

Median Survival Cytogenetic Abnormality (months) Rearrangements of 16q22 t(8;21)(q22;q22) Normal Abnormal 11q Abnormal 5 and/or 7 t(15;17)(q22;q11)

18 14 10 8 3 2

Acute Myelogenous Leukemia French-American-British (FAB) Classification AML - M0 (Acute undifferentiated leukemia) cells with undifferentiated morphology, with less than 3% MPO positive blasts AML - M1

>30% blasts with ≥3% MPO positivity, occasionally containing Auer rods, and showing little maturation beyond the myeloblast stage. The blasts can be NASD-negative

Acute Myelogenous Leukemia French-American-British (FAB) Classification >30% myeloblasts ( ≥3% MPO positive) with > 10% maturing AML-M2

granulocytic elements (progranulocyte through granulocytes) and <20% monocytic cells. Auer rods are often present, and some blasts show NASD positivity. Some cases are associated with t(8;21)

AML - M3

(Acute promyelocytic leukemia, APL) strong MPO positivity, showing a predominance of abnormal promyelocytes, with abnormally heavy granulation and occasional cells with bundles of Auer rods. A microgranular variant lacks the heavy granulation but maintains the other features. Both forms show strong NASD positivity and are associated with t(15;17).

Acute Myelogenous Leukemia French-American-British (FAB) AML -Classification M4 (Acute myelomonocytic leukemia) MPO positive, resembles M2 except that 20% of the cells are promonocytes (NSE-positive). A distinct subtype, associated with inv(16), has increased eosinophils with basophilic granules AML - M5 (Acute monocytic leukemia) leukemic cells are either monoblasts or promonocytes with abundant cytoplasm and eccentric nuclei. NSE and NASD positive; MPO staining is rare (<3%)

Acute Myelogenous Leukemia French-American-British (FAB) Classification AML - M6 (Erythroleukemia) consisted of M1, M2, or M4 blasts intermingled with dysplastic erythroid precursors, PAS positive AML - M7

(Acute megakaryoblastic leukemia) cytochemical stains are usually negative

Adult Acute Lymphocytic Leukemia FAB classification: L1: MPO negative , with small cells predominating L2: MPO negative, heterogeneous population with larger blasts L3: Burkitt type, MPO negative, homogeneous population of large blasts

Adult Acute Lymphocytic Leukemia  patients older than 15 to 18 years of age  biologically different from childhood ALL  Philadelphia chromosome (Ph)-positive is more frequent (15% to 30% v <5%) in adult ALL  Translocations t(1;19) and t(4;11) are less common. Back to Questions

Treatment of AML • Remission-induction therapy: combination of daunorubicin (45mg / m2 / d for 3 days) and cytarabine (100 to 200mg / m2 / d as continuous IV infusion for 7 days) • Post-remission therapy as: maintenance

therapy

consolidation

therapy

intensification

therapy

Prognosis: Acute Myelogenous Leukemia • De novo AML has a complete response (CR) rate of 60-75% • Long-term disease free survival occurs in 2550% of patients in CR • Secondary AML has remission rates of 3040%; long-term survivorship is unusual unless bone marrow transplantation is used

Prognostic Factors in AML Clinical

Factor

Favorable

Unfavorable

1 Age • < 45 • <2 yrs, years >60 yrs 2 Leukemia 3 Leukocyto • De Novo • Preceding • <25,000/ MDS sis 3 • >100,000/ mm 4 CNS 3 mm disease • Absent Greer JP and Kinney MC, Clinical Hematology; 1993 • Present 5 Cytoreduc • Rapid

Prognostic Factors in AML Morphology Factor

Favorable

Unfavorable

1 Auer • Pres • Abse rods ent nt 2 Eosinoph • Pres • Abse ils ent nt 3 Megalobl • Abse • Prese astic nt nt Greer JP and Kinney MC, Clinical Hematology; 1993 erythroid • M3, • M5, s

Prognostic Factors in AML Surface/Enzyme Markers

Factor

Favorable

1 Myeloid • MY4-, MY7-

Unfavorable

• MY4+(CD14), MY7+(CD13), MY10+(CD34) • Positive 2 HLA-DR • Negative • Absent • Present 3 TdT • Biphenotypic 4 Lymphoid• OKT11 (CD2), B4 ( ≥2 lymphoid Greer JP and Kinney MC, Clinicalmarkers) Hematology; 1993 (CD19)

Prognostic Factors in AML Cytogenetics

Favorable • t(15; 17), t(8; 21), inv(16)/del(1 6q)

Unfavorable • -7, del(7q); -5, del(5q); 11q23 abnormalities; 3q21 and 3q26 abnormalities

Greer JP and Kinney MC, Clinical Hematology; 1993

Adult Acute Lymphocytic Leukemia  Complete response rates (CR) range from 65% to 85%, and cure rates from 20% to 35%  Adults with ALL do not tolerate intensive chemotherapy as well as children.

Poor Prognostic Factors: ALL  Presence of Ph-positive disease and Burkitt leukemia before the intensive regimen  Older age  Leucocytosis

Poor Prognostic Factors  Longer time to achieve complete remission  Non-T-cell immunophenotype  Karyotypes: t(9;22) or t(4;11)

Treatment of Adult ALL  Induction therapy with vincristinecorticosteroids-anthracyclines is the current standard of care.  CR rate of 64% to 87%  Combining cyclophosphamide, asparaginase, or cytarabine does not improve the results except in a subset of patients.

Treatment of Adult ALL  Consolidation-intensification with higher doses of asparaginase, 6 mercaptopurine (6MP) plus methotrexate, and cyclophosphamide plus cytarabine improve overall outcome in specific adult ALL subsets (B-cell ALL, T-cell ALL)

Treatment of Adult ALL  Maintenance therapy with 6MP and methotrexate is beneficial except in Burkitt’s and other mature B-cell ALL, and in Ph-positive ALL

Central Nervous System Prophylaxis  CNS relapse rate in patients without prophylaxis: 21% to 50%  CNS prophylaxis with intrathecal chemotherapy and high dose systemic therapy using agents with good CNS penetration ( cytarabine, methotrexate, dexamethasone) is sufficient.  Radiation therapy limits the application of high dose chemotherapy and compromises TBI for BMT.

Myelodysplastic Syndromes (MDS)  Clonal refractory cytopenias whose marrows show characteristic dysplastic changes in at least 2 of 3 hemopoietic cell lines.  Propensity to transform to acute leukemia  Primary or secondary (therapy-related)

Myelodysplastic syndrome • Disease of the elderly More common above 50 years • Relatively common • Therapy related MDS not age-related  Late toxicity of cancer treatment: radiation,

alkylating agents: busulfan, nitrosourea, procarbazine, DNA topoisomerase inhibitors

Clinical presentation • Asymptomatic • Symptoms of  Anemia: gradual onset of fatigue, weakness, dyspnea, pallor  Some bleeding manifestations

• Physical examination  Signs of anemia  Spenomegaly (20%) commonly in CMML  lymphadenopathy is uncommon  Unusual skin manifestations (Sweet’s syndrome: febrile neutrophilic

dermatosis)  Autoimmune syndromes not infrequent

Diagnosis of MDS • No single morphologic finding is diagnostic • Combination of dysplastic features in the peripheral blood and bone marrow is necessary. • The diagnosis of MDS is a diagnosis of exclusion.

Diagnosis of MDS The following must always be excluded  Absolute exclusions  Vitamin B12 and / or folate deficiency  Proven exposure to heavy metals  Recent cytotoxic therapy  Relative exclusions  Ongoing inflammation including HIV and cancer  Chronic liver disease / alcohol use

Laboratory Studies in MDS • Serum B12 and folate • Serum iron and ferritin • Iron and reticulin stain of the marrow • Chromosomal studies • Flow cytometry

Peripheral Blood and Bone Marrow Findings Dyserythropoiesis

• Peripheral blood  Macrocytes  Hypochromic

microcytes, poikilocytosis

• Bone marrow  Megaloblastoid  Nuclear-cytoplasmic

asynchrony  Cytoplasmic tears or rents  Pathologic ringed

Peripheral Blood and Bone Marrow Findings Dyserythropoiesis • Nucleo-cytoplasmic maturation dissociation • Hyposegmentation / hypersegmentation of nucleus • Increase in myeloblasts • Abnormal localization of immature precursors

Peripheral Blood and Bone Marrow Findings Dysmegakaryocytopoiesis • Peripheral Blood  Thrombocytopenia  Giant forms  Lack of aggregation

• Bone Marrow  Mononuclear or bilobed forms  Hypersegmented forms  Cytoplasmic vacuolization  Increase in

micromegakaryocytes

FISH, MDS

French - American and British Morphologic Classification (FAB) • Refractory anemia (RA • Refractory anemia (RA) with ringed sideroblasts (RARS) • Chronic myelomonocytic leukemia (CMML) • Refractory anemia with excess of blasts (RAEB) • Refractory anemia with excess of blasts in transformation (RAEB-T)

WHO Classification of MDS • • • • • • • •

Refractory Anemia (RA) Refractory Anemia with Ringed Sideroblasts(RARS) Refractory Cytopenia with Multilineage Dysplasia(RCMD) Refractory Cytopenia with Multilineage Dysplasia and Ringed Sideroblasts (RCMD-RS) Refractory Anemia with Excess Blasts-1(RAEB-1) Refractory Anemia with Excess Blasts-2(RAEB-2) Myelodysplastic Syndrome, Unclassified (MDS-U) Myelodysplastic Syndrome Associated with del (5q)

Follow-up Observations of MDS • Those with stable clinical course with no life threatening cytopenias, follow-up examinations. • Cytogenetic studies may show change in karyotype; clonal evolution suggestive of imminent leukemic transformation.

Immunological Abnormalities in MDS • Immunoglobulins Polyclonal

hypergammaglobulinemia Hypogammaglobulinemia Monoclonal gammopathy Anti-red cell antibodies

• B cells Normal in number Functionally immature

International Prognostic Scoring System: MDS Prognostic variable

Score Value 0

0.5

Bone marrow blasts

<5%

510%

Karyotype

good inter medi ate

Cytopenia

0 or 1

1.0

1.5

2.0

Risk group scores

Score

Low

0

Intermediate-1

0.51.0

Intermediate-2

1.52.0

High

>2.5

11-20 21-30

poor

2 or 3

Therapy of MDS • Standard therapy: supportive care Anemia may be treated with transfusion Judicious use of red cell and platelet

transfusions to minimize the risk of alloimmunization Erythropoietin may be successful in low erythropoietin states Antibiotics when indicated

Treatment of MDS • Factors to be considered: clinical severity and patient age • Stable process: no treatment

Treatment of MDS • Treatment with hematopoietic growth factors (G-CSF, GM-CSF, IL-3) • Low-dose Ara-C, retinoids • Bone marrow transplantation • Aggressive anti-leukemic therapy

Novel Treatments • Anti-angiogenic : Thalidomide, lenalidomide, bevacizumab, arsenic trioxide • Tyrosine kinase inhibitors: Glivec • Farnesyl transferase inhibitors: tipifarnib • DNA methylation inhibitors: azacytidine, deoxycytidine

Case 2-02-01 • 55 year old female was referred because of hemoglobin of 19 mg/dL and hematocrit of 56 cv% • admitted because of right sided extremity weakness, dizziness and headache and was diagnosed to have left cerebral infarction • ROS: occasional pruritus • no prior history of hypertension or diabetes mellitus • did not take contraceptive pills • postmenopausic, G3P3 • family history of hypertension, no cancer • Physical examination  facial plethora  splenomegaly  neurologic deficits as described

Case 2-02-01 • • • • • • •

What are the signs and symptoms of erythrocytosis? What are the causes of secondary erythrocytosis? What is polycythemia rubra vera? What are the laboratory abnormalities in polycythemia vera? W hat are the diagnostic criteria for polycythemia vera? How do you manage this patient? What are the complications associated with this condition?

Polycythemia Rubra Vera • Myeloproliferative disorder affecting mainly red blood cells • Incidence varies considerably in different parts of the world • Age incidence: 6th and 7th decades of life • No obvious causative agent identifiable in majority of patients

Polycythemia Rubra Vera Pathophysiology

• primary defect involves a pluripotent stem cell capable of differentiating into both myeloid and lymphoid cells. • Increased sensitivity to EPO, interleukin-3 (IL-3), GM-CSF Alteration or activation of the EPO receptor

gives rise to autonomous erythropoiesis

• Lack of negative feedback mechanisms Back to Questions

Polycythemia Rubra Vera Clinical Features

• • • • • • • •

Headache Dyspnea Weakness Sweating Weight loss Plethora Dizziness Visual changes

• • • • • • • •

Epistaxis Angina Pruritus Paresthesia Gout Splenomegaly Hypertension Leg ulcers Back to Questions

Polycythemia Rubra Vera Laboratory Abnormalities

• Erythrocytosis, leucocytosis, thrombocytosis • Hyperuricemia • Elevated leucocyte alkaline phosphatase • pO2 > 92% • Elevated LDH • Elevated B12, unbound B12 binding capacity

PRV

Peripheral blood

Bone marrow biopsy Back to Questions

Polycythemia Rubra Vera Diagnostic Criteria

Major Criteria • A1 Hematocrit > 60% or rbc mass (ml/kg) > 36 in males and >32 in females •A2 Arterial O2 saturation of >95% •A3 Splenomegaly

Polycythemia Rubra Vera Diagnostic Criteria Minor Criteria Platelet count >400,000/uL • B1 WBC >12,000/uL • B2 Leucocyte alkaline • B3 phosphatase >100 Unbound vit B12 binding • B4 capacity >2,200pg/mL

Polycythemia Rubra Vera Diagnostic Criteria

Diagnosis is acceptable if: • A1 + A2 + A3 or • A1 + A2 + any two from category B Back to Questions

Differential Diagnosis of Polycythemia • Spurious polycythemia • Secondary polycythemia • Polycythemia Vera Back to Questions

Secondary Polycythemia Inappropriate • Renal cysts, hydronephrosis • Tumors Renal Uterine myoma Hepatoma Cerebellar hemangioma

Secondary Polycythemia Appropriate • Arterial hypoxemia  High altitude  Right-to-left shunt  Lung disease  Liver cirrhosis • Defective oxygen delivery  Congenital abnormal hemoglobin  Carboxyhemoglobin

Back to Polycythemia vera

Polycythemia Vera Treatment

• Removal of red cells through phlebotomy until the hematocrit is in the normal range. • Myelosuppressive drugs: hydroxyurea, busulfan, interferons • Anti-thrombotic therapy

Polycythemia Rubra Vera Course

• 15% will develop postpolycythemia myeloid metaplasia (PPMM), also termed the spent phase due to the waning of bone marrow proliferative activity. Appears at an average interval of 10 years No effective therapy for this phase

• Transformation to acute leukemia is a frequent cause of death

Back to Questions

Polycythemia Rubra Vera Thrombo-Hemorrhagic Complications • • •

Cerebral thrombosis Coronary thrombosis Peripheral vascular disease • Budd-Chiari syndrome • Erythromelalgia • Mesenteric vein thrombosis

• Raynaud’s phenomenon • Monocular blindness • Spontaneous abortion • Cardiac valve abnormalities • Cerebral hemorrhage • GI bleeding

Myeloproliferative Disorders • Polycythemia Rubra Vera • Primary (Essential) Thrombocythemia • Chronic Myelogenous Leukemia • Agnogenic Myeloid Metaplasia

Essential (Primary) Thrombocythemia • Clonal myeloid disorder characterized primarily by thrombocytosis • Median age at diagnosis is 60 years

Essential (Primary) Thrombocythemia Natural History

• Morbidity results from thrombohemorrhagic complications • 5% transforms to acute leukemia • 5 - 10% develop rises in hemoglobin and hematocrit in to the PV range

Essential (Primary) Thrombocythemia Diagnostic Criteria

• • •

Platelet count > 600,000/uL No cause for reactive thrombocytosis Hematocrit < 40% or red cell mass < 36 for males and < 32 for females • Normal red cell MCV or serum ferritin or marrow iron stores

Essential (Primary) Thrombocythemia Diagnostic Criteria

• Collagen fibrosis of marrow absent or < 1/3 of biopsy area without both splenomegaly and leucoerythroblastic reaction • No myelodysplastic changes on marrow smear • No Philadelphia chromosome or bcr/abl gene rearrangement

Essential Thrombocytosis

Reactive (secondary) Thrombocytosis • • • •

Infectious or inflammatory states Surgical procedure and tissue damage Malignancy Iron deficiency anemia, hemolytic anemia, acute blood loss

Reactive (secondary) Thrombocytosis • Postsplenectomy state • Rebound effect after chemotherapy or immune thrombocytopenia • Renal disorders (renal failure, nephrotic syndrome)

Essential (Primary) Thrombocythemia Pathophysiology

• Primary platelet overproduction from clonally proliferating megakaryocytes • In contrast, reactive thrombocytosis is related to overproduction of interleukin-6 ( IL-6)  during the acute phase response  chronic conditions associated with infection, inflammation, malignancy

Essential (Primary) Thrombocythemia Therapy

• Platelet-lowering therapy Hydroxyurea Anagrelide Interferons • Platelet pheresis • Anti-thrombotic therapy

Agnogenic Myeloid Metaplasia Pathogenesis

• Primary process: neoplasia of the hematopoietic stem cell • Second aspect of the disease is bone marrow fibrosis, consisting primarily of type I and type III collagen

Agnogenic Myeloid Metaplasia Pathogenesis

• Bone marrow fibrosis reactive process that is the result of functional and kinetic stimulation of nonclonal fibroblasts by growth factors shed from clonal megakaryocytes mediated predominantly by transforming growth factor-ß (TGF-ß) Others: platelet-derived growth factor (PDGF) and epidermal growth factor (EGF)

Agnogenic Myeloid Metaplasia Clinical Features

• Symptoms secondary to anemia and marked splenomegaly • Leucoerythroblastosis and dacryocytosis • Hypermetabolism: weight loss, night sweats and fever

Agnogenic Myeloid Metaplasia Clinical Features • Hepatomegaly in 50% • Bleeding tendencies secondary to intrinsic platelet dysfunction, acquired Factor V deficiency, DIC • Extramedullary hematopoiesis • Accelerated bone turnover demonstrated as increased bone density

Agnogenic Myeloid Metaplasia

Peripheral blood

Bone marrow biopsy

Bone marrow biopsy, Reticulin stain

Agnogenic Myeloid Metaplasia Prognosis • Median survival: 5 years • No curative therapy currently available • Palliation Androgen therapy Danazol Hydroxyurea Splenectomy Radiation treatment

Chronic Myelogenous Leukemia • Clonal MPD of a pluripotent stem cell with a specific cytogenetic abnormality: the Philadelphia chromosome • A causative factor can not be identified • The first phase of the disease, the chronic phase, terminates in a second, more acute course, the blastic phase. There may be an intervening accelerated phase in between.

Chronic Myelogenous Leukemia Clinical and Hematologic Features • Fatigue, anemia, progressive splenomegaly, leucocytosis • Myeloid cells in the peripheral blood show all stages of differentiation • Basophils and eosinophils are increased • Reduction in leucocyte alkaline phosphatase (LAP) • Hypercellular bone marrow

CML, peripheral blood A: myeloblasts B: Neutrophilic myelocyte C:Neutrophilic metamyelocyte D: Band E: Basophil

CML, cytogenetics

CML, cytogenetic abnormality

Chronic Myelogenous Leukemia Treatment • • • • •

Allogeneic stem cell transplantation Imatinib: tyrosine kinase inhibitor Interferon Hydroxyurea Busulfan

Case 2-03-01 • 70 year old male presented with masses in both sides of his neck of one year duration • gradual weight loss, low grade fever, anorexia and body weakness • no cough, shortness of breath, abdominal pain and leg swelling • PE: BP: 120/80 PR: 87/min, RR: 20/min, Temp: 38’C.  not pale, no jaundice  bilateral cervical lymph nodes, the largest measuring 3 x 2 cm, discrete,     

nontender and movable mass in the right axilla of the same character no inguinal lymph nodes heart and lung examination were normal spleen was palpable 3 cm below the left subcostal margin at the midclavicular line no pedal edema

Case 2-03-01 • • • • •

What are the possible causes of lymphadenopathy in this patient? How would you establish the diagnosis? What are the examinations necessary for diagnosis and staging? What are the types of lymphoma? What is the treatments available for patients with lymphoma?

Lymphoproliferative Disorders • Heterogenous group of diseases with protean manifestations  Lymph node enlargement  Bone marrow involvement  Anemia, lymphocytosis, thrombocytopenia  Involvement of secondary lymphoid organs  Constitutional “B” symptoms: fever, weight loss,

night sweats, pruritus Back to Questions

Diseases/ Exposures Associated with Increased Risk of Lymphoma •

•

Inherited immunodeficiency disease  Klinefelter’s syndrome  Chediak Hegashi syndrome  Ataxia telagiectasia syndrome  Wiskott-Aldrich syndrome  Common variable immunodefiency disease Acquired immunodeficiency  Iatrogenic immunosuppression  HIV-1 infection  Acquired hypogammaglobulinemia

• Autoimmune disease  Sjogren’s syndrome  Celiac sprue  Rheumatoid arthritis  Systemic lupus erythematosus • Chemical or Drug exposures  Phenytoin  Dioxin, phenoherbicides  Radiation  Prior chemotherapy & radiation therapy

Infectious Agents Agent

Lymphoid Malignancy

Epstein Barr virus

Burkitt’s lymphoma Post-transplant lymphoma Primary CNS Diffuse large B cell lymphoma Hodgkin’s disease Extranodal NK/T cell lymphoma, nasal type

HTLV-1

Adult T-cell leukemia/lymphoma

Human Herpes Virus-8

multicentric Castleman's disease Primary effusion lymphoma

Hepatitis C virus (HCV)

essential mixed cryoglobulinemia monocytoid B-cell lymphoma lymphoplasmacytoid lymphoma

Helicobacter pylori

gastric MALT lymphoma

A properly done biopsy is extremely important in the diagnosis of lymphoma

Benign reactive lymph node

Diffuse small lymphocytic (NHL)

Follicular, small cleaved cell (NHL)

Diffuse large cell (NHL)

Diagnosis of Hodgkin’s Disease • The presence of the Reed-Sternberg cell is a sine qua non for the diagnosis of Hodgkin’s disease

Evaluation for Diagnosis & Staging • Complete blood count • ESR • Biochemical studies of major organ function • For NHL  SLDH  B2 microglobulin  Serum protein electrophoresis

• Excision biopsy of lymph node  Flow cytometry  IHC

• Imaging studies  Contrast-enhanced CT scan

of the chest and whole abdomen  MRI if indicated  Gallium scan not necessary for primary staging  PET scan

• Bone marrow aspiration and biopsy

 Cytogenetics

Back

Revised European-American Lymphoma (REAL)/WHO Classification B cell neoplasms • Precursor B-cell neoplasm  Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) • Mature (peripheral) B-cell neoplasms  Chronic lymphocytic leukemia/B-cell small lymphocytic lymphoma  B-cell prolymphocytic leukemia  Lymphoplasmacytic lymphoma  Splenic marginal zone B-cell lymphoma (splenic lymphoma with villous lymphocytes)  Hairy cell leukemia  Plasma cell myeloma/plasmacytoma  Extranodal marginal zone B-cell lymphoma (MALT lymphoma)  Nodal marginal zone  B-cell lymphomaFollicular lymphoma  Mantle cell lymphoma  Diffuse large B-cell lymphomas  Burkitt's lymphoma/leukemia

T- and NK-cell neoplasms • Precursor T-cell neoplasm  Precursor T-lymphoblastic leukemia/lymphoma (precursor T-cell acute lymphoblastic leukemia)  Blastoid NK cell lymphoma • Mature (peripheral) T-cell neoplasms  T-cell prolymphocytic leukemia  T-cell large granular lymphocytic leukemia  Aggressive NK cell leukemia  Adult T-cell lymphoma/leukemia (HTLV1+)  Extranodal NK/T-cell lymphoma, nasal type  nteropathy-type T-cell lymphomaHepato  splenic T-cell lymphoma  Subcutaneous panniculitis-like T-cell lymphoma  Mycosis fungoides/Sézary syndrome  Primary cutaneous anaplastic large cell lymphoma  Peripheral T-cell lymphoma, not otherwise specified  Angioimmunoblastic T-cell lymphoma  Primary systemic anaplastic large cell lymphoma

Classification of Hodgkin’s Lymphoma Table 41.5-2: Classifications of Hodgkin's Lymphoma (HL) Jackson and Parkera

Lukes and Butlerb

Rye Conferencec

REAL Classificationd

WHO Classificatione

Paragranuloma

Lymphocytic and/or histiocytic, nodular

Lymphocyte predominant

Nodular lymphocyte predominant

Lymphocyte predominant, nodular

Classic HL

Classic HL

Lymphocyte-rich classic HLf

Lymphocyte-rich classic HL

Lymphocytic and/or histiocytic, diffuse

Granuloma

Sarcoma

Nodular sclerosis

Nodular sclerosis

Nodular sclerosis

Nodular sclerosis

Mixed cellularityg

Mixed cellularityg

Mixed cellularity

Mixed cellularity

Diffuse fibrosis

Lymphocytic depleted

Lymphocyte depleted

Lymphocyte depleted

Reticular

Unclassifiable classic HL

Histologic subtypes of Hodgkin’s Disease

Lymphocytic predominance

Nodular sclerosis

Mixed Cellularity

Lymphocyte depletion

Molecular Markers Disease

Cytogenetic abnormality

CLL/ Small lymphocytic lymphoma

t(14;15)(q32;q13)

MALT lymphoma

t(11;18)(q21;q21)

Precursor B cell acute lymphoid leukemia

t(9;22)(q34;q11) t(12;21)(p12;q22) 11q23/MLL

Oncogene

BCR/ABL ETV6 ETV6-CBFA2 TEL-AML1

Molecular Markers Disease

Cytogenetic abnormality

Oncogene

Mantle cell lymphoma

t(11;14)(q13;q32)

BCL-1

Follicular lymphoma

t(14;18)(q32;q21)

BCL-2

Diffuse large cell lymphoma

t(3;-)(q27;-) t(17;-)(p13;-)

BCL-6 p53

Burkitt’s lymphoma

t(8;-)(q24;-)

C-MYC

Anaplastic large cell lymphoma

t(2;5)(q23;q35)

ALK

Lymphoplasmacytoid t(9:14)(p13;q32) lymphoma

Management: NHL • Histologic subtype of lymphoma  Indolent vs. Aggressive

• Stage  Early vs. advanced disease

• Age • Performance status • Co-morbid conditions  Heart disease, liver disease, renal disease

Treatment: Intermediate to High Risk NHL • Chemotherapy • Targeted Agents  Rituximab: Anti-CD20 antibody

Treatment of Indolent Lymphomas • Watchful waiting • Single agent chemotherapy  Chlorambucil  Fludarabine

• Combination chemotherapy  CVP  CHOP

International Prognostic Index for NHL

Treatment Strategies: HD • Early stages, favorable: radiation alone (extended field) • Early stages, unfavorable: moderate amount of chemotherapy (typically four cycles) plus radiation • Advanced stages: extensive chemotherapy (typically eight cycles) with or without consolidating (usually local) radiation

Case 2-01-02 • 92 year old male has no complaints but has been noted to have chronic anemia for the past 3 years • consulted several physicians, given oral iron therapy with apparently some improvement in hemoglobin levels the maximum reached was 97 gm/L • requiring blood transfusions for the past year • no changes in his bowel movements, including changes in color • no changes in the urine volume or color • frequent episodes of cough but no fever • weight loss, which was not quantified • Physical examination: alert elderly male, wheelchair borne, with VS: BP: 110/70, PR: 100/min, regular, RR: 18/min, regular, Temp: 36.5’C.  pale, no jaundice, no lymphadenopathy  soft blowing systolic murmur in the left parasternal area, clear breath sounds  no hepatoslenomegaly  No pedal edema.

Case 2-01-02 CBC: HB: 89 gm/L, Hct: 0.26, WBC: 2.6 x 109/L segmenters: 39%, lymphocytes: 61%, platelets: 200 x 109/L

Case 2-02-02 • 63 year old female had recent onset of dizziness 4 days ago • accompanied by headache, palpitations, shortness of breath, and easy fatigability • no fever, cough, orthopnea, PND , nor pedal edema • Family history is negative for cancer or blood disease • past history of asthma • PE: VS: BP: 120/70, PR: 90/min, RR: 20/min, Temp: 37.5’C,  pale, no jaundice, no palpable lymph nodes  no murmurs, clear breath sounds, no crackles  liver not palpable but spleen palpable 3 fingerbreadths below LSCM.

Case 2-02-02 CBC: Hb: 71 gm/L Hct: 0.31 WBC : 389 x 109/L metamyelocytes: 24% bands 21% segmenters 36% lymphocytes 4% eosinophils 3 % Platelets: 1689 x 109/L

Case 2-02-04 • 55 year old female noted to have gradual abdominal enlargement for the past three years with significant increase during the past three months • nonproductive cough for the past three weeks • good appetite, no early satiety, weight loss or easy fatigability • Physical examination showed VS: BP: 120/70, PR: 84/min, RR: 20/min, Temp: 36.7’C. • pink palpebral conjunctivae, no jaundice, no lymphadenopathies • no murmurs • Lung examination: rhonchi on both lung fields • liver was palpable 5 cm below the RSCM, the spleen was palpable 21 cm below the LSCM at MCL • no pedal edema

Case 2-02-04 CBC showed HB: 158 gm/L, Hct: 0.50, WBC: 23 x 109/L Segmenters 87%, Lymphocytes 11%, Monocytes 2%, Platelets: 474 x 109/L