Hematologic Malignancy

Chantrapa Sriswasdi, M.D. Hematology Unit, Phramongkutkloa Hospital
22 Nov 2009

Topics
• Myeloproliferative neoplasms (MPNs) • Acute myeloid leukemia • Acute lymphoblastic leukemia • Lymphoproliferative disorders • Plasma cell dyscrasias

Myeloproliferative neoplasms (MPNs)

Common MPNs
• Chronic myelogenous leukemia (CML), BCR-ABL +ve

• Primary myelofibrosis (PMF)
• Polycythemia vera (PV) • Essential thrombocythemia (ET)

Characteristics of MPNs
• Clonal hematopoietic stem cell disease
• Overproduction of one or more blood cell lines

• Organomegaly • Extramedullary hematopoiesis • Leukemic transformation • Thrombosis: major cause of death

Complication
• Leukemic transformation
– Differ among the subgroups
• CML >90% • ET <5%

• Thrombosis
– Arterial and venous thrombosis
• Mechanism: leukocyte, vascular endothelium, coagulation system

– Microcirculatory disorder: erythromelalgia

• Bleeding
– High platelet count: acquired vWD

Erythrocytosis (Polycythemia)
• Definition: Hct male > 52%,female > 48% • Relative vs Absolute • Absolute erythrocytosis
– Hct male > 60%, female > 55%

Erythrocytosis (Polycythemia)
I. Relative or spurious erythrocytosis or Gaisbock's disease II. Absolute erythrocytosis
– Primary marrow diseases: PV,1ry erythrocytosis
– Reactive : increased EPO production

Erythrocytosis
– Reactive : increased EPO production
• Tissue hypoxia
– Lung diseases : COPD – Heart disease: Rt to Lt shunt – High attitude – Abnormal Hb, smoking – Hypernephroma – Hepatoma – Cerebellar hemangioblastoma – Uterine fibromyoma – Polycystic kidney – Renal artery stenosis

• Tumors produce EPO

• Renal diseases

Serum erythropoietin
Low Normal High

PV diagnosis probable
Bone marrow examination

PV diagnosis possible

Evaluate for secondary polycythemia

Characteristics for PV?
yes no

Specialized tests -JAK2 mutation -BM immunochemistry for c-mpl -PCR for PRV-1 gene -EEC formation
Mayo Clin Proc 2003;78:174-94.

PV

Specialized test Not consistent with PV

Consistent with PV

Reevaluate in 3 mo

Polycythemia vera
• Increase RBC production independent of normal mechanisms • Median age 60 years • Mutation of Janus 2 kinase gene (JAK2 V617F) • Panmyelosis • 3 phases
– Prepolycythemic phase – Polycythemic phase – Spent or post-polycythemic myelofibrosis

Pathogenesis
•Disease •Thrombosis

JAK2 mutation: MPNs
• Reported in 2005 • Mutation: JAK2V617F
– Valine to Phenylalanine
– Codon 617

• Myeloprolifertive disorders
– PV – ET
– MF

90-95% 50-70%
40-50%

Pathogenesis
Thrombosis • High Hct • Platelet
– No correlation with platelet count – Platelet defect
• Increase platelet thromboxane A2 production • Decrease response prostaglandin D2

• Abnormal in vivo activation of leukocyte, endothelial cell • Decrease natural anticoagulant • Decrease fibrinolytic activity

Clinical features
• • Physical Findings Frequency (%) Symptoms Headache 48 Fatigue 47 Pruritus 43 Dizziness 43 Diaphoresis 33 Visual disturbances 31 Weight loss 29 Erythromelalgia 29 Dyspnea 26 Joint symptoms 26 Epigastric discomfort 24 thrombosis 20 Signs Splenomegaly 70 Skin plethora 67 Conjunctival plethora 59 Engorged vessels in the optic fluid 46 Hepatomegaly 40 Systolic blood pressure > 140 mmHg 72 Diastolic blood pressure > 90 mmHg 32
Semin Haematol 1975;12:339-51

Erythromelalgia

•Burning pain in the feet or hands accompanied by erythema, pallor, or cyanosis •Microvascular thrombosis

WHO diagnostic criteria for PV

2 major + 1 minor or The first major + 2 minor

Laboratory
• CBC • Peripheral blood smear • Bone marrow examination • EPO level • JAK2 mutation

CBC
Red cell • Increase Hct, Hb • Not increase in PV with iron deficiency White cell • Leukocytosis • Band form, metamyelocyte, myelocyte (Lt shift) • Increase basophil, eosinophil Platelet • Increase or normal

Blood smear
RBC: excess red cells, NC, NC hypochromic microcytic red cells (iron deficiency) WBC: increase with band form, myelocyte ,metamyelocyte Platelet: increase

Bone marrow smear
• Hypercellular marrow • Increase erythroid, myeloid, megakaryocyte (panmyelosis) • Normal maturation of myeloid series • M:E = 2-3:1 • Increase megakaryocytes with different size • Negative iron stain

Natural course
• Survival
pre-phlebo non aggr phlebo Median sur 18 mo 3-4 yr • Cause of death
– – – – Thrombosis Malignancy : acute leukemia, non-RE malignancy Myelofibrosis Bleeding

aggr phlebo 9-12.8 yr

Risk of thrombosis
Both PVSG and ECLAP
– Old age: age > 60 years – Previous thrombosis – Phlebotomy treated group – Other cardiovascular disease:
• DM
• Smoking

Polycythemia vera
Phlebotomy to maintain Hct < 45% male, <42% female

Low dose ASA

high risk of thrombosis •Age>60 years •Previous thrombosis •Other cardiovascular risk Platelet > 1,500,000 /um

Age < 50 yr

Age 50-70 yr

Age > 70 yr

Interferon Hydroxyurea

Busulphan or 32P

Clue diagnosis PV
• • • • • • • • High Hct, absent secondary erythrocytosis Headache, plethora, thrombosis, pruritus Mild to moderate splenomegaly Hepatomegaly Leukocytosis, thrombocytosis Panmyelosis Low erythropoietin level JAK2 mutation

AMM
• Other name
– Chronic idiopathic myelofibrosis – Myelofibrosis with myeloid metaplasia (MMM)

• Atypical megakaryocytic hyperplasia
– Produce cytokine to stimulate fibroblastic proliferation

AMM
• Median age 67 years • Symptoms
– 15-30% no symptom – Severe fatigue ( anemia) – Symptom due to enlarged spleen – 5-20% weight loss, low grade fever, night sweats

• Signs
– Pallor – Splenomegaly (>90%): marked, hallmark – Hepatomegaly

Clinical features of AMM
Mechanism Hypercatabolic state Splenomegaly Anemia Portal hypertension/ascites Splenic infarct Esophageal varices/hemorrhoids Ectopic myeloid metaplasia Symptoms Fatigue, weight loss Pain, early satiety Dyspnea, palpitations Abdominal pressure, peripheral edema Acute left upper quadrant pain, fever GI bleeding Tumor mass effect (lung, GI, GU, CNS, spine/vertebral column) Thrombocytopenia/platelet dysfunction Bleeding, bruising Hyperuricemia Monoarticular arthritis, nephrolithiasis (synovitis, hematuria)

Laboratory findings
• Anemia
– Decrease production of bone marrow
– Splenic sequestration

– Bleeding from thrombocytopenia or varices – Autoimmune hemolysis
– Dilutional anemia

• WBC: leukocytosis, leukopenia in progressive disease • Platelet: thrombocytosis, thrombocytopenia

Laboratory findings
• Blood smear
–Teardrop red cell –Anisopoikilocytosis –Leukoerythroblastic blood picture –Increase basophil –Abnormal platelets –Fragmented megakaryocyte

Laboratory findings
• Bone marrow examination
–Dry tap –Marrow fibrosis with atypical megakaryocytic hyperplasia –Increase alkaline phosphatase –Increase LDH –Increase uric acid –Increase circulating CD34+ cells

• Other lab tests

Causes of Marrow Fibrosis
Nonhematologic Hematologic Infections Myeloproliferative disorders ET, PV, MMM TB Leishmaniasis Hypereosinophilic Histoplasmosis syndrome HIV Systemic mastocytosis Connective tissue disease CML Renal osteodystrophy Other AML-M7 Metastatic cancer MDS Vitamin D deficiency Multiple myeloma Hypothyroidism Hairy cell leukemia Hyperthyroidism Lymphoma Paget disease ALL Gaucher’s disease Grey platelet syndrome

Treatment
• Allogeneic stem cell transplantaio
– Limit by age and HLA match – 17% present age < 50 years

• • • •

Androgens + corticosteroid (1 month) Danazol 200-800 mg/day Erythropoitin or blood transfusion Chemotherapy
– Busulfan – Hydroxyurea

Treatment
• • • • • Splenectomy Splenic irradiation Anagrelide: for thrombocytosis Interferon Thalidomide+prednisolone (3 months)

Clue of Diagnosis
• Clue for diagnosis
–Elderly patients

–Splenomegaly: moderate to huge size –Teardrop red cells –Leukoerythroblastic blood picture –Dry tap with myelofibrosis

Essential Thrombocythemia (ET)

Essential thrombocythemia
• Other named
– Essential thrombocytosis – Primary thrombocytosis

• Diagnosis by
– Excluding cause of reactive thrombocytosis – Excluding other CMPDs

• Female:Male = 2:1 • Mean age at diagnosis 60 years

Clinical manifestation
• 50% asymptom • Vasomotor symptom: thromboxane, microvascular thrombosis
–Headache, lightheadedness, syncope –Atypical chest pain, acral paresthesia –Livedo reticularis, erythromelalgia –Transient visual disturbances

Clinical manifestation
• Thrombosis: common complication
– Arterial site: stroke, TIA, retinal artery occlusion, coronary ischemia digital ischemia – Venous site:DVT, PE, hepatic or portal vein

• Hemorrhage: risk
– Extreme thrombocytosis – Use ASA > 325 mg/day – Use NSAIDs

Clinical manifestation
• Transformation
– Myelofibrosis: 4% follow 9.2 years – Acute myeloid leukemia
• 1.4% follow 9.2 years • Previously treated by cytoreductive therapy

• Physical examination
– Splenomegaly 25-48%

WHO criteria for ET

Diagnosis requires all 4 criteria

Laboratory
PBS: RBC: NC,NC WBC: normal to mild leukocytosis Platelet: marked increase, vary in size, a few giant platelet Bone marrow smear: Hypercelularity Erythroid: adequate M:E= 3-4:1 Myeloid: adequate and normal maturation Megakaryocyte: numerous megakaryocytes, giant and hyperlobated nuclei

numerous megakaryocytes

giant and hyperlobulated nuclei

Reactive thrombocytosis
• Iron deficiency, asplenia, malignancy, bleeding, hemolysis, infection, inflammation, connnective tissue disease • Elevated acute-phase reactants
– C-reactive protein – Fibrinogen – ESR – Ferritin

Prognostic factors
• Thrombotic events
– 6.6%/patient-year vs 1.2%/patient-year

• Risk of thrombosis
– History of previous thrombosis – Age > 60 years – Cardiovascular risk

• No effect risk of thrombosis
– Degree of thrombocytosis – Abnormal platelet function

Risk factors
• Low, Intermediate and High risk • Low risk: have all of the followings
–Age < 60 years –No previous thrombosis –Platelet < 1,500x 109/L –No cardiovascular risk factors

• High risk: have one or both
–Age ≥ 60 years –Previous thrombosis

Treatment
• Near normal life expectancy • Vasomotor symptom
– Low dose ASA: 40-325 mg/day

• • • • • •

Hydroxyurea Anagrelide Alpha interferon Pipobroman Radioactive phosphorus Busulfan

Treatment
• Low risk
–Low dose ASA

• High risk
–Cytoreductive : hydroxyurea
–Low dose ASA

Clue diagnosis of ET
• Increase platelet • Asymptom, thrombosis, hemorrhage • Increase megakarycytes with giant and hyperlobated nuclei • Exclude reactive and other chronic MPN, MDS

Splenomegaly: causes
• Congestive diseases
– Cirrhosis – Splenic vein thrombosis

• Infection
– Tuberculosis – Virus, bacteria

• Malignancy
– Lymphoma – Chronic MPD

• Storage disease
– Gaucher disease

• Inflammatory disease
– SLE – Felty syndrome

• Hemolytic anemia
– Thalassemia – AIHA

• Miscellaneous
– Tropical splenomegaly

Splenomegaly
• Mild splenomegaly
–< 2 cm below Lt costal margin

• Massive splenomegaly
–Extend to Lt lower quadrant

• Moderate splenomegaly

Massive splenomegaly
• Chronic myeloproliferative disorders • Lymphoma, hairy cell leukemia • Chronic lymphocytic leukemia • Major thalassemia • Gaucher disease • Infection: TB, chronic malaria

• • • • • •

Clonal disease Ph chromosome positive t(9;22) (q34;q11) p210BCR-ABL oncoprotein p190BCR-ABL related-monocytosis p230BCR-ABL related-prominent neutrophilic maturation, obvious thrombocytosis • Mean age 50-60 yrs • 3 phases: chronic, accelerated, blastic

CML

Clinical features of CML
• Asymptom (20-40%) • Fatigue, weight loss • Splenomegaly: left upper quadrant abdominal pain, early satiety • Bleeding

• Priapism

WHO criteria
• Accelerated phase CML
– Blasts 10-19% in peripheral blood or marrow

– Peripheral blood Ba ≥ 20% – Thrombocytopenia : ≤ 100 x109/L
– Thrombocytosis: ≥ 1,000 x109/L

– Increase spleen: unresponse to treatment
– Increase WBC: unresponse to treatment – Cytogenetic evolution

WHO criteria
• Blastic phase (myeloid or lymphoid)
–Blasts ≥ 20% peripheral blood or marrow –Extramedullary blast proliferation –Large foci of blasts in marrow

Laboratory
Blood smear • NC, NC, NRC • Increase WBC, most are myeloid cells at varying stages of maturation, increase basophil and eosinophil • % of blast and basophil • Increase platelet

Marrow smear • Hypercellularity • Relatively increase erythoid M:E 10:1 • Increase myeloid with all stages, increase Ba,Eo • Increase small and hypolobated megakar. • % blast

CML present with thrombocytosis

หญิงอายุ 58 ปี ตรวจสุขภาพ พบ abnormal CBC จาก peripheral blood smear ให้การวินิจฉัย

Clue diagnosis
• • • • • Age Leukocytosis, all stage of myeloid cells Increase basophil Splenomegaly WBC >30,000 /µL Low neutrophil/leukocyte alkaline phosphatate (NAP or LAP) • + Philadelphia chromosome: t(9;22) important for diagnosis

• Tyrosine kinase inhibitor

Therapy

– disease control without cure – imatinib, dasatinib, nilotinib

• Allogeneic stem cell transplantation
– Potential cure

• Interferon alpha ± cytarabine • Other cytoreductive agents (palliative)
–Hydroxyurea –Busulfan

Diagnosis chronic phase CML Candidate for myeloablative allogeneic SCT?

Yes; age < 40

Possibly, age 40-55

No; age > 55; medical contraindication

HLA-matched sibling or unrelated donor

HLA-matched sibling

No family donor

Imatinib mesylate Discuss imatinib vs. transplant If patient chooses imatinib close follow-up is required •Q-PCR or FISH every 3 months •BM cytogenetics every 12 months Partial response Increase dose of imatinib as tolerated Failed response Dasatinib,Nilotinib or SCT or experimental protocol

Acute myeloid leukemia

Risk of AML
• Irradiation • Benzene • Chemotherapy
– Alkalating agents – Topoisomerase II inhibitor

• MPNs • MDS • Genetic disorders: Down syndrome

Clinical manifestation
• • • • • • Median age 65 years Fever : prolong, acute Marrow failure: anemia, bleeding Tissue invasion: gum, skin, chloroma Life-threatening bleeding: DIC Hyperleukocytic syndrome: dyspnea, altered mental status

Clinical manifestation
• Leukemia cutis syndrome or neutrophilic dermatosis
– erythematous to violaceous tender nodules and plaques – Neutrophil infiltrate

• Uncommon organomegaly (monoblast)

Leukemia cutis
•nodular and violaceous/gray-blue in color, no tender

Sweet syndrome
erythematous to violaceous tender nodules and plaques

Gum hypertrophy •Severe gingivitis •AML: monoblast •Cyclosporin •Dilantin •Nifedipine •Amyloidosis

Diagnosis
• Blasts ≥ 20% in PB or BM
–Myeloblast –Monoblast/promonocyte –Megakaryoblast

• Blasts < 20% combined with
–t(8:21) –Inv(16), t(16;16) –t(15;17)

FAB classification
M0 myeloblast MPO < 3% poor prognosis M1 myeloblast, without maturation M2 myeloblast with maturation M3 abnormal promyelocyte t(15;17) M4 myelomonoblast monocytic >20% M5 monoblast M6 erythroleukemia glycophorin A + M7 megakaryocytic acute myelofibrosis

Investigation
• CBC, PBS • Bone marrow exam • Cytogenetic study • Immunophenotype:
–Flow cytometry

• Biochemistry: LDH, uric acid, BUN, Cr, LFT

CBC
• Decrease Hct, platelet • WBC: increase with blast • Pancytopenia
–Severe –Relative lymphocytosis –Mimic aplastic anemia

Bone marrow aspiration
• Hypercellular marrow • Decrease megakaryocyte and erythroid series • Increase blast, blast with granules, auer rods • Myeloblast or monoblast ≥ 20%

Myeloblast with auer rods

Myeloblast

AML: M4

Monoblast

AML, M3

AML, M6

AML, M7

Prognostic factors
• Patient age: good
–< 40 years

• Cytogenetics: good
–t(8;21) –t (15;17) –Inv(16) or t(16;16)

Treatment
• Remission induction
– Cytarabine 7 days – Anthracycline 3 days

• Postremission therapy
– Consolidation – Intensive chemotherapy ; high DARC – Stem cell transplantation

Acute promyelocytic leukemia
• • • • • Increase abnormal promyelocytes t(15;17): PML – RARa Hypergranular and microgranular types Hypergranular type: pancytopenia Microgranular type: high white cells

Acute promyelocytic leukemia
• Hemorrhage- early death • High cure rate compare with other AML subtype • Coagulopathy
– Disseminated intravascular coagulation – Primary fibrinolysis – Direct proteolysis

Investigation
• • • • • • • CBC: leukocytosis, pancytopenia PBS D-dimer, coagulogram BUN, Cr Bone marrow exam Cytogenetic study Immunophenotype: flow cytometry

Hypergranular type
Abnormal promyelocyte with intense azurophilic granules Abnormal promyelocyte with numerous auer rods (faggot cells)

Microgranular type
Predominantly bilobed nuclear shape

Acute promyelocytic leukemia
• All-trans retinoic acid:
–Differentiated agent –Target : RARa moiety

• Arsenic trioxide (ATO)
–Apoptosis –Target: PML moiety

Acute promyelocytic leukemia
• Treatment: front line
–Induction
• ATRA + anthracycline

–Consolidation
• Anthracycline

–Maintenances (no benefit for molecularly negative
after consolidation )

• ATRA+ Low dose chemotherapy • 10% early death, 20-30% relapse

Acute promyelocytic leukemia Reduce bleeding or early death
• Start ATRA before cytogenetic confirmation • Maintain platelet ≥ 30,000-50,000 /µL • Fibrinogen level ≥ 150 mg/dL

Acute promyelocytic leukemia • Differentiating (Retinoic acid) syndrome
–Fever, dyspnea,fluid retention, weight gain, pleural or pericardial effusion, hypotension –Dexamethasone

Acute promyelocytic leukemia • Arsenic trioxide
–Relapse or refractory APL –Front line alone –Front line : ATO+ATRA

• Short duration for achieve CR (25±5 days)

Acute lymphoblastic leukemia

ALL
• Younger age compare to AML • Marrow failure • Mild organomegaly • CNS involvement • Testicular involvement

Adverse prognostic factors
• Age > 60 years • WBC > 50,000 /mL • Adverse cytogenetics
– Ph chromosome + – t(v;11q23) – Trisomy 8 – Hypodiploidy

• Prolonged time to CR

FAB classification

•ALL - L1 •ALL - L2 •ALL - L3

Treatment
• Induction
– Vincristine – Glucocorticoid – L-asperaginase – Anthracycline

• Consolidation • CNS prophylaxis • Maintenance therapy

Stem cell transplatation
• Secondary remission • High risk group
–Ph+ ALL –Undifferentiated phenotype –High leukocyte count –Long term to achieve CR

AML vs ALL
• Clinical presentation
– Age – Previous malignancy – Lymphadenopathy or splenomegaly

• Morphology
– Cytoplasmic granule: Auer rod – Nuclear chromatin – Nucleolus – Dysplastic features

Lymphoblastic lymphoma
• Young male • Anterior mediastinal mass (75%)
– Dyspnea, stridor, dysphagia, swelling of head and neck (SVC syndrome)

• Involvement
– Skin, bone, marrow, CNS, pleura

• Most common T cell

ALL – L2

ALL – L3

ชายอายุ 18 ปี ไข้ ไอ เหนื่อยง่าย 1 เดือน CXR: pleural Effusion ทา pleural tapping and smear จงให้การวินิจฉัยโรค

Lymphoma
•Non-Hodgin lymphoma •Hodgkin lymphoma

Diagnostic test for lymphoproliferative disorders

• Morphology • Immunophenotyping • Cytogenetics • Molecular genetics

Classification of lymphoid neoplasm
• B cell neoplasms
– Precursor B-cell neoplasm – Mature B-cell neoplasm

• Hodgkin lymphoma
– Nodular lymphocytepredominant Hodgkin lymphoma – Classic Hodgkin lymphoma • Nodular sclerosis
• Mixed cellularity

• T-cell and NK-cell neoplasms
– Precursor T-cell neoplasm – Mature (peripheral) T-cell neoplasms

NHL
• Indolent NHL
– – – – – Older age Present: organomegaly Advanced stage Long term survival Response to treatment but not curable – Low constitutional symptom – Follicular NHL : the most common type

• Aggressive NHL
– All age – More acute presentation – Present early stage

– B symptom: fever
– More curable – Diffuse large B cell: the most common type

NHL
• Indolent lymphoma
– B cell
• • • • CLL/SLL Follicular grade I,II,IIIa Marginal zone MALT

• Aggressive lymphoma
– B cell
• • • • • Mantle cell Follicular grade IIIb Diffuse large B cell Mediastinal large B cell Burkitt lymphoma

– T cell
• Mycosis fungoides/ Sezary syndrome • Primary cutaneous ALCL

– T cell
• Systemic ALCL • T-cell leukemia/ lymphoma

NHL

Approach to the diagnosis of NHL
• • • • • • • • Systemic complaints (B symptoms) Prolonged fever Lymphadenopathy Hepatosplenomegaly Specific organ involvement: testes, GI,CNS,lung Marrow involvement: anemia, bleeding Autoimmune manifestation History underlying disease: HIV, malignancy, Sjogren's syndrome

Emergency conditions
Conditions Spinal cord compression Pericardial tamponade SVC obstruction Hypercalcemia Hyperleukocytosis Acute airway obstruction Lymphomatous meningitis and/or CNS mass lesions Type of NHL Aggressive type Lymphoblastic lymphoma Primary mediastinum B cell NHL Aggressive type Lymphoblastic lymphoma Primary mediastinum B cell NHL Aggressive type

Emergency conditions
Conditions Hyperuricemia and tumor lysis syndrome Hyperviscosity syndrome
Intestinal obstruction, intussusception Ureteral obstruction Severe AIHA, ITP

Type of NHL Aggressive type
Waldenstrom's macroglobulinemia Aggressive type

Aggressive type B cell small lymphocytic lymphoma/CLL Venous thromboembolic disease Aggressive type Indolent type

Investigation in lymphoma
• Confirm cell type
– Immunophenotype: B or T cell

• Prognosis
– Staging: physical examination,CT abdomen, – LDH

• Associated disease
– Anti HIV

• Treatment-related mortality
– LFT, BUN, Cr – Hepatitis B virus

Aggressive NHL
• Local LN enlargement > generalized LN enlargement • Systemic symptoms – Fever – Anorexia and weight loss • Organ involvement – Liver : infiltrative lesion – CNS: mass or meningeal involvement – GI: stomach, colon – Chest: anterior mediastinal mass – Testis • DDx: TB, SLE

Etiologic risk factors
Virus Bacteria Impaired immune • Congenital •Acquired EBV, HTLV-1, HHV-8, HCV Helicobactor pylori Ataxia telangiectasia Wiskott-Aldrich syndrome AIDS Post transplantation Autoimmune disease Herbicides

Environment

HIV and Lymphoma
• 3 types
– Systemic NHL – Primary CNS lymphoma – Primary effusion lymphoma (PEL) or primary body cavity lymphoma

• Aggressive type • Large B cell type

Ann Arbor staging system
Stage I Single LN region (I) or single extranodal organ (IE) Stage II ≥ 2 nodal regions, same side of diaphragm Stage III Nodal involvement on both sides of diaphragm Stage IV Dissemination to extranodal organ A = asymptomatic, B = fever > 380 C, night sweats, Wt loss > 10% in 6 mo E = extranodal disease, X = bulky disease

Staging
• • • • Physical examination CT whole abdomen or other Bone marrow examination CT or MRI brain and LP
– Burkitt or lymphoblastic lymphoma – Large cell type involve
• Bone marrow • Testis • sinonasal

Prognosis
• IPI risk factors
– Age > 60 years – LDH > normal – Performance status 2-4 – Stage III or IV – > 1 extranodal sites

• Age-adjusted IPI (<60 yr)
– LDH > normal – Performance status 2-4 – Stage III or IV

Treatment
• Chemotherapy
– Anthracycline-based regimen

• Rituximab • Radiotherapy
– Reduced mass effect – Combined with chemotherapy in 1st line for early stage

Post complete remission
• Follow every 3 months : 2-3 years
– Hx and physical exam – CBC and LDH – CT every 6 months

• Follow every 4-6 months: year 4 and 5
– Hx, physical exam – CBC, LDH

• Follow every 1 year: > year 5

NHL – large cell type

Indolent B cell lymphoma
• Follicular lymphoma grade I, II • Marginal zone lymphoma

• MALT lymphoma
• CLL/SLL

Indolent B cell lymphoma
• Old age • Generalized lymphadenopathy • Advanced stage: marrow involve • Autoimmune cytopenia

MALT lymphoma
Location • Gastric: most common • Intestine • Lung, salivary gland, thyroid, periorbital Associated with
– H. pylori – Sjögren syndrome – Hashimoto thyroiditis

Lymphoplasmacytic lymphoma
• + monoclonal IgM = Waldenström macroglobulinemia • Mature plasmacytoid lymphocyte • Present
– Anemia, lymphadenopathy – Purpura, splenomegaly – Hyperviscosity – Tissue deposit of IgM: neuropathy, amyloidosis

Rouleaux formation

Lymphoplasmacytoid lymphocyte

CLL
• The most common leukemia in the western country • Old age: 60-65 years • Increase skin, lung and GI cancers • B cell malignancy • CD19, CD20, CD5, CD23 positive • FMC7 negative

Clinical presentation
• • • • • • Old age Asymptom Lymphadenopathy Hepatosplenomegaly Infection Immune cytopenia: AIHA, ITP

Diagnostic criteria
• Sustained lymphocyte count ≥ 10,000 /µL • If lymphocyte count ≤ 10,000 /µL + monoclonal B cell phenotype

Rai clinical staging system
Risk group, stage Low risk Stage 0 Features Med surv. (mo)

Blood and marrow lymphocytosis (L)
L + adenopathy L+ splenomegaly or hepatomegaly

> 120

Intermediate risk Stage I Stage II
High risk Stage III Stage IV

108 94

L+anemia (Hb<11 g/dL) L+thrombocytopenia (100,000/µL)

60 60

Treatment
• Chronic but incurable • No treatment for
– Early stage – No symptom

• Criteria for treatment
– Worsening of constitutional symptom – Progressive symptomatic adenopathy or hepatosplenomegaly – Cytopenia – Recurrent infection – Short doubling time of blood lymphocytes

Treatment
• Alkalating agents: chlorambucil, CVP • Fludarabine : infection, AIHA • Monoclonal antibody therapy
–Alemtuzumab : anti CD52 –Rituximab : anti CD20, low CD20 density

Blood smear, CLL

Bone marrow, CLL

CLL with AIHA

Multiple myeloma

Clinical presentation
Presentation General
Hematology

Symptom and sign Fatigue, anorexia, weight loss
Anemia : chronic, NCNC, macrocytic anemia Bleeding : platelet, coagulation, vessel pancytopenia

Orthopedics

Bone pain: back, chest Pathological facture

Clinical presentation
Presentation Neurology Symptom and sign Radiculopathy : thoracic, lumbosacral area Cord compression Peripheral neuropathy: • Amyloid • Paraneoplastic syndrome • POEMS syndrome Alteration of consciousness • Hypercalcemia • Hyperviscosity

Clinical presentation
Presentation Infection Symptom and sign Bacteria: hypogammaglobulin, neutropenia, steroid • Pneumonia • Septicemia
Renal failure Proximal RTA Amyloidosis: nephrotic syndrome

Nephrology

Clinical presentation
• Rare presentation
–Prolonged fever –Lymphadenopathy –Hepatosplenomegaly –CNS involvement

Laboratory findings
• CBC , PBS
– Cytopenia: anemia – Rouleaux formation 50%, (polyclonal, monoclonal) – Plasma cell in PBS

• Demonstrate monoclonal protein
– – – – Protein electrophoresis (PEP) Immunoelectrophoresis (IEP) Immunofixation Serum free light chain

• Reciprocal Ig changes

Total protein 13 mg% IgG 8280 mg% (650-1500) IgA 19 mg% (80-310) IgM 40 mg% (55-300) total = 8339 mg% IEP. Monoclonal IgG, k type, IgM, IgA,  decrease

Total protein 7 mg% IgG 879 mg% (650-1500) IgA 70 mg% (80-310) IgM 52 mg% (55-300) total = 1001 mg% IEP. light chain disease  Bence Jones protein

Laboratory findings
• Imaging
–Bone survey:
• diffuse osteopenia • punched-out lytic lesion

–Bone scan
• Technetium-99m • Detect osteoblastic activity • Should not be used

Diagnostic criteria for MM
International myeloma working group
– Presence of M-protein

– Bone marrow plasma cell > 10% or plasmacytoma
– Presence of organ damage (one of following)
• Increased serum Ca • Renal failure (Cr > mg/mL)
• Anemia • Lytic bone lesion

Dx = all criteria

International staging system
Stage I Parameters Median survival
(months)

I
II III

β2 microglobulin < 3.5 mg/L
and albumin > 3.5 g/dL Neither stage I nor III β2 microglobulin > 5.5 mg/L

62
44 29

Prognosis
• Cytogenetics
Prognosis Poor Abnormal cytogenetics t(4;14)(p16;q32) t(14;16)(q32;q23) -17p13 Median survival (months) 25

intermediate
Good

-13q14
All others

42
50

Treatment
Specific treatment • Chemotherapy
– Alkalating agents

• Thalidomide or lenalidomide
– MP, MPT, Thal+dex, VAD, Len+dex

• Autologous transplantation
– Thalidomide maintenance

• Bortezomib
– Alone, +dex and doxorubicin

Treatment
• Supportive treatment
–Hypercalcemia –Hyperviscosity syndrome –Prevent fracture
• Bisphosphonates: pamidronate, zolendronate

–Radiation
• Pain • Cord compression

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