Hematologic Malignancy

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)

• Clonal hematopoietic stem cell disease

• Overproduction of one or more blood cell lines

• Organomegaly

• Extramedullary hematopoiesis

• Leukemic transformation

• Thrombosis: major cause of death

Characteristics of MPNs

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

• Tumors produce EPO– Hypernephroma– Hepatoma– Cerebellar hemangioblastoma– Uterine fibromyoma

• Renal diseases– Polycystic kidney– Renal artery stenosis

Serum erythropoietin

Low Normal High

PV diagnosisprobable

PV diagnosispossible

Evaluate for secondary polycythemia

Bone marrow examination

Characteristics for PV?

yes no

PV Specialized test

Consistent with PV Not consistent with PV Reevaluate in 3 mo

Specialized tests-JAK2 mutation-BM immunochemistry for c-mpl-PCR for PRV-1 gene-EEC formation

Mayo Clin Proc 2003;78:174-94.

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 90-95%

–ET 50-70%

–MF 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 48Fatigue 47Pruritus 43Dizziness 43Diaphoresis 33Visual disturbances 31Weight loss 29Erythromelalgia 29Dyspnea 26Joint symptoms 26Epigastric discomfort 24thrombosis 20

• SignsSplenomegaly 70Skin plethora 67Conjunctival plethora 59Engorged vessels in the optic fluid 46Hepatomegaly 40Systolic blood pressure > 140 mmHg 72Diastolic 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

CBCRed 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 aggr phlebo

Median sur 18 mo 3-4 yr 9-12.8 yr

• Cause of death

– Thrombosis

– Malignancy : acute leukemia, non-RE malignancy

– Myelofibrosis

– Bleeding

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 maintainHct < 45% male, <42% female

high risk of thrombosis•Age>60 years•Previous thrombosis•Other cardiovascular risk

Platelet > 1,500,000 /um

Age < 50 yrAge 50-70 yr Age > 70 yr

Interferon Hydroxyurea Busulphan or32P

Low dose ASA

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

• 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

AMM

Clinical features of AMM

Mechanism Symptoms

Hypercatabolic state

Splenomegaly

Anemia

Portal hypertension/ascites

Splenic infarct

Esophageal varices/hemorrhoids

Ectopic myeloid metaplasia

Thrombocytopenia/platelet dysfunction

Hyperuricemia

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)

Bleeding, bruising

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

• 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• Other lab tests

–Increase alkaline phosphatase–Increase LDH–Increase uric acid–Increase circulating CD34+ cells

Laboratory findings

Causes of Marrow Fibrosis

Nonhematologic Hematologic

Infections TB

Leishmaniasis

Histoplasmosis HIV

Connective tissue disease

Renal osteodystrophy

Metastatic cancer

Vitamin D deficiency

Hypothyroidism

Hyperthyroidism

Paget disease

Gaucher’s disease

Myeloproliferative disorders ET, PV, MMM Hypereosinophilic

syndrome

Systemic mastocytosis

CML

Other

AML-M7 MDS

Multiple myeloma Hairy cell leukemia

Lymphoma

ALL

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

• Splenectomy

• Splenic irradiation

• Anagrelide: for thrombocytosis

• Interferon

• Thalidomide+prednisolone

(3 months)

Treatment

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

• 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%

Clinical manifestation

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

• Congestive diseases

– Cirrhosis

– Splenic vein thrombosis

• Malignancy

– Lymphoma

– Chronic MPD

• Hemolytic anemia

– Thalassemia

– AIHA

• Infection

– Tuberculosis

– Virus, bacteria

• Storage disease– Gaucher disease

• Inflammatory disease

– SLE

– Felty syndrome

• Miscellaneous– Tropical splenomegaly

Splenomegaly: causes

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

CML• 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

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

• Blastic phase (myeloid or lymphoid)

–Blasts ≥ 20% peripheral blood or marrow

–Extramedullary blast proliferation

–Large foci of blasts in marrow

WHO criteria

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 CBCจาก 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

Therapy • Tyrosine kinase inhibitor

–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

HLA-matched sibling or

unrelated donor

Discuss imatinib vs. transplantIf patient chooses imatinib close follow-up is required•Q-PCR or FISH every 3 months

•BM cytogenetics every 12 months

HLA-matched sibling

No family donor

Possibly, age 40-55 No; age > 55; medical

contraindication

Imatinib mesylate

Partialresponse

Failedresponse

Increase dose ofimatinib astolerated

Dasatinib,Nilotinibor

SCTor

experimentalprotocol

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

• Leukemia cutis syndrome or neutrophilic dermatosis

– erythematous to violaceous tender nodules and plaques

– Neutrophil infiltrate

• Uncommon organomegaly (monoblast)

Clinical manifestation

Leukemia cutis•nodular and

violaceous/gray-blue

in color, no tender

Sweet syndromeerythematous 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

• Increase abnormal promyelocytes

• t(15;17): PML – RARa

• Hypergranular and microgranular types

• Hypergranular type: pancytopenia

• Microgranular type: high white cells

Acute promyelocytic leukemia

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

Microgranular type

Abnormal promyelocyte

with intense azurophilic

granules

Abnormal promyelocyte

with numerous auer rods

(faggot cells)

Predominantly bilobed

nuclear shape

• 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 promyelocytic leukemia

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 – L3

ALL – L2

ชายอายุ 18 ปี ไข้ ไอ เหน่ือยง่าย 1 เดือน CXR: pleural Effusion ท า pleural tapping and smear จงให้การวินิจฉัยโรค

Lymphoma •Non-Hodgin lymphoma

•Hodgkin lymphoma

Diagnostic test for lymphoproliferative disorders

•Morphology

• Immunophenotyping

•Cytogenetics

•Molecular genetics

• B cell neoplasms

– Precursor B-cell neoplasm

– Mature B-cell neoplasm

• T-cell and NK-cell neoplasms

– Precursor T-cell neoplasm

– Mature (peripheral) T-cell

neoplasms

• Hodgkin lymphoma

– Nodular lymphocyte-

predominant Hodgkin

lymphoma

– Classic Hodgkin lymphoma

• Nodular sclerosis

• Mixed cellularity

Classification of lymphoid neoplasm

• 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

– T cell

• Mycosis fungoides/ Sezary syndrome

• Primary cutaneous ALCL

• Aggressive lymphoma

– B cell

• Mantle cell

• Follicular grade IIIb

• Diffuse large B cell

• Mediastinal large B cell

• Burkitt lymphoma

– T cell• Systemic ALCL

• T-cell leukemia/ lymphoma

NHL

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 conditionsConditions Type of NHL

Spinal cord compression Aggressive type

Pericardial tamponadeSVC obstruction

Lymphoblastic lymphomaPrimary mediastinum B cell NHL

Hypercalcemia Aggressive type

Hyperleukocytosis Lymphoblastic lymphoma

Acute airway obstruction Primary mediastinum B cell NHL

Lymphomatousmeningitis and/or CNS mass lesions

Aggressive type

Emergency conditionsConditions Type of NHL

Hyperuricemia and tumor lysis syndrome

Aggressive type

Hyperviscosity syndrome Waldenstrom'smacroglobulinemia

Intestinal obstruction, intussusception

Aggressive type

Ureteral obstruction Aggressive type

Severe AIHA, ITP B cell small lymphocytic lymphoma/CLL

Venous thromboembolic disease Aggressive typeIndolent 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 factorsVirus EBV, HTLV-1, HHV-8, HCV

Bacteria Helicobactor pylori

Impaired immune• Congenital

•Acquired

Ataxia telangiectasiaWiskott-Aldrich syndromeAIDSPost transplantationAutoimmune disease

Environment Herbicides

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

• 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

Prognosis

• Chemotherapy

–Anthracycline-based regimen

• Rituximab

• Radiotherapy

–Reduced mass effect

–Combined with chemotherapy in 1st line for early stage

Treatment

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

• Old age

• Generalized lymphadenopathy

• Advanced stage: marrow involve

• Autoimmune cytopenia

Indolent B cell lymphoma

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

• 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

CLL

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 systemRisk group, stage Features Med surv. (mo)

Low risk

Stage 0 Blood and marrow lymphocytosis (L)

> 120

Intermediate risk

Stage I L + adenopathy 108

Stage II L+ splenomegaly or hepatomegaly

94

High risk

Stage III L+anemia (Hb<11 g/dL) 60

Stage IV L+thrombocytopenia(100,000/µL)

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

• Alkalating agents: chlorambucil, CVP

• Fludarabine : infection, AIHA

• Monoclonal antibody therapy

–Alemtuzumab : anti CD52

–Rituximab : anti CD20, low CD20 density

Treatment

Blood smear, CLL

Bone marrow, CLL

CLL with AIHA

Multiple myeloma

Clinical presentationPresentation Symptom and sign

General Fatigue, anorexia, weightloss

Hematology Anemia : chronic, NCNC, macrocytic anemiaBleeding : platelet, coagulation, vesselpancytopenia

Orthopedics Bone pain: back, chestPathological facture

Presentation Symptom and sign

Neurology Radiculopathy : thoracic, lumbosacral areaCord compressionPeripheral neuropathy: • Amyloid• Paraneoplastic syndrome • POEMS syndromeAlteration of consciousness• Hypercalcemia• Hyperviscosity

Clinical presentation

Presentation Symptom and sign

Infection Bacteria: hypogammaglobulin, neutropenia, steroid • Pneumonia• Septicemia

Nephrology Renal failureProximal RTAAmyloidosis: nephroticsyndrome

Clinical presentation

• Rare presentation

–Prolonged fever

–Lymphadenopathy

–Hepatosplenomegaly

–CNS involvement

Clinical presentation

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

• Imaging

–Bone survey:

• diffuse osteopenia

• punched-out lytic lesion

–Bone scan

• Technetium-99m

• Detect osteoblastic activity

• Should not be used

Laboratory findings

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 β2 microglobulin < 3.5 mg/L

and albumin > 3.5 g/dL

62

II Neither stage I nor III 44

III β2 microglobulin > 5.5 mg/L 29

• Cytogenetics

Prognosis

Prognosis Abnormal

cytogenetics

Median survival

(months)

Poor t(4;14)(p16;q32)

t(14;16)(q32;q23)

-17p13

25

intermediate -13q14 42

Good All others 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

• Supportive treatment

–Hypercalcemia

–Hyperviscosity syndrome

–Prevent fracture

• Bisphosphonates: pamidronate, zolendronate

–Radiation

• Pain

• Cord compression

Treatment

ขอบคุณ