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
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