Myeloproliferative and

Lymphoproliferative Disorders
Section of Hematology & Oncology
Department of Medicine
 Clonal Bone Marrow Disorders
PNH
RARS RA
RAEB, T MYELODYSPLASTIC
CLL LEUKEMIAS
SYNDROMES
AML
ALL CML
CMML
MMM

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

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 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 Myeloperoxidase stain:

lymphoblasts are negative

Alpha naphthyl esterase stain:

PAS stain: lymphoblasts positive
lymphoblasts are negative
 Immunophenotyping: AML
CD GrpAntibodies Reactivity
CD33 MY9, LeuM9, CFU-GEMM to promyelo-
L4F3 cyte and mature mono-
cytes
CD13 MY7, LeuM7 CFU-GM to mature granulo-
cytes and monocytes
CD14 MY4, LeuM3, Monocytes
MO2
CD15 LeuM1, MY1 Promyelocytes to granulo-
cytes, monocytes
 Immunophenotyping: AML
CD GrpAntibodies Reactivity
CD34 MY10, Progenitor cells, B-
HPCA-1, lymphocytes, monocytes,
HLA-DR, Ia activated T-cells
CD41 GPIIbIIIa, Platelets and
PL-273 megakaryocytes
CD42 GP1b, FMC-25, Monocytes
Glycophorin A,
10F7
CD56 Leu19, NKH1 Natural killer cells
 Cytogenetic Abnormalities:
Significance
(Overall Survival in De Novo AML)
Median Survival
Cytogenetic Abnormality (months)
Rearrangements of 16q22 18
t(8;21)(q22;q22) 14
Normal 10
Abnormal 11q 8
Abnormal 5 and/or 7 3
t(15;17)(q22;q11) 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
AML-M2 >30% myeloblasts ( ≥3% MPO positive) with > 10% maturing
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.

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 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 25-
50% of patients in CR
• Secondary AML has remission rates of 30-
40%; long-term survivorship is unusual
unless bone marrow transplantation is used
 Prognostic Factors in AML
Clinical
Factor Favorable Unfavorable
1 Age • < 45 • <2 yrs,
2 Leukemia years >60 yrs
3 Leukocyto • De Novo • Preceding
sis • <25,000/ MDS
4 CNS mm 3
• >100,000/
3
disease • Absent mm
Greer JP and Kinney MC, Clinical Hematology; 1993
5 Cytoreduc • Rapid • Present
 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 Unfavorable
1 Myeloid • MY4-, • MY4+(CD14),
MY7- MY7+(CD13),
MY10+(CD34)
2 HLA-DR • Negative • Positive
3 TdT • Absent • Present
4 Lymphoid• OKT11 • Biphenotypic
(CD2), B4 ( ≥2 lymphoid
(CD19)
Greer JP and Kinney MC, Clinicalmarkers)
Hematology; 1993
 Prognostic Factors in AML
Cytogenetics
Favorable Unfavorable
• t(15; 17), • -7, del(7q); -5,
t(8; 21), del(5q); 11q23
inv(16)/del(1 abnormalities;
6q) 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 vincristine-
corticosteroids-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 Score Risk group Score
variable Value scores
0 0.5 1.0 1.5 2.0 Low 0
Bone <5% 5- 11-20 21-30
marrow 10% Intermediate-1 0.5-
blasts 1.0
Karyotype good inter poor
medi Intermediate-2 1.5-
ate 2.0
Cytopenia 0 or 2 or 3
1 High >2.5
 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
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 Polycythemia Rubra Vera
Clinical Features

• Headache • Epistaxis
• Dyspnea • Angina
• Weakness • Pruritus
• Sweating • Paresthesia
• Weight loss • Gout
• Plethora • Splenomegaly
• Dizziness • Hypertension
• Visual changes • Leg ulcers
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 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

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

Diagnosis is acceptable if:

• A1 + A2 + A3 or
• A1 + A2 + any two from
category B
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Differential Diagnosis of
Polycythemia
• Spurious polycythemia
• Secondary polycythemia
• Polycythemia Vera

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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
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 Polycythemia Rubra Vera
Thrombo-Hemorrhagic Complications

• Cerebral thrombosis • Raynaud’s

• Coronary thrombosis phenomenon
• Peripheral vascular • Monocular blindness
disease • Spontaneous abortion
• Budd-Chiari • Cardiac valve
syndrome abnormalities
• Erythromelalgia • Cerebral hemorrhage
• Mesenteric vein • GI bleeding
thrombosis
 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
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Diseases/ Exposures Associated with
Increased Risk of Lymphoma
• Inherited immunodeficiency • Autoimmune disease
disease  Sjogren’s syndrome
 Klinefelter’s syndrome
 Celiac sprue
 Chediak Hegashi syndrome
 Rheumatoid arthritis
 Ataxia telagiectasia syndrome
 Wiskott-Aldrich syndrome
 Systemic lupus

 Common variable erythematosus

immunodefiency disease
• Acquired immunodeficiency
 Iatrogenic
immunosuppression
 HIV-1 infection
 Acquired
hypogammaglobulinemia
• 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 Follicular, small cleaved cell (NHL)

Diffuse small lymphocytic (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 • Imaging studies
• ESR  Contrast-enhanced CT scan
• Biochemical studies of major of the chest and whole
organ function abdomen
• For NHL  MRI if indicated
 SLDH  Gallium scan not necessary
 B2 microglobulin for primary staging
 Serum protein electrophoresis  PET scan
• Excision biopsy of lymph node • Bone marrow aspiration
 Flow cytometry
and biopsy
 IHC
 Cytogenetics

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 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 (HTLV-
1+)
 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 Lukes and Butlerb Rye Conferencec REAL Classificationd WHO Classificatione
Parkera
Paragranuloma Lymphocytic and/or Lymphocyte Nodular lymphocyte Lymphocyte predominant,
histiocytic, nodular predominant predominant nodular
Lymphocytic and/or Classic HL Classic HL
histiocytic, diffuse
Lymphocyte-rich classic Lymphocyte-rich classic
HLf HL
Granuloma Nodular sclerosis Nodular sclerosis Nodular sclerosis Nodular sclerosis

Mixed cellularityg Mixed cellularityg Mixed cellularity Mixed cellularity

Sarcoma Diffuse fibrosis Lymphocytic Lymphocyte depleted Lymphocyte depleted

depleted
Reticular Unclassifiable classic HL
Histologic subtypes of Hodgkin’s
Disease

Lymphocytic predominance Nodular sclerosis

Mixed Cellularity Lymphocyte depletion

 Molecular Markers
Disease Cytogenetic Oncogene
abnormality

CLL/ Small lymphocytic t(14;15)(q32;q13)

lymphoma
MALT lymphoma t(11;18)(q21;q21)

Precursor B cell acute t(9;22)(q34;q11) BCR/ABL

lymphoid leukemia t(12;21)(p12;q22) ETV6
ETV6-CBFA2
11q23/MLL TEL-AML1
 Molecular Markers
Disease Cytogenetic Oncogene
abnormality
Mantle cell t(11;14)(q13;q32) BCL-1
lymphoma
Follicular lymphoma t(14;18)(q32;q21) BCL-2

Diffuse large cell t(3;-)(q27;-) BCL-6

lymphoma t(17;-)(p13;-) p53
Burkitt’s lymphoma t(8;-)(q24;-) C-MYC

Anaplastic large cell t(2;5)(q23;q35) ALK

lymphoma
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