By MD, PhD. Marta R. GerasymchukBy MD, PhD. Marta R. Gerasymchuk1616thth January 2013 January 2013By MD, PhD. Marta R. GerasymchukBy MD, PhD. Marta R. Gerasymchuk1616thth January 2013 January 2013

Plan of the lecturePlan of the lecture1. Leucopoesis.1. Leucopoesis.

2. Leucocytosis. Deffinition. Classification.2. Leucocytosis. Deffinition. Classification.

3. Pathogenesis of leucocytosis.3. Pathogenesis of leucocytosis.

4. Leucopenias. Deffinition.Classification.4. Leucopenias. Deffinition.Classification.

5. Pathogenesis of leucopenias.5. Pathogenesis of leucopenias.

6. Agranulocytosis.6. Agranulocytosis.

7. Leucemias. Deffinition. Classification. Pathogenesis. 7. Leucemias. Deffinition. Classification. Pathogenesis. Clinical signts.Clinical signts.

8.8. Treatment of leucemias.Treatment of leucemias.

9.9. Leucemoid reactions.Leucemoid reactions.

Actuality of the lectureActuality of the lecture

Leucocytosis are considered as a reaction hematopoietic system due to action Leucocytosis are considered as a reaction hematopoietic system due to action of physiological and pathological irritations. Leucocytosis is a pathological of physiological and pathological irritations. Leucocytosis is a pathological symptom of many diseases. In a basis of leucocytosis lay pathophysiological symptom of many diseases. In a basis of leucocytosis lay pathophysiological mechanisms connected with proliferation, maturation going out of leucocytes and mechanisms connected with proliferation, maturation going out of leucocytes and their flow into vessels and redestribution. Different kinds of leucocytosis may be their flow into vessels and redestribution. Different kinds of leucocytosis may be the additional criteri for establish the diagnosis. Eosinophilia, for example, is the additional criteri for establish the diagnosis. Eosinophilia, for example, is characterized for allergy reactions, neutrophile leucocytosis - for acute characterized for allergy reactions, neutrophile leucocytosis - for acute inflamation processes. inflamation processes.

Leucopenia may depend upon oppressive influence of some toxines on the Leucopenia may depend upon oppressive influence of some toxines on the maturation and outflow of leucocytes from the bone-marrow. Often these maturation and outflow of leucocytes from the bone-marrow. Often these phenomenas are observed during the infectious diseases. They have phenomenas are observed during the infectious diseases. They have significanse for the differential diagnostic. If for the disease is characterised significanse for the differential diagnostic. If for the disease is characterised leucocytosis, the availability of leucopenia testifies on depression of hemopoietic leucocytosis, the availability of leucopenia testifies on depression of hemopoietic system. It is regarded as a criteri weakenes of reactivity of the body on action of system. It is regarded as a criteri weakenes of reactivity of the body on action of pathological factors.Directness and character of changes of white blood cells due pathological factors.Directness and character of changes of white blood cells due to various diseases - significant for the diagnosis and control of the treatment.to various diseases - significant for the diagnosis and control of the treatment.

WBC’sWBC’s

Neutrophil

PMN-Polymorphonuclear Leucocytes.

60-70% WBCAppearance: pink granules in cytoplasm, nucleus has 3-4 lobes Function:

Margination Rolling Adhesion Transmigration (Diapedesis) Chemotaxis Phagocytosis: Recognition,

Engulfment, Killing (digestion)Equilibrium with splenic pool

Azurophilic (1°) granules are "lysosomes of PMNs", occur in all leukocytesDÖHLE BODIES and TOXIC GRANULES are often seen with NEUTROPHILIAAccompanied by a “LEFT” shift

PELGER-HUET ANOMALYPELGER-HUET ANOMALY GeneticGenetic Sometimes ACQUIRED (Pseudo-PELGER-HUET)Sometimes ACQUIRED (Pseudo-PELGER-HUET) All neutrophils look like BANDSAll neutrophils look like BANDS NOT serious, mostly a cute incidental findingNOT serious, mostly a cute incidental finding

CHEDIAK-HIGASHI SYNDROMECHEDIAK-HIGASHI SYNDROMECHEDIAK-HIGASHI SYNDROMECHEDIAK-HIGASHI SYNDROME Also geneticAlso genetic Abnormal LARGE Abnormal LARGE

irregular neutrophil irregular neutrophil granulesgranules

Impaired lysosomal Impaired lysosomal digestion of bacteriadigestion of bacteria

Associated with pigment Associated with pigment and bleeding disordersand bleeding disorders

CAN be serious, CAN be serious, especially in kidsespecially in kids

Eosinophil (Eos)Eosinophil (Eos)Eosinophil (Eos)Eosinophil (Eos) Bilobed nucleusBilobed nucleus 2-4% of WBC2-4% of WBC Recruited to sites of Recruited to sites of

inflammationinflammation Function: Involved in Function: Involved in

allergy, parasitic allergy, parasitic infectionsinfections

Contains: eosinophilic Contains: eosinophilic granules granules

Granules contain: Granules contain: major basic proteinmajor basic protein

Terminally Terminally differentiateddifferentiated

Azurophilic granuels

BasophBasophililBasophBasophilil

• Circulating form of mast Circulating form of mast cellscells

• Terminally differentiatedTerminally differentiated

• <1% WBC (< 1 x 10*9/L)<1% WBC (< 1 x 10*9/L)

• Contains: basophilic Contains: basophilic granulesgranules

• Granules contain: Granules contain: histamine and heparinhistamine and heparin

• IgE receptorsIgE receptors

• Involved in allergyInvolved in allergy

Monocyte / MacrophageMonocyte• 3-8% WBC• Circulating form (precursor)

of tissue macrophages• Recruited to sites of

inflammationMacrophages• Phagocytosis, bacterial

killing, antigen presentation• Peritoneal cavity: peritoneal

macrophages• Lung: alveolar macrophages• Spleen: splenic macrophages• Liver: Kupffer cells

LymphocyteLymphocyteLymphocyteLymphocyte•Appearance: small

(same size as RBCs), little visible cytoplasm

•NO specific granules

• 20-25% of WBC

•T cells: CMI (for viral infections)

• B cells: humoral (antibody)

• Natural Killer Cells

T B

T

B

Primary Secondary

Absolute RelativeAbsolute Relative

Leukocytosis

Stimulation of leukopoiesis- Leukocytosis of pregnant (5-6 mounts of pregnancy)

Redistribution of

leukocytes in vascular bed- alimentary,- emotional,- myogenic,- static

1. Stimulation of leukopoiesis2. Increase of leukocytes transport from bone marrow3. Increase of tumoral type of leukopoiesis during leukosis

1.Hemoconcentrational

2.Redistributional

LeukocytosisLeukocytosisLeukocytosisLeukocytosis

LeukocytosisLeukocytosis 4000-9000

• Neutrophylia – Acute bacterial infection,

sterile inflammationEosinophylia – Allergy (allergic rhinitis, other

hypersensitivity reactions,including drug

reactions), parasites (ascaris, hookworm, strongiloides), certain skin diseases, cancer (adenocarcinoma)

• Basophilia – rare (leukemia)

• Monocytosis – chronic infections,

bacterial endocarditis, rickettsiosis,

malaria, collagen vascular disorders,

inflammatory bowel diseases

• Lymphocytosis – some viral infections

(hepatitis, measles), tuberculosis, CLL

Leukopenias

Primary (hereditary) Secondary (Acquired)

1. Deficit of maturity factors

- constant hereditary neutropenia

-periodic hereditary neutropenia

2. Deficit of myeloperoxidase, G-6-PhDG

- hereditary monocytopenia with phagocytic insufficiency deficit (disease of Chediak-Higashi)

1. Inhibition of leukopoiesis2. Increase of leukodieresis3. Increase of leukocyte loss4. Decrease of leukocyte emigration from bone morrow

1. Redistributional e.g. shock, civere muscular work etc.2. Hemodilutional e.g. blood plasma, transfusion of blood substitutes, hydremia etc.

Absolute Relative

Causes of Neutropenia

CauseCause MechanismMechanism

Accelerated removal (Accelerated removal (e.g.e.g., inflammation and , inflammation and infection) infection)

Removal of neutrophils from the circulation exceeds Removal of neutrophils from the circulation exceeds productionproduction

Drug-induced granulocytopeniaDrug-induced granulocytopenia Defective productionDefective production Cytotoxic drugs used in cancer therapyCytotoxic drugs used in cancer therapy Phenothiazine, thiouracil, Phenothiazine, thiouracil,

chloramphenicol, phenylbutazone, and others chloramphenicol, phenylbutazone, and others Hydantoinates, primidone, and others Hydantoinates, primidone, and others Immune destructionImmune destruction Aminopyrine and others Aminopyrine and others

• Predictable damage to precursor cells, usually Predictable damage to precursor cells, usually dose dependent dose dependent

• Idiosyncratic depression of bone marrow Idiosyncratic depression of bone marrow functionfunction

• Intramedullary destruction of granulocytesIntramedullary destruction of granulocytes• Immunologic mechanisms with cytolysis or Immunologic mechanisms with cytolysis or

leukoagglutinationleukoagglutination

Periodic or cyclic neutropenia (occurs during infancy Periodic or cyclic neutropenia (occurs during infancy and later) and later)

UnknownUnknown

Neoplasms involving bone marrow (e.g., leukemias Neoplasms involving bone marrow (e.g., leukemias and lymphomas)and lymphomas)

Overgrowth of neoplastic cells, which crowd out Overgrowth of neoplastic cells, which crowd out granulopoietic precursors granulopoietic precursors

Idiopathic neutropenia that occurs in the absence of Idiopathic neutropenia that occurs in the absence of other disease or provoking influence other disease or provoking influence

Autoimmune reactionAutoimmune reaction

Felty’Felty’s syndromes syndrome Intrasplenic destruction of neutrophilsIntrasplenic destruction of neutrophils

Myelotoxic Immune

AGRANULOCYTOSIS

1. Cytolytic influence,

e.g. ionizing radiation

etc.

2. Antimetabolic

influence e.g.

cytostatics etc.

1. Autoimmune e.g.

lupus erythematosus,

rheumatoid arthritis

2. Heteroimmune

Leukemias Bone marrow, blood, blast cellsAcute / Chronic & Myeloid / LymphoidAML / ALL & CML / CLL

Lymphomas – Lymph nodes, tumorHodgkins - Non-Hodgkins. MyelomaHigh grade & Low grade

Premalignant conditions:Myeloproliferative syndromes (MPS)Myelodysplastic syndromes (MDS)

WBC Neoplastic disorders :

Mechanisms of bone Mechanisms of bone marrow neoplasiamarrow neoplasia Blast cells (malignant)Blast cells (malignant) overpopulate the bone marrow overpopulate the bone marrow

and replace the normal cells causing bone destruction and replace the normal cells causing bone destruction and/or blood or lymphoid cell deficiencies.and/or blood or lymphoid cell deficiencies.

Malignant cellsMalignant cells or their descendents may appear in the or their descendents may appear in the peripheral blood (leukemia), in extramedullary sites such peripheral blood (leukemia), in extramedullary sites such as the spleen and liver (as the spleen and liver (hepatosplenomegalyhepatosplenomegaly) and in ) and in lymph nodes (lymph nodes (lymphadenopathylymphadenopathy).).

Bone marrow malignancyBone marrow malignancy may be accompanied by may be accompanied by myelofibrosis (the extensive deposition of collagen by non-myelofibrosis (the extensive deposition of collagen by non-neoplastic fibroblasts).neoplastic fibroblasts).

Types of bone marrow neoplasia:Types of bone marrow neoplasia: Malignant Malignant transformation of hematopoietic and lymphoid cell transformation of hematopoietic and lymphoid cell precursors may occur at any point in their maturation. precursors may occur at any point in their maturation. Malignant cells are classified as Malignant cells are classified as myeloid, lymphoid or myeloid, lymphoid or plasmacyticplasmacytic. The characteristic behavior of particular . The characteristic behavior of particular malignant stem cells determines the presentation of the malignant stem cells determines the presentation of the disease.disease.

Types of bone marrow neoplasia1. Myeloproliferative disorders: Characterized by

the malignant transformation of developmentally pluripotent myeloid stem cells and their linage-restricted descendants.

2. Myelodysplastic syndromes: Characterized by ineffective hematopoiesis and pancytopenia.

3. Leukemia: Characterized by the appearance of neoplastic WBCs in the peripheral circulation.

4. Plasma cell disorders: Characterized by the monoclonal proliferation of neoplastic plasma cells and plasmacytoid lymphocytes usually in the bone marrow

Neoplastic WBC Disorders:Neoplastic WBC Disorders: No Benign Neoplasms – All are

considered malignant or premalignant.

Cells flood blood stream – Leukemia. Arise in marrow(myeloid/lymphoid)

or Lymphnode (lymphoid), then spread to blood & other organs Malignant Malignant LeukemiasLeukemias Lymphomas Lymphomas

Premalignant:Premalignant: MyeloproliferativeMyeloproliferative Myelodysplastic Sy.Myelodysplastic Sy.

Myeloproliferative Disorders These disorders include:• polycythemia rubra vera (proliferation of RBC

precursors), • essential thrombocytemia (proliferation of platelet

precursors)• chronic myelocytic leukemia (proliferation of

neutrophil precursors) and • myelofibrosis (proliferation of fibroblasts). These entities are interrelated and may transform one into

another or into acute myeloblastic leukemia (AML). Features common to all myeloproliferative disorders:

1. Peak incidence in 40-70 years of age2. Marrow hypercellularity, except myelofibrosis which is

dominated by fibrosis3. Splenomegaly due to extramedullary hematopoiesis4. Peripheral blood abnormalities and hyperviscosity,

except for myelofibrosis

MPS: ClassificationMPS: Classification

MPS - P. Rubra Vera (PV)MPS - P. Rubra Vera (PV)

Myelodysplastic syndromesMyelodysplastic syndromes Myelodysplastic syndromesMyelodysplastic syndromes (MDS, formerly known as (MDS, formerly known as

""preleukemiapreleukemia") are a diverse collection of hematological ") are a diverse collection of hematological conditions united by ineffective production of blood cells and conditions united by ineffective production of blood cells and varying risks of transformation to acute myelogenous leukemia varying risks of transformation to acute myelogenous leukemia (AML). Anemia requiring chronic blood transfusion is frequently (AML). Anemia requiring chronic blood transfusion is frequently present. present.

Myelodysplastic syndromes (MDS)Myelodysplastic syndromes (MDS) are bone marrow stem cell are bone marrow stem cell disorders resulting in disorderly and ineffective hematopoiesis disorders resulting in disorderly and ineffective hematopoiesis manifested by irreversible quantitative and qualitative defects in manifested by irreversible quantitative and qualitative defects in hematopoietic cells. In a majority of cases, the course of disease is hematopoietic cells. In a majority of cases, the course of disease is chronic with gradually worsening cytopenias due to progressive chronic with gradually worsening cytopenias due to progressive bone marrow failure.bone marrow failure.

Approximately one-third of patients with MDS progress to AML Approximately one-third of patients with MDS progress to AML within months to a few years.within months to a few years.

The median age at diagnosis of a MDS is between 60 and 75 The median age at diagnosis of a MDS is between 60 and 75 years; a few patients are less than 50; years; a few patients are less than 50; MDS are rare in childrenMDS are rare in children. . Males are slightly more commonly affected than females. Signs Males are slightly more commonly affected than females. Signs and symptoms are nonspecific and generally related to the and symptoms are nonspecific and generally related to the blood blood cytopeniascytopenias (anemia, neutropenia, thrombocytopenia). (anemia, neutropenia, thrombocytopenia).

A significant proportion of the morbidity and mortality attributable A significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML but rather from the to MDS results not from transformation to AML but rather from the cytopenias seen in all MDS patients. Anemia is most common and cytopenias seen in all MDS patients. Anemia is most common and responds to transfusion, patients often suffer from iron overload. responds to transfusion, patients often suffer from iron overload. The two most serious complications in MDS patients resulting from The two most serious complications in MDS patients resulting from their cytopenias are their cytopenias are bleedingbleeding ( (due to lack of plateletsdue to lack of platelets) or ) or infectioninfection ((due to lack of white blood cellsdue to lack of white blood cells). ).

Myelodysplastic Syndromes:Myelodysplastic Syndromes:

Excess proliferation in marrow.Excess proliferation in marrow. But functional & Structural But functional & Structural

abnormalityabnormality Ineffective Myelopoiesis.Ineffective Myelopoiesis. Peripheral pancytopenia. Peripheral pancytopenia. Also known as Refractory Anemia’sAlso known as Refractory Anemia’s Not responding to hematenics.Not responding to hematenics.

MPS : E.T. Bleeding MPS : E.T. Bleeding

LEUKEMIASLEUKEMIAS

■ Leukemias are malignant neoplasms arising from the transformation of a single blood cell line derived from hematopoietic stem cells.

■ The leukemias are classified as acute and chronic lymphocytic (lymphocytes) or myelogenous (granulocytes, monocytes) leukemias, according to their cell lineage.

■ Because leukemic cells are immature and poorly differentiated, they proliferate rapidly and have a long life span; they do not function normally; they interfere with the maturation of normal blood cells; and they circulate in the bloodstream, cross the bloodbrain barrier, and infiltrate many body organs.

Leukemia Leukemia ClassificationClassification

Leukemia Leukemia ClassificationClassification

Acute Leukemias:Acute Leukemias: Acute Myeloid Leukemia - Acute Myeloid Leukemia - AMLAML

AML AML M0, M1, M2, M3M0, M1, M2, M3, , M4, M5, M6 & M7M4, M5, M6 & M7 Acute Lymphoid Leukemia - Acute Lymphoid Leukemia - ALLALL

ALL - ALL - L1, L2 & L3L1, L2 & L3 - maturity - maturity

Chronic Leukemias:Chronic Leukemias: Chronic Myeloid Leukemia- Chronic Myeloid Leukemia- CMLCML Chronic Lymphoid Leukemia - Chronic Lymphoid Leukemia - CLLCLL

Acute Leukemias:Acute Leukemias: Acute Myeloid Leukemia - Acute Myeloid Leukemia - AMLAML

AML AML M0, M1, M2, M3M0, M1, M2, M3, , M4, M5, M6 & M7M4, M5, M6 & M7 Acute Lymphoid Leukemia - Acute Lymphoid Leukemia - ALLALL

ALL - ALL - L1, L2 & L3L1, L2 & L3 - maturity - maturity

Chronic Leukemias:Chronic Leukemias: Chronic Myeloid Leukemia- Chronic Myeloid Leukemia- CMLCML Chronic Lymphoid Leukemia - Chronic Lymphoid Leukemia - CLLCLL

Leukemia – Leukemia – Clinical Clinical FeaturesFeatures

Anemia Anemia (low RBC)(low RBC) Fever - Infections Fever - Infections (low WBC)(low WBC) Bleeding tendency Bleeding tendency (low PLT)(low PLT) Tender bones, lymphadenopathy, Tender bones, lymphadenopathy,

spleenomegaly etc. spleenomegaly etc. (Leukemic (Leukemic infiltration)infiltration)

IntoxicationIntoxication Autosensitization (esp. lymphogenic L.)Autosensitization (esp. lymphogenic L.)

AML-M5 - Gum Hypertrophy:AML-M5 - Gum Hypertrophy:

AML- Marked Purpura:AML- Marked Purpura:

ALL:Cervical ALL:Cervical LymphadenopathyLymphadenopathy

LEUKEMIASLEUKEMIAS Acute or ChronicAcute or Chronic Myeloid or LymphocyticMyeloid or Lymphocytic Childhood or AdultChildhood or Adult All involve marrowAll involve marrow All ACUTE leukemias suppress normal All ACUTE leukemias suppress normal

hematopoesis, i.e., have anemia, hematopoesis, i.e., have anemia, thrombocytopeniathrombocytopenia

Most have chromosomal aberrationsMost have chromosomal aberrations Some can respond DRASTICALLY to chemo, Some can respond DRASTICALLY to chemo,

most notably ALL in children, even be cured!!!!most notably ALL in children, even be cured!!!!

BLASTBLASTBLASTBLAST

WHITE CELL NEOPLASMS WHITE CELL NEOPLASMS Leuk/LymphLeuk/Lymph

Many have chromosomal translocationsMany have chromosomal translocations Can arise in inherited and/or genetic Can arise in inherited and/or genetic

diseases:diseases: Downs Syndrome (Trisomy 21)Downs Syndrome (Trisomy 21) Fanconi’s anemia (hereditary aplastic Fanconi’s anemia (hereditary aplastic

anemia)anemia) Ataxia telangiectasia Ataxia telangiectasia

May have a STRONG viral relationship:May have a STRONG viral relationship: HTLV-1 (lymphoid tumors)HTLV-1 (lymphoid tumors) EBV (Burkitt Lymphoma)EBV (Burkitt Lymphoma) Human Herpesvirus-8 (B-Cell Human Herpesvirus-8 (B-Cell

Lymphomas) (also KS)Lymphomas) (also KS)

WHITE CELL NEOPLASMS WHITE CELL NEOPLASMS Leuk/LymphLeuk/Lymph

Can be caused by H. Pylori (gastric B-Can be caused by H. Pylori (gastric B-Cell lymphomas)Cell lymphomas)

Can follow celiac disease (gluten Can follow celiac disease (gluten sensitive enteropathysensitive enteropathy T-Cell T-Cell lymphomas)lymphomas)

Are common in HIV, B-Cell Are common in HIV, B-Cell lymphomas, CNS lymphomaslymphomas, CNS lymphomas

Types of Leukemias 1. Acute Lymphoblastic leukemia (ALL) ~30% of all

leukemias, the most common among children under 5 years old. The marrow contains more than 30% lymphoblasts. The prognosis is inversely proportional

to age.2. Acute myelogenous leukemia (AML) ~80% of acute

leukemias in adults. Marrow has >20% myeloblasts. Overall prognosis is poor with relapse after chemotherapy and most do not survive more than 5 years after diagnosis. Two forms; acute denovo AML or as an end-stage of CML and myelofibrosis.

AML ALL

Types of LeukemiasTypes of Leukemias

3. 3. Chronic lymphocytic leukemia (CLL)Chronic lymphocytic leukemia (CLL) Peak incidence is in Peak incidence is in elderly males >60years old. Bone marrow has >40% lymphoid elderly males >60years old. Bone marrow has >40% lymphoid cells, peripheral blood has >15 X10↑6. Neoplastic cells cells, peripheral blood has >15 X10↑6. Neoplastic cells resemble B-lymphocytes. CLL has an indolent course over 7-resemble B-lymphocytes. CLL has an indolent course over 7-10 years, it responds poorly to chemotherapy. It is closely 10 years, it responds poorly to chemotherapy. It is closely related to small cell lymphoma and lymphadenopathy is related to small cell lymphoma and lymphadenopathy is common.common.

4. 4. Chronic myelogenous leukemias (CML)Chronic myelogenous leukemias (CML) Peak incidence is Peak incidence is ~60years old. Symptoms are related to loss of normal marrow ~60years old. Symptoms are related to loss of normal marrow functioning; anemia, bleeding & infection. Peripheral WBC functioning; anemia, bleeding & infection. Peripheral WBC counts in the 20-50,000 range with large component of myeloid counts in the 20-50,000 range with large component of myeloid precursors. Frequently terminates in a “blast” crisis with precursors. Frequently terminates in a “blast” crisis with peripheral WBCs of >100,000 with immature myeloid cells. peripheral WBCs of >100,000 with immature myeloid cells. Prognosis is poor despite chemotherapy.Prognosis is poor despite chemotherapy.

ALL-Acute Lymphocytic Leuk.ALL-Acute Lymphocytic Leuk.

Common in Children.Common in Children. FAB classification L1, L2 FAB classification L1, L2

& L3& L3 B cell, T cell & histiocytic B cell, T cell & histiocytic

types.types. CD10 +ve, Pre B cell type CD10 +ve, Pre B cell type

common.common. Lymphadenopathy, Lymphadenopathy,

bleeding tendencybleeding tendency Moderate Moderate

HepatosplenomegalyHepatosplenomegaly

ALL-L1ALL-L1

ALL-L2ALL-L2

ALL-L3ALL-L3

AML-Acute Myeloid Leuk.AML-Acute Myeloid Leuk.AML-Acute Myeloid Leuk.AML-Acute Myeloid Leuk.

Malignancy of myeloid progenitor Malignancy of myeloid progenitor cells.cells.

Adults commonAdults common Hepatosplenomegaly moderateHepatosplenomegaly moderate No significant lymphadenopathyNo significant lymphadenopathy Bleeding tendency Bleeding tendency Gum bleeding common in M5/M4Gum bleeding common in M5/M4 FAB classification - M0 to M7.FAB classification - M0 to M7.

Malignancy of myeloid progenitor Malignancy of myeloid progenitor cells.cells.

Adults commonAdults common Hepatosplenomegaly moderateHepatosplenomegaly moderate No significant lymphadenopathyNo significant lymphadenopathy Bleeding tendency Bleeding tendency Gum bleeding common in M5/M4Gum bleeding common in M5/M4 FAB classification - M0 to M7.FAB classification - M0 to M7.

AML-Acute Myeloid Leuk.AML-Acute Myeloid Leuk.►M0 - AML No maturation M0 - AML No maturation (<3% Peroxidase (<3% Peroxidase

+ve)+ve)

►M1 - AML Min.MaturationM1 - AML Min.Maturation(>3% Peroxidase (>3% Peroxidase +ve)+ve)

►M2 - AML With full maturation M2 - AML With full maturation ►M3 - A.Promyelocytic leukemiaM3 - A.Promyelocytic leukemia►M4 - A.Myelomonocytic leukemiaM4 - A.Myelomonocytic leukemia►M5 - A.Monocytic LM5 - A.Monocytic L(a-Monocytic, b-M.blastic)(a-Monocytic, b-M.blastic)

►M6 - A. ErythroleukemiaM6 - A. Erythroleukemia►M7 - A. Megakaryocytic leukemia.M7 - A. Megakaryocytic leukemia.

AML-M0 - Undifferentiated:AML-M0 - Undifferentiated:

AML-M1 - without AML-M1 - without maturationmaturation

AML-M2 - with maturationAML-M2 - with maturation

AML-M3 - Auer RodsAML-M3 - Auer Rods

M3M3Acute promyelocytic leukemia, remember promyelocytes

have BOTH nucleoli AND nonspecific granules,

true BLASTS do NOT have granules.

AML-M3 - Promyelocytic

AML-M4 - MyelomonocyticAML-M4 - Myelomonocytic

AML-M5b - Monoblastic Leuk

AML-M6 : Erythroleukemia

AML-M7 : Megakaryocytic AML-M7 : Megakaryocytic

Chronic Myeloid Leukemia• Middle age 40-60y

• Philadelphia chromosome, t(9:22)

• Leucocytosis (>50x109/L), abnormal cells

• Marked splenomegaly

• Anemia, Bleeding

• Hypermetabolism,

• Hyperuricemia- gout, renal impairment.

Chronic Myelogenous Leukemia, BCR-ABL1+

• Chronic myelogenous leukemia presenting in blast phase including lymph node involvement.

• A, Peripheral blood smear with leukocytosis, massive left shift with “myelocyte bulge” and 7% blasts (Wright-Giemsa).

• B, Inguinal lymph node with sheets of blasts (H&E).

• C, Blasts positive for CD3 antigen. Contributed by N. Vajpayee and colleagues.

Chronic Myelomonocytic Leukemia

• Circulating promonocytes are present (A and B) in a sample from a patient with chronic myelomonocytic leukemia (A and B), blood sample.

C.L.L.• Unexplained sustained (months) lymph count of

> 4000/mm3 is CLL, usually picked up on CBC• M>F

• Lymphs look normal and are NOT blasts

• No need for marrow exam for dx, but progressive involvement of marrow, nodes, and other organs is the usual biologic behavior

• Liver can be involved portally or sinusoidally

• Translocations RARE, but trisomies and deletions common

C.L.L.

C.L.L.• HYPO-gammaglobulinemia

• 15% have antibodies against RBC’s or PLATS

• CANNOT be classified as separate from lymphomas

LymphomasNeoplasms of lymphoid cells may be divided into two major

groups:• Non-Hodgkin’s lymphoma ~70%• Hodgkins lymphoma ~30%Predisposing factors1. Oncogenes, both lymphomas & leukemias may share

the same oncogenes.2. Radiation increases the risk of lymphomas particularly

radiation therapy for neoplastic disorders.3. Environmental factors, Burkitt lymphoma is related to

EBV infection. 4. Immunodeficiency states (congenital or acquired) are

associated with an increased incidence of lymphomas; HIV is associated with CNS lymphoma.

(MALIGNANT) (MALIGNANT) LYMPHOMASLYMPHOMAS

► Terms in historic classifications:Terms in historic classifications: Diffuse/Follicular, Small/Large, Cleaved/Non-cleavedDiffuse/Follicular, Small/Large, Cleaved/Non-cleaved Hodgkins (REED-STERNBERG CELL) /NON-HodgkinsHodgkins (REED-STERNBERG CELL) /NON-Hodgkins Lukes, Rappaport, etc.Lukes, Rappaport, etc. Working Formulation, WHO, NIH, FAB, Intl., etc.Working Formulation, WHO, NIH, FAB, Intl., etc.

BB TT PRECURSOR (less mature looking)PRECURSOR (less mature looking) PERIPHERAL (more mature looking)PERIPHERAL (more mature looking)

Hodgkins Lymphoma:Hodgkins Lymphoma: Hodgkin’s disease is a group of cancers

characterized by Reed-Sternberg cells that begins as a malignancy in a single lymph node and then spreads to contiguous lymph nodes

Lymphadenopathy, painless, firm Lymphadenopathy, painless, firm Pel-Ebstein fever, Eosinophilia, Pel-Ebstein fever, Eosinophilia, Reed-Sternberg cells - B lymphocytesReed-Sternberg cells - B lymphocytes Histological Types:Histological Types:

– Lymphocyte predominant.Lymphocyte predominant.– Nodular Sclerosis.Nodular Sclerosis.– Mixed cellularity.Mixed cellularity.– Lymphocyte depleted.Lymphocyte depleted.

Non-Hodgkins Lymphoma:Non-Hodgkins Lymphoma: Non-Hodgkin’s lymphomas represent a group of

heterogeneous lymphocytic cancers that are multicentric in origin and spread to various tissues throughout the body, including the bone marrow.

According to cell type According to cell type T cell NHLT cell NHL B cell NHL B cell NHL Miscellaneous NHL Miscellaneous NHL

Ex: Lennert’s lymphoma is a low grade T cell NHL. Ex: Lennert’s lymphoma is a low grade T cell NHL. Burkitt’s lymphoma is a high grade B cell NHLBurkitt’s lymphoma is a high grade B cell NHL

According to Clinical grade According to Clinical grade •Low grade NHLLow grade NHL•High grade NHL High grade NHL •Intermediate grade NHLIntermediate grade NHL

Non-Hodgkin lymphomas

Burkitt lymphoma is a rapidly growing B-cell lymphoma affecting children and adults. It is related to EB virus infection. Solid tumors are often located in extranodal tissue. Response to chemotherapy is inversely related to age.

Hodgkin’s disease comprise several closely related neoplastic lymph node disorders that resemble lymphoma

Areas of involvement: This usually involves a neoplastic process in contiguous lymph nodes usually in the neck and mediastinum. Extranodal involvement and disease above and below the diaphragm portend poor prognosis.

Clinical Differences Between Hodgkin and Non-Hodgkin Lymphomas

Hodgkin Lymphoma Non-Hodgkin Lymphoma

More often localized to a single axial group of nodes (cervical, mediastinal, para-aortic)

More frequent involvement of multiple peripheral nodes

Orderly spread by contiguity

Noncontiguous spread

Mesenteric nodes and Waldeyer ring rarely involved

Waldeyer ring and mesenteric nodes commonly involved

Extranodal involvement uncommon

Extranodal involvement common

Leukemoid ReactionLeukemoid Reaction

an excessive leukocytic responsean excessive leukocytic response

leukocytosis of 50 x10leukocytosis of 50 x1099/L or higher /L or higher with shift to the left with shift to the left

oror lower counts with considerable lower counts with considerable

numbers of immature granulocytesnumbers of immature granulocytes quantitative or qualitative changes quantitative or qualitative changes

in lymphocytes or monocytesin lymphocytes or monocytes

Leukemoid ReactionLeukemoid Reaction

neutrophilicneutrophiliceosinophiliceosinophilic

lymphocyticlymphocytic

hemolysishemolysishemorrhagehemorrhagemalignancymalignancyHodgkin diseaseHodgkin diseasemyelofibrosismyelofibrosisTBTBburnsburnseclampsiaeclampsia

parasiteparasite

infectious infectious lymphocytosislymphocytosispertussispertussisTBTB

Plasma cell disordersPlasma cell disordersPlasma cell disordersPlasma cell disorders

Main typesMain types Multiple myelomaMultiple myeloma Waldenstrom macroglobulinemia: A malignancy of Waldenstrom macroglobulinemia: A malignancy of

plasmacytoid lymphocytes that secrete IgM resulting in a plasmacytoid lymphocytes that secrete IgM resulting in a hyperviscosity syndrome with renal, retinal and cerebral hyperviscosity syndrome with renal, retinal and cerebral ischemia as a result of microvascular occlusion.ischemia as a result of microvascular occlusion.

Monoclonal gammopathy of unknown significance: often Monoclonal gammopathy of unknown significance: often diagnosed in asymptomatic elderly patients. It is present in diagnosed in asymptomatic elderly patients. It is present in ~1% of patients over 60 years old and 3% of patients over 70. ~1% of patients over 60 years old and 3% of patients over 70. There is a 1% risk of developing multiple myelomaThere is a 1% risk of developing multiple myeloma. .

Clinical featuresClinical features Tend to occur in those >45 years old.Tend to occur in those >45 years old. Neoplastic plasma cells produce a monoclonal Neoplastic plasma cells produce a monoclonal

immunoglobulin component that can be identified by serum immunoglobulin component that can be identified by serum electrophoresiselectrophoresis

Deposition of light chain immunoglobulin may form amyloid Deposition of light chain immunoglobulin may form amyloid deposits in the kidneys, vessels and other organs.deposits in the kidneys, vessels and other organs.

Multiple MyelomaMultiple MyelomaMultiple MyelomaMultiple Myeloma

• A neoplasm of mature plasma cells that respond poorly to chemotherapy and usually survive ~3 years after diagnosis. Renal damage due to protein deposition is the most common cause of death. Infection, systemic amyloidosis, anemia, hyperviscosity and metabolic disorders contribute to the poor outcome.

Multiple MyelomaMultiple MyelomaClinical Presentation:Clinical Presentation:   - Pts present in their middle fifties or - Pts present in their middle fifties or

older (60-70 yr)older (60-70 yr)- Constitutional symptoms, anemia, - Constitutional symptoms, anemia,

thrombocytopenia, and renal thrombocytopenia, and renal failure;failure;

- Approx 80% of pts have chief - Approx 80% of pts have chief complaint of bone pain w/ diffuse complaint of bone pain w/ diffuse bone tenderness, particularly over bone tenderness, particularly over the sternum and pelvis.the sternum and pelvis.

- Pathological fracture of spine or - Pathological fracture of spine or femur may be heralding event;femur may be heralding event;

- Symptoms range in duration from - Symptoms range in duration from as short as few wks to as long as 2 as short as few wks to as long as 2 yrs.yrs.

Neoplastic cells secrete a Neoplastic cells secrete a monoclonal monoclonal immunoglobulin: IgG 60%, immunoglobulin: IgG 60%, IgA 20% and IgD, IgE or IgA 20% and IgD, IgE or the heavy or light chain the heavy or light chain 20%. Normal 20%. Normal immunoglobulins are immunoglobulins are suppressed increasing the suppressed increasing the risk of infection.risk of infection.

Multiple bone lesions are Multiple bone lesions are composed of nests of composed of nests of neoplastic cells and appear neoplastic cells and appear as “punch” lesions in as “punch” lesions in bones. Bony lesions may bones. Bony lesions may cause symptomatic cause symptomatic hypercalcemia, metastatic hypercalcemia, metastatic calcification also occurs.calcification also occurs.

Excess immunoglobulin Excess immunoglobulin may be deposited in may be deposited in peripheral tissue forming peripheral tissue forming amyloid. They may be amyloid. They may be secreted in the urine as secreted in the urine as Bence-Jones proteins, Bence-Jones proteins, occasionally proteins occasionally proteins obstruct renal tubules obstruct renal tubules resulting in renal failure.resulting in renal failure.

SUMMARYSUMMARY

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Dexter star Michael C. Hallfights against Hodgkin’s Lymphoma