MOD7 Malignant Disorders

WHO system

based on genetics; uses all info to classify → morphology, cytochemical staining, immunophenotype, clincal features

FAB (french american british) system

based on morphological characteristics of wright stained cells in PBS or marrow slides + cytochemical staining of blasts

malignancies

disorders characterized by malignant monoclonal proliferation of affected cell line

presence of malignant cells in PBS and marrow → abnormal changes in morphology

malignant monoclonal proliferation

production of abnormal and nonfunctional cells originating from a single damaged/mutated cell

inappropriate, uncontrolled, widespread, often irreversible growth

clinical findings in most leukocyte malignancies

anemia → fewer RBCs produced

myelophthisic → crowding out of normal cells by malignant ones in the marrow

abnormal bleeding → fewer PLTs produced

inc susceptibility to infc → fewer phagocytes/lymphocytes produced

organ damage/failure → infiltrated and damaged

causes of malignancies

chromosomal damage

suppressed immune function

pre existing/genetic susceptibility

irritant/inciting condition/event

chromosomal damage

cause of malignancies

inherited or acquired

translocation → chromosome breaks and exchanges segments with another experiencing a break

oncogenes

normal genes that control the rate of proliferation of the cell/substances in the cell → inappropriately activated → abnormal growth of mutated cell

responsible for initiating a malignant proliferation

acute leukemia

fast developing, mostly immature/blast cells

high WBC count

chronic leukemia

slower developing, more mature cells

only 3-5% blasts, see entire neutrophil line

subleukemic leukemia

normal WBC count but abnormal cells in PBS

aleukemic leukemia

characterized by normal or low WBC count in blood despite leukemic changes

pancytopenia, no blasts in PBS (yes in marrow)

chronic myeloproliferative disorders (neoplasms)

too many stem cells develop into 1+ types of cells

slow developing as number of extra cells inc

most cells → mature

most cases → leukoerythroblastic myelophthisic anemia and extramedullary hematopoiesis

chronic myelogenous leukemia CML

[(t(9;22), BCR-ABL positive]

malignant proliferation of pluripotent stem cell (CFU-GM)

gene produces tyrosine kinase enzyme → myeloid proliferation → unrestrained growth of granulocyte series

CML peripheral blood findings

leukocytosis; markedly increased WBC >50×10^9/L

whole granulocyte series, mature cells predominate

inc baso and eos

pelgroid granules → boobs

CML bone marrow findings

markedly hypercellular → myeloid hyperplasia

inc granulocytes

inc megakaryocytes

myeloid:erythroid ratio increased → 10:1 instead of 3:1 → more myeloid precursors than erythroid

CML cytochemistry findings

decreased LAP score

→ send to look for Ph’ chromosome → diagnose

LAP score

leukocyte alkaline phosphate

enzyme found in membranes of secondary granules of neuts

quantitative measurement of LAP staining in segs

decreased in CML

increased in PV

CML cytogenetics findings

Philadelphia chromosome Ph’

Ph’t(9;22) (q34;q11)

incomplete chromosome in granulocytes, megakaryocytes, monocytes, normoblasts

CML that doesnt have Ph’

10% of cases

lacks BCR-ABL fusion gene

atypical CML

worse prognosis, more acute, therapy ineffective

CML treatment

chemo → remission → usually converts to acute phase: less responsive to tx

cure → allogeneic bone marrow transplant w HLA matched donor

CML v neutrophilic leukemoid reaction

dec LAP // inc LAP

normochromic normocytic anemia // no anemia

pos Ph’ // neg

splenomegaly // no

polycythemia vera PV

inc proliferation of erythroblasts, granulocytes, megakaryocytes from abnormal myeloid stem cell

ruddy cyanosis of skin → inc total blood volume

extramedullary hematopoiesis and hepatosplenomegaly

PV v secondary polycythemia cause

proliferation of erythroblasts, granulocytes, megakaryocytes

proliferation of only erythrocytes

PV peripheral blood findings

RBC → v inc → v thick; slow moving in vessels + inc PLTs → greater chance of clotting

LAP → inc > 100

PLT → mod inc

PV bone marrow findings

hypercellular w big megakaryocytes

PV molecular findings

mutation in JAK2 gene janus kinase 2

provides instructions for production of protein → stim proliferation of cells

substitution of valine w phenylalanine at pos 617 (Val617Phe)

renders hematopoietic cells more sensitive to growth factors → erythropoietin and thrombopoietin

overproduction of abnormal RBCs and megakarys

PV diagnosis criteria

both major + one minor // first major + two minor

major:

• hb >185g/L (M) // >165g/L (F) or other evidence of inc RBC volume

• presence of JAK2 V617F

minor:

• bone marrow trilineage myeloproliferation

• serum erythropoietin level below normal

• endogenous erythroid colony growth → in vitro growth of erythroid colonies w/o erythropoietin

PV treatment/prognosis

venipuncture/phlebotomy → dec RBCs

15% of cases → CML → AML

30% of cases → myelofibrosis

secondary polycythemia

caused by natural or artificial inc in production of erythropoietin → inc RBCs

PV v secondary polycythemia differential diagnosis

pO2 → normal // dec

EPO → normal // dec

LAP → inc // normal

spleen → splenomegaly // normal

idiopathic/primary myelofibrosis CIMF

fibrosis of bone marrow → proliferation of fibroblasts and replacement of hematopoietic cells w fibrous secretions

extramedullary hematopoiesis

primary myelofibrosis peripheral blood findings

leukoerythroblastic → shift to left of RBCs + WBCs

marked poikilocytosis → tear drops + ovalocytes

dwarf megakaryocytes + giant plts

pancytopenia → mod to marked anemia

primary myelofibrosis bone marrow

dry taps → filled w fibrous tissues and no cells

primary myelofibrosis other findings

may resemble chronic granulocytic leukemia but inc LAP score and no Ph’

often converts to acute myeloid leukemia

diagnosis criteria for primary myelofibrosis

all 3 major and 2 minor

major:

• megakaryocyte proliferation w abnormal morph, + collagen/reticulin fibrosis

• evidence of JAK2V617F or other mutations

• not meeting criteria for other MPNs

inor:

• leukoerythroblastosis

• anemia

• inc serum lactic dehydrogenase LDH levels

• splenomegaly

essential thrombocythemia ET

rare primary megakaryocytic proliferation

marked thrombocytosis → abnormal plt function

inc risk of thrombosis and hemorrhage

ET peripheral blood findings

thrombocytosis → >450×10^9/L

platelet anisocytosis (diff sizes)

pleomorphism (abnormal shape)

megathrombocytes → large/giant plts

ET bone marrow findings

greatly inc numbers of giant megakaryocytes

ET diagnosis criteria

all 4 criteria

• persistent elevation of plts in PB

• evidence of JAK2V617F or other mutation

• not meeting criteria for other MPNs

• megakaryocyte hyperplasia in marrow

which chronic myeloproliferative disorder doesnt involve the JAK2 mutation

chronic myelogenous leukemia

myelodysplastic syndromes MDS

dysplastic changes in myeloid cells, singly or in combo w or w/o inc in blasts

proliferation of abnormal stem cells

dont make it into circulation

predominately affects elderly

many convert into acute myeloid leukemia AML

MDS peripheral blood/marrow findings

progressive cytopenia

dyspoiesis

macrocytic anemia

cellular bone marrow

inc blasts <20%

dyserythropoiesis morphology

ringed sideroblasts, oval macrocytes, hypochromic microcytes, dimorphic, howell-jolly bodies, basophilic stippling

dysmyelopoiesis morphology

basophilic cytoplasm, abnormal granulation, abnormal nuclei (pseudo-pelger huet, hypersegs)

dysmegakaryopoiesis morphology

giant plts, circulating small megakaryocytes, large mononuclear megakaryocytes

ringed sideroblasts

NRBCs w iron deposits surrounding nuclei

seen w iron stain

only found in bone marrow

auer rods

needle-like projections in cytoplasm

only found in myeloblasts and promyeloblasts

can be single or multiple

associated w acute myeloid leukemia AML

refractory anemia w ringed sideroblasts RARS

BM: single lineage (erythroid) → >15% ringed sideroblasts

refractory cytopenia w multilineage dysplasia RCMD

BM: multilineage (neut/eryth/megakaryocytes) → <5% blasts → ± 15% ringed sideroblasts

no auer rods

refractory anemia w excess blasts 1 RAEB-1

BM: 5-9% blasts → no auer rods

refractory anemia w excess blasts 2 RAEB-2

BM: 10-19% blasts → ± auer rods

RAEB-1 v RAEB-2

2 has more blasts and can have auer rods

MDS associated w isolated del(5q)

megakaryocytes → hypolobulated nuclei

<5% blasts

no auer rods

del(5q) cytogenetic abnormality

acute myeloid leukemia AML

malignant proliferation of myeloid blasts (non-lymphoid) in marrow and blood

>20% blasts

AML with characteristic genetic abnormalities

AML w translocations btwn ch 8 and 21

AML w inversions in ch 16

APL w translocations btwn ch 15 and 17 → great risk of DIC

AML w multilineage dysplasia

dysplasia in atleast 2 myeloid cell lines

pts who have had prior MDS or myeloproliferative disease MPD → transformed into AML

AML and MDS, therapy related

pts who have had chemo/radiation → developed AML/MDS

FAB M2

acute myeloblastic leukemia w maturation

most common

FAB M3

promyelocytic or acute promyelocytic leukemia APL

inc risk of DIC

AML clinical presentation

nonspecific

typically shows dec production of normal elements

myeloblasts in PBS

normochromic/normocytic anemia

thrombocytopenia, neutropenia

auer rods !

AML cytochemical stains

myeloperoxidase

sudan black b

esterases → specific // nonspecific

periodic acid schiff

used bcs cheap and easy

myeloperoxidase

enzyme in primary granules of neuts, eos, monos

differentiate granulocytic from lymphoid cells

cytochemical stain for AML

sudan black b

stains cellular lipids

little more sensitive than myeloperoxidase for early myeloid cells

cytochemical stain for AML

butyrate esterase

nonspecific esterase

stains pos in monocytes but not granulocyte precursors

naphthol AS-D chloroacetate

specific esterase

stains pos in granulocytic cells and wk/neg in monocytic cells

AML flow cytometry/immunophenotype

cell surface membrane receptors/markers

use flow cytometry to ID cell types

AML cytogenetic/molecular

aids classification

determines disease aggressiveness, response to tx, prognosis

gives us ability to tailor tx to the genetic abnormality → target malignancy

acute lymphoblastic leukemia ALL

most common leukemia in children

most progress in tx and obtaining remissions

no blast cutoff (vs AML)

ALL peripheral blood/marrow

small lymphoblasts → 1-2x size of lymphs, scant blue cytoplasm, indistinct nucleoli

large lymphoblasts → 2-3x size of lymphs, prominent nucleoli

normochromic/normocytic anemia

thrombocytopenia

ALL flow cytometry/immunophenotype

terminal deoxynucleotidyl transferase TdT → nuclear enzyme in stem cells/precursor B/T lymphoid cells

use to differentiate from AML

ALL cytochemical

periodic acid schiff

lymphoblasts → block staining

chronic lymphocytic leukemia CLL

malignant proliferation of B cells/T cells

B cells more frequent

typically asymptomatic

CLL bone marrow findings

hypercellular

predominated by small lymphs

CLL peripheral blood findings

normochromic/normocytic anemia

inc WBC

absolute lymphocytosis

small lymphs + hypermature nucleus → “soccer ball”

smudge cells present → lymphs fragile

neutropenia

complications associated w CLL

autoimmune hemolytic anemia

immune thrombocytopenic purpura

hairy cell leukemia

chronic lymphocytic leukemia of B call origin

cells look hairy

typically older patients

characterized by splenomegaly and pancytopenia

hairy cell leukemia peripheral blood findings

hairy cells → resemble immature lymphs

pancytopenia

hairy cell leukemia bone marrow findings

inc reticulin fibres due to production of fibrogenic cytokines by leukemic cells

hairy cell leukemia cytochemistry stain

tartrate-resistant acid phosphatase TRAP positive

tartrate-resistant acid phosphatase TRAP

stains acid phosphatase → cells stain pink → add tartrate → tests to see if the stain gets removed

stain stays (cells stay pink) → TRAP pos

cells are tartrate resistant → wont wash out of cells

multiple myeloma/plasma cell leukemia

malignant disorder of plasma cells → originates in bone marrow

overproduction of single class of immunoglobulin and excessive light chain production → monoclonal gammopathy → hypergammaglobulinemia

multiple myeloma key features

abnormal proliferation of plasma cells in BM

overproduction of monoclonal and dec lvls of normal polyclonal immunoglobulin

destructive done disease due to overproduction of various cytokines released by plasma cells → affect bone structure and function

OLD CRAB

multiple myeloma/plasma cell leukemia

OLD → old age

C → calcium elevated (hypercalcemia)

R → renal failure

A → anemia

B → bone lytic lesions

multiple myeloma bone marrow findings

inc number of plasma cells

single ecentric nucleus

may see nucleoli

fine chromatin

multiple myeloma peripheral blood findings

normochromic/normocytic anemia

rouleaux

late stage → plasma cells in PBS

pancytopenia

lymphoma

malignant proliferations of lymphoid cells in peripheral lymphatic tissues w limited/later blood involvement

becomes lymphocytic leukemias when large numbers of abnormal lymphs enter blood from infiltrated BM or other tissues

lymphoma classification

non-hodgkins lymphomas

hodgkins lymphomas

non-hodgkins lymphoma

malignant proliferations of B/T lymphs

originates in single lymph node/lymphoid tissue → peripheral

moves to other lymph nodes/organs w/o warning

non-hodgkins lymphomas classifications

cell size + morphology → cleaved/noncleaved

proliferative pattern → follicular/diffuse

cell type → B or T

proliferative intensity → high grade to low

large cell lymphoma grade

usually intermediate or high

small cell lymphomas grade

low grade

follicular lymphomas

always B cells

frequently involve small cells and low grade proliferations

proliferation of cleaved vs noncleaved cells

cleaved → slower

non-cleaved → quicker

mycosis fungoides

chronic cutaneous CD4 T-cell lymphoma

severe pruritis (itch) and psoriasis-like skin lesions

progress to lymph nodes → organs

sezary syndrome

develops as part of mycosis fungoides

lymphadenopathy and erythroderma → redness/scaling/shedding of skin

sezary cells

tartrate-resistant acid phosphatase positive

medium to large cell w convoluted nucleus

cerebriform lymphocytes

hodgkins lymphoma

og in malignant cell w mixed lineage w characteristics of B cells, T cells, monocyte/macrophage

begins in lymph nodes

above diaphragm → confined to nodes

below diaphragm → blood involvement → disorder spreads to BM, spleen, liver

probable infectious agent of hodgins lymphoma

epstein-barr virus

requirement for hodgkins diagnosis

reed-sternberg cell in lymph node section

large multi-binucleate abnormal cell

each nucleus contains gint nucleolus