CHRONIC LEUKEMIAS Flashcards
-Increased MATURE rather than immature cells in the lymphoid or myeloid lines
-The basic defect in growth control presumably affects [precursor/progenitor] cells, but in these disorders most ________ cells differentiate
-Progression is [slower/faster]; can be [weeks or months] up to years
CHRONIC LEUKEMIAS
progenitor
neoplastic cells
slower
months
2 TYPES OF CHRONIC LEUKEMIAS
- MYELOPROLIFERATIVE NEOPLASMS [MPN]
- LYMPHOPROLIFERATIVE DISORDERS/ MATURE LYMPHOID NEOPLASMS.
-are clonal hematopoietic disorders caused by
genetic mutations in the hematopoietic stem cells (HSCs) that result in expansion, excessive production, and accumulation of mature erythrocytes, granulocytes, platelets, and mast cells
MYELOPROLIFERATIVE NEOPLASMS
MYELOPROLIFERATIVE NEOPLASMS
Each has a chronic course that may terminate as ________ ________, ____________, or a ___________.
Acute leukemia
Myelofibrosis
Coagulopathy
MYELOPROLIFERATIVE NEOPLASMS
Mutation in_________; this discovery allowed for refinement of the classification of MPNs.
Myeloproliferation largely is due to [hyposensitivity or hypersensitivity] or [dependence or independence] of normal cytokine regulation resulting from genetic mutations that reduces ______ levels through _______ _________ systems normally induced by mature cells
JAK2/Janus Kinase 2 [JAK2V617F mutation]
hypersensitivity
independence
cytokine
negative feedback
it is a [pluripotent/multipotent] HSC ______where all of the MPNs involve dysregulation
multipotent hematopoietic stem cell (CD34)
WHO CLASSIFICATION OF MPNs
● ________ MUTATION
-CHRONIC MYELOID LEUKEMIA (CML)
● ________ MUTATION
-POLYCYTHEMIA VERA (PV)
-ESSENTIAL (PRIMARY) THROMBOCYTHEMIA (ET)
-PRIMARY MYELOFIBROSIS (PMF)
BCR-ABL1
JAK2V617F
is an MPN arising from a [single/multiple] genetic translocation in a pluripotential HSC producing a clonal overproduction of the myeloid cell line, specifically __________.
-occurs at _____ ages but is seen predominantly in those aged 46 to 53 years.
CHRONIC MYELOID LEUKEMIA
single
Granulocytes
all ages
it represents about 20% of all cases of leukemia, is slightly more common in men than in women
CHRONIC MYELOID LEUKEMIA
CML begins with a chronic clinical phase and, if untreated, progresses to an accelerated phase in ___ to ____ years and often terminates as _____ leukemia (_____ crisis phase).
3-4
acute, blast
CML
CYTOGENETIC ABNORMALITY:
-Presence of the _______ gene (_________/_____)
-Reciprocal translocation between the [short-p/long-q] of chromosomes___and _____ t(__;__)
-This acquired somatic mutation specifically reflects the translocation of an _____ proto-oncogene from band _____ of chromosome ____ to the ___________ of band q11 of chromosome ____ (___;q11)
-The _______ protein has constitutive kinase activity that deregulates _____ transduction pathways, causing abnormal cell ______, inhibition of _______, and increased proliferation of cells
-Also found in FAB ___ (3-5%) and FAB ___ and ____(10-25%)
BCR-ABL1
Philadelphia Chromosome/Ph’
long, q arms
9 and 22, t[9;22]
ABR- q34 -9
Breakpoint Cluster Region [BCR]- q11-22
[q34;q11]
BCR-ABL: signal, cycling, apoptosis
M1, L1, L2
_______
Most cases (____%) are diagnosed in this phase -Frequent ______, ______ secondary to massive massive pathologic accumulation of myeloid progenitor cells in bone marrow, peripheral blood, and extramedullary tissues
-_________ WITH ALL MATURATIONAL STAGES PRESENT, _________, __________
-Progressive fatigue and malaise, low-grade fever, anorexia, weight loss, and bone pain
-Night _______ and _____, associated with an increased metabolism caused by granulocytic cell turnover
-EM: ______; _______ infarction is common because of the abnormal overproduction and accumulation of granulocyte precursors in the bone marrow, _____, and blood
-On fresh incision, extramyeloid masses appear [color] (_______), presumably because of the presence of the myeloid enzyme _________.
CML
85%
Infection, anemia
Neutrophilia, Basophilia, Eosinophilia
sweat, fever
Splenomegaly, splenic, spleen
green [Chloromas]
myeloperoxidase
________
ACCELERATED PHASE:
-[Increased/Decreased] splenomegaly
-Worsening ______ and _______.
-Gradual failure of response to treatment
-[+/=] cytogenetic abnormalities
-___-___% blasts
______ CRISIS (______):
-involves the peripheral blood, bone marrow, and extramedullary tissues
-Based on AL definitions, blasts constitute more than ___% of total BM cellularity, and the peripheral blood exhibits increased [matured cells or blasts]
-Clinical symptoms of blast crisis mimic those of AL, including severe anemia, leukopenia of all WBCs except _____, and __________.
CML
Increased
anemia, thrombocytopenia
+
10-19% blasts
Blast Crisis [Acute]
20%
blasts
blasts, thrombocytopenia
-referred to as a latter of extramedullary growth may occur as lymphocytic or myeloid cell proliferations.
Granulocytic sarcoma
CML
LABORATORY FINDINGS:
BLOOD:
-Marked expansion of the ________ pool
-Anemia and thrombocytopenia (variable)
-[left/right] shift with few blasts in the peripheral blood
-Extramedullary hematopoiesis (_____, _____)
OTHER LABORATORY FINDINGS:
-_________ and _________ (from cell turnover)
-Detection of t(9;22) translocation (cytogenetic analysis, _______,________)
-[DECREASED/INCREASED] ____ SCORE (is used to differentiate CML from leukemoid reaction)
granulocytic pool
left shift
spleen, liver
Hyperuricemia, uricosuria
FISH, RT-PCR
DECREASED, LAP
CML
LABORATORY FINDINGS:
BONE MARROW:
-Intense [hypocellularity/hypercellularity]
-_______ fibers are increased in approximately 20% of patients
-Increased _________ density is associated with an increase in myelofibrosis
-Presence of _____________ cells
hypercellularity
Reticulin
megakaryocyte
Pseudo-Gaucher cells
__________
-Is a clonal stem cell proliferation affecting primarily the _______ series, characterized by excessive proliferation of it and also usually granulocytic and megakaryocytic elements in the marrow
-The very slow evolution of the malignant erythroid clone leads to overexpansion of the [red/white] cell mass, [hypovolemia/hypervolemia], and splenomegalic red cell pooling
-These consequences eventually cause generalized _______ _______ with subsequent increases in the quantity of all three cell lines.
Polycythemia Vera
erythroid
red
hypervolemia
marrow hyperplasia
PV
Associated with the _____ mutation; is detected in more than 95% of patients with PV and is found on chromosome band __p___ ; also associated with ______________[another type]
-__________ phosphorylates signal transducers and activators of transcription______ proteins, eventually generating transcription proteins that bind promotor regions and signal gene expression
-Controls transphosphorylation through conformational _________.
-Constitutive ______ _______ activity of the mutated causes [continous/non-continuous] activation of several signal transduction pathways— that are normally activated after erythropoietin stimulation via the erythropoietic receptor.
-Mutated is active and will phosphorylate ____ proteins in the absence of ________ or will overphosphorylate in its presence
JAK2V617F
9p24
JAK2 exon 12 mutation
JAK2 protein– Tyrosine kinase
STAT
inhibition
tyrosine kinase
continous
STAT
EPO
________ POLYCYTHEMIA VERA
>Increased Hct: increase BM production
>Types: Primary, secondary with appropriate EPO production, inappropriate production of EPO
> PRIMARY
-_________
-Increased BM production of erythrocytes, leukocytes, and thrombocytes
-EPO: [increased/decreased]
> SECONDARY WITH APPOPRIATE EPO PRODUCTION
-Occurs in response to ______
-Patients with _______disease
-Increased BM production of erythrocytes, leukocytes, and thrombocytes
-EPO: [increased/decreased]
> SECONDARY WITH INAPPROPRIATE EPO PRODUCTION
-_____ of kidneys, liver, brain, adrenals
-Increased erythrocytes, leukocytes, and thrombocytes
-EPO: [increased/decreased]
ABSOLUTE
Panmyelosis
Decreased
hypoxia
cardiac/pulmonary
Increased
Tumors
Increased
> RELATIVE POLYCYTHEMIA VERA
Increase ______; Decrease ______ volume
Dehydration, stress, spurious polycythemia, anxiety
_________ ________: spurious polycythemia
Hct, Plasma
Gaisbock’s syndrome
CLINICAL FINDINGS:
>PV often presents with a history of [mild/severe] symptoms occurring for several [months/years]
- Increased RCM produces blood [hypoviscosity/hyperviscosity] , often resulting in __________ disease
- In the early stages of the disease, before treatment, extended periods of high HCT (60%) and hyperviscosity produce ________ in about 50% of patients with PV
- Hyperviscosity and hyperproliferation and include headache, weakness, [a skin condition], weight loss, and fatigue
- About half of PV patients have ________ and 1/3 experience ______ or ________ episodes
mild
years
hyperviscosity– cardiovascular disease
hypertension
pruritis
thrombocytosis
hemorrhagic and thrombotic episodes
> PV patients older than __ years of age or those associated with a history of thrombosis are considered high risk for thrombotic or hemorrhagic events
> The stable phase of PV can progress to a ____ phase in a few patients, usually within ____ years from diagnosis
- Splenomegaly (palpable spleen)
- Hypersplenism
- BM hyperplasia
- ________ [low RBC, WBC. PLT]
___________: Triad of ________, _________, and _______ with [abnormal RBC morphology] and develops in about 30% of PV patients within 20 years
60
Spent phase
10 years
Cytopenia
Postpolycythemic myeloid metaplasia
myelofibrosis, splenomegaly, anemia
teardrop-shaped poikilocytes
_______________
LABORATORY FINDINDS:
>Common morphologic patterns in peripheral blood and BM _______ and cellular changes
>BM normoblasts may collect in large clusters, __________ are enlarged and exhibit lobulated nuclei, and BM ______ are enlarged without fibrosis
>Pseudo-Gaucher cells are rare
> 80% of patients manifest BM ________.
PV
morphologic
megakaryocytes
sinuses
panmyelosis
_____________:AKA [name three]
-a clonal MPN with increased megakaryopoiesis and thrombocytosis, usually with a count greater than _____ x 109/L ; sometimes with a count greater than ______ x 109/L
-However, WHO criteria require a sustained thrombocytosis with a platelet count of ______ x 109/L –
Associated with mutations in:
_____ (64.1%) ____ (4.3%) ____ (15.5)
ESSENTIAL THROMBOCYTHEMIA
Primary thrombocytosis, Idopathic thrombocytosis, Hemorrhagic thrombocythaemia
600
1000
400
JAK2, MPL, CALR [calreticulin]
____
CLINICAL FINDINGS:
-_______ ______ [increased clots] are often the result of microvascular thromboses in the digits or thromboses in major arteries and veins that occur in a variety of organ systems, including splenic or hepatic veins, as in __________ syndrome
-Repeated splenic infarcts can result in ______ _______.
-Thrombosis can result in ______ emboli and ______ complications like headache, paresthesis of the
extremities, visual impairments, and tinnitus
-[Venous/Arterial] thrombi can cause _________ infarction, transient ischemic attack, and cerebral vascular accident
-_______ occurs most often from mucous membranes in the gastrointestinal, skin, urinary, and upper respiratory tracts.
ET
Vascular occlusions
Budd-Chiari syndrome
splenic atrophy
pulmonary emboli and neurologic complications
Arterial thrombi– myocardial
Bleeding
In ET, platelets often appear normal, [4] but ___ _____ platelets, platelet _______, ___________, and megakaryocyte ________ can also be observed.
Platelets are present in clusters and tend to [be depleted/accumulate] [far/near] the thin edge of the blood film ; abnormal platelet function testing can occur.
BM has marked megakaryocytic [hypocellularity/hypercellularity] , clustering of megakaryocytes, and increased megakaryocyte diameter with nuclear hyperlobulation and density
giant bizarre platelets
platelet aggregates
micromegakaryocytes
megakaryocyte fragments
near
accumulate
near
hypercellularity
DIAGNOSIS OF ESSENTIAL THROMBOCYTHEMIA (ET)
WHO CRITERIA FOR DIAGNOSIS OF ET:
MAJOR CRITERIA:
Megakaryocyte [depletion/proliferation] with large and mature morphology, [little to no/many] granulocyte or erythroid proliferation]
[Major/Minor] increase in reticulin fibers
MINOR CRITERIA: presence of a ____ marker or absence of evidence of reactive ________.
Based on WHO standards, a diagnosis of ET requires meeting all _____ major criteria or the first _____ major criteria and one minor criteria
proliferation
little to no
Minor
clonal marker
reactive thrombocytosis
four, three
___________:AKA [NAME THREE]
-associated with areas of marrow hypercellularity (______________), extramedullary hematopoiesis, fibrosis, and increased ________; it is the least common but most aggressive form of MPN.
-Can form __ ____ or as an evolutionary consequence of PV or ET
- ASSOCIATED MUTATIONS: ____ (V617F) – 60% ; _____ - 30% ; _____ – 5%
MYELOFIBROSIS
-Fibroblasts produce ____ to provide structural support for HSCs
-In PMF a reactive process causes overproduction of _____ that eventually disrupts the normal architecture of the BM and replaces hematopoietic tissue resulting in _________.
EXTRAMEDULLARY HEMATOPOIESIS
-recognized as __________ or _________, seems to originate from release of clonal stem cells into the circulation
-The cells accumulate in the spleen, liver, or other organs, including adrenals, kidneys, lymph nodes, bowel, breasts, lungs, mediastinum, mesentery, skin, synovium, thymus, and lower urinary tract
Primary Myelofibrosis
Chronic Idopathic Myelofibrosis, Agnogenic Myelofibrosis, Myelofibrosis with myeloid metaplasia
leukoerythroblastosis
megakaryocytes
de novo
JAK2, CALR, MPL
collagen
collagen
Pancytopenia
hepatomegaly, splenomegaly
is an uncommon disease with an incidence one-third that of CML
Chronic Idiopathic Myelofibrosis [CIM]
-The disease may be asymptomatic and usually progresses as a slow, chronic condition
Symptoms result from anemia, myeloproliferation, or splenomegaly and include fatigue, weakness, shortness of breath, palpitations, loss of appetite, weight loss, night sweats, pruritis, pain in the extremities and bones, bleeding, and discomfort or pain in the left upper quadrant associated with splenomegaly
PMF
-Major _______ _______ occur in 15% of PMF patients during the course of their disease and 10% of patients demonstrate _________ and decreased blood _________ levels suggesting _________ hemolysis
-Some patients develop ________ ________resulting from a combination of thrombocytopenia, abnormal platelet function, and hemostatic abnormalities suggestive of chronic_______ [disease]
hemolytic episodes
hemosiderinuria
haptoglobin
=intravascular hemolysis
bleeding diathesis
DIC
PMF
LABORATORY FINDINGS:
In the EARLY STAGES, anemia, _______ with a ____ shift, and _________ are identified that are consistent with a MPN. [ALL INC but immature]
As the fibrosis DEVELOPS in the BONE MARROW, blood cell counts fall and _______ eventually develops, along with leukoerythroblastosis, _______, and _________.
Examination of the ___ ______specimen provides most of the information for diagnosis
____Abnormal cell morphology
leukocytosis, thrombocytosis, left shift
pancytopenia
poikilocytosis
anisocytosis
BM Biopsy
Dacryocytes
Are a diverse collection of disease entities with varying clinical presentations and natural histories; however, common to all is identification with a particular lineage
Disease states in large part can be identified with a
normal counterpart in the ______, _______ or_______. Neoplastic transformation of these cells results in abnormal changes in growth and differentiation patterns, resulting in disease.
Lymphoproliferative disorders in which the primary site of disease is the blood or bone marrow are classified as ________; disorders in which the localization of disease is in the lymph nodes and spleen are considered _______.
MATURE LYMPHOID NEOPLASMS
blood, BM, lymph nodes
leukemias
lymphoma
is the most common leukemia in adults in Western countries
Chronic Lymphocytic Leukemia
is a clonal proliferation of small B lymphocytes [CALLED AS:__________] involving BM, blood, and lymph nodes
-generally a disease of the older adult; median age of diagnosis is approximately ___ years which is common in _____.
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
72, males
Most patients are asymptomatic on presentation, and the disease is often detected by an abnormality in a routine CBC
Chronic Lymphocytic Leukemia
In CLL, The (IWCLL) requires the presence of at least __ x 109 cells/L of circulating B lymphocytes for more than ___ months to establish the diagnosis of CLL, with confirmation of clonality performed by ____ ________.
5
3
flow cytometry
CLL CYTOGENETIC ABNORMALITIES: [5]
13q14.3 –> DLEU2/MIR15A/MIR16A
6q21
Trisomy 12
ATM gene –> 11q23del
TP53 gene –> 17p13del
Typical CLL presents with ____% of the lymphocytes appearing small and mature with ____ cytoplasm and a dense nucleus with a condensed chromatin pattern without a defined nucleolus.
This characteristic chromatin pattern has been labeled as _______ or likened to a [basket/soccer] ball.
85%
scant
cobblestone
soccer
________ _____
-Seen in 20% of patients
-_________ or ______ lymphoid cells represent less than 10% or less than 15% of circulating lymphocytes
-Associated with biologic markers indicating more aggressive disease
> Subtypes:
-___/___>10% but <55% of total lymphocytes
(>55% is associated with _____________)
-_______/atypical CLL >15% large atypical lymphoid cells
ATYPICAL CLL
Prolympochytes
Atypical
CLL/PLL
Prolymphocytic leukemia
Mixed-type
are a common finding on peripheral blood film review in CLL
SMUDGED LYMPHOCYTES
CLL POSITIVE MARKERS: [6]
CD__, CD__, CD__, CD__, CD__, ___ surface Ig (single light chain with IgM or IgM/IgD)
NEGATIVE:
CD__, _____, _____.
> This pattern is very useful in distinguishing CLL/SLL from mantle cell, follicular, and marginal zone lymphomas
BUT ANTIGEN EXPRESSION IS VARIABLE.
5, 19, 20, 23, 79a, dim surface Ig
10, BCL-6, Cyclin D1
