ICL 10.1 & 10.2: Leukemia Flashcards
which cell types are in the myeloid cell line?
platelets
RBCs
granulocytes: neutrophils, basophils, eosinophils
monocyte
macrophages
which cell types are in the lymphoid cell line?
NK cells
B cells –> plasma cells
T cells
What differentiates leukemia from lymphoma?
leukemia arises from lymphoid or myeloid cells, starts in the bone marrow, and then spreads to the blood stream
lymphoma arises from lymphocytes, and starts in lymph nodes then spreads to blood stream
but both are malignant diseases of hematopoietic cells
what are the two major groups of leukemias?
- acute leukemia vs. chronic leukemia
2. myeloid vs. lymphoid leukemias
what are the main characteristics of acute leukemias?
- appear suddenly
- have a devastating clinical course if untreated
- composed of very immature hematopoietic cells
what are the main characteristics of chronic leukemias?
- much more indolent
- may persist for years even without treatment
- composed of cells at a more mature stage of development
what is the marker for lymphoid vs. myeloid leukemia?
Tdt is a marker for lymphoid leukemia
MPO is a marker for myeloid leukemias
what does ALL stand for?
Acute Lymphoblastic Leukemia
what is ALL?
a malignant entity in which very early lymphocyte precursors called lymphoblasts proliferate in the bone marrow and blood
these malignant lymphoblasts divide very quickly, filling up the bone marrow and crowding out normal hematopoietic precursor cells, leading to serious consequences for the patient if not treated immediately
so eventually the amount of mature functioning cells decreases a lot - so you have less RBCs, platelets, everything!
what are the three main types of lymphocytes?
- B cells (adaptive immune system)
- T cells (adaptive immune system)
- NK cells
(innate immune system)
what are B cells?
make antibodies
in charge of the humoral arm of the adaptive immune response
what are T cells?
they use cytokines and other cell surface molecules to mediate the cellular arm of the adaptive immune response
what cells are malignant in ALL?
acute lymphoblastic leukemia comes from either malignant B cell or T cell precursors
NK cells and their precursors have their own malignancies that are separate from ALL
what’s the clinical presentation of ALL?
- neutropenia = bacterial infections, fever
- anemia = fatigue, no energy
- thrombocytopenia = bleeding, petechiae, epistaxis, gum bleeding
- hepatosplenomegaly
- lymphadenopathy
- testicle enlargement (esp. ALL)
- bone pain
- possibly asymptomatic
what population is ALL more common in?
MUCH more common in children
also associated with Down’s Syndrome
T cell vs. B cell ALL
B cell ALL – typically bone marrow involvement first
T cell ALL – Lymph node involvement first
what does the bone marrow of an ALL patient look like?
diffuse, massive proliferation of lymphoblasts
the lymphoblasts are medium-sized cells with a super high nuclear/cytoplasmic ratio and fine chromatin
basically there’s just a ton of big plain purple cells with like no cytoplasm (go look at slide 24)
nucleoli can also be seen which is typically not visible in more mature cells
what does the CBC of an ALL patient look like?
severely increased WBC count because you’re making all these immature lymphoblasts (like 70,000/mmˆ3!!!)
normal blood cells like RBCs, normal WBCs, and platelets are usually decreased in number
what is flow cytometry allow us to do?
it enables us to determine immunophenotype
this test is looking for specific cell surface antigens
these surface markers sometimes change as the cell matures
flow cytometry helps us determine what kind of leukemia and lymphoma it is!
also it’s not invasive…
what are the surface proteins found on T cells?
CD3 and CD5
flow cytometry will show you which surface markers on which molecules to help you identify them!
which are the surface proteins found on helper T cells?
CD4
flow cytometry will show you which surface markers on which molecules to help you identify them!
which are the surface proteins found on cytotoxic T cells?
CD8
flow cytometry will show you which surface markers on which molecules to help you identify them!
which are the surface proteins found on B cells?
Ig, CD10, CD23, CD19, CD20, CD21
flow cytometry will show you which surface markers on which molecules to help you identify them!
which cell marker is specific to lymphoblasts and therefore important in ALL diagnosis?
TdT
all lymphoblasts express TdT!! (terminal deoxynucleotidal transferase)
this is supposed to disappear as cell matures
so if there’s a lot of TdT it tells you that there’s lots of immature cells
then you can do flow cytometry to determine if it’s B cell ALL (CD10, 19, 21, 23) or T cell ALL (CD2, 3, 4, 8)
what is the overall prognosis for ALL?
children have a good prognosis!
most children achieve a complete and durable remission that lasts at least 5 years
however, adults have a lower survival rate
if pt. has CD10 B-ALL, better overall prognosis
what are some good prognostic features of ALL?
- WBC count at presentation (<10,000 = good prognosis)
- Hyperploidy (presence = good prognosis)
- Immunophenotype: B-ALL better prognosis vs. T-ALL
what does it mean if a blood sample is Tdt+?
it means there’s lots of immature lymphoblasts!
what does AML stand for?
acute myeloid leukemia
what population is AML most common in?
most common in adults over age 45!!!!
what is AML?
a cancer of the blood arising from myeloid precursor cells
this includes platelets, RBCs, granulocytes and monocytes aka everything except lymphocytes….
the bone marrow is making abnormal myeloblasts (a type of white blood cell), red blood cells, or platelets
progresses quickly if left untreated
what must be present in a bone marrow biopsy or blood smear for AML to be diagnosed?
≥ 20% blast cells or “blast equivalents” must be present in the bone marrow for a diagnosis of AML
what is a blast equivalent?
in some types of AML, the malignant cell is a somewhat more mature than a blast
ex. in acute promyelocytic leukemia, for example, there are numerous malignant promyelocytes but not very many myeloblasts…
in these types of AML, we use the term “blast equivalent” instead of blasts for whatever immature call that is proliferating the most
what’s the clinical presentation of AML?
decreased amounts of normal cells
increased risk of infection due to neutropenia and too few neutrophils
increased risk of bruising and bleeding due to thrombocytopenia
anemia due to too few RBCs
pretty similar clinical presentation to ALL
what does the blood smear of an ALL patient show?
> = 20% blasts or blast equivalents
presence of Auer rods!! (cytoplasmic inclusions that are formed from the abnormal fusion of azurophilic, or primary, granules)
Auer rods are present in a certain subset of AML so just remember that the absence of Auer rods doesn’t exclude AML!!
so if a blast has Auer rods, you can be sure it’s a myeloblast. If it doesn’t have them, though, it could still be a myeloblast (or it might be a lymphoblast)
what are Auer rods?
cytoplasmic inclusions that are formed from the abnormal fusion of azurophilic, or primary, granules
diagnostic of AML
slide 33
how are the different types of AML categorized by the FAB system?
based on the FAB system
AML subtypes were made because myeloid progenitor cells can form form RBCs, platelets, basophils, neutrophils, eosinophils, and monocytes
M0-M7 subtypes
focuses on morphology and cell line
what are the 8 AML subtypes according to the FAB system?
M0-M3 involve neutrophil precursors;
M4-M5 involve monocytic precursors.
M6 involves immature RBCs
M7 involves immature cells from the platelet lineage
what is the M0 subtype of AML?
acute myeloblastic leukemia with minimal differentiation
involves neutrophil precursors
what is the M1 subtype of AML?
acute myeloblastic leukemia without maturation
involves neutrophil precursors
what is the M2 subtype of AML?
acute myeloblastic leukemia with maturation
involves neutrophil precursors
what is the M3 subtype of AML?
acute promyelocytic leukemia (APL)
involves neutrophil precursors
this is the AML that has Auer rods!!!
what is the M4 subtype of AML?
acute myelomonocytic leukemia
involves monocytic precurors
what is the M5 subtype of AML?
acute monocytes leukemia
involves monocytic precursors
what is the M6 subtype of AML?
acute erythroid leukemia
involves immature RBC
what is the M7 subtype of AML?
acute megakaryoblastic leukemia
involves immature cells from platelets linage
which AML is the one with Auer rods?
acute promyelocytic leukemia (APL)
involves neutrophil precursors
this is the AML that has Auer rods!!!
what is the WHO classification system of AML?
classifies AML into five categories, which take into consideration genetics (chromosome translocations), immunophenotype, morphology, and clinical features:
- AML with recurrent genetic abnormalities
- AML with myelodysplasia-related changes
- Therapy-related AML
- AML, not otherwise specified
- Myeloid sarcoma
How does the classification of AML differ from the FAB and the WHO classification systems?
the FAB system classifies AML based on cellular morphology while the WHO system classifies AML based on genetics, such as chromosomal translocations, as well as immunophenotype and morphology
Acute promyelocytic leukemia (AML subtype M3) is due to a translocation between which two chromosomes?
APL is due to a translocation between chromosomes 15 and 17
this is written as t(15;17).
how is APL treated?
APL can be treated with all-trans retinoic acid, a form of vitamin A,
this prompts differentiation of the WBCs, effectively putting an end to the predominance of blast cells and, therefore, the cancer
what are chronic lymphoproliferative disorders?
a group of diseases arising from a malignant clonal proliferation of lymphocytes
typically, CLPD involves proliferation of mature B cells and rarely T cells***
can involve peripheral blood, bone marrow, spleen, and/or lymph nodes and other lymphoid tissues
pts. have a prolonged, indolent course = little, to no pain
nonetheless, only a subset of patients will have a normal life span
what does CLPD stand for?
chronic lymphoproliferative disorders
what is the treatment for CLPD?
treatment is only required if symptoms of the lymphoproliferation are bothersome or progressive
typically a “watch-and-wait” approach is taken
what’s the clinical presentation of CLPD?
- may be completely asymptomatic
- lymphadenopathy
- fevers/chills; night sweats
- weight loss
- splenomegaly
- do not manifest the signs of bone marrow failure until late in the disease
- often, new leukocytosis on a routine CBC
what is CLL?
chronic lymphocytic leukemia
a type of cancer in which the bone marrow makes too many lymphocytes
it’s a type of chronic lymphoproliferative disorder
what cellular abnormalities are associated with CLL on a peripheral blood smear?
leukocytosis = increased # of WBCs
smudge cells!!!
slide 48
what are smudge cells and in which disease are they often seen?
they are lymphocytes that have been destroyed in the blood smear process
often seen in the blood smear of CLL patients!
literally look like smudgy clouds
what is the immunophenotype of CLL?
negative for TdT
positive for B-cell antigens CD19, CD20, CD21
positive for monoclonal surface Ig
positive for T-cell antigen CD5 (hmmm, weird)
why does CLL test positive for T-cell antigen CD5??
CLL is a disease with malignant B cells
but for a short period of time during maturation, B cells actually express CD5
what are chronic myeloproliferative disorders?
a group of malignant diseases in which the bone marrow produces too many maturing myeloid cells, which subsequently circulate out into the blood
they involve non-lymphoid cells aka neutrophils, eosinophils, basophils, monocytes, red blood cells, and/or platelets and their precursors
chronic myeloproliferative disorders can turn / progress into acute leukemias, sometimes even lymphoblastic due to undifferentiation
what cell types are involves in chronic myeloproliferative disorders?
non-lymphoid cells
aka neutrophils, eosinophils, basophils, monocytes, red blood cells, and/or platelets and their precursors
what are the four main types of chronic myeloproliferative disorders?
- Chronic Myeloid Leukemia (CML)
- Polycythemia Vera (PV)
- Essential Thrombocythemia (ET)
- Primary Myelofibrosis (PMF)
in each disorder of the group one cell line proliferated more than all the others
what is panmyelosis?
proliferation of all major myeloid cell lines in the bone marrow
what does the bone marrow look like in a patient with a chronic myeloproliferative disorder?
typically hypercellular, with a panmyelosis with an obvious predominance of a particular myeloid cell line
what does the blood look like in a patient with a chronic myeloproliferative disorder?
leukocytosis, along with a unique features in each disorder
which cell type is most increased in CML?
CML = chronic myeloid leukemia
markedly increased number of neutrophils and precursors in BM and blood
which cell type is most increased in PV?
PV = polycythemia vera
increased erythroid precursors in the BM
increased RBCs in blood
which cell type is most increased in ET?
ET = essential thrombocythemia
increased megakaryocytes in BM
increased platelets in blood
which cell type is most increased in PMF?
PMF = primary myelofibrosis
bone marrow initially panmyelocytic, but eventually fibrotic
What unusual finding is seen in the blood of a patient with PMF?
dacrocytes
tear shaped RBCs
slide 58
what’s the pathogenesis of chronic myeloproliferative disorders?
a constitutively active kinase is the pathogenesis in almost all cases of myeloproliferative disorders
which kinase is active without control in polycythemia vera?
JAK2 kinase
in almost all cases of PV, and in about half of the cases of ET and PMF, there is a mutation in a protein called JAK2, which is part of a hematopoietic cell growth pathway
the mutation leads to constitutive signaling resulting in the proliferation of myeloid cells, especially RBCs (in the case of PV) or platelets (in the case of ET)
what population are chronic myeloproliferative disorders most common in?
typically occur in older patients
what is the clinical presentation of patients with chronic myeloproliferative disorders?
insidious onset
splenomegaly
fatigue
dragging sensation in left upper quadrant (from splenomegaly)
as the marrow is replaced by malignant cells, normal hematopoietic cells have less and less room to grow, and patients may suffer infections or bleeding episodes due to the low numbers of normal white cells and platelets
what’s the clinical presentation of PV?
symptoms related to hyperviscosity such as headaches, visual disturbances, ruddy/plethoric appearance of face
pruritus (itch) after a hot shower
thrombotic events
what’s the clinical presentation of PMF?
massive spleen due to extramedullary hematopoiesis
what’s the clinical presentation of ET?
bleeding AND thrombosis!!!
due to massive platelet counts and abnormal platelet/endothelium interactions
what disease are patients with chronic myeloproliferative disorders at risk of developing?
there is a risk of transformation into an acute leukemia (either myeloid or lymphoblastic), which is very difficult to treat
what does MDS stand for?
myelodysplastic syndromes
what is MDS?
a group of clonal stem cell disorders characterized by maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to AML
the body no longer makes enough healthy, normal blood cells in the bone marrow
BM is partly or wholly replaced by the clonal progeny of a transformed multipotent stem cell that retains the capacity to differentiate into red cells, granulocytes, and platelets, but in a manner that is both ineffective and disordered
BM is hyper cellular or normocellular
peripheral blood has one or more cytopenias
what are the two types of MDS?
- idiopathic (primary) MDS
no known exposure history, elderly adults
- therapy-related (secondary) MDS
2-8 years post radiation or chemo, any age
what’s the difference between myeloproliferative diseases and myelodysplastic syndrome?
myeloproliferative diseasesare characterized bylarge numbers of abnormal blood cells (red, white or platelets) growing and spreading in bone marrow and blood
myelodysplastic syndrome includes various clonal hemopathies characterized by decreased production of blood cells and are associated with a risk for development of acute leukemia
what do you see in the blood smear of someone with MDS?
- Pelger-Huet neutrophils which are bi-lobed neutrophils…normal neutrophils have 3-5 lobes (slide 66)
- monocytosis > 1000
- MCV >100
- dysplastic nucleated RBCs (slide 67/68)
what does the BM of an MDS patient look like?
- ring sideroblasts
due to iron in mitochondria around the nucleus - you can see them with a prussian blue stain
- dysplastic megakaryocytes (slide 70)
what is CML?
it’s a type of chronic myeloproliferative disorder
these diseases have malignant, maturing myeloid cells filling up the marrow and subsequently circulating out into the blood
in CML, the neutrophil line is proliferating even more than the other myeloid lines causing a neutrophilic leukocytosis and a left shift
what are some of the characteristics of CML?
basophilia (not sure why)
neutrophils appear normal, however lack leukocyte alkaline phosphatase (LAP)
BM is hyper cellular
what’s wrong with the neutrophils in CML?
there’s a ton of them
they look normal but lack leukocyte alkaline phosphatase (LAP)
What is the characteristic blood smear picture in patients with CML?
the blood in CML shows neutrophilic leukocytosis with a left shift as well as a basophilia
go look at slide 76
answers are on slide 77
what population is CML most common in?
occurs in older adults
what are the phases of CML?
untreated, the disease has three phases: chronic phase, accelerated phase, and blast crisis
patients normally present in chronic phase, and with treatment, many will remain there indefinitely
without treatment, about 50% of patients enter accelerated phase (and then blast crisis)
the other 50% progress directly to blast crisis, without an intervening accelerated phase
what is the chronic phase of CML?
may be completely asymptomatic
the disease may be discovered on a routine CBC for some other reason
may have vague symptoms such as fatigue or a dragging feeling in the left upper quadrant due to splenomegaly
blast count is low (usually ~ 2-3% - but <= 10%)
CBC remains stable
with time, HgB, Plts, leuks. etc. may drop
what is the accelerated phase of CML?
general destabilization of counts
WBCs goes over 10,000
symptoms worsen, typically transitions into blast crisis in 6-12 months
what is the blast crisis phase of CML?
same as acute leukemia
blast count > 20% (most of the time blast crisis is myeloid)
difficult to treat, survival on the order of weeks to months.
CML is characterized by what chromosomal abnormality?
the chromosomal translocation t(9;22)
the new chromosome 22 is called the Philadelphia chromosome
ABL on chromosome 9 gets translocated and fused to the BCR gene on chromosome 22
What is the mechanism through which hybrid BCR-ABL gene causes uncontrolled cell growth?
overactive tyrosine kinase protein
what treatment is used for CML?
CML is due to a t(9;22) translocation and fusion of the BCR-ABL genes
this leads to an overactive tyrosine kinase protein
so there’s a tyrosine kinase inhibitor called imatinib (gleevec) that specifically blocks the BCR-ABL fusion tyrosine kinase seen in CML
this changes the prognosis of CML from a five-year survival to a chronic treatable condition
what is multiple myeloma?
a malignant proliferation of plasma cells in the bone marrow
all arise from a single malignant plasma cell, so they all express the same kind of immunoglobulin as that original cell
this monoclonal immunoglobulin production is sometimes called an M spike – helpful in diagnosis and following patients during and after treatment
almost always remains in bone marrow
what population is MM most common in?
elderly patients
what’s the clinical presentation of MM?
CRAB
hyperCalcemia
Renal dysfunction
Anemia
Bone pain
what is the major cause of death in MM patients?
infections
what test helps you look for MM?
SPEP = an electrical field separates the proteins in the serum based on size, shape, and charge
it will show you the M spike!
“M” stands for monoclonal, and monoclonal refers to the monoclonal immunoglobulins that are secreted in myeloma
the immunoglobulins most commonly present in myeloma are IgA and IgG, with IgG being the most common
which immunoglobulins are most common in MM?
IgA and IgG
IgG is more common
what do you do if you suspect MM but there’s no M spike on the SPEP?
do a urine protein electrophoresis (UPEP)
this is an instance when MM produces only the light chain portion, which is small enough to be filtered into the urine
SPEP and/or UPEP are used during and after treatments to follow the patients
what do you see in the x-rays of a patient with MM?
looks like holes in the skull
What are the best first tests to order on a patient that you suspect has myeloma?
SPEP and UPEP
what percentage of the marrow must consist of malignant plasma cells in order to make the diagnosis of myeloma?
BM must contain at least 10% plasma cells!!
due to the focal nature of myeloma lesions, multiple bone marrow core biopsies—usually two on each side—are obtained
what is commonly seen in the blood smears of MM patients?
rouleaux formation (stacked RBCs)
this occurs because the increased amount of immunoglobulin in the patient’s serum interferes with the normal repellant force that pushes red cells apart from each other, allowing the red cells to stack upon each other
what does MGUS stand for?
Monoclonal Gammopathy of Undetermined Significance
what is MGUS?
<10% of monoclonal plasma cells found within the bone marrow and a small monoclonal spike on SPEP or UPEP
patients that have MGUS have a small, but increased risk of eventually developing MM
*****patients lack lytic bone lesions, anemia, and kidney dysfunction
what is smoldering myeloma?
patients have have an M spike
however, they do NOT have any MM defining events; they do NOT have end organ damage or biopsy proven amyloidosis
but they do have >10% plasma cells to diagnose myeloma so they’re at a higher risk of transforming into MM than those with MGUS
what’s the difference between plasma cell myeloma and Waldenstrom’s macroglobulinemia?
- Plasma cell myeloma
- IgG > IgA
- plasma cells in BM
- bone lytic lesions
- hypercalcemia
- renal failure
- Bence-Jones proteins - Waldenstrom’s macroglobulinemia
- IgM always
- plasma cells, lymphocytes and plymphocytes
- lymphadenopathy
- hyper viscosity syndrome; Raynaud phenomenon
- no bone lytic lesions
- no hypercalcemia
- no renal failure
what are the normal stages of progression of myeloid maturation?
- blasts
- progranulocytes
- myelocytes
- metamyelocytes
- bands
- neutrophils
what is Waldenstrom macroglobulinemia?
WM typically occurs in a lymphoma called lymphoplasmacytic lymphoma
patient has a monocloncal gammopathy – but the immunoglobulin in this case is IgM
IgM is a pentamer, and as such it can easily clump red blood cells together in the serum so patients may present with symptoms of “sludgy” serum (e.g., visual difficulties due to sluggish flow in retinal veins; or even stroke).
what is hairy cell leukemia?
HCL is a rare, B-cell leukemia
BRAF mutation
flow cytometry is +CD11c, 22, 25, 103
TRAP+ cells
triad = older male, massive splenomegaly, pancytopenia
good prognosis
what does the blood smear of HCL patient look like?
slide 108/109
