deck_4820548 Flashcards
What is acute leukemia?
- Acute leukemia is a clonal, neoplastic proliferation of immature myeloid or lymphoid cells (two types as a result: AML and ALL)
- Acute means it is rapidly fatal without treatment
How does acute leukemia work?
Immature leukemic cells that do not mature past a blast or other precursor stage accumulate in bone marrow and cause bone marrow dysfunction and there for loss of peripheral blood cells
What is the etiology of AML?
Chromosomal abnormalities affecting oncogenes, TS, or regulation of apoptosis lead to inability for cells to mature/differentiate and for them not to be regulated by external factors for growth and also inexhaustibly self-renews
For AML, genetic disturbance at myeloid precursor –> AML types affecting myeloid lineages (granulocytes, monocytes, eythrocytes, megakaryocytes)
What is the etiology of ALL?
Similar to AML, but defect in lymphoid stem cell –> either B cell or T cell affected, but these cells don’t fully mature75% of ALL cases occur in kids
What are risk factors for acute leukemia?
Chemotherapy (especially DNA alkylating agents and topoisomerase II inhibitors), smoking, ionizing radiation, benzene, other genetic syndromes (Down, Bloom, Fanconi anemia, ataxia-telangiectasia)
What are the signs and symptoms of acute leukemia?
Same things related to cytopenia: anemia (fatigue, dyspnea), thrombocytopenia (bruising, hemorrhage) neutropenia (fever/infection)
However, sometimes present due to leukemic cells: thrombosis due to inc. WBC –> inc. blood viscosity, DIC initiated by WBCs, and can infiltrate mucouse membranes
What expresses CD34?
Immature lymphoblasts and myeloblasts
What expresses TdT?
Only lymphoblasts (no myeloblasts and no lymphocytes)
What do B-lymphoblasts express?
CD19, CD22, and/or CD79a, but not CD20 or surface Ig
Describe the cytogenetics of BALL
1) t(9:22)(q34;q11.2); BCR-ABL1 [Philadelphia chromosome]
- 25% of adult cases (2% of child)
- worst prognosis
2) 11q23; MLL
- neonates/young infants
- poor prognosis
3) t(12:21)(p13;q22); ETV6-RUNX1
- 23% of childhood BALL
- very favorable prognosis
Describe T-ALL
Only 25-30% of ALL casesIn adolescents/young adults primarily
Presents more commonly with LBL with masses
More likely to present with high WBC
Males>females
What do T-lymphoblasts express?
CD2, CD3, and/or CD7; also CD4, CD8; also CD99, CD1a
What are other prognostic factors for ALL aside from cytogenetic findings?
Worse prognosis for 10yo/adults
Worse if WBC is elevated
Worse if hypodiploidyWorse if T-ALL
What is the diagnostic criteria for AML?
Either myeloblasts accounting for >20% of nucleated cells in the marrow/peripheral blood (detected through smears, flow cytometry, or immunohistochemistry on marrow biopsy) OR one of the genetic mutations
What do immature myeloblasts express?
CD34 (but also on lymphoblasts), CD117, myeloperoxidase,
For monocytic diff –> CD64, CD14
For megakaryoblastic diff –> CD41, CD61
Also contain Auer rods (which help to distinguish from lymphoblasts)
Describe the cytogenetics of AML
Typically balanced translocations
1) t(8;21)(q22;q22); RUNX1-RUNX1T1
- 5% of cases
- AML w/ maturation (some neutrophil production)
- blocked transcription of CBF-dep genes –> blocked differentiation
- good prognosis
2) inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB-MYH11
- 5-10% of cases
- lots of immature eosinophils with abnormal basophilic granules (baso eos)
- inc. myeloblasts and monocytes (myelomonocytic leukemia)
- similar to CBF in (1)
- good prognosis
- 3) t(15;17)(q22;q12);PML-RARA
- important
- promyelocytes instead of blasts
- 5-10% of cases
- hypergranular (normal promyelocytes with lots of granules, Auer rods)
- retinoic acid receptor alpha (RARA) needed for promyelocytes to deveop, but can overcome by giving retinoic acid
- can cause DIC**
4) t(1;22)(p13;q13);RBM15-MKL1
- megakaryoblastic diff
- seen in infants w/ Down syndrome
- good prognosis w/ chemo
5) 11q23; MLL
- monocytic diff
- poor prognosis
Describe the differences between therapy related AML secondary to alkylating agents/radiation and topoisomerase II inhibitors
AA/radiation
- 2-8yrs of latency
- goes through MDS before AML- whole or partial loss from chromosome 5 and/or 7
topoisomerase II inh
- 1-2 years of latency
- de novo AML skipping MDS
- rearrangement of MLL gene (11q23)
both have poor prognoses
What if there are no cytogenetic findings but you suspect AML?
Then called AML, NOS (not otherwise specified) and you look at differentiation of leukemic cells:
- myeloid if myeloblasts
- myelomonocytic if myeloblasts and monoblasts/monocytes
- monoblastic/monocytic if monoblasts and monocytes (may infiltrate skin)
- eyrthroid if myeloblasts but erythroid precursors are inc- megakaryblastic
- if megakaryoblasts/cytes and have marrow fibrosis
However, are finding some genetic abnormalities:
- FLT3 ITD: poor prognosis
- NPM1 - good prognosis
- CEBPA - good prognosis
What about overall prognosis of AML?
If poor prognosis, then 10years
60% of AML will go into remission after chemo
Stem cell transplant is preferred treatment
What two factors characterize MDS?
Ineffective hematopoiesis and increased risk of transformation to AML
(basically similar to AML)
How do you diagnose MDS?
Look for 2+ cytopenias: anemia, thrombocytopeia, or neutropenia
Look at marrow- >10% of cells should show dysplastic changes
- dyserythropoiesis - RBC precurosors with moth-eaten and/or multi-lobed nuclei, sideroblastic
- dysgranulopoiesis - moth eaten bi-lobed (Pelger-Huet) nuclei, abnormally pale (instead of pink) cytoplasm due to lack of granules
- dysmegakaryopoiesis - small and single lobed nuclei
Look at cytogenetics- partial or whole deletions of chr 5 and/or 7, deletion 7q, deletion 5q, trisomy 8
If no cytogenetics or increased myeloblasts and only dysplasia, then what (MDS)?
Then need to exclude findings due to:
- chemo
- B12/folate def
- viral infection
- toxins
What is low and high grade MDS?
Low grade: myeloblasts 5% of marrow and/or >2% of peripheral
What are the types of low grade MDS?
Refractory cytopenia with unilineage dysplasia
- good prognosis
- low grade MDS with dysplasia in only one lineage (usually anemia)
Refractory cytopenia multilineage dysplasia
- worse prognosis
- 2+ lineagesMDS w/ isolated deletion 5q- anemia, inc platelets, megakar with small, round, non lobed nuclei
What are the high grade MDS?
Refractory anemia w/ excess blasts 1- 5-9% blasts in marrow or 2-4% in peripheral blood
RAEB2
- 10-19% in marrow, 5-19% in peripheral bloodbad prognosis
Why do MPNs present with hepatosplenomegaly?
because of the sequestration of excess blood cells and extramedullary hematopoiesis
What can happen in MPNs if not treated?
can transform to AML
can transform to MDS
can have marrow fibrosis
What are the 4 types of MPNs?
Chronic myelogenous leukemia (CML) Polycythemia vera (PV) Primary myelofibrosis (PMF) Essential thrombocythemia (ET)
What are the initial symptoms of CML?
Fatigue, weight loss, night sweats, splenomegaly, anemia
But can be asympotmatic and diagnosed by CBC indicating inc neutrophil
Describe the progression of CML
Starts in chronic phase
- blasts not elevated
- neutrophils elevated
- basophils and platelets are often increased
- hypercellular due to granulocytic hyperplasia
- small, round, non-lobed nuclei megakaryocytes
- no dysplasia
If not treated, moves to blast phase
- basically AML (>20% blasts in marrow/blood)
- blasts usually myeloblasts (70%) or lymphoblasts (30%)
Describe the cytogenetics of CML
BCR-ABL1 gene fusion
t(9;22)9q34;q11.2) - Philadelphia chromosome
Results in 210 kD fusion protein as opposed to 190 kD in BALL
How do you treat and diagnose CML?
Diagnose with karyotype or FISH and look for BCR-ABLPTKIs (protein tyrosine kinase inhibitors) - Gleevec;
What is polycythemia vera characterized by?
Increase in RBC mass and inc neutrophils and platelets (trilineage hyperplasia)
Large, weird megakaryocytes
Mutation of JAK2 gene with V617F point mutation
If the JAK2 mutation isn’t found in PV, what could it be?
If persistent erythrocytosis, then maybe secondary erythrocytosis seen in smokers and chronic hypoxia
Describe the progression of PV
Starts in a polycythemic phase with inc peripheral blood
Progresses to spent phase where marrow fibrosis and peripheral blood dec and becomes similar to PMF
What other symptoms are associated with PV?
Symptoms include headache, dizziness, visual problems, paresthesias, plethora, itching, splenomegaly (70%), and hepatomegaly (40%)
Thrombosis of mesenteric, portal, or splenic vein
How do you treat PV?
Good prognosis
Phlebotomy (bloodletting) with aspirin to prevent clots
Mild chemo
What is PMF characterized by?
Proliferation of granulocytic and megakaryocytic lineages –> progressing to myelofibrosis (similar to PV but no erythrocytosis)
JAK2 mutations in 50% of cases
What is the course of PMF?
In prefibrotic stage:
- hypercellular marrow with granulocytes and megakaryocytes
- Megakaryocytes are large and weird and clustered
- Thrombocytosis in blood and sometimes neutrophilia
Progresses to fibrotic stage:
- reticulin (type 4 collagen) fibrosis in marrow –> hematopoiesis in marrow sinusoids
- leukoerythrobastosis - inc immature granulocytes and nuc RBCs and dacrocytes
- splenomegaly
How do you treat PMF?
Not diagnosed until fibrotic stage usually, so not that good of prognosis
What is ET characterized by?
Sustained marked thrombocytosis
No granulocytic hyperplasia in marrow
Clustered large weird megakaryocytes in marrow
JAK2 mutations in 50%
What are the symptoms of ET?
Transient ischemic attacks due to occlusion of small blood vessels
Digital ischemia with paresthesia
Thrombosis of major arteries and veins
What is the prognosis of ET?
Symptom free for long periods, with occasional severe thrombotic of hemorrhagic events
Describe the anatomy of lymph nodes
- Capsule: thin and fibrous, but thick and fibrotic in reactive/neoplastic conditions
- Cortex: contains mainly B cells; follicles
- Paracortex: contains mainly T cells;
- Medulla: histiocytes (macrophages, dendrite cells, etc.) and medullary sinuses
- Margin around mantle around follicle
- Follicle: light zone - mixed B cells (centrocytes), T cells, macrophages; dark zone - mostly B cells (centroblasts)
What are the three kinds of small cell non-Hodgkin lymphomas?
Follicular
Mantle cell
Marginal zone
Describe Follicular Lymphoma
- Lymphoma of germinal center B cells
- Follicle-like nodules in LNs, spleen, and BM, GI, skin, soft tissue
- Occurs in late adult and has painless lymphadenopathy
- t(14:18)
- BCL2 translocated to Ig heavy chain; BCL2 prevents apoptosis by stabilizing mitochondrial membrane, however you want apoptosis in the follicle with somatic hypermutation –> lymphoma
- chemo or rituximab helps treat
- may develop into DLBCL
hyperplasia vs. neoplasia?
- architecture (white spots of macrophages; follicles in cortex) generally kept in hyperplasia
Describe mantle cell lymphoma
- expansion of mantle cells around follicle
- t(11:14)
- cyclin D1 regulates G1 to S normally but promotes G1 to S more in this case so leads to proliferation
Describe marginal zone lymphoma
- chronic inflammatory states
- only have a marginal zone during inflammation and activation of cells
- can see marginal zone lymphoma in mucosal sites
Describe Burkitt lymphoma
- intermediate size
- associated with EBV
- extranodal mass
- presents in young adults and children
- t(8:14)
- c-myc translocation; promotion of growth
- starry sky histology
- African type: jaw; otherwise sporadically in abdomen
Describe diffuse large B cell lymphoma
- large size
- diffuse so not anywhere specifically in lymph node
- most common
- aggressive
- poorly differentiated
- late adult
- extranodal mass
What markers highlight B cells and T cells respectively?
B-cell - CD20
T-cell - CD3
Describe B-cell development
- undergo maturation in bone marrow (stem cell pro-B, pre-B, immature B, mature naive B)
- migrate to peripheral organs and form primary follicles
- activate in paracortex by DCs and T cells
- some become 1st plasma cells (secrete IgM), others go back to follicles and become 2nd plasma cells (secrete IgG) or memory B cells
What is the definition of CLL?
Chronic Lymphocytic Leukemia
- mature lymphocytosis >5E9/L for >3mo
- monoclonal B cell w/ mature immunophenotype
What is the definition of SLL?
Small Lymphocytic Leukemia
- Extramedullary sites
- Diffuse infiltrate of small lymphocytes
- similar phenotype to CLL
What are clinical features of CLL/SLL?
- CLL: most common leukemia in western world (30%)
- SLL: 7% of NHLs
- Male predominance
- 65yo
- 70% are asymptomatic, but some can have fatigue, infection, AIHA, hepatosplenomegaly, LAD, extrandoal involvement
What are the morphologic features of CLL/SLL?
In peripheral blood:
- Size: small and monotonous (soccer ball)
- Nuclei: round w/ condensed chromatin
- Nucleoli: inconspicuous
- Cytoplasma: scant and agranular
- Promyelocytes (large, round nuc; delicate chromatin; distinct nucleoli; lots of cytoplasm)
In lymph node:
- loss of architecture and infiltration diffusely
- small cells w/ round nuclei and clumped chromatin
- pseudofollicles: pale areas of larger transformed cells
Micronodules in spleen
Infiltration in bone marrow
What is the immunophenotype of CLL/SLL?
Positive: CD5, CD23, CD19
Weak: CD20, surface immunoglobulin, CD22, CD11c
Negative: CD10, FMC7
What are common genetic findings in CLL/SLL?
- deletion of 13q14
- trisomy 12
- deletion of 11q22-q23
- deletion of 17p13
Define Follicular Lymphoma
Lymphoma of germinal center B cells
What are the clinical features of Follicular Lymphoma?
- mostly adults
- male:female 1:1
- lymph nodes, spleen, bone marrow, GI, skin, soft tissue
- at diagnosis, most are at stage 3 or 4, but mostly asymptomatic besides LAD
What are the morphologic features of Follicular Lymphoma?
- follicles throughout lymph node, not just in cortex
- loss of nodal architecture
- extranodal or intramedullary
- follicles become poorly defined with no mantle zone
- follicles lose dark/light zones and no “starry sky” appearance from loss of tingible-body macrophages
- reacts positively for BCL2
Explain the difference between centroblasts and centrocytes
Centrocytes: small to medium, scant cytoplasm, elongated/twisted nuclei, inconspicuous nucleoli
Centroblasts: large, round/oval nuclei, narrow rim of cytoplasm
What is the immunophenotype of Follicular Lymphoma?
B cell markers pos: CD19, CD20
BCL2
Germinal center B cell markers pos: CD10, BCL6
Describe the cytogenetics of Follicular Lymphoma
most cases have t(14;18)(g32;q21)
- BCL2 gene from chr18 under IgH promoter on chr14
- BCL2 is an oncogene (prevents apoptosis)
- BCL2 down-reg in germinal center because you want apoptosis during selection of B cells
Is t(14;18) enough to cause FL?
No; it can cause massive follicular lymphoid hyperplasia, but by itself is not enough for neoplasm
How do you distinguish between Reactive Follicular Hyperplasia and Follicular Lymphoma?
Architectural
- RFH: loosely packed follicles, distinct mantle zones, no invasion
- FL: tightly packed follicles, no mantle zones, extension into perinodal soft tissue
Cytological:
- RFH: high mitotic rate, tingible-body macrophages, normal lymphoid cells b/w follicles
- FL: low mitotic rate, no tingible body macrophages, cleaved cells b/w follicles
Special:
- BCL2 expression in FL
Define Mantle Cell Lymphoma
- B-cell neoplasm; small-medium sized lymphocytes; irregular nuclei; resemble centrocytes;
- BCL1 gene arrangement –> overexp of cyclin 1
What are the clinical features of Mantle Cell Lymphoma?
- 3-10% of NHLs
- more common in males
- adult onset
- lymph nodes, spleen, bone marrow, GI
- diagnosed at stage 3 or 4 with LAD, HSM
- moderately aggressive
What are the morphologic features of Mantle Cell Lymphoma?
- effacement of LN architecture
- infiltration diffusely or nodular or mantle zone growth pattern
- small to medium size cells; larger than lymphocytes; irregular nuclei
- resemble centrocytes, but not centroblasts, or follicles
- hyalinized small vessels
What is the immunophenotype of Mantle Cell Lymphoma?
Bcell markers pos: CD19, CD20
CD5, CD23
Cyclin D1 (BCL1)
Germinal center Bcell marker pos: CD10, BCL6
What is the cytogenetics of Mantle Cell Lymphoma?
t(11;14)(q13;q32)
- BCL1 onto IgH
- BCL1/cyclin D1 leads to G1 to S phase transition –> overexp of cyclin D1 = proliferation
What is Burkitt’s Lymphoma?
- highly aggressive B cell lymphoma
- extranodal sites
- intermediate size cells
- basophilic cytoplasm and high mitotic rate
- c-myc oncogene
What are the clinical features of Burkitt’s lymphoma?
- endemic: in african children affecting jaw, distal ileum, cecum, or omentum; 95% EBV positive
- sporadic: in children or young adults, 30% of lymphomas (mostly ileocecal); 30% EBV associated
- immunodeficiency associated in HIV patients; 25-40% EBV infection
What are the morphologic features of Burkitt’s lymphoma?
- starry sky patten (such a high mitotic rate, so have a lot of cells aka “sky” and have a high turnover rate with cells apoptosing so macrophages seen with a white spaces as “stars”)
- round nuclei with one or several small nucleoli
- basophilic cytoplasm w/ lipid vacuoles; squared of borders
What is the immunophenotype of Burkitt Lymphoma?
B cell markers positive: CD19, CD20
High proliferation index by Ki-67
EBV in endemic BL and 30% in sporadic/immunodeficient
Negative: BCL2, CD5, CD23, TdT
Positive of MYC
Describe the cytogenetics of Burkitt Lymphoma
t(8;14)(q24;q32)
- MYC gene at IgH locus
- promotes growth
What is the prognosis of Burkitt Lymphoma?
- highly aggressive but potentially curable with aggressive therapy in 60% of cases
What is DLBCL?
Diffuse Large B Cell Lymphoma
- medium to large sized B cells
- diffuse
What are the clinical features of DLBCL?
- most common NHL (31% of cases)
- late onset
- males favored
- rapidly growing nodal (70%) or extranodal (30%) tumors
- B symptoms (fever, night sweats, weight loss, etc.)
Describe the morphology of DLBCL
- effacement of LN architecture by diffuse infiltration
- coagulative necrosis and permeation into surrounding tissues
- tumor cells are large and have features of centroblasts, immunoblasts
What is the immunophenotype of DLBCL?
B cell markers pos: CD19, CD20
What is the clinical outcome of DLBCL?
- fairly aggressive
- potentially curable w/ chemo
- complete remission in 2/3; with 2/3 of those staying relapse-free
- survival rate is 46%
What is a plasma cell neoplasm?
It is where you have a proliferation of clonal plasma cells that produce one type of Ig (that can be detected on SPEP or in urine)
Mos start out as bone marrow tumors but can present extramedullarily
What is plasma cell myeloma or multiple myeloma?
- bone marrow based plasma cell neoplasm
- abnormal Ig (M protein) present in high amounts in serum and urine
What are the diagnostic criteria for plasma cell myeloma?
- M protein in serum or urine (M spike)
- clonal plasma cells in bone marrow
- hypercalcemia, renal insufficiency, anemia, bone lesions (CRAB)
What are the clinical features of plasma cell myeloma?
- 4/100000
- usually diagnose >50yo
- bone pain in back or extremities; weakness, tiredness, anemia
- inc infection due to loss of antibody diversity
What are the lab findings usually seen in plasma cell myeloma?
- serum/urine electrophoresis is best
- IgG and IgA M proteins most common; sometimes light chain
- Anemia in 2/3
- Hypercalcemia
- elevated creatinine
- lytic lesions/osteoporosis
- Rouleaux formation/stacking of RBCs due to loss of charge
- proteinuria due to light chain deposit in kidney tubules –> renal insuff
- amyloidosis due to light chain in serum and deposit in tissues
- BM biopsy to confirm (lots of neoplastic plasma cells)
- binucleated “owl eyes” plasma cells
What is MGUS?
Monoclonal Gammopathy of Undetermined Significance
- monoclonal IgM leading to M spike in serum or urine, but NO signs like in PCM (i.e. no amyloidosis, no lytic lesions, no hypercalcemia)
What are the features of MGUS?
- M spike but none of the signs in PCM
- in elderly and most common monoclonal gammopathy
- Waldenstroms macroglobulinemia (produces IgM so macro)
- LAD
- IgM –> CV problems and bleeding
How do you diagnose MGUS?
- M component less than myeloma levels
- Marrow plasmacytosis
What is solitary plasmacytoma of bone?
- localized tumor of bone
- similar to PCM
How do you diagnose solitary plasmacytoma of bone?
- single bone lesion w/ monoclonal plasma cells
- no other bone lesions
- no renal failure
- no hypercalcemia
- no anemia
- no M protein
What is extraossesous plasmacytoma?
- localized plasma cells tumors in tissues outside of bone marrow
- different from solitary plasmacytoma of bone and PCM
- usually diagnosed at 55yo; males favored
- 75% of lesions occur in upper respiratory tract
- histology is similar to SP of bone
How does Hodgkin’s Lymphoma differ from non-Hodgkin’s Lymphoma?
- NHL has the whole mass of malignant cells
- HL mass is not entirely malignant, but due to presence of reactive cells due to in cytokines from a Reed Sternberg cell (large cells, lobated nucleus, large nucleoli, ample and amphophilic cytoplasm)
- this causes B symptoms
- CHL express CD30 and CD15
What are the 4 subtypes of classic Hodgkin’s Lymphoma?
1) Nodular sclerosis
2) Lymphocyte-rich
3) Mixed cellularity
4) Lymphocyte-depleted
Describe Nodular Sclerosis CHL
- most common subtype
- usually young adults and favors females
- typically occurs in cervical neck and mediastinal LNs
- thick LN capsule with broad bands of collagen/fibrosis which cuts LN into nodes
- RS cells in open spaces called lacunar cells
- 10-25% of cases also associated with EBV
Describe Mixed Cellularity Variant CHL
- second most common
- similar cell comp to NSHL
- in children and older patients
- usually in stage 3 or 4 with B symptoms
- below or on both sides of diaphragm
- no broad fibrosis like in NSHL
- 75% have EBV
- increased eosinophils due to inc IL-5
Describe Lymphocyte Rich Variant CHL
- 5% of CHLs
- nodular growth pattern w/ remnants of germinal centers
- best prognosis
- RS cells are rare
Describe Lymphocyte Depleted CHL
- least common
- few lymphocytes
- lots of RS cells, which might look weird
- usually with EBV
- worst prognosis
- usually in elderly and HIV patients
