Neoplastic WBC disorders_Clinical Pathology Boards Review
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When can AML be diagnosed without meeting the 20% blast threshold?
- 1) Acute erythroleukemia
- 2) Cytogenetic abnormalities: t(8;21)
- 3) Leukemias where other cells counted as blasts: APL, acute monocytic leukemia (promyelos and promonos)
What is the prognosis for the translocations that are diagnostic of AML? Age group affected?
All good prognosis; younger pts
All of the following translocations are diagnostic of AML and don't require 20% blasts except:
What is the FAB category/categories for the following AML types:
1) Minimal differentiation
3) With maturation + Auer rods
4) Without maturation
- 1) Minimal differentiation = M0
- 2) Promyelocytic = M3
- 3) With maturation + Auer rods = M2
- 4) Without maturation = M1
- 5) Monocytic/Monoblastic = M5
- 6) Erythroid = M6
- 7) Megakaryoblastic = M7
- 8) Myelomonocytic = M4
Which AML tends to present in DIC? What is their IHC expression for CD33, CD34, and HLA-DR?
APL/M3; strong CD33+, negative for CD34 and HLA-DR
Which AML is associated with gingival hyperplasia and CNS infiltration? What is the MPO expression for these blasts?
Monocytic AML (M5); monoblasts are MPO negative
All of the following are myeloblast markers except:
C - CD15 is on promyelocytes
Which of the following markers (more than one may apply) are lost in transition from the myeloblast to promyleocyte stage:
A and C: CD34 and HLA-DR are lost at the promyelocyte stage (which is why APL is negative for these two markers!)
What marker is temporarily lost in transition from a promyelocyte to myelocyte?
CD13, which is gained again at the neutrophilic band stage
What two markers are acquired in the transition from a monoblast to promonocyte and monocyte? What marker is lost in myeloid maturation but retained in monocytic maturation?
CD15 and CD14; HLA-DR
Which hematologic lineage does not express CD45? What is the earliest marker for these cells?
Erythroid; CD71 (transferrin receptor)
Which markers define the GPIIb/IIIa complex and are the first markers in megakaryocytic differentiation? Name three subsequent glycoprotein markers of maturation.
CD41 and CD61; CD42, CD62P and CD63
What cells do the following cytochemical stains target:
1) Sudan black B
2) NSE/α-Napthyl Acetate & α-Napthyl Butyrate
4) Chloroacetate esterase (CAE)
- 1) Stains myeloid lipid in granule membranes
- 2) Monocytes; acetate also stains megas
- 3) Lymphoblasts (blocks encircle nucleus like rosary beads - see picture above), Myeloblasts (diffuse, granular hue), and erythroblasts (esp AML M6b)
- 4) Granulocytes only
- 5) Primary azurophilic granules of granulocytes
What causes MPO stain degradation? What inhibits monocyte NSE activity?
Wet specimens; Sodium fluoride
What cytochemical stain can highlight the vacuoles of L3 ALL blasts?
Oil red O
Name 3 markers that may be aberrantly expressed in AML t(8;21)(q22;q22). Which one indicates a worse prognosis? What are the morphologic findings? What genes are translocated?
CD19, PAX-5, CD79a, coexpression of CD34 with CD15 (late devt marker), and CD56; CD56; pronounced azurophilic granularity, sometimes large Chediak-Higashi type granules and Auer rods; AML1 (encodes α chain core binding factor/CBFα) & ETO genes
In AML inv(16)(p13q22) or t(16;16)(p13;q22), what two cell types predominate? What genes are involved? What stain abnormally highlights one of the populations? What marker is often aberrantly expressed?
Myelomonocytic cells & abnormal eosinophils (basophilic granules)/equivalent to AML M4Eo; MYH11 (myosin) & CBFβ genes; α-naphthyl acetate esterase+ in BM (normally granules negative); CD2
What is the expression pattern for this acute leukemia with respect to CD34, HLA-DR and CD2? How do the peripheral blood findings differ?
More commonly express all of these stains; high leukemic count
In t(15;17)(q22;q21), what genes are involved? What three breakpoints are involved and what is their lengths? Which breakpoint is common in the microgranular variant (M3v)? How does it differ in clinical course and tx?
RARA & PML; bcr1 (intron 6) is long, bcr2 (exon 6) is variable and bcr 3 (intron 3); bcr3 is short, associated with M3v, shorter survival, and insensitive to retinoic acid
Which genetic mutations have a good prognosis for AML with normal karyotype? Bad prognosis? What is the relative frequency of these mutations?
NPM (50%) & CEBPA (15-18%) both good unless there's also FLT3 mutation!; FLT3 (30%)
Under the FAB classification, which AML types are PAS+? SBB-/MPO-? CAE+? NSE+?
- PAS+ = M5 to M7
- SBB-/MPO- = M0 (min diff), M5 (monos), M7 (megas)
- CAE+ = M2 to M4 (stains grans so more mature myeloids)
- NSE+ = M1 (50%), M4-5, M7+/- (stains monos and megas)
In FAB M0, which markers are typically negative due to lack of myeloid differentiation? Fewer than 3% are positive for which cytochemical markers? What marker is aberrantly expressed in up to 30%? What % of the blasts must stain with myeloid stains like MPO?
CD11b, CD14, CD15; SBB, MPO and NSE; TdT; 3%
Which AML FAB type mostly does not mature to the promeylocyte stage and are positive for SBB, MPO and CAE?
FAB M1 (without maturation)
How are blasts counted to reach the 20% threshold in AML M2 (with differentiation)? What chromosomal abnormality is associated with increased basophils?
myeloblasts are <89% of cells and promyelos represent 10% or more of nucleated cells; Chromosome 12p
How are blasts counted in AML M4?
- 1) >20% blasts overall (count myeloblasts, monoblasts and promonocytes); and
- 2) At least 20% of nonerythroid cells are monocytic (NSE+)
- 3) At least 20% of nonerythroid cells are myeloid (SBB+ or MPO+)
How are blasts counted in AML M5a? M5b?
- M5 overall: >20% blasts (monoblasts & promonocytes) + >80% of nonerythroids are monocytic (monoblasts, promonocytes and monocytes)
- M5a: >80% of moncytic cells are monoblasts (MPO negative)
- M5b: <80% monoblasts and more promonocytes
How are blasts counted in AML M6a? What is the cutoff for the erythroid precursors? How does it differ from M6b? What glycophorin marker is expressed in the neoplastic cells?
At least 20% of non-erythroids are myeloblasts; at least 50% erythroid precursors; M6b is at least 80% erythroid precursors (pure erythroid leukemia); CD235a
What is the morphology of M6b erythroblasts? How does it stain for PAS?
Vacuolated basophilic cytoplasm; block rosary bead staining
What are the criteria for AML M7? EM and IHC profile? Other associated neoplasm? Associated syndrome? What is the characteristic finding when doing a BM biopsy?
At least 20% blasts with at least 50% of these being megakaryocytic blasts; platelet peroxidase (PPO) technique with EM and by IHC CD41+, CD61+; mediastinal germ cell tumors with i(12p); Down syndrome; *dry tap from fibrotic marrow
How does ALL in Down syndrome differ from the normal type? AML?
Increased sensitivity to MTX tx, overall favorable prognosis; looks like AML M7, and highly sensitive to ctx
How can transient MPD in Down syndrome be distinguished from DS-related AML? What mutation do they share?
Arises in first wk of life, blasts CD11b and CD13 negative, no tx needed; GATA-1 gene mutation
What alternative RARα translocations are insensitive to ATRA?
5;17 (NPM/RARα) and 11;17 (PLZF/RARα)
Core binding factors are involved in which three hematopoietic malignancies?
inv16, 8;21, and t12;21 in B-ALL
What age group commonly has AML with 11q23 (MLL) abnormalities? In t(9;11)(p21;q23), what genes are fused? In B-ALL, t(4;11)? What cell type are the leukemic cells?
Children & young adults; AF9 with MLL; AF4 with MLL; monoblasts (M4 and M5)
What cell type is increased in t(6;9)(p23q34)? What other morphologic findings are found? What genes are fused? What does CBC show? 70% show what associated genetic mutation?
Basophils; multilineage dysplasia; DEK-NUP214; Pancytopenia with low WBC; FLT3-ITD (poor prog)
Which AML translocation looks like AML M7? What population does it affect and what is one characteristic physical finding? What do the megakaryocytes in inv(3)(q21q26.2) AML look like?
t(1;22)(p13q13) fusing RBM15 and MLK1; peds and organomegaly; atypical hypolobated megakaryocytes in BM
Which genes are fused in inv(3)? What marker is often aberrantly expressed? Prognosis?
RPM1-EVI1; CD7; poor
What are all the weird aberrant markers for the following AML mutations:
1) AML M0
- 1) AML M0: TdT (30%)
- 2) inv(3): CD7 (poor prog)
- 3) t(8;21): CD19, PAX5, CD79a, CD56, coexpression of CD34 with CD15
- 4) inv(16): CD2
- 5) AML t(15;17) with M3v: CD2
Which AML is found in patients w/h/o Topoisomerase II inhibitors?
AML with 11q23 (MLL)
Which ALL morphology type constitutes 60% of adult ALL and looks similar to AML blasts?
L2 (L1 in 85% of all childhood ALLs)
All of the following are poor prognostic indicators for ALL except:
A) Markedly increased WBC
B) Age <1 or >10yo
D) t(9;22), hypodiploidy, and t(4;11)
E) hyperdiploidy and t(12;21) with TEL-AML1 rearrangement
E - this is a good prognosis
What is the earliest lineage specific B-cell marker? What two markers can be aberrantly expressed?
CD19; CD13 or CD33
What are all the weird aberrancies for the following ALL mutations:
- 1) t(1;19) characteristic immunophenotype of CD9+/CD10+/CD19+ with CD34-, CD20-
- 2) t(4;11)(q21;q23): CD10- and myeloid antigens (CD15+)
- 3) t(9;22): myeloid markers
Which chromosomal abnormalities have a favorable prognosis with ALL?
t(12;21)/TEL-AML1 and hyperdiploidy (>52 chromosomes)
What is the predominant ALL cell type in lymphoblastic lymphomas? Where does it typically present? What defines leukemia?
T-ALL; mediastinal (associated with hypercalcemia), LN, skin, liver, spleen, etc.; >25% blasts in BM
What markers can be aberrantly expressed in T-ALL?
CD10, CD13, CD33, and rarely CD117 or CD79a
What markers are most often positive in T-ALL?
cCD3 and CD7
What cytogenetic abnormalities are involved in T-ALL? Any translocations?
- 1) All involve TCR:
- 14q11.2 in αδ
- 7q35 in β
- 7p15-15 in γ
- 2) t(7;9) in <1% of cases - NOTCH1 under control of TCRβ enhancer/promoter
- 3) Partner genes: Myc (8q24), TAL1 (1q32), RBTN1 (11p15), RBTN2 (11p13), HOX11 (10q24)
- 4) NOTCH1 activating mutations present in >50% of T-ALLs (GOOD PROGNOSIS)
What are the defining markers for the myeloid, monocytic, T-cell, and B-cell lineages?
- Myeloid: MPO
- Monocytic: at least two of these: CD11c, CD14, CD64, NSE, lysozyme
- T-cell: cCD3 or sCD3
- B-cell: PAX5 (most sensitive and specific marker and present in precursor B cells), strong CD19 or weak CD19 + at least two of these: CD10, cCD79a, cCD22
What marker(s) are most specific for AML? What % of AML have anomalous T-cell Ag expression (CD4, CD5, and CD7 most commonly)? What % have B-cell Ag (usu CD19) expression?
CD13, CD33, and most specific is CD117 (nearly 100% specific); 20-40%; 10-20%
In t(9;22)(q34;q11), what size protein results from the major breakpoint for CML? ALL?
Which ALL chromosomal abnormalities result in a favorable prognosis? Unfavorable?
- Favorable: t(12;21), hyperdiploidy
- Unfavorable: t(9;22), t(1;19), 11q23 MLL, and hypodiploidy
What is the mutation and frequency of that mutation in MPDs? What chromosome is the mutation on?
Jak2 is Janus kinase with valine to phenylalanine substitution (V617F); >80% PV, ~50% in ET and PMF; chrom 9p
What are the peripheral blood findings in the following MPDs:
- 1) Polycythemia +/- leukocytosis (neutrophilia or basophilia) and +/- thrombocytosis +/- teardrops in fibrotic spent phase
- 2) Thrombocytosis
- 3) cellular phase: anemia, mild leukocytosis, mild thrombocytosis; fibrotic phase: leukoerythroblastosis + teardrop cells
What are important BM findings in PV?
- Initial phase: panmyelosis (myeloid metaplasia), hypercellular, low M:E, megakaryocyte hyperplasia
- Spent phase: peripheral myelophthisic pattern, fibrosis, extramedullary hematopoiesis
How do BM findings differ btw ET and PMF?
- ET: increased mature, hyperlobated megas in clusters and paratrabecular, marked emperipolesis, NORMOCELLULAR and NO FIBROSIS
- PMF: cellular stage with hypercellularity, increased & abnml megas; fibrotic phase: fibrosis, intrasinusoidal hematopoiesis, increased abnml & clustered megas, osteosclerosis
In CML, what is the functional result of the translocated BCR-ABL product? What physical finding is common? What is the rate of progression to acute leukemia?
Enhanced tyrosine kinase activity; splenomegaly; 95% within 3-7 yrs
How is the chronic phase of CML characterized?
- PB has leukocytosis with increased neuts at various stages, myelocyte "bulge" basophilia, eosinophilia, thrombocytosis, blasts <1%, low LAP score
- BM: hypercellular with ↑M:E and immature cells esp at paratrabecular cuff, myelocyte "bulge," ↑ micromegas with hypolobation & clustering, fibrosis, Gaucher-like sea blue histiocytes d/t ↑ turnover
What defines the accelerated phase of CML?
- ≥1 of the following:
- 1) progressive basophilia (>20%)
- 2) thrombocytopenia (<100x109/L) or thrombocytosis (>1000x109/L)
- 3) Leukocytosis
- 4) Clonal cytogenetic progression (Ph chrom + other like trisomy 8, i(17q), trisomy 19, other Ph, etc.)
- 5) ≥10% blasts but <20%
- *Also tendency for ↑LAP score
What does an increased LAP score indicate in a PB with leukocytosis?
Leukemoid rxn (CML has low LAP score)
How and polycythemia vera be distinguished from Gaisbock syndrome? 2nd causes of polycythemia (high altitude, smoking)? other neoplasms?
- Gaisbock is relative polycythemia in setting of stress or dehydration
- 2nd causes: low PaO2 states
- Other neoplasms: ↑EPO
What are the defining features of CMML that differ from CML?
- 1) No Ph chromosome
- 2) Persistent monocytosis in PB (>1x106/mL) but normal morphology
- 3) <20% blasts
- 4) Marrow dysplasia
How is atypical CML different from classic CML?
- 1) No Ph chrom
- 2) No monocytosis
How is juvenile myelomonocytic leuk different from CML?
- 1) No Ph chrom but other chrom abnml (esp monosomy 7)
- 2) ↑Hb F
- 3) No monocytosis
- *Both have monocytosis and/or granulocytosis
What disease has JMML in almost 10% of patients?
What in vitro test confirms the dx of JMML?
Formation of granulocyte-mac colonies that are hypersensitive to GCSF
What is the genetic abnormality in CMML with eosinophilia?
t(5;12) with TEL gene on chrom 5
What is the prognosis of JMML?
What is the likelihood of MDS progression to acute leukemia? What is the typical cause of morbidity?
All of the following MDS-related cytogenetic abnormalities have a good prognosis except:
A) loss of Y
B) del 5q
C) del 7q
D) del 20q
What is the most common cytogenetic abnormality in MDS and what is its prognosis? 2nd and 3rd most common?
Complex (2+ abnmls) constitutes 25% of cases with poor prognosis; monosomy 7; 5q- (good prognosis)
What percent blasts can be found in the PB and BM of pts with RAEB 1 MDS? RAEB 2?
- RAEB1: <5% PB, 5-9% BM
- RAEB2: 5-19% PB, 10-19% BM
What percent dysplasia must be seen in the BM for MDS? What percent ringed sideroblasts are required for RARS? What are the criteria for ringed sideroblasts?
≥10%; ≥15%; at least 10 siderosomes that surround at least 1/3 of nucleus
What plt aggregation defect is seen in all MPDs? What vitamin level is elevated in CML?
Impaired aggregation with epi; B12
What acute monocytic leukemia has a translocation that is associated with erythrophagocytosis and what genes are involved?
All of the following AML chromosomal abnmls have a poor prognosis except:
D) abn (3q-)
A - this is megakaryoblastic leuk and is the AML associated with Downs, which is responsive to tx
Hematopoietic disorders that have fibrotic marrow with dry tap?
MPD or idiopathic myelofibrosis, Acute megakaryoblastic leukemia, hairy cell leukemia, CML (+ metastatic carcinoma but not part of the Q)
Dysgranulopoiesis in CML has a strong association with what chromosome abnormality? What does this herald?
17p; accelerated phase
What does leukocyte alkaline phosphatase (LAP) hydrolyze? What is the nml range? What conditions cause elevated LAP scores? Decreased LAP scores?
- Naphthol-AS-biphosphate; 40-120
- Increase: MPD, glucocorticoids, leukemoid rxn, 3rd trimester pregnancy
- Decrease: CML, PNH, MDS, neonatal septicemia, congenital hypophosphatasia
Dx? How can it be distinguished from villous lymphos of splenic marginal zone lymphoma?
HCL: fine circumferential cytoplasmic hairy projections; splenic marginal zone has prominent nucleolus
Rheumatoid arthritis pts can sometimes show increased B-cells w/ what phenotype?
CD1a stains all of the following except:
B) Touton GCs
C) Interdigitating reticulum
D) Cortical thymocytes
E) dendritic reticular cells
T/F: CD4-/CD8- cells are most often associated with a neoplastic condition.
These malignancies all have what positive marker in common: Ewing's, Lymphoblastic lymphoma, Granulosa Cell tumor, Synovial Sarcoma, rhabdomyosarcoma, solitary fibrous tumor
CD99 is positive
Surface CD3 expression appears along with what T cell marker?
T cell receptor on the cell surface (cytoplasmic CD3 indicates less mature T, and is restricted to the cytoplasm)
What is the order of heavy chain domain assembly? What domain on the heavy chain is not found on the light chain?
DJ, then add V; D domain (no diversity domain)
All of the following MDS-related cytogenetic abnmls have a good prognosis except:
B) single chrom abnmly
E) complex cytogenetics
What translocation is in CMML with eosinophilia?
JMML shows what typical mutation? What would Hb electrophoresis show? Peripheral blood? Responsiveness to GM-CSF? Other dz associated with this?
Monosomy 7; Increased Hb F; anemia and thrombocytopenia; hypersensitive to GM-CSF; NF1
LGL leukemia typically p/w what additional peripheral smear finding?
What does abnormal localization of immature precursors (ALIP) refer to?
Clusters of immature cells away from marrow trabeculae or vessels - indicates strong propensity for leukemia
What gene product is associated with chronic neutrophilic leukemia?
Are blasts normal in an infectious process with neutrophilia?
Hell to the NO!
What is the classic CBC finding in HCL?
Pancytopenia, especially monocytopenia
What is the most sensitive marker of AML?
What is the rate of progression to MM in MGUS?
What do MPDs show in plt aggregation studies?
impaired aggregation w/epinephrine
What leukemia can cause elevated Vit B12 levels?
What is the expression pattern w/respect to HLA-DR and CD34 in the microgranular variant of APL? What variant shows increased expression of these markers?
Negative for both; M3 variant
Most common congenital AML (presenting within 1 mo of birth)?
What markers are associated with neoplastic mast cell disorders?
CD25 (associated with c-kit mutations) and aberrant CD2
What defines morphologic AML remission?
<5% blasts (unless they have abnormalities)
What lymphomas have a fried egg appearance with pale cytoplasm and centrally located nucleus?
Hairy cell in BM (diffuse infiltrate) & some cases of small cell variant of ALK+ ALCL
What is the unique IHC pattern in T-PLL?
CD2+, CD3+(sts wk), CD7+, CD52+ (target of tx) with 60% CD4+/CD8-, 25% CD4+/CD8+, 15% CD4-, CD8+
How does the immunophenotype of aggressive NK leukemia differ from NK/T-cell lymphoma? Cytogenetically?
- Similar except aggressive NK leukemia is also CD16+ in 75% of cases
- aggressive NK leukemia: 7p-, 17p-, 1q+
- NK/T: 6q-
How does splenic marginal zone differ from other sites?
No t(11;18), no BCL-2 rearrangements, have allelic loss of 7q in 40%
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