Hematologic Malignancies I (part 2) Flashcards
1
Q
What is the most common form of acute leukemia in adults?
A
AML
2
Q
There are 14+ subtypes of AML. Four of these are classified by genetics alone, regardless of blast count. What are the three we need to know?
A
- t(8,21)(q22:q22): RUNX1-RUN1T1
- inv(16)(p13.1:q22) or t(16, 16)(p13.1:q22) CBFB-MYH11
- t(15,17)(q22;q12) PML-RARA
3
Q
There are 14+ subtypes of AML. Four of these are classified by genetics alone, five are classified by different criteria. What is it?
A
5 subtypes with characteristic cytogenetic findings and >20% Blast count
4
Q
What is AML with t(8,21)(q22:q22)?
A
Fusion protein of two transcription factors (RUNX1-RUN1T1). 5% of AML cases
It’s a dominant negative repressor of myeloid maturation
5
Q
Is AML with t(8,21) class 1 or 2 mutant?
A
Class II that requires concurrent class I mutation
6
Q
Does AML with t(8,21) present in kids or adults typically?
A
Younger pts/kids
7
Q
What is the morphology of AML with t(8,21)?
A
Some maturation to myelocytes. Occasional crystallization of granule contents (Auer rods)
8
Q
What is the immune phenotype of AML with t(8,21)?
A
CD34, HLA-DR+, CD13, CD33 weak
9
Q
What is the prognosis of AML with t(8,21)?
A
Good response to chemo
10
Q
What is AML with t(15,17)?
A
Fusion of two transcriptions factors PML with RARA (retinoic acid receptor). 5-8% AML cases
11
Q
What is the result of the AML with t(15,17) fusion protein?
A
Dominant neg. blockade of normal RARA. Inhibits granulocyte differentiation
12
Q
Why is AML with t(15,17) a good example of hoe genetics lead to clinical utility?
A
PML-RARA itself can be blocked with RA analogue (All Trans Retinoic Acid or ATRA) which results in ATRA inducing differentiation of the blasts to granulocytes -> Clinical Remission
13
Q
What class mutation is AML with t(15,17)?
A
Class II that requires concurrent class I
14
Q
What is the clinical presentation of AML with t(15,17)?
A
DIC. Severe thrombocytopenia
15
Q
What is the morphology seen in AML with t(15,17)?
A
Big blasts, cleaved “bat wing” nuclei, many cytoplasmic granules, Auer rods in stacks
16
Q
What is the immunophenotyping of AML with t(15,17)?
A
Weak/absent CD34, HLA DR, CD13, CD33
17
Q
What is the prognosis of AML with t(15,17)?
A
Good, if diagnosis can be made
18
Q
Can translocations to RARA from other places produce the same leukemia [AML with t(15,17)]?
A
Yes. BUT, they may not respond to ATRA
19
Q
What is AML with inv(16) or t(16,16)?
A
Fusion protein of transcription factor (CBFB) with MYH11. 5-8% of AML cases
20
Q
What class is AML with inv(16) or t(16,16) in?
A
Class II that probably requires concurrent class I
21
Q
Does AML with inv(16) or t(16,16) present clinically in kids(younger pts) or adults?
A
Younger pts/kids
22
Q
What is the morphology of AML with inv(16) or t(16,16)?
A
Mixed granuloctye-monocyte feature (myelomonocytic). Increased Eosinophils in blood and bone marrow
23
Q
What is the immunophenotype of AML with inv(16) or t(16,16)?
A
CD34, CD17 (blasts), CD13, CD33 (granulocytes), CD14, CD11b (monocytes)
24
Q
What is the prognosis for AML with inv(16) or t(16,16)?
A
Variably poor; optimal with high dose cytarabine
25
What is the clinical presentation of AML with normal cytogenetics?
Any age group. 40-50% of cases. They can trend toward any morphologic type (granulocytes, monocytes, red cell precursors. megakaryocytes)
26
What is the morphology of AML with normal cytogenetics?
Undifferentiated or variably granulocytic or monocytic/monoblastic
27
What is the immunophenotype of AML with normal cytogenetics?
Blast markers (CD34, CD117). Can show any lineage markers
28
What is the prognosis of AML with normal cytogenetics?
Depends on the molecular genetics
29
What is the prognosis for AML with normal cytogenetics in individuals who have NPMN1 or CEBPA+, FLT3-ITD-?
60% 4 yr survival. BM transplant doesn't help
30
What is the prognosis for AML with normal cytogenetics in individuals who have FLT3-ITD+ or NPMN1-, CEBPA-, FLT3-ITD-?
About 29% 4 yr survival. BM transplant helps
31
For ALL, are two classes of mutations/translocations required?
Maybe. What is known is that there are a number of transcription factors which regulate early B cell development that are involved in the genesis of ALL
32
What are some key markers of early, middle, and late B cell development? Which myeloid markers can they express?
CD34, Tdt, CD19, CD10, muCD20. They can express myeloid markers CD13, CD33
33
Are the myeloid markers expressed in ALL a major contributor to clinical management?
No
34
What is the clinical presentation of ALL?
75% of ALL cases occur in kids under 6. There is about an 80% cure rate in kids, but 50% for adults
35
What is the primary determinant for the clinical management of ALL?
Genetic characterization
36
What is ALL with t(9,22)?
```
Fusion protein of part of a serene kinase (BCR) to a tyrosine kinase (ABL1); Proliferation activator (class II equivalent)
The IKZF1 transcription factor is mutated in 84% of cases; differentiation inhibitor (class I equivalent)
```
37
What is the clinical presentation of ALL with t(9,22)?
Older adults (25% of ALL cases); kids ,1 (2-4% of peds ALL)
38
What is the morphology of ALL with t(9,22)?
Big agranular blasts
39
What is the immunophenotype of ALL with t(9,22)?
CD10, CD19, Tdt
40
What is the prognosis of ALL with t(9,22)?
Poor
41
What is ALL with t(v;11q23); MLL rearranged?
Fusion of a transcription regulator (histone methyl transferase) to any of several partners. Inhibits differentiation (equivalent of class II mutation). Also found in AML
FTL4 mutation in 20% of cases (known class II mutation in AML)
42
What is the clinical presentation of What is ALL with t(v;11q23)?
Most common leukemia in kids <1
43
What is the morphology of What is ALL with t(v;11q23)?
Big agranular blasts
44
What is the immunophenotype of ALL with t(v;11q23)?
CD10-, CD19+, TdT+
45
What is the prognosis of ALL with t(v;11q23)?
Poor
46
What is ALL with t(12, 21)(p13,q22) TEL-AML1 (ETV6-RUNX1)?
Fusion protein that acts as a dominant neg. transcription factor. Inhibits differentiation (equivalent of a class II mutation).
47
28% of ALL with t(12, 21) show what other deletion?
Pax5 deletion (predicted to inhibit differentiation)
48
What is the clinical presentation of ALL with t(12, 21)?
Kids. 25% of pediatric B-ALL
49
What is the morphology of ALL with t(12, 21)?
Big agranular blasts
50
What is the immunophenotype of ALL with t(12, 21)?
TdT+. CD34+, CD20-
51
What is the prognosis of ALL with t(12, 21)?
Good. 90% cure rate
52
Is genetics currently a good clinical guide to the management of T-ALL?
Nope
53
What results in a comparable survival rate to B-ALL with kids?
More intense chemotherapy regimen
54
Genetically, what do most T-ALL have?
Translocation of an oncogene to a T-cell receptor promoter, 3 TCR loci, multiple possible partners
55
What is a common motif for lymphoid malignancies?
Oncogenes translocating to Ig or TCR promoter
56
What is the clinical presentation of T-ALL?
25% of pediatric B-ALL. Often with thymic mass, or lymph node/spleen involvement
57
What is the morphology of T-ALL?
Big agranular blasts
58
What is the immunophenotype of T-ALL?
TdT+, CD3+, CD5+, can express myeloid or B cell antigens as well
59
What is the prognosis for T-ALL?
High risk
60
What's the basic definition of a myeloproliferative disease?
Chronically proliferating clones which differentiate to circulation blood cells
61
What is the prototype myeloproliferative disease?
CML
62
What are some basic characteristics of CML?
High WBC. All stage of granuloctyes end up in the blood
63
What is a less well understood condition that can show both myelpdysplastic and myeloproliferative features?
CMML
64
What are some basic characteristics of CMML?
High WBC. Monocytes, promonocytes, and weird hybrids between monocytes and granuloctyes
65
What are the two diagnostic categories that distinguish between two types of myeloproliferative neoplasm which both present with an elevated eosinophil count?
Chronic eosinophilic leukemia (CEL) or PDGFR neoplasm.
66
Do CEL and PDGFR neoplasms respond the same to different therapies?
No. Reason for why they are in different categories
67
Aside from increases eosinophils, what other things can be seen with an increase?
Increased mature neutrophils and increase mast cells
68
What is Increased mature neutrophils?
Chronic neutrophilic leukemia (rare)
69
What is increased mast cells?
Mastocytosis, which often presents outside the bone marrow and lymph nodes, but in most cases the BM is also involved
70
What is the name of myeloproliferative diseases of the erythroid lineage?
Polycyathemia Vera
71
What is the name of myeloproliferative diseases of the megakaryocyte lineage?
essential thrombocythaemia or primary myelofibrosis.
72
What is condition often presents with myeloproliferative diseases of the megakaryocyte lineage?
Thrombosis
73
What is a high WBC count with lots of granulocytes and many granulocyte precursors indicative due to most commonly?
Infection, like pneumonia
74
On examining a peripheral blood smear, you see toxic granulations and left shift composed mostly of progressively fewer cells representing more immature precursors. What's your likely diagnosis?
Infection, sepsis
75
What if you see a patient with elevate WBC, no evidence of toxic granulations, and more myelocytes than metamyelocytes?
More likely pt. has a myeloproliferative neoplasm
76
What would the bone marrow look like in a patient with CML?
Hypercellularity with many myeloid precursors, and a little in the way of dysplasia, and no increase in blasts
77
How would currently make the diagnosis for CML?
Order an RT-PCR assay for the BCR-Abl1 fusion protein from peripheral blood
78
Why is CML the model of biomedical research?
1960. Identified an abnormal chromosome "Ph"
1973. Identify the translocation t(9,22)
1982. Identify the fusion protein (BCR-Abl)
1998. Find an inhibitor of the kinase (imatinib)
With a clinical result of >90% complete hematologic response and 70-90% complete cytogenetic response.
79
B/c CML is treatable, you should have a low threshold of suspicion for sending RT-PCR. How many should you send?
Enough so that you get more neg. results than positives
80
If you suspect CML and get a RT-PCR, what should your next step be?
BM biopsy (10% of pts show normal cytogenetics)
81
Why do you need a BM in pts. with suspected CML?
Because pts. can progress to an accelerated phase, with increased blasts in the marrow, or to a "blast" phase that is essentially the same as an acute leukemia (usually myeloid, but sometimes lymphoid)
82
What is becoming a common motif in myeloproliferative neoplasms?
Increased activity of a tyrosine kinase, whether from a fusion protein or due to a pt mutation
83
Do other myleoproliferative neoplasms with tyrosine kinase translocations respond to Imatinib?
Yesh
84
Are more drugs that inhibit specific kinases like Jak2 likely to emerge?
Yes
85
How does Jak 2 work?
It operates downstream of other cellular receptors like the thrombopoietin receptor(MpI) in in megakaryocytes
86
What is the main function of mast cells?
Release of histamine, after IgE receptor cross links
87
What plays a big role in the growth and migration of mast cells?
SCF
88
How do neoplasms of mast cells usually present?
Benign cutaneous lesions in kids ( most common being uticaria pigmentosa). They usually don't spread beyond the skin
89
When mastocytosis neoplasms spread beyond the skin, how do they present?
Histamine release causing symptoms of flushing, abdominal pain,tachycardia, hypotension
90
Where is the most common site of mastocytosis systemic involvement?
Bone marrow. Other organs that can be involved are lymph nodes, spleen, liver
91
What are the BM findings in mastocytosis?
Bland looking cells, round, or spindle shaped. 30% associated with a secondary hematologic malignancy
92
What are the genetics associated with mastocytosis?
cKIT mutations or PDGFRA activation (FIP1 translocation)
93
What is the clinical presentation of mastocytosis?
Variable and confusing
94
What is the morphology of mastocytosis?
aggregates of bland looking cells, round or spindle shaped, sometimes with eosinophils
95
What is the immunophenotype of mastocytosis?
Tryptase, CD117 (cKIT, the SCF receptor), CD25
96
What is the prognosis of mastocytosis?
Highly variable, depends on a complex sub classification scheme
97
What is the mutation in polycythemia vera?
Jak2 in >95% of cases, detectable in peripheral blood leukocytes
98
What is the clinical presentation of What is the morphology of polycythemia vera?
Thrombosis, HTN, stroke, or MI. Increases RBCs can also be seen due to lung disease
99
What is the morphology of polycythemia vera?
Hypercellular marrow, erythroid hyperplasia, increased megs
100
What is the immunophenotype of polycythemia vera?
None known
101
What is the prognosis of polycythemia vera?
10 yr survival is common. Can progress to myelofibrosis, MDS, acute leukemia
102
For the overlapping myeloproliferative neoplasm( polycythemia vera, essential thrombocythemia, and primary myelofibrosis) what differential diagnostic characteristics distinguishes the three neoplasms?
Polycythemia vera: increases RBCs, complication=HTN, thrombosis
Essential Thrombocythemia: Increases platelets, complication=thrombosis
Primary myelofibrosis: increases platelets, complication=thrombosis
103
What mutation is found in essential thrombocythemia (ET)?
Jak2 in about 50%
104
What is the clinical presentation of ET?
Thrombosis, increases platelets; can also be due to Fe deficiency, infection, and chronic inflammation
105
What is the morphology of ET?
Increases Megs, they're large and extra weird looking and tend to cluster
106
What is the immunophenotype of ET?
None known
107
What is the prognosis of ET?
>10 yr survival is common, can progress to myelofibrosis, MDS, acute leukemia
108
What is the pathogenesis of primary myelofibrosis (PM)?
Pathogenesis poorly understood, unknown percentage of Jak2 mut. involvement. A reticulin stain shows more reticulin fibers in PM than ET
109
What is the clinical presentation of PM?
Thrombosis, thrombocytosis, and/or leukoerythroblastic picture
110
What is the morphology of PM?
Increased Megs, bizarre shapes, clustering, fibrosis
111
What is the immunophenotype of PM?
None known
112
What is the prognosis of PM?
Usually shorter survival than ET. Can progress to marrow failure, acute leukemia
113
What is myleodysplasia?
Poorly functioning clones. Usually present as unexplained cytopenia, bicytopenia, or pancytopenia
114
What is the criteria for being in the myleodysplasia category?
They're poorly understood and lumped together because they have similar presentations. Some have high risk for progressing to acute leukemia while others dont
115
What are the key diagnostic features of myleodysplasias (MDS)?
Abnormal "dyspoietic" BM
Abnormal immunophenotypes of maturing precursors
Abnormal cytogenetics
Increases morphologic blasts (>5%, <20%)
116
What are the 5 major adult forms of MDS (best to worse prognosis)
1. Refractory cytopenia with unilineage of dysplasia
2. Refractory anemia with ring sideroblasts
3. Myelodysplastic syndrome with isolated del 5(q)
4. Refractory cytopenia with mutilineage dysplasia
5. Refractory anemia with excess blasts
117
What is ped. MDS?
Rare and complex
118
What does the diagnosis of Refractory cytopenia with unilineage of dysplasia depend on?
Morphologic findings Nonspecific cytogenetic abnormalities may be present. See weird looking precursors, binucleation or irregular nuclei, can show fibrosis, high or low cellularity, megaloblastoid features
119
What is the clinical presentation of Refractory cytopenia with unilineage of dysplasia?
Unexplained cytopenia , usually pta. over 65
120
What is the immunophenotype of Refractory cytopenia with unilineage of dysplasia?
Can show abnormal acquisition of surface markers
121
What is the prognosis of Refractory cytopenia with unilineage of dysplasia?
Survival not clearly less than normal for the age group; rare progression to AML
122
What is the key morphologic feature of Refractory anemia with ringed sideroblasts?
Fe; ringed sideroblasts present (red cell series only)
123
What's a key feature of MDS with isolated del(5q)?
All of the Megs are mononuclear. Cytogenetics shows only loss of large arm of chromosome 5
124
What is the clinical presentation of MDS with isolated del(5q)?
Anemia, often severe. Usually elderly pts., more often women
125
What is the prognosis of MDS with isolated del(5q)?
Good median survival, treatable with lenalidomide. 10% progression to AML
126
What is the morphology of MDS with del(5q)?
All of the Megs are mononuclear
127
What is refractory cytopenia with multilineage dysphasia?
Two or more lineages show dysplastic changes. About half show nonspecific cytogenetic abnormalities
128
What is the clinical presentation of refractory cytopenia with multilineage dysphasia?
Anemia often severe, usually elderly pts.(>65) often women
129
What is the morphology of refractory cytopenia with multilineage dysphasia?
Granulocytes (if affected); don't granulate normally, nuclei don't lobulate normally
130
What is the immunophenotype of refractory cytopenia with multilineage dysphasia?
Can show abnormal acquisition of surface markers
131
What is the prognosis of refractory cytopenia with multilineage dysphasia?
Median survival 30mo, 10% progress to AML in 2 yrs
132
What is refractory anemia with excess blasts?
5-10% morphologic blasts (RAEB-1)
10-20% morphologic blasts (RAEB-2)
About half show non specific cytogenetic abnormalities
133
What is the clinical presentation of refractory anemia with excess blasts?
Cytopenias, usually elderly patients (over 65)
134
What is the morphology of refractory anemia with excess blasts?
Blasts and dyspoeitic maturation
135
What is the immunophenotype of refractory anemia with excess blasts?
Blast population, CD34 and CD117 usually evident
136
What is the prognosis of refractory anemia with excess blasts?
RAEB-1: 25% progress to AML
| RAEB-2: 33% progress to AML
