Hematologic Malignancies Total!!! Flashcards
When did cytogentics studies beging?
1970
What did reed and sternberg do and when?
1898 and 1902
found a cell/ histoloic correlation with Hodgkins lymphoma, R/S cells
-large binucleated cells
What are 5 morphologic characteristics of a blast cell?
1) big cell
2)high nuclear / cytoplasmic ratio
3) immuature chromatin
4) big nucleus
5) bunch of cells that look alike
(may not have all 5)
What should the ratio of myeloid cells to erythroid prcursors be?
2:1
what is the percentage of Blast cells that should be in the PB?
<5%
What can BM biopsies give you an indication of?
iron stores
erythroid, myeloid, adn megakaryocyte lineages
What are the B-Cell markers?
CD45 CD79a CD20 Kappa Light chain or Lamba light chain
What are the T-cell markers?
CD45 CD3 (TCR) CD7 CD4 or CD8
What does the expression of CD34 mean?
BLSAT CELL!
What does the expression of CD33 mean?
Granulocytes– myeloid blasts
What is routien cytogenetics?
identify an enumerate the chrs present in dividing cells
- use growth medium and arrest cells in mitosis
- squash cells onto slide
- stain
What is the philadelphia CHR and what does it mean?
abnormal CHR 22
- t(9;22) characteristic of CML
- founded by Janette Rowely 1973
What is Florescent in situ Hybridization?
protease digestion
- red or green tag
- prob to a specific gene and or chr
What are class I mutations?
promoting proliferation ext AML: -FLT3-TID FLT3-TKD Kit RAS PTRNII Jak2
What are class II mutations?
inhibiting differentiation exp: AML -PML-RARA RUNX1-RUNX1T1 CBFB-MYHII MLL Fusion CEBOA NPM1
What are acute Leukemias?
rapidly proliferating clones of BLAST cells in marrow and ofen in blood stream
- can arise from myeloid, erythroid, MEGs, or lymphocyte lineages
- look normal but ^ in #
What are myeloproliferative diseases?
chronically proliferating clones which differnetate for circulating blood cells
- can arise from myeloid, erythroid, MEGs, or lymphocyte lineages
- look normal but ^ in #
What are Myelodysplastic syndromes (MDS)?
Poorly functioning clones
- can arise from myeloid, erythroid, MEGs, or lymphocyte lineages
- look normal but ^ in #
What cells are likely to defferentiate adn go toward AL?
myeloproliferative and myleodysplastics
What cell lineage does AML arise from?
myeloid leange of rapidly prolerating clones: BLASTs in marow and oftern blood stream
-can also arise from megs, erythroids, and meyloid
What cell lineage does ALL arise from?
-lymphocytes (naive) rapid proliferating clones: blasts in marrow and often in blood stream
What cell lineage doe Acute undifferentiated Leukemia arise from?
heamtopoietic stem cells– very rare!
-rapidly proliferating clones: BLASTS in marrow and often, bloodstream
What is the arbitrary count that implies AL when in the marrow?
Blast # of 70%
What are the cell markers for myeloid blasts?
CD34 and CD33
What are the surface markers for lymphoid blasts?
CD19 and CD10
What is the common AML genetic translocation?
t(15;17) (q22;q12) PML-RARA t(8;21) (q22;q22) RUNX1-RUNXT1 inv16 cytogenetics - with FLT3 mutation
What are the common ALL translocations?
t(12;21) (q13;q22)
TEL-AML1
What are the things that go into makting a diagnosis?
1) blast coundt
2) blast morphology
3) immunophenotype
4) genetics
What is Gilland’s Hypothesis?
2 mutations needed to get cancer
1 from Class I and 1 from Class II
What are the characteristics of AML with t(8;21) (q22;q22) mutation?
Runx1-Runx1T1
- fusion protin of 2 TF (5% of AML cases)
- Dominant - repressor of myeloid maturation (class II muation)
- requires a class I mutation also
What are the clinical presentations of AML with t(8;21) (q22;q22) mutation?
younger pts (kids)
What are the cellular morphlogy of AML with t(8;21) (q22;q22) mutation?
some maturation to myelocytes
ocassional cyrstalization of granulocyte contents (auer rods- myeloperoxidase percipitates)
What is the immunophenotype of AML with t(8;21) (q22;q22) mutation?
CD34+
HLA-DR+
CD13+
CD33 weak!
What is the prognosis of AML with t(8;21) (q22;q22) mutation?
Good response to chemo!
What are the characteristics of AML with t(15;17) (q22;q12) mutation?
PML-RARA
-fusion of PML (TF) with RARA (TF -retinocic acid R)
-5-8% of AML cases
results in dominant - blockade of normal RARA, and inhibits granulocte differentiation
-requires a class I mutation
How can AML with t(15;17) (q22;q12) mutation be treated?
using an RA analoque to block PML-RARA itself using All trans retinoci acid (ATRA)
What are the clinical presentations of AML with t(15;17) (q22;q12) mutation?
DIC
Sever thrombocytopenia
What are the cellular mophologies of AML with t(15;17) (q22;q12) mutation?
big blast cleaved “Bat wing” nuclei
many cytoplasmic graules
Auer rods in stacks
What is the immunophenotype of AML with t(15;17) (q22;q12) mutation?
weak/absent CD34
HLA-DR
CD13
CD33
What is the prognosis of AML with t(15;17) (q22;q12) mutation?
good if make diagnosis
what are the B cell development markers?
CD34 and TdT are stem cells
CD19 and CD10 are lymphoid precursors
Cyto adn uCD20 are pre-B-cell
-they can also express myeloid markers CD13 and CD33
what are the main 2 TF that regulate early B-cell development?
IKZF1 and PAX5
What is TdT?
a marker for VDJ recombination of B and T cells
what are the genetic markers for ALL?
t(9;22) (q34;q11.2) BCR-ABL1 t(v;11q23) MLL rearranged t(12;21)(q13;q22) TEL-AML1 t(5;14) (q131;q32) IL3-IgH t(1;19) (q23;p13.3) E2A-PBx1 Hperdiploid (>50 chr) good prognosis Hyodiploid (<40 Chrs) poor prognosis
What are the characteristics of ALL with t(9;22) (q34;q11.2) mutation?
- BCR-ABL1
- fusion protein of part of a serine threonine kinase (BCR) to a tyrosine kinase (ABL1)
- class I mutation
- different size than seen in CML!!!!! so not a Philadelphia chromosome!
What are the clinical presentations of ALL with t(9;22) (q34;q11.2) mutation?
older adults (25% ALL cases) kides <1 (2-4 % of all peds ALL)
What is the cellular morphology of ALL with t(9;22) (q34;q11.2) mutation?
big agranular blasts
What is the immunophenotype of ALL with t(9;22) (q34;q11.2) mutation?
CD10+
CD19+
TdT
What is the prognosis of ALL with t(9;22) (q34;q11.2) mutation?
Poor :(
What are the characteristics of ALL with t(v;11q23) rearranged mutation?
- MLL rearranged
- fusion of a T regulator (histone methyl transferase) to any several partners
- inhibit differentiation
- class II mutation
- FLT3 mutation -20% of cases in ALL
What are the clinical presentations of ALL with t(v;11q23) rearranged mutation?
most common leukemia in kids <1
What is the cellular morphology of ALL with t(v;11q23) rearranged mutation?
big agranular blasts
What is the immunophenotype of ALL with t(v;11q23) rearranged mutation?
CD10-
CD19+
TdT+
What is the prognosis of ALL with t(v;11q23) rearranged mutation?
Poor :(
What are the characteristics of ALL with t(12;21) (p13;q22) mutation?
- TEL-AML1 (ETV6-RUNx1)
- fusion protein that acts as a dominant negative TF
- inhibits differentiation (class II)
- 23% show a PAX5 deleation - predictited to inhibit differentation
What are the clinical presentations of ALL with t(12;21) (p13;q22) mutation?
kids 25% of pediatric B-ALL
What is the celllular morphology of ALL with t(12;21) (p13;q22) mutation?
big a granular blasts
What is the immunophenotype of ALL with t(12;21) (p13;q22) mutation?
TdT+
CD34+
CD20+
What is the prognosis and txment of ALL with t(12;21) (p13;q22) mutation?
good :)!!!
90% cure rate
give loads of chemo!!!!!!
What are most of the T-ALL genetic muations?
a translocation of an ocogene to a T-cell receptor promoter
example: TCR-alpha;HOX11 t(14q11;10q24)
What is a common motife for lymphoid maligancies?
oncogene»» IG or TCR promoters
What are the clinical presenations of T-ALLs?
kides-25% of pedeatric B-ALLs
often with thymic mass or lymph node, spleen involments
What are the cellular morphologies of T-ALL
big agranular blasts
What is the immunophenotype of T-ALL
TdT+
CD3+
CD5++
-can express myeloid or B-cell antigens
What are myeloproliferative diseases?
from chronically proliferating clones which differentiate to circulating blood cells
What is CML?
Chronic Myelogenous Keukemia, from high WBC; All stages of granulocytes maturation ends up in blood
What is CMML?
chronic myelomonocytic leukemia
myleodysplastic/myleoproliferative
-high WBC monocytes, promonocytes, weird hybrids btn monocytes adn granulocytes
What do increased eosinophils cause?
chronic eosinophilic leukemia or PDGFT neoplasm
What do increased mature neutrophils cause?
chronic neutrophilic leukemia (quite rare)
What do increased mast cells cause?
mastocytosis (primarily tissue targeted)
-bone marrow usually involved
What is polycythemia vera?
elevated RBC count from the erythroid lineage
What is Essentail thrombocytopeina or primary myelofibrosis?
Elevated platelets from megs
What is the differance btn sepsis and myeloproliferative disease?
- both have ^ WBCs with lots of granulocytes
- toxic granulation and a left shit– Sepsis (infection) (bands>metamyelocytes> myelocytes
- pts with ^ WBCs but! not toxic granuations and mor myelocytes than meta myelocytes (myeloid bulge)–> myeloproliferatve neoplasm
What is important about sample testing for CML?
you should be sending more sample with - than + b/c it is an easy thing to identify and to treat if diagnosed!!!
How should a clinician work up a pt?
WL and night sweats–>CDC and maunal diff–> suspect CML–> TR-PCR of PS for BCR-ABL1–> BM biposy
What are the phases of CML?
chronic phase–>acclerated phase–> acute leukemia (myeloid or lymphoid)
What is common about myeloproliferative disease genetics?
Tyrosine Kinase RULE!!!
-many of these disease have a defect in an TK making it hyperactive
What are activating translocations of TKs, and what disease do they correcpond too?
BCR-ABL (CML) FIP1L1-PDGFRA (CEL) -vPDGFRB (5q33) (mastocytosis) (above respond to imatinib) vPDGFRB (3 partners identified) (CMML) --no response to imatinib
What are the activating pt. mutations and what disease do the correlate with?
Jak2 or MpI (ET in 5% of cases)
Jak2 (P.Vera in 95% of cases)
How does Jak 2 work?
it acts down stream of TK in megakaryocytes, and the thrombopoietin receptor (MpI) and mutation in MpI have been found to minic effect of Jak 2 mutations
-also downstream of EPOR, so cells can have EPO response with out EPO
What is mastocytosis?
mast cells are similar to basophils- but live loner,a nd non-circulatory
- main funtion is to release histamine, when their Fc receptor binds to IgE antigen complex
- A mitogen called SCF plays a big role in their growth and migration
- neoplasems of mast cells usually present as a benign cutaneous lesion in kids (urticaria pigmentosa)
- usually dont spread beyond skine (except when they do…..WHAT)
- in cases that release a lot of histamine and other mediators causeing systemic symptoms (flushing abd pain, tachycardia, hypotension) can confuse clinician
- bone marrow is most common site of systemic involvement, but multiple organs (lymph nodes, spleen liver) can e involved
What are the bone marrow findings in mastocytosis?
bland looking cells, round or spindle shaped
-30% are associated w/ a second hematolgic maligancy
What are the genetic of mastocytosis?
either cKit mutation or PDGFRA activation (FIP1 tranlocation)
What are the clinical presentations of mastocytosis?
variable and confusing
What are the cellular morphologies of mastocytosis?
aggregates of bland looking cells round or spindle shaped sometimes with eosinophila
What are the immuniophenotypes of mastocytosis?
tyrytase
CD117 (cKit, the SCF receptor)
CD25+
What is the prognosis of mastocytosis?
highly variable; depends on a complex subclassification scheme
What is plycythemia vera?
its pathologenesis is poorly understood
- Jak2 mutation in >95% of cases
- detectable in PBleukocytes
What is the clinical presentation of p. vera?
thrombosis/ hypertension/stroke or MI
^ RBCs- due to lung disease
What is the morphology of p. vera?
hypercellular marrow
erythroid hyperplasia
^ megs
what is the immunophenotype of p. vera?
no known features
What is the prognosis of p. vera?
> 10 yr survival is common
can progress to myelofibrosis
MDS
acute leukemia
What is the difference btn reactive and neoplastic?
- W^ RBCs
- Chest X-ray
- Hypoxic- not likely to be neoplastic
- EPO levels (^ if reactive)
- Jak 2 is distal to EPOR
What are the differential diagnosis for P.vera?
^RBCs
hypertension and thrombosis
What are the differential diagnosis for ET?
^ Platelets
Thrombosis
What are the differential diagnosis for Priamry myelofibroiss?
^ platelets
Thrombosis
What is essentail thrombocythemia?
pathogenesis poorly understood
Jak2 mutation in ~50% of cases
(decteable in PB leukocytes)
What can also cause an increase in platelets?
iron deficenty, infection, and chronic inflammation along iwth ET and Primary myelofibrosis
What are the cellular morphology in ET?
^ Megs – they are large!!! (2x size) and weird looking, even for megs, and tend to clusters
what are the immunophotypic markers for ET?
No known
What is the prognosis of ET?
> 10 yr survival is common
-can progress to myelofibrosis, MDS, AL
What is primary myelofibrosis?
previously agnogenic myeloid metaplasia pathogenesis poorly understood -Jak 2 mutation in ~50% of cases - detectable in PB leukocytes -Diagnostic criteria in dispute!!!
What is the clinical presentation of primay myelofibrosis?
thromboisis and thrombocytosis and or leukoerythroblastic picture
What is the celluar morphology in primary myelofibrosis?
^ meg- bizzare shape adn clusters
-fibrosis
What are the immunophenotypic markers for primary myelofibrosis?
No known!!! (like of the myloproliferative disesase)
What is the prognosis for primary myelofibrosis?
usually shorter survival tahn ET
-can progress to marrow failure, AL
What is myelodysplasia?
- poorly understood entities
- lumped together b/c similar presentations
- some have high risk to progress to AL
- poorly functioning cells
What are usually unexplaned in myelodysplasia?
cytopenia
bicytopenia
pancytopenia
What are the key diagnositic feature of myelodysplasias?
abnormal “dyspoietic” BM morpholies
abnormal “dyspoietic” immunophenotypes of maturing precursors
Abnormal cytogenetics
^ morphologic blasts (75%,<20%) with normal cytogenetis (if cytogenetics –AL)
What are the 5 mj. adut forms (best to worst)?
!)refractory cytopenia with unilineage dysplasia
2) refreactor anemia with ring sideroblasts
3) myelodysplastic syndrome with isolated del (5q)
4) refractory cytopenia with multilineage dysplasia
5) refreactory anemia with excess blasts
What is refractory cytopenia with unileange dysplasia?
- diagnosis depends on morphologic findings
- non specific cytogeneti abnormalities (trisomies and monosomines)
- hard if cytogenetics are normal
What are the clinical presentations of refractory cytopenia with unileange dysplasia?
unexplaned cytopeina
usually elderly pts. (>65yo)
What is the cellular morphology of refractory cytopenia with unileange dysplasia?
- weird looking precursors
- binucleation or irregular nuclei
- can show fibrosis high or low cellularity
- megaloblastoid features
What are the immunophontype markers of refractory cytopenia with unileange dysplasia?
-can show abnormal acquistion on surface markers
What is the prognosis of refractory cytopenia with unileange dysplasia?
survival not clearly less than normal for age rearely progress of AML
What is refractory anemia with ring sideroblasts?
diagnosis depends on morphologic finding and iorn staining results
nonspecific cytogenetic abnormaliteis (tir and monosomies) maybe present
What are the clinical presentations of refractory anemia with ring sideroblasts?
- unexplained cytopenieas
- usually elderly pts. (>65)
What is cellular morphology of refractory anemia with ring sideroblasts?
rig sideroblasts, usually with dyspoietic features (in red cell series only)
What are the immunophenotic markers in refractory anemia with ring sideroblasts?
-can show abnormal acquistion on surface markers
What is prognosis of refractory anemia with ring sideroblasts?
survival not clearly less than normal for age rarely progress to AML
What is MDS with isolated del (5q)?
- all the meakaryocytes are monocuclear
- cytogenetis chow only loss of the 1q arem of chr 5
What is clinical presentation of MDS with isolated del (5q)?
Anemia - often severe
-usually elderly pts (>65yo) - more often than women
What is cellular morphology of MDS with isolated del (5q)?
all the megs are mononuclear
What is immunophenotype of MDS with isolated del (5q)?
no known markers
What is prognosis of MDS with isolated del (5q)?
good median survial
txable iwth Lenalidomide!!!
10% progress to AML
What is refractory cytopenia with multilenage dysplasia?
-2 or more lineages show dysplastic changes
~1/2 show nonspecific cytogenetic abnormalities
What is the clinical presentation of refractory cytopenia with multilenage dysplasia?
anemia - often severe usually elderly (>65yo)- more often wo
What is the cellular morphology of refractory cytopenia with multilenage dysplasia?
granulocytes (if affected) dont granulate normally
neucli doint lobulate normally
What is the immunophenotype of refractory cytopenia with multilenage dysplasia?
can show abnomral auistion of surface markers
What is prognosis of refractory cytopenia with multilenage dysplasia?
mean survial 20 mo
10% progress to AML in 2 yrs
What is refractory anemia with excess blasts?
-5%-9% morpholoigic blasts (RAEB-1)
-10-19% morphologic blasts (RAEB-2)
~1/2 show nonspecific cytogenetic abnormalites
What is the clinical presentation of refractory anemia with excess blasts?
cytopenia
usually elderly pts (>65 yo)
What is cellular morphology of refractory anemia with excess blasts?
Blasts and dyspoietic maturation
What is immunophenotype of refractory anemia with excess blasts?
blast proluation os CD34+ or CD117+
usually evidant
What is prognosis of refractory anemia with excess blasts?
RAEB-1 25% progress of AML
RAEB-2 33%
POOR :(
