DDx Malignancies Flashcards
In diseases resulting from the following 3 translocations, which would you expect to increase the risk of uncontrolled bleeding?
- what pt. population would you expect to see any of these 3 diseases in?
- immunophenotype?
Diseases:
t(15,17) t(8,21) inv(16)
t(15,17) - PMF-RARA fusion prot.
• INCREASED RISK OF THROMBOCYTOPENIA
• ANY AGE GROUP
t(8,21) - RUNX1-RUNX1T1 and inv(16) CBF-MYH11
• Kids only
ALL have CD33, CD34 immunophenotype!
What 3 subtypes of acute MYELOID leukemia can be diagnosed by genetics alone?
- Causative Mutation and Pathophysiology
- Morphology
- What is the common result of these mutations, how does this tie into morphology?
3 Subtypes of AML (acute myeloid leukemia)
RUNX1-RUNX1T1 gene pdt. of t(8;21)(q22, q22)
• pathophysiology: disrupts CBFß histone acetylace (HAT) path is down regulated b/c RUNX1-RUX1T1/CBFß actives Histone Deacetylace (DHAT) - PREVENTS DIFFERENTIATION
• morphology: some maturation to myelocytes…Some Auer Bodies
PML-RARA gene pdt. of t(15;17)(q22; q12)
• pathophysiology: normally RARA is preventer of Differentiation (in granulocytes) binding of Retinoic Acid pulls RARA off DNA and allows for transcription. PML works on nuc. localization. Fusion prot. binds DNA and PREVENTS DIFFERENTIATION without inhibition of Proliferation
• morphology: Big Blasts with BAT winged nuclei and AUER RODS
CBFß-MYH11 gene pdt. of inv(16)(p13.1;a22)
• pathophysiology: CBFß has normal function as described above, CBFß-MLL combines with RUNX1 to co-repress transcription of genes. PREVENTS DIFFERENATION
• morphology: monomyelogenic (granulocyte and monocyte properties)
Common theme is prevention of differentiation, this explains the cells looking a bit BLASTIC
Which leukemia could be potentially be treated by eating excessive amounts of carrots, liver, and apple juice?
Promyelocytic Leukemia (PML-RARA, t(15,17)) **PML - kill switch is K160, activated by ArO3, a contaminant common in apple juice - cause ubiquitination and degradation of PML
**RARA - unbound from DNA by binding ATRA (all-trans retinoic acid)
ALLOWS FOR CELL DIFFERENTIATION
Would you ever expect to see Auer Bodies in an Acute Lymphoblastic Leukemia?
• Why or Why not?
NO, Auer bodies are not associated with LYMPHOblastic leukemia, they ARE associated with MYELOCYTIC leukemias
WHY?
• Auer bodies are made from MPO, a protein essential to GRANULOCYTE function, the differentiated product of a Myelocyte
Divide the acute cancer that results in the formation of large agranular blasts into cancers with a good Px and those with a poor Px and those that are high risk. • Define these mutations • Define gene pdts • pathophysiology • root of prognostic differences?
ACUTE LYMPHOBLASTIC LEUKEMIAS (ALL)
Good Px:
ETV6-RUNX1 gene pdt. t(12;21)(p13;q22)
• pathophysiology - ETV6-RUNX1 prevent CBFß from unreg. HAT, HDACs are recruited instead PREVENTING DIFFERENTIATION
Hyperdiploid Cells causing ALL also have a good Px.
Bad Px:
BCR-ABL gene pt. t(9,22)(q34,q11.2)
• pathophysiology: ABL is a tyrosine kinase receptor (PROMOTER OF PROLIFERATION) that fuses with BCR; often IFZK1 (84% of the time) is also upregulated and it PREVENTS DIFFERENTIATION
MIXED LINEAGE LEUKEMIA, MLL t(v,11q23)
• pathophysiology: Histone METHYL transferase (a transcription regulator) may link up with other genes to unregulate transciption PREVENTING DIFFERENTIATION; Flt3 (tyrosine kinase) mutations are also implicated (20%) PROMOTING PROLIFERATION
HIGH RISK
T-ALL, translocation of oncogenes to T cell Receptor gene location on Chromosome 14
Prognostic differences lie in the fact that PROLIFERATION being promoted as well as inhibition of differentiation leads to a much more aggressive cancer
What immunophenotype is associated with T-ALL?
• immunophenotype of other acute lymphoblastic leukemias?
• include mutations
• Note any common themes
T-ALL
t(v, 14) (various-TCR)
- TdT+, CD3+, CD5+
B-ALLs
ETV6-RUNX1 - t(12; 21)
• TdT+, CD10+, CD34+**, CD20-
BCR-ABL - t(9;22)
• TdT+, CD10+
Mixed Lineage Leukemia (MLL) - t(v, 11q23)
• TdT+, CD10-
Note: these all have markers of Primitive cell types such as TdT (only in bone marrow and thymus, CD10, and CD34 - a marker of hematopoietic stem cells*
Compare the ages at which the diseases resulting from t(v, 14) (TCR - Var.); t(9,22) (BCR-ABL); t(v, 11) (Var.-MLL); t(12,21) (ETV6-RUNX1) occur.
***Prognosis.
Acute Lymphoblastic Leukemias
INFANTS:
- MLL t(v, 11) - most common leukemia in this age group
- BCR-ABL t(9,22) - sometimes (2-4%)
KIDS:
- ETV6-RUNX1 t(12,21) - 25% peds. B-ALL
- T-ALL t(v, 14) - 25% of T-ALL
ADULTS:
- BCR-ABL t(9, 22)
T-ALL of often presents as a thymic mass in a teenager
T-ALL of often presents as a thymic mass in a teenager
In what subset of primary bone marrow malignancies do you see a common theme of tyrosine kinase mutation (specifically ones involving JAK2 and other TKs)?
• Diseases in this category
• Mutations for these diseases
Many bone marrow malignancies have Tyrosine Kinases upregulated, BUT MYELOPROLIFERATIVE DISEASES ALL have this**
Myeloid:
Chronic Myeloid Leukemia - BCR-ABL t(9,22)
Erythroid:
Polycythemia Vera - JAK2-V617F point mutation
Megakaryocyte:
Essential Thrombocytopenia - JAK2-V617F point mutation or Calreticulin
MAST cell:
Mastocytosis - FIP1L1-PDGFRA v, PDGRB (5q13)
also cKIT mutations
Primary Myelofibrosis - JAK 2 often times
What is generally the prognosis of people with JAK2-V617F mutations?
• Diseases caused by this mutation
• Bone marrow Morphology
JAK2-V617F causes 3 main myeloproliferative disorders
Greater than 10 year survival rate in PV and ET, but Primary Myelofibrosis is less
Polycythemia Vera
• Hypercellular bone marrow with a Myeloid: Erythroid ratio exceeding 2:1
Essential Thrombocytopenia
• Inc. Megakaryocytes that tend to cluster
Primary Myelofibrosis
• Inc. Megakaryocytes with Bizarre shape along with FIBROSIS
• Greater Chance of causing bone marrow failure or acute leukemia
What is a common complication of Myeloproliferative diseases arrising in the Megakarycyte and Erythroid cells?
THROMBOSIS - heart attack, stroke
PV - also gives you higher Blood Pressue
What do you expect to see on the CBC of a patient with:
- Polycythemia Vera
- Essential Thrombocythemia
- Primary Myelofibrosis
***In which of these diseases is a JAK2-V617F mutation diagnostic of disease?
Polycythemia Vera:
- High RBC
(probably high platelets too)
**JAK2-V617F mutation diagnostic
Essential Thrombocthemia:
- High Platelets
Primary Myelofibrosis:
- High Platelets
- High Low RBC (teardrop cells from getting squeezed through fibers)
In which myeloproliferative disease would immunophenotyping be most useful?
Mastocytosis - (immunophenotype: TRYPTASE+, CD25+, CD117+)
If you see a cells in ALL stages of GRANULOCYTE differentiation in the peripheral smear and suspect CML, what should you do next?
- what would you be looking for with this test?
- what subsequent test would you do to confirm the dx. and what would you be looking for?
- what would the CBC look like?
• CBC shows immature granulocytes
• Suspect CML then test PERIPHERAL blood using RT-PCR BEFORE taking bone marrow biopsy
***looking for the BCR-ABL mutation t(9,22)
• IF Positive THEN do BONE MARROW biopsy. Look to see if pt. is in CHRONIC phase (few blasts, mostly granulocytic appearance in marrow), ACCELERATED PHASE, or BLAST PHASE (the last two involving increased blasts in marrow)
If you see high platelets on someone who has just come into your office what should you suspect first?
Iron Deficiency - most common cause of elevated platelets
THEN you could start to consider Essential Thrombocythaemia, and Primary Myelofibrosis
If you have PV or ET that progresses, what disease are they most likely to progress to?
Most likely to myelofibrosis, myelodysplastic syndrome, or acute leukemia
What bone marrow morphology would you expect to see in someone who presented with a myeloproliferative disease that caused: flushing, abdominal pain, tachycardia, an hypotension?
- what blood test might you run next? (what should you be weary of?)
- how is a diagnosis typically made?
Suspected Disease: Mastocytosis
Morphology: Bland Cells with LOTS of CLUMPY chromatin that are sometimes spindle shaped
Blood test: Look at Serum Tryptase Levels (note: Elevated Serum Tryptase can become elevated in other types of mast cell response as well)
Dx: Immunohistochemical staining (for Tryptase, CD117 (c-KIT, SCF receptor, and CD25+)
T or F: mastocytosis is usually an isolated condition and there is little reason to worry about another malignancy.
FALSE, 30% of the time Mastocytosis occurs along with a 2nd hematologic malignancy
What differences should you look for to determine between sepsis and myeloproliferative disease?
- CBC (manual differential)
- Peripheral Smear
Sepsis:
Manual Diff: Granulocytes > Bands > Myelocytes
Smear: TOXIC GRANULATION
Myeloproliferative:
Manual Diff: Myelocyte BULGE out of proportion to granulocytes and bands
Smear: Myelocytes next to neutrophils
What fundamental similarity and difference are you likely to observe on the CBC of a patient with Polycythemia Vera vs. one with Primary Myelofibrosis?
In both CBC will indicate Thombocytosis
PV - pt. will be Hyperemic
PM - pt. will be Anemic
What patient population typically presents with myelodysplasia?
• CBC?
• Should you treat these patients?
Elderly Patients typically present with myelodysplasia
CBC:
- Cytopenia, dicytopenia, or pancytopenia
- WBC 5-20%, in bone marrow or in periphery
Treatment:
- Variable - in some pts. treatment could actually be worse
What are the 5 types of myelodysplasias?
• Divide those that have little to no affect on lifespan from those that negatively affect lifespan of affected individuals.
• Prognosis?
• Comment on impact of gender on likelihood of getting the disease
Remember myelodysplasias affect older individuals (>65); WBC 5%-20%
Little to No affect:
- Refractory Cytopenia with Unilineage Dysplasia (RCUD) - rarely progress to AML
- Refractory ANEMIA with Ringed Sideroblasts (RARS) - rarely progress to AML
- Myelodysplastic Syndrome with isolated del(5q) - 10% progress to AML
Impactful:
- Refractory Cytopenia with MULTIlineage Dysplasia (RCMD) - Median Survival 30 mon.
- Refractory ANEMIA with Excess Blasts (RAEB) - RAEB-1 (25% to AML), RAEB-2 (30% to AML)
Name and differentiate the 3 myelodysplastic syndromes with the best prognoses on the bases of bone marrow morphology.
Refractory Cytopenia with Unilineage Dysplasia
• May see Binucleated Erythroid precursor and Erythroblasts in the Periphery (Very blue cytoplasm with dense, more eosinophilic nuc.)
• Abnormalilities could be seen in other cell lines, but only one cell line at a time should be affected.
Refractory Anemia with Sideroblastic Dysplasia
• Ringed Sideroblasts that are Dysplastic (nuclear atypia, clumpy cytoplasm)
Myelodysplastic Syndrome with del(5q)
• Big Ass MonoNuclear Megs
What are the 2 myelodysplastic syndromes that have poorer prognoses and what important differences exist in their morphology?
Refractory Cytopenia with MULTIlineage Dysplasia (30 mon. median survival, 10% progress to AML in 2 yrs):
• Neutrophils (as defined by nuc.) without many granules
• Binucleated or Irregular Erythroid Precursor
Refractory Anemia with Excess Blasts ( 25 -30% progress to AML):
• Lots of Blasts with dyspoietic maturation
Which myelodysplasias may present clinically in an elderly person with SEVERE anemia?
• Prognosis
• Morphology
• Is this person more likely male or female?
Myelodysplastic Syndrome with del(5q)
• Px: Good median Survival, 10% progress to AML
• Morphology: GIANT MEGAKARYOCYTES
Refractory Cytopenia with MULTIlineage Dysplasia
• Px: BAD - 30 mon. median survival, 10% progress to AML in 2yrs
• Morphology: 2 cells lines showing dypoietic features (e.g. Binucleate RBCs and agranular Neutrophils)
MOST LIKELY A FEMALE, all others are just ppl. over 65 with cytopenia
T or F: Immunophenotype is a better way to tell myelodysplasias apart than morphology
False, immunophenotype for myelodysplasias is ambiguous
