Hematologic Malignancies II/III Flashcards
What 3 malignancies arise from the bone marrow?
- Acute Leukemias
- Myeloproliferative Diseases
- Myelodysplasia
What defines an acute leukemia?
• What arbitrary number is set to indicated and acute leukemia?
• Problem with this number?
BLASTS (rapidly proliferating clones) in the marrow and often in the bloodstream
Number:
• Marrow Blast Number GREATER than 20%
**Problem is that some people have acute leukemia and their marrow number is not yet greater than 20% blasts
What is the problem with using blast morphology as a diagnostic Characteristic for Acute Leukemias?
METHOD OF MORPHOLOGY HAS LITTLE CLINICAL UTILITY
*Not indicative of the clinical course the disease will take
What method would you use to distinguish between an Acute Myeloblastic Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL)?
• How can this method be misleading?
• How do we try to prevent ourselves from being mislead?
Immunohistochemical Staining or Flow Cytometry
- These methods can be misleading because cells can show MIXED phenotypes
- We try to prevent being mislead by using Mutliple markers.
***Still not a perfect system
Whats the the most useful clinical criterion for determining what type of Acute Leukemia (or cancer in general) your patient has?
• What are the specific advantages over immunohistochemistry or any other current criterion?
Genetics
Advantages:
• Increased Prognostic Value
• Predicts Response to Therapy
• Identifies Molecular Targets for Therapy Development
Describe what happens in the t(15:17)(q22;q12) translocation.
• Resultant disease?
PML-RARA fusion protein is formed by this translocation in which RAR-alpha (RARA), transcription factor, is linked to PML.
PML is responsible for organizing the nuclear structures
***When PML is fused to RARA, RARA can no longer be activated by Retinoic acid
- THIS INHIBITS GRANULOCYTE DIFFERENTIATION*
- **ACUTE MYELOID LYMPHOMA****
How was t(15:17)(q22:q12) translocation AML cured?
• What treatment do we use today to cure it?
Original Hypothesis:
• RA-binding domain, and DNA binding domain are still in tact on RARA even when its bound to PML
• RARA is activated by Retinoic acid aka VITAMIN A
Treatment:
• IV vitamin A put the cancer into remission
TODAY:
• VIT A. as well as Arsenic Trioxide is used because ArO3 inhibits K160 on the PML protein
Why did the VIT A put AML caused by PML-RARA into remission?
It destabilized the RARA protein (did not activated as was hypothesized), but it still worked
T or F: while indicative of cancer, Auer rods are often seen in reactive conditions.
False, they are totally indicative of MYELOID LEUKEMIAS
BE SURE TO LOOK AT THIS MINDMAP
BE SURE TO LOOK AT THIS MINDMAP
What is wrong with the following scenario?
A patient is diagnosed with AML and their cytogenetic (chromosomes) findings are normal and the physician begins treatment.
**YOU MUST do MOLECULAR studies if the cytogenetics are normal
What is the prognosis of someone who has AML with 3 or more cytogenetic findings?
*What gene can you assume is mutated?
BAD prognosis
p53 has probably been mutated leading to the genomic instability seen on the karyotype
Who is most often affected by acute LYMPHOBLASTIC leukemia (ALL)?
• cure rate?
75% of cases = KIDS
• in 80% of cases KIDS can be cured
ADULTS
• Cured in less than 50% of cases
What cells do you expect to see MORPHOLOGICALLY in acute Lymphoblastic Leukemia?
- Large Cells
- Large N/C ratio
- NO CYTOPLASMIC GRANULES
What transcription factor is mutated in 84% of cases of t(9,22)?
• Disease?
Disease:
Acute Lymphoblastic Leukemia via BCR-ABL mutation
Transcription factor:
• IKZF1 - loss causes inhibition of differentiation
What in the manual differential would help you to differentiate between sepsis and a myeloproliferative disease?
Sepsis:
Bands > Metamyelocytes > Myelocytes
Myeloproliferative:
“Myloid Bulge” - myelocytes are present greater proportion than bands and metamyelocytes
Why should your threshold for suspecting CML be low?
Its Very treatable
What are the 3 methods that have been used to measure treatment efficacy in CML patients?
Old - Hematologic Response Measured
- look for normalized RBCs
Newer - Cytogenetic Response Measured
- Look for translocation in cells
Newest/BEST - Molecular Response Measured
- Look at genotype
What is the risk of missing the diagnosis in a patient with CML?
CML can progress to an Acute Leukemia
What is the ultimate role of STATS?
Upregulated PROLIFERATION AND DIFFERENTIATION
How can a Jak 617F mutation result in BOTH Polycythemia Vera and Essential Thrombocythemia?
Same Mutation may take place in 2 different lineages that have already committed to a given cell type
What is the MOST COMMON reason to see increased platelets in a patient?
IRON deficiency, this is way more common than Essential Thrombocythemia
What mitogen plays a big role in Mast Cell Growth and Differentiation?
SCF
How do neoplasms of mast cells usually present in t kids?
Benign Cutaneous Lesions
e.g. Urticaria Pigmentosa
Where are mastocytosis most commonly localized to?
• Can they spread?
• If so where do they usually go?
SKIN, typically they do NOT spread but they definitely CAN.
Most common place to spread:
• BONE MARROW, but may also involve the Lymph Nodes, Spleen, and/or Liver
How are myeloproliferative Diseases usually diagnosed?
- Unexplained Cytopenia
* Morphologic Findings in the Bone Marrow
What is the general Rule about B cell Malignancies if they are well differentiated?
• They can transform into more aggressive forms by acquiring more mutations
***So you can’t just assume you’re safe because its well differentiated
What percentage of B cells are lost in Class Switching, Somatic Hypermutation, and Clonal selection (positive selection)?
99%
What genetic mutation is key to cancer formation in B and T cells?
*why are these cells so susceptible to cancer?
**Mutations that TRANSLOCATE an oncogene into the Ig promoter region
**Susceptibility to cancer arises from the fact that SOMATIC RECOMBINATION IS ESSENTIAL TO THEIR Developement
What is the location of the B cell promoter regions?
IgH (14q32) Ig Lamda (22q11) Ig Kappa (2p12)
What measure do we use to determine the level of clinical involvment of a lymphoma or leukemia?
Staging
**Note: there are different Staging Schemes for Different Lymphomas
What are the 2 immunophenotypic markers that are bad prognostic indicators in Chronic Lymphocytic Leukemia/Lymphoma?
• Why are they bad?
CD38
ZAP-70
**These are bad because they indicate lots of Somatic Hypermutation
What disease must you often differentiate CLL from?
* How do you do this?
CLL often must be differentiated from Mantle Cell Lymphoma (MCL)
**There are no proliferation centers in the lymph nodes in MCL (NO PSEUDOFOLLICULAR APPEARANCE)
T or F: in Hodgkin’s Lymphoma there is no Ig present on the B cell surface.
False, this is ONLY true for the Classical Form, Nodular Lymphocyte Predominant Hodgkin lymphoma (NLPHL) DO express Ig receptor
Can morphology help differentiate Hodkins Lymphomas?
• Is this sufficient to make a Dx?
Yes, morphology is different, in Hodgkin you see R/S cells, in NLPHL you see Popcorn (lympho-histocytic - L&H cells)
What is the correlation for morphology and severity of B-cell malignancy?
• Is the same true for T cell malignancies?
B-cell malignancy:
Well Differentiated cells result in less severe malignancy
T-cell malignancy:
NO CORRELATION between cell morphology and severity of malignancy
T or F: like in B cell lymphomas and Leukemias, T cell lymphomas and Leukemias often involve the translocation of an oncogene into the T-cell receptor promoter.
FALSE, This is NOT a recurrent theme in T-cell lymphomas
What is the most useful genetic tool in defining a T cell lymphoma?
• What about NK cell lymphoma?
Most Useful Tool for T-cell = PCR to determine CLONALITY
DOES NOT APPLY TO NK CELLS
How do you reassure yourself that someone has Mycosis Fungoides when you see a tissue biopsy of Lymphocytes infiltrating epidermis?
- Make sure its T cells that stain for CD3, 4, and 5
- MAKE SURE THEY ARE MONOCLONAL
**Reactive or Autoimmune conditions will by polyclonal
What is the defining feature of a Myeloproliferative Disease?
Chronically Proliferating Clones which differentiate to circulating blood cells
What feature of neutrophil granules can help to assure you that you’re looking at a reactive condition and not a malignant one?
TOXIC GRANULATION - large basophilic granules in the cytoplasm
T or F: if someone has polycythemia Vera they will have elevated EPO.
NO, the JAK2V216F is mutated so (renal peritubular) cells will never get signals to synthesize more EPO
