Hematologic Malignancies II/III Flashcards by Barrett Thompson

What 3 malignancies arise from the bone marrow?

Acute Leukemias
Myeloproliferative Diseases
Myelodysplasia

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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

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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

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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

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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

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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****

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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

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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

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T or F: while indicative of cancer, Auer rods are often seen in reactive conditions.

False, they are totally indicative of MYELOID LEUKEMIAS

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BE SURE TO LOOK AT THIS MINDMAP

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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

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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

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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

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What cells do you expect to see MORPHOLOGICALLY in acute Lymphoblastic Leukemia?

Large Cells
Large N/C ratio
NO CYTOPLASMIC GRANULES

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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

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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

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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?

1. Make sure its T cells that stain for CD3, 4, and 5 2. 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