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Flashcards in Blood and Lymph Unit 3 Deck (123)
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1

List the main manners in which hematologic malignancies may manifest, and explain how these may overlap.

-diseases share fact that they are clonal populations of malignant cells arising from transformed marrow derived cells (doesn't have to take place in marrow itself)
-can be neoplasms of hematopoietic cells, lymphocytes, granulocytes, marrow derived

-lukemia: malignancy of hematopoietic cells, involvement of blood/marrow. myelogenic cells
-lymphoma: malignancy of hematopoietic cells derived from lymphocytes and precursors. solid mass
-extramedullary myeloid tumor (granulocytic sarcoma): malignancy of hematopoietic cells, from myeloid cells or precursors (granulocytes, monocytes) presents as solid mass

-many prefer one type of manifestation, these types of disease manifestations are not exclusive-often overlap
-overlap of CLL and SLL: same biologic disease, but differs if blood and marrow (CLL) vs. enlarged lymph node due to growth (SLL). both may appear

2

Contrast basic concepts of high versus low grade lymphomas, and of acute versus chronic leukemias.

-high grade: lymphoma=present as rapidly enlarging mass.
-low grade: mildly enlarged neck lymph node (example) present for years or as mild degree of lymphadenopathy on imaging study.

-chronic: leukemia=subtle symptoms noticed incidentally on CBC.
-acute: leukemia=present as WBC replacement of marrow.

3

Recall the biological reason that many lymphomas contain balanced translocations involving the immunoglobulin and T cell receptor genes.

-translocations seen in majority of hematologic abnormalities, are important since
a) presence=they can be used as diagnostic markers for hematologic malignancies
b) persistent presence=play critical role in development of malignancy they are associated with

-found in lymphomas and myeloid neoplasms.
-due to natural susceptibility of genome to translocations in periods of genomic instability, especially in initial Ig/Tcell receptor rearrangement
-this occurs during B/T cell maturation and class recombination and somatic hypermutation in B cell activation.

4

Relate the importance of specific recurrent translocations in certain hematologic malignancies in regard to the clinical care of patients.

-inherited immunodeficiencies and genomic instability can predispose/increase risk
-radiation exposure and certain chemo can increase risk
-not sure if this is what he was looking for.....

5

List three viruses known to have oncogenic roles in some cases of lymphoma.

-Epstein-Barr Virus: cases of classical Hodgkin lymphoma, Burkitt lymphoma, other B cell non-hodgkin lymphoma

-Human T cell Leukemia Virus 1 (HTLV-1): causative factor in adult T cell leukemia/lymphoma (ATLL)

-Kaposi Sarcoma Herpesvirus/Human herpesvirus 8 (KSV/HHV-8): primary effusion lymphoma

6

Contrast the incidences of leukemia and lymphoma in adult populations versus childhood populations.

-for all ages/races, Non-hodgkin lymphoma is 7th most frequent cancer (but 4-5x's lower than breast/prostate

-leukemia doesn't appear in the 15 deadliest cancers. most are indolent/curable

7

Recall the currently recommended classification system for hematologic malignancies, and list parameters this system may use to aid in the classification of these malignancies.

-WHO classification of tumors and haematopoietic and lymphoid tissues
Categories:
-microscopic appearance of malignant cells
-histologic growth pattern of cells in marrow, ln, other tissue
-presence/absence of malignant cells in blood/marrow
-relative amt. of malignant cells in blood/marrow
-presence/absence of certain cell surface markers/cytoplasmic markers/nuclear markers

-goal is to allow recognition of many distinct clinical entities by the pathologist

8

List the basic functional categories for hematologic malignancies, as outlined in the notes, and contrast the basic expected findings in the blood and marrow for these categories.
myeloid
lymphoid
acute
tools for evaluating
myelodisplastic syndrome
myeloproliferative neoplasms
classical hodgkin lymphoma
non-hodgkin lymphoma
plasma cell neoplasms
other

-myeloid malignancies: arising from mature/immature members of granulocytic, monocytic, erythroid, megakaryociytic, mast cells

-lymphoid malignancies: arising from mature/immature members of B, T, NK cells

-acute leukemia: majority are classified as AML or ALL. due to rapid accumulation immature cells in marrow. replace many normal marrow cells resulting in cytopenias. often is the blast.

Tools for evaluating
-morphology:appearance can differentiate
-immunophenotyping: use of antibodies to determine substances cells express. done with flow cytometry and immunohistochemistry. allows you to place non-distinct cells into definite lineages.

Myelodisplastic syndrome (MDS): clonal population of neoplastic hematopoietic stem cells takes over marrow. cannot make normal blood cells, falling peripheral blood cell counts. low incidence.

Myeloproliferative neoplasms (MPN): neoplastic clonal proliferation of marrow where clone makes normal blood cells in multiple lineages but makes too many. tend to progress to acute leukemia.

Classical Hodgkin Lymphoma (CHL): driven by HRS cells. derive from B cells.

Non-Hodgkin Lymphoma: any malignancy derived from mature B, T, NK cells. Majority are B cells

Plasma Cell Neoplasms: includes MGUS, plasmocytoma, multiple myeloma.

Other: histiocytoses, dendritic cell tumors/sarcomas, other

9

Contrast acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in regards to demographics of affected patients, and prognosis.

AML
Demographics: chromosomal abnormalities in 95% of patients. genetic perturbations at level of pluripotent stem cells or progenitors.
Affected Patients: average age diagnosis=65 (rare in children/young adults)
Prognosis:
-mean survival time ranges from 10 years if favorable cytogenetics
-60% will reach remission after chemo, relapse varies according to prognostics
-stem cell transplant is preferred treatment, but performance status must be taken into account

ALL
Demographics: chromosomal abnormalities in 90% of patients. occur a level of lymphoid stem cell. Morphology identifies them as blasts-(can't differentiate as lymphoblast)
Affected Patients: 75% are children
-WBC= worse if elevated at time of diagnosis
-worse prognosis if slow response to therapy/disease resides post treatment
-hyperploidy=favorable
-T-ALL is worse than B-ALL

10

Explain the concept of a "leukemic stem cell".

-has the potential for self-renewal. patients with acute leukemia have an inexhaustible source of leukemic cells that replace the marrow.

11

List risk factors for acute leukemia, while recalling that the majority of acute leukemias occur in the apparent absence of risk factors.

risk factors are associated with conditions that cause genetic damage/instability.
-previous chemotherapy, especially DNA alkylating agents and topisomerase2 inhibitors.
-tobacco smoke
-ionizing radiation
-benzene exposure
-genetic syndromes: downs, bloom, fanconi anemia, ataxia-telangiectasia

12

List common signs and symptoms exhibited by patients with acute leukemia at initial presentation, and explain the reasons for these findings.

Related to decreased numbers of peripheral blood cells due to marrow interaction by leukemic cells. Rarely leukemic cells may cause hyper viscosity or thrombotic problems.

-symptoms:
fatigue, malaise dyspnea
easily bruise, weight loss
bone or abdominal pain
neurological symptoms

-signs:
anemia and pallor
thrombocytopenia, hemorrhage, eccymoses, petichiae, fundal hemmorage
fever and infection
adenopathy, hepatosplenomegaly, mediastinal mass
gum or skin infiltration
renal enlargement/insufficiency
cranial neuropathy

13

List methods for immunophenotyping in acute leukemias (covered in notes for previous Introduction lecture), and list a few basic markers (bolded in notes) that would help to assign blasts to a:
precursor-B,
precursor-T,
or myeloid lineage.

-Lymphoblasts, whether B or T lineage, tend to be smaller than myeloblasts. However, definitive identification of a blast as a lymphoblast, and assignment of B or T lineage, requires some type of immunophenotyping.
-Peripheral white blood cell count (WBC) may be markedly increased, normal, or decreased.

-Lymphoblasts express TdT, a nuclear enzyme that is specific to lymphoblasts (i.e. not usually expressed by myeloblasts). TdT is also not expressed by mature lymphocytes.
-myeloblasts express antigens like CD117 (C-Kit), myeloperoxidase that allow them to be identified, express CD34 (generic marker of immaturity).

-T lymphoblasts express T lineage antigens CD2, 3, 7. may express CD4, 8. often express antigens only seen in mature T cells (CD99, 1a).
-B lymphoblasts express B lineage antigens: CD19, 22, 79a. do not express markers of mature B cells (CD20, surface Ig)

14

Contrast B-ALL and T-ALL in regards to patient age and sex, manner of manifestation, and prognosis.

B-ALL 80-85% of ALL cases
Age: childhood and adulthood (school age children 4-10 is most likely)
Sex: ?
Manifestation: B lineage antigens, as leukemia
Prognosis: Ph+ has worst prognosis of all ALL, MLL abnormalities are poor prognosis in neonates/young infants. Translocations have favorable prognosis

T-ALL 25-30% of ALL cases (ALL IN CONTRAST TO B-ALL)
Age: adolescents/young adults
Sex: males over females
Manifestation: large mediastinal mass, frequently present also with components of lymphoblastic lymphoma (T-LBL). more likely to present with high WBC count than B-ALL.
Prognosis: ALL generally good prognosis disease in children. complete remission rate following chemo is >95%, cure rates around 80%. adults=worse disease with cure rates

15

List three commonly observed cytogenetic abnormalities in B-ALL, and recall the usual patient age group and prognosis associated with these abnormalities.

1) t(9;22)(q34;q11.2) BCR-ABL1
age group: 25% of adults=t(9;22), philladelphia chromosome.
prognosis: worst prognosis of any subtype

2) translocation of 11q23; MLL
age group: neonates/ young infants
prognosis: poor.

3) t(12;21)(p13;q22); ETV6-RUNX1
age group: 25% of cases of childhood B-ALL
prognosis: very favorable

16

List five factors affecting prognosis in ALL.

Prognostic factors include:
(1) Age: worse prognosis for infants (10 years) or adults,
(2) White blood cell count: worse prognosis if markedly elevated white blood cell count at time of diagnosis,
(3) Slow response to therapy / small amounts of residual disease after therapy,
(4) Number of chromosomes: very favorable prognosis for hyperdiploidy (>50)

17

List two types of findings that would allow for a diagnosis of AML.

-it is a very heterogeneous disease (morphologically and clinically) that may involve 1 or more or all myeloid lineages
1) increased myeloblasts accounting for 20% or more of nucleated cells in marrow or peripheral blood
Some cases of AML show monocytic differentiation, and thus the leukemic cells may express monocytic antigens (CD64, CD14) instead of typical myeloblast antigens.

2) Some cases of AML show megakaryoblastic differentiation, and thus the leukemic cells may express megakaryocytic antigens (CD41, CD61).

18

Recognize an Auer rod, and relate its clinical significance

-fused azurophilic granules forming small stick-like structures in cytoplasm.
-allows for identification of blast as myeloblast, only seen in abnormal myeloblasts

19

Recall the associated prognosis for the five recurrent cytogenetic abnormalities for AML listed in the notes, and recall their typical patient populations if one is listed.

1) t(8;21)(q22;q22); RUNX1-RUNX1T1
population: younger patients, 5% of AML
prognosis: good
RUNX1 encodes alpha unit of CBF (needed for hematopoiesis)

2) inv(16)(p13.1;q22) or t(16;16)p(13.1;q22); CBFB-MYH11
population: younger patients, 5-10% of cases
prognosis: relatively good
presence in marrow of immature eosinophils w/ abnormal granules-baso eos.

3) Acute promyelotic leukemia w/ t(15;17)(q22;12); PML-RARA
population: 5-10% of cases, ?
prognosis: better remission rates than any other AML
abnormal promyelocytes predominate instead of blasts. hyper granular cells, multiple Auer rods
-flow cytometry shows abnormal population, also order FISH and karyotype for confirmation.

4) t(1;22)(p13;q13); RBM15-MKL1
population: infants with downs
prognosis: relatively good with intensive chemo

5) 11q23; MLL
population: infantile or congenital ALL. infantile is very bad. less than 1% of all acute leukemia (approx 1 in 6 million)
prognosis: poor
-B-all-rearrangement of MLL gene.

20

Explain two reasons why it is important to recognize at initial diagnosis that a case of AML is the AML with t(15;17)(aka acute promyelocytic leukemia (APL)) subtype of AML.

1) the gene fusion fuses the retinoic acid receptor alpha (RARA) gene to another gene. this gene is needed for differentiation of promyelocytes; fused product doesn't work well, blocks differentiation.
block can be overcome with supra-physiologic doses all trans retinoic acid (ATRA) with arsenic salts.
don't require chemo.

2) some cases give rise to disseminated intravascular coagulation (DIC). be on the lookout! Can be fatal!!! Test Fibrinogen and clot length tests.

21

Contrast the two main categories of therapy-related AML, and compare their prognosis.

t-AML is defined as AML secondary to DNA damage from prior therapy. due to previous treatment with DNA alkylating agents or topoisomerase 2 inhibitors. 10-20% cases of AML

secondary to alkylating agents/radiation:
-2-8 year latency
-progresses through MDS stage before outright AML
-complex karyotype (whole or partial loss of chromosomes 5, 7)

secondary to topoisomerase 2 inhibitors:
-latency of 1-2 years from treatment
-presents as de novo AML with no prior MDS phase
-rearrangment of MLL gene (11q23)

all types of t-AML have v. poor prognosis

22

List three molecular markers currently used to predict prognosis in patients with AML with normal karyotype (lacking recurrent cytogenetic abnormalities), and know which of these "trumps" the other two as a driving prognostic factor.

-FLT3 ITD: positivity for internal tandem duplications in FLT3 gene ar a negative prognostic factor for AML, NOS
trumps!

-NPM1: positivity for mutation of nucleophosmin-1 gene is positive prognostic factor in AML, NOS (only if negative for FLT3)

-CEBPA: positive for mutation in CEBPA gene is positive prognostic factor in AML, NOS (only if negative FLT3)

23

Draw an outline diagram of lymphocyte development. On the diagram, indicate locations of abnormalities of development in:
DiGeorge syndrome,
severe combined immunodeficiency (SCID),
X-linked (Bruton's) hypogammaglobulinemia,
hyper IgM,
and common variable immunodeficiency.

-most defects are x linked. if not x linked, autosomal.

-Block 1--SCID: untreated children don't survive past 1 year. lymphopenia of T and B cells, absent Thymus, limited ability to make antibodies and T cells. More than half are x-linked recessive. mitogen responses=slow. lack ADA: adenosine deaminase. cannot develop immune cells. Adenosine accumulates in all cells, impairs lymphocyte development selectively. Defects in V(D)J recombination (rare, in Navajo and Apache children)

-Block 2--X linked hypogammaglobulinemia (Bruton): non functioning B cell but functioning T cells. why we don't use oral vaccines. Have pre-B cells, but deficient B cells. IgG is

-Block 3--X linked hyperIgM syndrome: High IgM with low IgG and A. defect in M to G switching. Tfh cell has CD154/CD40 that interacts with B cell CD40 that tells them to switch and activate. If defective, B cell is driven but can't get the signal to switch past IgM. (deficiency in CD40 or CD40 ligand). Real good at bacterimia, but not bacteria deep in tissues (too big to get out of blood). 

-Block 4--common variable immunodeficiency (CVID): normal numbers pre B-cells and B cells but they are difficult to trigger. Serum IgG is low, and is milder than other conditions. Main phenotype: recurrent bacterial infection, treat with IVIG or SCIG. Increased risk lymphoma, enteropathy, autoimmunity. 

-Block 5--DiGeorge: abnormal development of thymus. absent T cells with normal B cells. cause of a large deletion on chromosome 22. parathyroids are deficient, which control calcium-can lead to convulsions in infancy. great vessels of heart develop abnormally. imunity is depressed, viral/fungal infections common. nude mouse have no T cells, similar to DiGeorge kids. "CATCH-22" defect on Chromosome 22. Calcium, Appearance, Thymus, Clefts (palate), Heart

24

Characterize the infections you would expect in a pure B cell deficiency and in a pure T cell deficiency.

-T deficiency are associated with severe infections-w/intracellular pathogens including viruses, bacteria, yeasts, fungi (esp. Candida and pneumonia).
- DiGeorge Syndrome: They can be susceptible to viruses, certain bacteria, and yeasts and fungi. Especially, Candida albicans and Pneumocystis carinii (P. jirovecii).

-B cell deficiency is characterized by "high grade" bactrial pathoges like Staph, flu, strep.  (extracellular, pyrogenic=pus producing)
- Brunton's: They have bacterial infections presenting as pneumonia and chronic diarrhea due to enteroviruses entering through mucous membranes unprotected by IgA (e.g. poliovirus).
- Be cell deficiency characterized by: S. aureus, H. influenzae, S. pneumoniae.

25

Describe the clinical features which, although not immunological, are part of DiGeorge syndrome.

-CATCH-22
- Unexplained convulsions controllable by calcium in infancy
- Abnormally developing heart
- Viral/fungal infections

26

Discuss the incidence of selective IgA deficiency, and the associated syndromes.

-most common immunodeficiency disease (200/100,000)-most cases=asymptomatic. also have more incidence of respiratory infections, allergies.
-may have diarrhea. 
-familial tendency, 10-15 times more common in Celiacs

27

Describe the immunological problem of the Nude mouse, and name the human immunodeficiency condition it resembles.

-cannot make T cells, similar to DiGeorge
-Nude mice fail to make a thymic strome (and hair), so they have no T cells and are thus immunologically similar to DiGeorge kids.

28

Name the enzyme which is absent in some cases of SCID. Discuss possible approaches to replacing this enzyme.

-group of diseases with similar phenotype. 
most common: SCID-X1. defect is in gene for gamma gain that forms part of receptors fo IL-2 and other cytokines. 

-most patients lack adenosine deaminase (ADA): adenosine accumulates in all cells, impairs lymphocyte development.

-marrow transplants has about 50% success rate. better to transplant purified stem cells than whole bone marrow. 
-note: you must irradiate cells before you administer them (to account for T cells that may still be in there!)

-Purified ADA stabilized with polyethylene glycol (PEGylated) available for use. 

-gene replacement therapy. 

29

Discuss transplantation therapy in immunodeficiency diseases. Include a consideration of possible complications.

- In DiGeorge, they have tried to use fetal thymus or cultured thymic stromal cells to minimize the risk of GvH disease (graft vs. host).

- In SICD, bone marrow transplants have a 50% success rate, but GvH disease is a problem. It's better to transplant purified stem cells than whole bone marrow. Sibling donors are best and a good Class II MHC match is imperative.

-Purified ADA, gene replacement

30

Given a child with recurrent infections, describe in principle tests which could be done to determine if there is a:
T cell problem

T Cell
-skin test with recall Ag panel
-total lymphocyte count
-CD3, CD4, CD8 counts
-advanced tests: mitogen responses, MLR, cytokine measurements, sequence suspect genes