Exam 3 Flashcards
(108 cards)
1
Q
Leukemia
A
A malignancy of hematopoietic cells, where the chief manifestation is involvement of the blood and marrow.
2
Q
Lymphoma
A
A malignancy of hematopoietic cells, derived from lymphocytes or their precursors, which presents primarily as a solid mass
3
Q
Extramedullary myeloid tumor (aka granulocytic sarcoma)
A
A malignancy of hematopoietic cells, derived from myeloid cells or their precursors (granulocytes, monocytes, etc.), which presents primarily as a solid mass.
4
Q
grade of a tumor
A
refers to the clinical aggressiveness of a malignancy, often related to its rate of growth, with higher grades being more aggressive / more rapidly growing.
5
Q
What is the most common Chromosomal abnormalities found in hematologic malignancies?
A
chromosomal translocations
6
Q
why are conserved chromosomal abnormalities important?
A
a) their persistent presence allows them to be used as diagnostic markers for certain hematologic malignancies b) their persistent presence suggests they place a critical role in the development of the hematologic malignancy they are associated with
7
Q
What is thought to be the reason for frequent chromosomal translocations in lymphomas?
A
thought to be due to the natural susceptibility of the genome to translocations during normal periods of genomic instability, namely during the initial immunoglobulin / T-cell receptor rearrangement during the maturation of B cells / T cells, and during the class recombination and somatic hypermutation process during the activation of B cells.
8
Q
what three viruses are known to play a role in the genesis of some lymphomas?
A
1) Epstein-Barr virus (EBV): Some cases of classical Hodgkin lymphoma, some cases of Burkitt lymphoma, some other B cell non-Hodgkin lymphomas 2) Human T cell leukemia virus-1 (HTLV-1): Causative factor in adult T cell leukemia/lymphoma (ATLL) 3) Kaposi sarcoma herpesvirus/Human herpesvirus-8 (KSV/HHV-8): Primary effusion lymphoma
9
Q
what is the most common type of childhood cancer?
A
Leukemia is the most common type (37% of all childhood cancers) Lymphoma is the 3rd most common type of cancer representing 24% of childhood cancers
10
Q
Myeloid malignancies
A
those arising from mature or immature members of the granulocytic, monocytic, erythroid, megakaryocytic, and mast cell lineages.
11
Q
Lymphoid malignancies
A
those arising from mature or immature members of the B cell, T cell, and NK cells lineages.
12
Q
what is included in multi parameter classification?
A
The WHO classification system draws from various different sources of information to diagnostically define entities. This information can include: - microscopic appearance of the malignant cells - histologic growth pattern of the malignant cells in the marrow, lymph node, or other tissue - presence or absence of specific cytogenetic findings or molecular findings - relative amount of malignant cells present in the blood or marrow - presence or absence of certain cell surface markers / cytoplasmic markers / nuclear markers
13
Q
ACUTE LEUKEMIAS
A
Acute leukemias are usually due to the rapid accumulation of (usually) immature cells in the marrow. These immature cells often replace many of the normal marrow cells, resulting in cytopenias (thrombocytopenia, anemia, neutropenia, etc.) Often, but not always, the immature cell is the generic-appearing blast.
14
Q
MYELODYSPLASTIC SYNDROME (MDS)
A
MDS is a group of conditions where a clonal population derived from a neoplastic hematopoietic stem cell takes over the marrow, and is not capable of making normal blood cells in one or more lineages (dysplasia). This disease is categorized in most cases by falling peripheral blood cell counts. Although many people regard MDS as a precursor to acute myeloid leukemia (AML), due to the high rate of progression from MDS to AML, MDS is arguably a malignancy in its own right, as many people die of MDS without progressing to acute leukemia, due to the failure of the marrow to make normal blood cells.
15
Q
MYELOPROLIFERATIVE NEOPLASMS (MPNs)
A
MPNs are neoplastic clonal proliferations of the marrow where the clone makes normal functioning blood cells, usually in multiple lineages, but makes too many of them in one or more lineages. MPNs are classified into different types based on the underlying cytogenetic abnormality, the types of blood cell(s) being overproduced, and other data. MPNs also have a tendency to progress to acute leukemia, though this tendency in much less than for MDS.
16
Q
CLASSICAL HODGKIN LYMPHOMA (CHL)
A
CHL is a very distinct clinical entity, driven by the infamous Hodgkin-Reed-Sternberg (HRS) cells. For a long time, the derivation of the HRS cell was not well understood; thus, CHL was classified as its own entity. Today we know HRS cells derive from B cells, but the disease still remains its own unique clinical entity, due to its unique natural course and unique treatment regimens.
17
Q
NON-HODGKIN LYMPHOMA
A
The term non-Hodgkin lymphoma refers to any malignancy derived from mature B cells (excluding CHL or plasma cell neoplasms), T cells, or NK cells. The large majority are derived from B cells.
18
Q
PLASMA CELL NEOPLASMS
A
This category is self-explanatory, and includes MGUS, plasmacytoma, and multiple myeloma.
19
Q
two major categories of acute leukemia?
A
acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
20
Q
at what level of differentiation do the genetic perturbations that cause AML occur?
A
at the level of the pluripotential stem cell or the level of one of the committed progenitors
21
Q
at what level of differentiation do the genetic perturbations that cause ALL occur?
A
at the level of the lymphoid stem cell
22
Q
Risk factors for acute leukemia:
A
A. Previous chemotherapy, especially DNA alkylating agents and topoisomerase-II inhibitors B. Tobacco smoke C. Ionizing radiation D. Benzene exposure E. Genetic syndromes including Down syndrome, Bloom syndrome, Fanconi anemia, and ataxia-telangiectasia.
23
Q
Signs and symptoms of acute leukemia:
A
The signs and symptoms of acute leukemia are related to decreased numbers of normal peripheral blood cells due to marrow infiltration by leukemic cells. Symptoms - fatigue, malaise, dyspnea - easy bruisability, weight loss - bone pain or abdominal pain (less common) - neurologic symptoms (rare) Signs - anemia and pallor - thrombocytopenia, hemorrhage, ecchymoses, petechiae, funded hemorrhage - fever and infection (pneumonia, sepsis, perirectal access) - adenopathy, hepatosplenomegaly, mediastinal mass - gum or skin infiltration (rare) renal enlargement and insufficiency (rare) - cranial neuropathy (rare) Rarely, in acute leukemia patients who present with very high white blood cell counts, the leukemic cells themselves may cause hyperviscosity or thrombotic problems. In these instances, a pheresis machine may be used to selectively remove white blood cells from the blood (leukopheresis)
24
Q
two subdivisions of acute lymphoblastic leukemia?
A
B-lymphoblastic ALL (B-ALL) and T-lymphoblastic ALL (T-ALL)
25
ALL - incidence
ALL has an incidence of between 1 and 5 cases per 100,000 persons per year (about 3,000 news cases per year in U.S.) 75% of cases of ALL occur in children under 6 years old
26
ALL - diagnosis
- Peripheral white blood cell count (WBC) may be markedly increased, normal, or decreased. - Lymphoblasts often express CD34, a marker of immaturity also often expressed by myeloblasts. - 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.
27
B-lymphoblastic ALL (B-ALL)
B-ALL accounts for the majority (80-85%) of cases of ALL. B-lymphoblasts express B-lineage antigens (e.g. CD19, CD22, and/or CD79a). B-lymphoblasts usually do not express markers of mature B cells, such CD20 or surface immunoglobulin.
28
Cytogenetics of B-ALL
B-ALL with t(9;22)(q34;q11.2); BCR-ABL1: 25% of cases of adult B-ALL (but only 2% of childhood B-ALL) contain a t(9;22) resulting in the Philadelphia chromosome, similar to what is seen in chronic myelogenous leukemia (CML). In these cases of Ph+ B-ALL, the BCR-ABL fusion protein differs from that typically seen in CML, in that it is only 190kd (p190) (instead of the 210 kd fusion protein seen in CML). This is due to the use of a different breakpoint in the BCR gene in ALL than in CML. In both adults and children, Ph+ ALL has the worst prognosis of any subtype of ALL.
29
B-ALL with translocations of 11q23; MLL:
B-ALL with abnormalities of MLL is frequently seen in B-ALL in neonates and young infants. These have a poor prognosis, and the frequency of this finding is the reason for the generally poor outcome of neonatal ALL.
30
B-ALL with t(12;21)(p13;q22); ETV6-RUNX1
This finding is seen in 25% of cases of childhood B-ALL. Like AMLs with translocations of RUNX1 (see below), these cases of ALL have a very favorable prognosis.
31
T-lymphoblastic ALL (T-ALL)
T-ALL accounts for a minority of ALL cases (25-30%) In contrast to B-ALL, T-ALL more frequently occurs in adolescents and young adults than in children. In contrast to B-ALL, T-ALL more frequently present with a component of lymphoblastic lymphoma (T-LBL), often manifesting as a large mediastinal mass. If the disease does have leukemic (T-ALL) component, the disease is more likely to present with a high white blood cell count than B-ALL. T-ALL / T-LBL favors males over females. T-lymphoblasts express T-lineage antigens CD2, CD3, and/or CD7. They may express both CD4 and CD8 concurrently, or may express just one or neither of these. They often express T-lineage antigens only seen in immature T cells, such as CD99 and CD1a.
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ALL - THERAPY AND PROGNOSIS
ALL is generally a good prognosis disease in children. In children, the complete remission rate following chemotherapy is greater than 95%, with cure rates of around 80%. In adults, ALL is a worse disease, with complete remission rates of 60-80%, and cure rates of less than 50%.
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PROGNOSTIC FACTORS FOR ALL:
- Age: worse prognosis for infants (10 years) or adults - White blood cell count: worse prognosis if markedly elevated white blood cell count at time of diagnosis. - Slow response to therapy / small amounts of residual disease after therapy: worse prognosis if either of these occurs - Number of chromosomes: very favorable prognosis for hyperdiploidy (\>50 but
34
AML - INCIDENCE
Worldwide incidence of around 3 cases per 100, 000 persons per year Average age at diagnosis: 65 years old Rare in children and young adults (AML only accounts for around 10% of childhood leukemia)
35
AML - DIAGNOSIS
The diagnosis of AML is usually based on the identifications of increased myeloblasts accounting for 20% or more of nucleated cells in the marrow or peripheral blood. This diagnosis can be made by microscopic review of bone marrow aspirate smears or peripheral blood smears, or by flow cytometric review of marrow aspirate material or peripheral blood, or by microscopic (and possibly immunohistochemical) review of the marrow core biopsy. There are other, rarer ways, not worthy for discussion here, by which the diagnosis of AML can be established. An exception to the requirement for 20% myeloblasts for the diagnosis of AML occurs if one can document the presence of certain recurrent cytogenetic findings. These will be mentioned below.
36
AUER ROD
Auer rods are fused azurophilic granules forming small stick-like structures in the cytoplasm. The presence of Auer rods allows the identification of a blast as a myeloblast. Furthermore, they are only seen in abnormal myeloblasts
37
CD34
a generic marker of immaturity commonly seen on myeloblasts, but can also be seen in lymphoblasts.
38
cytogenetic analysis
(karyotyping - less sensitive; and FISH - more sensitive)
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molecular analysis
(RT-PCR of mRNA transcript of fused genes - very sensitive)
40
AML - PROGNOSIS
Mean survival times for AML patients range from less than 1 year for patients with adverse risk cytogenetics, to more than 10 years in patients with favorable risk cytogenetics. Approximately 60% of AML cases will reach complete remission after chemotherapy. Rate of relapse varies according to prognostic factors. For many patients with AML with poor prognostic factors, or for many patients with relapsed AML, autologous stem cell transplant (SCT) is the preferred treatment. Due to the high morbidity of the transplant process, consideration of SCT must take into account the patient's performance status (i.e. a measure of the patient's overall health/robustness).
41
Contrast acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in regards to demographics of affected patients, and prognosis.
AML is a much more heterogeneous disease than ALL (many more types) AML is typically a disease of adults: - average age at diagnosis of AML: 65 - only ~10% of childhood leukemias are AML AML incidence is around 3 cases per 100K persons per year (similar to ALL)
42
List risk factors for acute leukemia, while recalling that the majority of acute leukemias occur in the apparent absence of risk factors.
Previous chemotherapy, especially DNA alkylating agents and topoisomerase-II inhibitors Previous exposure of active marrow to ionizing radiation Tobacco smoke Benzene exposure Genetic syndromes, including Down syndrome, Bloom syndrome, Fanconi anemia, and ataxia-telangiectasia
43
List common signs and symptoms exhibited by patients with acute leukemia at initial presentation, and explain the reasons for these findings.
Presenting signs/symptoms usually result from replacement of the normal marrow cells by leukemic cells. They might include: Signs/symptoms of anemia: fatigue, malaise, pallor, dyspnea Signs/symptoms of thrombocytopenia: bruising, petechiae, hemorrhage Signs/sympyoms of neutropenia: fever, infections More rarely, presenting signs/symptoms may be directly attributable to effects of the leukemic cells. These include: Thrombotic events due to increased blood viscosity (known as leukostasis; seen in the setting of leukemia with very high WBC count) Disseminated intravascular coagulation (DIC), which can be initiated by the leukemic cells in some types of AML Direct infiltration of skin, gums, lymph nodes, and/or other tissues by leukemic cells
44
List three commonly observed cytogenetic abnormalities in B-ALL, and recall the usual patient age group and prognosis associated with these abnormalities.
1) B-ALL with t(9;22); BCR-ABL1 - t(9;22) results in a derivative chromosome 22, the so-called Philadelphia chromosome, encoding the BCR-ABL fusion tyrosine kinase protein (thus, these cases often called “Ph+ ALL”) - t(9;22) seen in 25% of cases of adult ALL, but only 2% of cases of childhood ALL - Fusion protein differs from the BCR-ABL fusion protein in CML, as it is only 190 kilodaltons (p190), due to its resulting from a different breakpoint in BCR than the typical CML breakpoint - Presence of t(9;22) is an unfavorable prognostic factor 2) B-ALL with translocations of 11q23; MLL MLL may be rearranged with any of multiple possible partner genes Frequently seen in neonates and young infants Poor prognosis 3) B-ALL with t(12;21); ETV6-RUNX1 - 25% of cases of childhood B-ALL - Very favorable prognosis
45
Contrast B-ALL and T-ALL in regards to patient age and sex, manner of manifestation, and prognosis.
T-ALL accounts for only around 25% of cases of ALL When compared to B-ALL….. T-ALL more frequently occurs in adolescents and young adults T-ALL more frequently presents with a component of T-lymphoblastic lymphoma (T-LBL), often present as a mediastinal mass T-ALL is more likely to have a markedly elevated WBC count T-ALL favors males over females
46
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.
Immunophenotyping: combination of flow cytometry and immunohistochemistry precursor-B: CD19, CD22 precursor-T: CD3, CD7 myeloid lineage: Common lymphoblast marker: TdT Generic markers of immaturity (also on myeloblasts): CD34
47
precursor-B cell markers
CD19, CD22
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precursor-T cell markers
CD3, CD7
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common lymphoblast marker
TdT
50
generic marker of immaturity seen in ALL
CD34
51
List five factors affecting prognosis in ALL.
factors associated with worse prognosis: Infants (10 yo) Very High WBC count T-lymphoblastic Hypodiploidy (
52
List two types of findings that would allow for a diagnosis of AML.
increased myeloblasts accounting for 20% or more of nucleated cells in the marrow or peripheral blood. An exception to the requirement for 20% myeloblasts for the diagnosis of AML occurs if one can document the presence of certain recurrent cytogenetic findings (typically balanced translocations determined by cytogenetic analysis and molecular analysis )
53
Recognize an Auer rod, and relate its clinical significance.
¢In some cases of AML (or MDS), some of the myeloblasts may contain Auer rods, allowing for their identification as myeloblasts by morphology alone
54
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 RARA gene encodes the retinoic acid receptor alpha protein. Signalling through this receptor is required for differentiation past the promyelocyte stage.
In APL, the PML-RARA fusion protein functions poorly as a retinoic acid receptor. However, adequate levels of signalling activity can be obtained with supraphysiologic doses of all-trans retinoic acid (ATRA)
Thus, APL patients do not required traditional induction chemotherapy (initial treatment) with the usual chemotherapeutic agents, which have significant rates of morbidity and mortality. They can be treated instead with ATRA and arsenic salts, which have very little morbidity and almost no mortality
2) APL is often associated with disseminated intravascular coagulation (DIC), a condition of widespread ongoing clotting and clot lysis, which can be a medical emergency. Thus, identification of the acute leukemia as APL alerts the clinician to the possibility of DIC, and appropriate measures can be taken if necessary.
55
Contrast the two main categories of therapy-related AML, and compare their prognosis.
Both treatments have very poor prognoses
56
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.
1) FLT3 Internal Tandem Duplication (ITD) -\> poor prognosis
2) Nucleophosmin-1 (NPM1) Mutation -\> GOOD (as long as negative for FLT3 ITD)
3) CEBPA Mutation -\> Good (as long as negative for FLT3 ITD)
57
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) AML with t(8;21); RUNX1-RUNX1T1
Prog: relatively good. PP: younger patients
2) ¢AML with inv(16) or t(16;16); CBFB-MYH11
prog: relatively good. PP: younger patients
3) ¢AML with t(15;17); PML-RARA
prog: not listed PP note listed
4) ¢AML with t(1;22); RBM15-MKL1
prog: relatively good PP: most often seen in infants with Down syndrome
5) ¢AML with abnormalities of 11q23; MLL
prog: poor prognosis PP: none listed
58
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, and common variable immunodeficiency.
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types of immunodeficiency
**primary** **immunodeficiency:** there are mutations in genes required for normal development of parts of the immune system. Variable penetrance—the degree to which a mutation is expressed phenotypically—means that children with these mutations may have symptoms along a spectrum of seriousness. If the thymus or bone marrow were congenitally dysfunctional that would result in primary immunodeficiency,
**Secondary immunodeficiency**: immunodeficiency that follows treatment with immunosuppressive drugs, or that is seen in patients with advanced cancer, measles, or AIDS, is **secondary** to those conditions. Another way of putting it is that immunodeficiency can be congenital or acquired, depending upon whether the condition existed at birth or not. Acquired immunodeficiency will usually be secondary to some other condition.
61
Name the enzyme which is absent in some cases of SCID. Discuss possible approaches to replacing this enzyme.
**Most of these patients lack the enzyme adenosine deaminase (ADA);** so adenosine accumulates in all cells but impairs lymphocyte development selectively. Among the rarest globally are defects in V(D)J recombination, although that is the most common form of SCID in Navajo and Apache children (incidence about 50/100,000 births.)
For SCID, bone marrow transplantation has about a 50% success rate, but graft-versus-host disease is always a problem. ►It is better to transplant purified stem cells than whole bone marrow. Sibling donors are the best, and a good Class II MHC match is imperative. For ADA- deficient patients, transfusions of irradiated red cells can be helpful.
Severe Combined Immunodeficiency Disease (overview)
There is lymphopenia of both T and B cells
SCID is a group of diseases with a similar phenotype. More than half the cases are X-linked recessive
In the commonest of these (SCID-X1), the defect is in ►the gene for the gamma chain that forms part of the receptors for IL-2 and other cytokines necessary for lymphoid development, or their signaling pathways. The rest of SCID cases are autosomal recessive.
62
Characterize the infections you would expect in a pure B cell deficiency and in a pure T cell deficiency.
B cell deficiency is characterized by infections with “high-grade” (extracellular, pyogenic = pus-producing) bacterial pathogens such as Staphylococcus aureus, Haemophilus influenzae and Streptococcus pneumoniae.
T deficiencies are associated with severe infections with intracellular pathogens, including viruses, certain bacteria, and yeasts and fungi, especially Candida albicans and Pneumocystis jirovecii.
All of this makes good sense if you remember antibody and T cell-mediated mechanisms. But keep in mind that every infection involves multiple immune responses, so these generalizations are not hard and fast rules. Gut organisms may be abnormal in either type of disease, so diarrhea and malabsorption are frequent complaints, as is failure to grow normally.
63
Describe the clinical features which, although not immunological, are part of DiGeorge syndrome.
DiGeorge Syndrome -\> cause is a large (45 gene) deletion on chromosome 22.
patient will have absent T cells with normal B cells.
The parathyroids also derive from the pharyngeal pouches, so this diagnosis is sometimes made in infancy when there are unexplained convulsions controllable by calcium
Cell-mediated immunity is depressed; viral and fungal infections are common.
64
Discuss the incidence of selective IgA deficiency, and the associated syndromes.
is the most common immunodeficiency disease, with a prevalence of about 200 in 100,000. Although it is usually asymptomatic, the patient may have diarrhea and sinopulmonary infections, or an increased frequency and severity of allergies. There is a familial tendency, and although several mechanisms have been proposed, none is yet clearly established. It is 10-15 times more frequent (or more frequently diagnosed) in people with celiac disease.
65
Describe the immunological problem of the Nude mouse, and name the human immunodeficiency condition it resembles.
Nude mice fail to make a thymic stroma (and hair) and so they have no T cells, and are immunologically similar to DiGeorge kids.
66
Discuss transplantation therapy in immunodeficiency diseases. Include a consideration of possible complications.
For SCID, bone marrow transplantation has about a 50% success rate, but graft-versus-host disease is always a problem. ►It is better to transplant purified stem cells than whole bone marrow. Sibling donors are the best, and a good Class II MHC match is imperative. For ADA- deficient patients, transfusions of irradiated red cells can be helpful.
Infection still is a great problem in bone marrow transplantation, before the marrow has a chance to “take;” major culprits are latent viruses of the herpes family, like CMV (cytomegalovirus) and EBV (Epstein- Barr virus).
67
On a diagram of a lymph node, label T and B cell areas.
68
Given a child with recurrent infections, describe in principle tests which could be done to determine if there is a T, B or combined immunodeficiency, or a PMN, macrophage or complement problem.
69
Describe the contents and routes of administration of commercial gamma globulin (IVIG) and indicate the conditions in which it can be useful replacement therapy.
Human immunoglobulin, where B cell function is deficient. This must be given approximately monthly. It is pooled from many donors, and is usually about 99% IgG, with a half-life of 3 weeks. The standard of treatment now is a form for IV use (IVIG) from several manufacturers; effective but expensive, and often in short supply. Recently, a preparation for slow subcutaneous infusion (SCIG) that can be done at home has been approved.
70
Name two viruses which are immunosuppressive in humans and discuss a possible mechanism for the immunosuppression caused by one of these viruses.
Many viral illnesses, especially measles, mononucleosis, and cytomegalovirus (CMV) infection, are immunosuppressive, and secondary infection is common. Acquired Immune Deficiency Syndrome or AIDS is the most serious condition involving secondary immunodeficiency.
71
List the two main features that characterize myelodysplastic syndrome (MDS).
MDS is a group of conditions where the marrow is replaced by a malignant clone, derived from a transformed stem cell or progenitor cell, characterized by:
1) ineffective hematopoiesis: the clone is not able to make normal functioning blood cells. In fact, they are often die before leaving the marrow, and usually look abnormal (dysplastic)
2) increased risk of transformation to acute leukemia: MDS is often regarded as a precursor to acute myeloid leukemia (AML)
72
List the two clinical scenarios of MDS.
1) Primary (idiopathic) MDS
* Median age at diagnosis: 70; usually over 50
* Incidence of 3-5 cases per 100K persons per year; incidence is significantly higher in elderly persons
2) Secondary MDS (usually therapy-related MDS (t-MDS))
* Occurs as part of the spectrum of therapy-related AML
* Usually diagnosed 2-8 years following therapy with DNA-alkylating agents or ionizing radiation
* Usually contains complex karyotype with whole or partial deletions of chromosomes 5 and/or 7
73
List three different types of tests that could be performed to make a diagnosis of MDS.
1) Morphologic evidence of dysplasia
2) Increased myeloblasts, but less than 20% of blood and marrow cells
3) Presence of a clonal cytogenetic abnormality
74
List four possible causes of secondary myelodysplasia that might mimic MDS.
In a patient with suspected MDS, but negative for elevated myeloblasts and negative for a clonal cytogenetic abnormality, and only having morphologic evidence of dysplasia, be sure to exclude potential causes of secondary myelodysplasia. These include:
1. VITAMIN DEFICIENCY (B12, folate, etc.)
2. TOXIN EXPOSURE (e.g. heavy metals)
3. EXPOSURE TO CERTAIN DRUGS
4. VIRAL INFECTIONS
75
Contrast low grade MDS and high grade MDS with regards to diagnostic criteria and prognosis.
LOW GRADE MDS: Myeloblasts are not increased in frequency (myeloblasts account for \<5% of marrow cells and \<2% of blood cells)
* relatively good prognosis
HIGH GRADE MDS: Myeloblasts are increased in frequency, but less than 20% (myeloblasts account for 5-19% of marrow cells, and/or 2-19% of blood cells)
* relatively dismal prognosis
76
Compare and contrast MDS and myeloproliferative neoplasms (MPNs) in regards to usual number and appearance/functionality of cells in the blood and marrow.
MDS: Cells look all fucked
MPN: The neoplastic clone usually gives rise to increased numbers of normal (not dysplastic) blood cells in one or more lineages
77
List two reasons for the frequent occurrence of splenomegaly and hepatomegaly in patients with MPNs.
1) sequestration of excess blood cells
2) extramedullary hematopoiesis
78
List three possible negative end points for MPNs.
Prognosis for high grade MDS is dismal; even if patients don't
1) progress to AML they
2) die secondary to their bone marrow failure.
3) ???
79
Compare and contrast the four MPNs covered in the notes with regard to
blood cell counts,
marrow findings, and
usual cytogenetic and molecular abnormalities.
1) Chronic myelogenous leukemia (CML) - CML is a clonal hematopoietic stem cell disorder, associated with the presence of the BCR-ABL1 gene
* Blood cell counts:
* The WBC count: 12,000 to 1,000,000 (average 100,000) (average upper limit of normal for WBC count at UCH is 11,000)
* neutrophilia, basophils are also almost always increased, and platelets are often increased but may be normal.
* Marrow: markedly hypercellular marrow,
* Morphology: no dysplasia seen in the marrow or blood.
2) Polycythemia vera (PV) - increase in RBC mass (erythrocytosis)
* Blood cell counts: increased neutrophils and platelets
* Marrow: showing trilineage hyperplasia, clusters of large, bizarre megakaryocytes.
* Morphology:
3) Primary myelofibrosis (PMF)
* Blood cell counts: characterized by proliferation of the granulocytic and megakaryocytic lineages, with eventual progression to myelofibrosis (thus, it's very similar to PV, but lacks the erythrocytosis).
* Marrow: significant reticulin fibrosis (reticulin is type 4 collagen), with loss of much of the marrow space.
* Morphology:
The peripheral blood shows a picture known as leukoerythroblastosis, where there are increased immature granulocytes (myelocytes, metamyelocytes) and increased immature nucleated red blood cells present. In addition, there are many tear drop shaped red blood cells (dacrocytes).
4) Essential thrombocythemia (ET)
* Blood cell counts: markedly increased platelet counts (thrombocytosis)
* Marrow: clustered atypical megakaryocytes in the marrow are even larger and more bizarre than in PMF
* Morphology:
80
Explain why there is a need for a second and third generation of protein tyrosine kinase inhibitors (PTKIs).
Some CML patients developed resistance to imatinib, largely through mutations altering the imatinib binding site of the fusion protein; thus, second and third generation PTKIs are now in use for CML
81
Recall the most common method of death attributable to disease in polycythemia vera (PV) patients, and list three sites where thrombosis should always make one consider the possibility of PV.
PV is an MPN chiefly characterized by an increase in RBC mass (erythrocytosis)
Thrombotic events are the most common PV-related cause of death
Thrombosis of the following should always raise the possibility of PV.
1) mesenteric vein
2) portal vein
3) splenic vein
82
Recall the (somewhat archaic) most common treatment for PV.
bloodletting (serial phlebotomy) - apparently still used
83
Describe findings that might be seen in a peripheral blood smear of a patient with leukoerythroblastosis and how these findings relate to patients with marrow fibrosis.
leukoerythroblastosis: increased immature granulocytes (myelocytes, metamyelocytes) and increased immature nucleated red blood cells present. In addition, there are many tear drop shaped red blood cells (dacrocytes).
Marrow fibroblasts: Bone marrow with significant reticulin fibrosis (reticulin is type 4 collagen), with loss of much of the marrow space.
both of those suggest PRIMARY MYELOFIBROSIS
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85
Describe the molecular and cellular details of the immunologic mechanisms by which tissue damage occurs in a Type II ("cytotoxic antibody") reaction.
Type II: Pathology due to IgG, IgM, or IgA auto antibodies
1) neutralization
2) complement-mediated damage
3) "stimulatory hypeersensitivity" - mimicks whatever hormone or factor normally works at that receptor.
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MYASTHENIA GRAVIS
autoantibodies against AChR in the muscle (complement and neutrophil mediated destruction)
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DRESSLER SYNDROME
people make autoantibodies to heart pericardial or myocardial antigens after a heart attack
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Rhematic Heart disease
disease occurring shortly after a streptococcal infection. cross-reaction between a Group A Streptococcus M-protein antigen and structure on heart endothelial lining (probably laminin on heart valves)
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Goodpastrue syndrome
antibodies to basement membranes - persistent glomerulonephritis, and pneumonitis with pulmonary hemorrhages.
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AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)
this may follow a viral infection, or be associated with another autoimmune syndrome, or cancer. ►Many drugs, such as penicillin, methyldopa, chlorpromazine and quinidine, can induce AIHA, usually temporarily. In the rare condition paroxysmal cold hemoglobinuria (PCH), the patient experiences hemolysis after exposure to cold. It is due to an autoantibody which only binds to red cells at about 15 C.
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AUTOIMMUNE THROMBOCYTOPENIC PURPURA (ATP)
These patients have bleeding abnormalities due to destruction of platelets (thrombocytes) by autoantibody
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GRAVES disease
‘stimulatory autoimmunity’ to the TSH receptor on thyroid cells.leading cause of hyperthyroidism.
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Hashimoto disease
thyroglobulin (the molecule in which iodine is stored) and thyroid peroxidase, and the pathological process is inflammatory and destructive (with both antibody and T cells involved). leading cause of hypothyroidism
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Describe the mechanism of rheumatic heart disease, and discuss reasons its incidence has declined in the West but not in developing countries.
Cross reaction of antibodies between Group A Streptococcus M-protein antigen due to infection and heart valves. This trend has been attributed to improved living conditions, the use of antibiotics for Strep pharyngitis and possibly shifting strep serotypes.
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Compare and contrast the immunopathologic mechanisms of Graves and Hashimoto thyroiditis.
GRAVES disease- ‘stimulatory autoimmunity’ to the TSH receptor on thyroid cells. leading cause of hyperthyroidism.
Hashimoto disease - thyroglobulin (the molecule in which iodine is stored) and thyroid peroxidase, and the pathological process is inflammatory and destructive (with both antibody and T cells involved). leading cause of hypothyroidism
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Distinguish between the "lumpy-bumpy" and "linear" immunofluorescent patterns in terms of the most probable immunopathologies they represent.
In Goodpasture the antibody is directed against the basement membrane, not trapped as clumps, so the staining by immunofluorescence is
sharp and ‘linear,’ (Type II)
not ‘lumpy-bumpy’ as it is in Type III, immune complex conditions.
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Given patient's serum, fluorescent antibody to human immunoglobulins, and slices of normal kidney, describe how you could tell if the patient's glomerulonephritis was due to Goodpasture's Disease.
1) incubate slices with primary antibody found in serum
2) stain antibody from serum with fluor tagged anti-human ab
3) visualize under microscope. look for smooth, linear curvatures
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Describe how antibody-mediated tissue damage could result from the innocent bystander phenomenon, cross-reaction of a foreign antigen with self, coupling self antigen with a foreign antigenic "carrier," exposure of a sequestered antigen, and inadequacy of regulatory T cells.
A common mechanism, in which there is damage to normal tissue which happens to be associated with or infected by the antigen, which is truly foreign. Imagine a drug adhered to your red blood cells, and you made antibody against the drug. What would get lysed by complement—the drug? No, the poor innocent red cell.
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Discuss how the Aire gene is involved in preventing autoimmune disease.
AIRE controls the expression of proteins from other parts of the body in the thymus. It does this to present those proteins to developing T-cells to make sure they do not cross react to them. If they do cross react, they are removed via clonal deletion
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Describe the basic anatomy of a normal lymph node
Basic lymph node architecture
* *Capsule:** usually thin and fibrous. Can be thickened and fibrotic in reactive conditions (i.e. syphilitic lymphadenitis) or neoplastic processes (i.e. nodular sclerosis Hodgkin lymphoma)
* *Cortex**: lymphoid follicles (primary and secondary), and paracortex (interfollicular T-cell zone)
* *Medulla**: medullary cords (lymphocytes, plasma cells, macrophages, and dendritic cells) and medullary sinuses Sinuses: subcapsular, cortical and medullary
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classic B cell marker and T cell marker
B cell - CD20
T cell - CD3
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where in the body are BCL6 and CD10 expressed on B-cells?
expressed on B cells in the germinal center
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Follicular lymphoma
Lymphoma of the germinal center. B cell origin
40% of adult lymphomas in the US, 20% worldwide
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what is the origin on Mantle cell lymphoma?
B cells. should express CD19 and CD20
They charicteristically express cyclin D1 (BCL1)
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Burkitt Lymphoma (BL)
§Endemic BL
* Typically in the malaria belt of equatorial Africa
* Age: peak 4-7 years of age
* Locations: jaw or abdomen
* 95% associated with Epstein-Barr virus infection (EBV)
§Sporadic BL
* Mostly in children or young adults
* Common location: Ileocecal area
* ~30% associated with EBV infection
§Immunodeficiency-associated BL
* Primarily in HIV patients
* 25-40% associated with EBV infection
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what precursor gives rise to neutrophils, basophils, and eosinophils?
Myeloblast
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