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Flashcards in Path Exam 2 Review Deck (53):
1

Iron deficiency anemia may be characterized as what type of maturation defect?

Cytoplasmic

2

 What is the functional classification of iron deficiency anemia? morphologic classification?

Iron deficiency is an example of ineffective erythropoiesis.  The marrow has increased numbers of erythroid precursors, but they fail to mature appropriately, resulting in decreased production of mature red cells.  Iron deficiency is morphologically an example of microcytic hypochromic anemia, along with thalassemia minor and some examples of anemia of chronic disease.

3

_________ is a special stain that colors hemosiderin (a storage form of iron) blue.

Prussian blue

4

What is the biochemical basis of delayed nuclear maturation in megaloblastic anemias?

Folate is required for the synthesis of deoxythymidylate monophosphate, which in turn is required for DNA synthesis.  Vitamin B12 is essential for the synthesis of the biologically active form of folic acid, tetrahydrofolate. Thus, in vitamin B12 deficiency, there is an internal folate deficiency.

5

What are other causes of macrocytic anemia?

Other causes of macrocytic (but not megaloblastic) anemia include reticulocytosis, alcoholism, liver disease, dyserythropoietic bone marrow disorders, and hypothyroidism, but the MCV rarely reaches levels above 110 to 115 fL in these disorders.  These are not due to impaired DNA synthesis.

6

Why does the normoblast contain increased mRNA?
 
 

The reason the normoblast has increased mRNA is because it is assembling the cellular machinery to engage in protein production: specifically, the hemoglobin alpha and beta globin molecules.

7

How does one explain the marked hypercellularity of the marrow in megablastic anemia if the cell cycle is slowed down?
 

While each proliferating cell is progressing through the cell cycle at a considerably slower rate than normal, a much higher proportion of marrow cells are cycling than in normal marrow.

8

What is the pathogenesis of aplastic anemia? How is it treated?

Aplastic anemia is characterized by anemia, neutropenia, and thrombocytopenia. It results from a primary failure or immunologically mediated suppression of multipotent myeloid stem cells. As a result, there is inadequate production or release of the differentiated cell lines. Some cases follow exposure to chemicals, drugs, or viral infections (particularly hepatitis). Bone marrow transplantation is curative. In cases where transplantation is not possible, immunosuppressive therapy (eg, antithymocyte globulin, steroids, cyclosporine) is implemented.

9

 What are the major categories of intrinsic red blood cell abnormalities?

Hemoglobin disorders, membrane disorders, and enzyme deficiencies.

10

What laboratory test results may be used to document increased red cell destruction?

Increased serum indirect bilirubin, increased serum lactate dehydrogenase, decreased serum haptoglobin, and increased fecal urobilinogen.

11

How does one distinguish ß-thalassemia minor from iron deficiency anemia?

Hemoglobin A2 is elevated in §-thalassemia minor (trait) and normal in the other microcytic anemias.

12

What are the inheritance pattern, red cell defect, mechanism of hemolysis, and treatment in hereditary spherocytosis?
 

This disease is caused by a genetic defect (most commonly autosomal dominant) in the red cell membrane cytoskeleton. Abnormal red cells get trapped within the cords of the splenic red pulp and are destroyed by macrophages. Transfusions and/or splenectomy are sometimes necessary.

13

 What is the cause of hemolysis in immune hemolysis?

The in vivo agglutination property of these antibodies is not the cause of the hemolysis; rather, their ability to fix complement on the red cell surface at relatively low temperatures results in intravascular hemolysis. In addition, at 37ĄC, IgM antibody is released from the cell surface, leaving a coating of C3b. This is an opsonin, and such opsonized red cells are destroyed by monocyte-macrophages. Thus, there is extravascular hemolysis as well.

14

 What is the molecular consequence of the t(9;22)?

Translocation of the ABL oncogene on chromosome 9 to the BCR gene on chromosome 22.

15

 Do all cases of CML have a Philadelphia chromosome?

No. It is absent in ~5% of cases. However, these cases lacking cytogenetic evidence of a Philadelphia chromosome possess an occult BCR/ABL translocation. Thus, the BCR/ABL rearrangement, rather than the cytogenetically evident translocation, is the necessary genetic event in CML.

16

What is the prognosis of blast transformation of CML?

Dismal. Once blast phase has occurred, the clinical course is generally one of rapid progression to death. Therapy at this time generally confers little benefit.

17

 What does the existence of a lymphoid blast phase imply about the nature of the transformed cell in CML?

It implies that the pluripotent stem cell that is transformed in CML has the capacity to differentiate into B cells. In fact, patients with CML commonly have circulating mature B cells containing the Philadelphia chromosome. 

18

Is there any clinical significance to distinguishing lymphoid from myeloid blast phase?

The two forms of blast phase are treated differently. Lymphoid blast phase responds better to therapy than does myeloid blast phase, and thus there is a somewhat longer survival (although it is still poor).

19

 What are the main clinical manifestations of P. vera?

Thrombosis and hypertension.

20

Does P. vera undergo any type of transformation? Is the rate of transformation related to the form of therapy?

Blast phase supervenes in 1-10% of patients. The low end of this range is seen in patients who are treated with phlebotomy, whereas much higher rates of blast phase occur in patients treated with alkylating agents or 32P. A second type of transformation is known as the spent phase. This represents progressive marrow fibrosis with eventual marrow failure and death due to the consequences of cytopenia. This occurs in 10-20% of patients.

21

 What are the clinical manifestations of ET?

Hemorrhage (most commonly) and thrombosis. The paradoxical presence of hemorrhage in a state with increased platelets is due to abnormalities of platelet function in this disorder.

22

Is it easy to distinguish ET from reactive thrombocytosis?

NO

23

What is the treatment for ET?
 

A variety of agents are used to reduce the number and function of the platelets in ET. However, it is very difficult to determine which patients will suffer significant morbid complications and which will have benign courses. As a result, some oncologists will not treat routinely until the appearance of complications.

24

 What is the clinical course of PM?

Patients with PM experience progressive marrow fibrosis and failure, resulting in death from cytopenia after a median survival from diagnosis of 5 years. Blast phase occurs in 5-10% of patients.

25

 How do PM and the spent phase of P. vera differ?

The spent phase of P. vera has essentially identical hematologic and pathologic features to PM, emphasizing the relatedness of these disorders. It differs only in that patients with the spent phase of P. vera tend to have a relatively rapid, progressive, downhill course.

26

What is the molecular abnormality associated with the t(15;17), and how does it relate to disease pathogenesis and treatment?
 

The t(15;17) results in rearrangement of the retinoic acid receptor alpha gene on chromosome #17 with the PML gene on  chromosome #15. Retinoic acid is important for granulocyte maturation, and the rearrangement disrupts that pathway. Thus, the neoplastic cells are arrested at the promyelocyte stage of differentiation. Interestingly, treatment with pharmacologic doses of all-trans retinoic acid (ATRA) can overcome this maturational block and cause the neoplastic cells to mature. This treatment also ameliorates the DIC. Although remissions may be obtained with ATRA, treatment with conventional chemotherapy is necessary as well to prevent certain relapse.

27

 What is the primary criterion for a diagnosis of acute leukemia?

20% blasts in blood or bone marrow. Note that the proliferating cells of acute promyelocytic leukemia, while not strictly blasts, are considered as such for the purpose of diagnosis.

28

How are myelodysplastic syndromes distinguished from myeloproliferative disorders?

While both types of disorders characteristically have hypercellular bone marrows, the hematopoiesis of myeloproliferative  disorders is effective, producing increased peripheral counts (at least initially), whereas that of myelodysplastic syndromes is ineffective, producing blood cytopenias.

29

Do diffuse large B cell lymphomas show any translocations?

About 20% of these tumors have a t(14;18) translocation similar to the one seen in follicular lymphomas. About 30% of large cell lymphomas show rearrangement of the BCL6 gene in chromosome band 3q27.

30

 What are Bence Jones proteins?

Free light chains of the immunoglobulins.

31

 What is the prognosis of transformed follicular lymphoma?

Poor; the median survival is less than 1 year. Interestingly, if the large cell transformation is successfully treated, it is not uncommon for the follicular lymphoma to recur.

32

What is a distinctive immunophenotype characteristic of CLL/SLL?

In addition to the expression of typical B-cell markers such as CD19, CD20, and surface immunoglobulin, the cells also express the T-cell-associated antigen CD5. This antigen is expressed on a small normal B-cell population in adults that is thought to be involved with autoimmunity. Among B-cell lymphomas, CD5 is expressed primarily in CLL/SLL and mantle cell lymphoma.

33

 What is the primary determinant of prognosis in CLL/SLL?

Traditionally, clinical stage. The staging of CLL depends on such factors as the presence of lymphadenopathy, splenomegaly, and cytopenias.  More recently, other biologic features of CLL/SLL have been discovered that may be more important than clinical staging.  These include the presence or absence of somatic mutation in the variable region of immunoglobin genes and expression of CD38 or Zap-70. 

34

From what stage of B-cell differentiation is MCL thought to derive?
 

Pregerminal center; specifically, primary follicle/mantle zone cells.

35

 What are the most common sites of MALT lymphoma?

The stomach, salivary glands, orbit, thyroid gland, and lung are the most common sites.

36

 Are there any common cytogenetic translocations seen in MALT lymphomas?

The most common abnormality is the t(11;18) involving the API2 and MALT1 genes.  This translocation produces a fusion protein that activates transcription factor NFKB.  The t(11;18) is seen in up to 30% of MALT lymphomas.  In the stomach, its presence is associated with high stage and refractoriness to antibiotic therapy.

37

What is the prognosis of MF?

Relatively good with a median survival of 8-9 years. Like indolent B-cell lymphomas, however, MF is commonly disseminated at presentation and is essentially incurable. Also, a small proportion may transform to a more aggressive subtype.

38

 What do you think is causing enlargement of this thyroid gland, in Hashimoto disease?

In Hashimoto disease, enlargement of the thyroid gland occurs due to infiltration by lymphoid cells.

39

 When the inflammation subsides, what will replace the damaged thyroid follicles, in Hashimoto?

Collagen will replace thyroid follicles.

40

 What does the presence of collagen tell you about the duration of this inflammatory process?

It indicates the presence of chronic inflammation which caused tissue damage and subsequent repair.

41

What factors determine whether a tissue damaged by inflammation will be replaced by a scar or by normal cells of that tissue?

This is determined by two factors.  The first is the type of cells (ie, labile, stable, or permanent). The former two types can regenerate. The second factor is whether damage to the supporting framework has occurred. If the supporting stroma collapses, then even if cells can regenerate, the normal tissue architecture cannot be replaced. This occurs, for example, in cirrhosis of the liver.

42

What are the major cells involved in the proliferative process, in lupus nephritis?

The cells that proliferate are mesangial cells and endothelial cells. Hypercellularity is also contributed to by neutrophil infiltration. In some cases (not this one) with severe glomerular injury, the epithelial cells lining the Bowman capsule may also proliferate.

43

Can you relate the low complement levels seen in this patient to the pathogenesis of SLE?
 

SLE is an immune complex disease, in which immune complexes deposited in tissues activate complement. Thus complement is consumed, and its levels in the serum are lowered. Complement levels tend to return to normal when the disease enters spontaneous or therapy-induced remission.

44

Can you name a situation in which immune complex formation occurs in the wall of the blood vessel?

In the Arthus reaction, immune complexes form in the vessel wall. Morphologically, polyarteritis nodosa resembles an Arthus reaction.

45

 What is the difference in the histologic manifestations of cellular vs. humoral rejection?

Cellular rejection is manifested as an interstitial infiltrate of lymphocytes and macrophages. These lymphocytes are T cells. Humoral rejection manifests as endothelial injury with thrombosis and resultant coagulative necrosis.

46

What are the primary target organs of acute GVHD?

The primary targets are skin, gut epithelium, bile ducts, and lymphoid tissue.

47

What are the primary determinants of successful bone marrow transplantation?

The primary determinants are:   1) Closeness of the HLA types     2) Severity of the GVHD    3) Ability of the host to withstand the conditioning regimen.

48

To prevent GVHD, can one simply deplete donor marrow of lymphocytes prior to transplantation?
 

One can deplete donor T cells, but unfortunately, the catch is that this impairs engraftment.

49

We have learned that donor T cells are necessary for bone marrow engraftment. What might be the mechanism for this phenomenon?

The exact mechanism is not known, but two possibilities are likely: (1) the donor T cells activated by host antigens could secrete cytokines like GM-CSF that help the growth of stem cells; and (2) the donor T cells could inactivate host anti-donor NK cells and T cells.

50

 How would you expect lymphoid tissues to appear during early GVHD? Late GVHD?

 

Early during GVHD, the donor cells are activated in the host lymphoid tissues, and they undergo proliferation, so the lymphoid tissue appears full of activated cells. Later, however, there is hypoplasia and atrophy of the lymphoid tissue; lymph nodes, spleen, tonsils, and thymus all look empty.

51

How long does impairment of immunologic function last post transplant without acute GVHD? With acute GVHD?

From months to about a year with only acute GVHD, and even longer in those who develop chronic GVHD.

52

Target of acute GVH in colon

The target cells are the stem cells within the crypts. 

53

What prognostic features have been identified in ALL?

Good prognostic features include: Age between 2 and 10 years; early pre-B phenotype; t(12;21); hyperdiploidy. Bad prognostic features include: Age under 2 or >10 years; t(4;11) and other rearrangements involving the MLL gene on chromosome 11; t(9;22) (the Philadelphia chromosome translocation; the presence of this abnormality in ALL is a particularly poor prognostic feature).