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Heme and Lymph Midterm > Ch 13 > Flashcards

Ch 13 Flashcards

1
Q

Blood cell progenitors first appear during _ weeks of embryonic development in _

A

3rd week,

Yolk sac

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2
Q

Definitive hematopoietic stem cells first arises where?

A

aorta/gonad/mesonephros regions

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3
Q

By 3rd month hematopoietic stem cell (HSC) migrates to what organ?

A

Liver and becomes the chief site of blood cell formation until shortly before birth

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4
Q

By what month does HSC shift location to bone marrow?

A

4th

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5
Q

until puberty hematopoietically active marrow is found where? what about after puberty?

A

Until puberty found throughout skeleton. After puberty it becomes restricted to axial skeleton (bones of head and trunk)

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6
Q

To maintain hematopoiesis, what two properties are essential of HSC? explain explain what the properties mean

A
  1. pluripotency - ability of single HSC to general ALL mature blood cells
  2. Capacity for self-renewal - during cell division, one daughter cell retains self-renewal characteristic
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7
Q

Marrow response to short-term physiologic needs is regulated by hematopoietic growth factors through effects on which cells?

A

committed progenitor cells such as CFU-G, CFU-M, CFU-eo, CFU-b, CFU-Mg, BFU-E

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8
Q

In maintaining growth and differentiation of blood cells, which growth factors act on receptors located on VERY early progenitor cells? which ones act on committed progenitor cells?

A

Early: KIT ligand, and FLT3-land

Committed: EPO, GM-CSF, G-CSF, and thrombopoietin

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9
Q

Where are hematopoietic cells located in the bone marrow?

A

within interstitium

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10
Q

what is leukoerythroblastosis?

A

abnormal release of immature precursor into peripheral blood. usually due to disease

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11
Q

what is the best way to assess morphology of hematopoietic cells?

A

Marrow aspirate smears - helps to differentiate between mature and precursors

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12
Q

best modality for estimating marrow activity

A

bone marrow biopsy - cells to get ratio of hematopoietic cells vs fat cells

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13
Q

what is the normal ratio of fat cells to hematopoietic cells?

A

normal 1:1
hypoplastic: increased fat cells ratio
Hyperplastic (cancer): increased hematopoietic cells ratio

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14
Q

what is the difference between neutropenia and agranulocytosis?

A

Neutropenia is reduced number of neutrophils in blood. Agranulocytosis is severe clinically significant reduction of leukocytes, esp neutrophils, putting pt at risk of bacterial and fungal infections

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15
Q

Common cause of neutropenia

A

1) inadeqaute or ineffective granulopoiesis (aplastic anemia, suppression of precursors with drugs, congenital disorders such as Kostman syndrome)
2) Increased destruction (immune mediated such as SLE, splenomegaly, increased peripheral utilization)
3) idiopathic (LGL leukopenia)

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16
Q

with Neutropenia and granulocytosis, how does the marrow respond?

A

Neutropenia –> marrow hypercellularity

Agranulocytosis –> marrow hypocellularity (usually cuz of drugs)

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17
Q

Main clinical feature of neutropenia and agranulocytosis

A

related to infection: malaise, chills, fevers, weakness, fatigability

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18
Q

Serious infections are likely with neutrophils below what level?

A

500

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19
Q

Main treatment in pts with neutropenia/agranulocytosis

A
  • braod-specturm abx to prevent infections

- in case of mylosuppressive chemo treat with G-CSF

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20
Q

Factors that influence of leukocytosis

A
  • size of myeloid and lymphoid precursor and storage cell pools
  • rate of release
  • proportion of cells struck to endothelial cells
  • rate of extravasation into tissue
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21
Q

Common cause of increased production in the marrow leading to leukocytosis

A
  • chronic infection or inflammation; paraneopastic, myloproliferative disorders
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22
Q

common causes of increased release from marrow stores leading to leukocytosis

A
  • endotoxemia
  • infection
  • hypoxia
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23
Q

common cause of decreased margination leading to leukocytosis

A
  • exercise

- catecholamines

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24
Q

common cause of decreased extravasation into tissues leading to leukocytosis

A

glucocorticoids

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25
Q

During acute infection what leads to egress of mature leukocytes from marrow pool?

A

TNF and IL1

IL5 –> eosinophils
G-CSF–> neutrophils

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26
Q

Common cause of neutrophilic leukocytosis

A
  • acute bacterial infection, esp pyogenic organism
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27
Q

common cause of eosinophilic leukocytosis

A
  • allergic disorders such as asthma, hay fever, parasites, malignancies
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28
Q

Common cause of basophilic leukocytosis

A
  • rare but indicative of myeloproliferative diseases (e.g. CML)
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29
Q

Common cause of Lymphocytosis

A
  • accompanies monocytosis and seen in chronic immunologic stmulation (TB, viral infection; Bordetella pertussis
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30
Q

Common cause of monocytosis

A
  • chronic infection (TB), bacterial endocardittis, rickettsiosis, malaria, autoimmune disorders (SLE),; IBD
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31
Q

In sepsis or severe inflammatory disorders, what morphological changes in neutrophils are seen

A
  • toxic granulation: cells are coarser and darker (represents abnormal azurophilic (primary) granules)
  • Dohle bodies: patches of dilated ER that appears sky blue cytoplasmic puddles
  • Cytoplasmic vacuoles
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32
Q

Usually it’s easy to distinguish from reactive and neoplastic leukocytoses. In what situation does it become uncertain?

A
  1. acute viral infection, esp in kids where theres increased number of lymphocytes
  2. severe infection leading to immature granulocytes in blood mimicking myeloid leukemia (Leukemoid reaction)
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33
Q

Morphology of nonspecific lymphadenitis

A
  • nodes are swollen, grey red, engorged
  • large reactive germinal center with many mitotic figures
  • with pyogenic infection: neutrophils are prominent
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34
Q

In chronic nonspecific lymphadenitis, follicular hyperplasia is seen with activation of what kind of immune response?

A

humoral

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35
Q

what is tingible body macrophages?

A

found in germinal center of follicular hyperplasia in chronic nonspecific lymphadinitis. They represents DC and macrophages that are interspersed among B cells

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36
Q

What features favor reactive (nonneoplastic) vs hyperplasia of neoplasm?

A
  • presevation of lymph nodes architecture
  • marked variation in shape and size of follicles
  • presence of frequent mitotic figures, phaogcytic macrophages and recognizable light and dark zones
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37
Q

Paracortical hyperplasia of lymph nodes are seen in what kind of response?

A

T cell triggered response such as viral infection

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38
Q

what is sinus histiocytosis?

A

increased number of size of cells that line lymphatic sinusoids, common in lymph nodes draining cancers such as breast cancer.
- linings of lymphatic cells are marked hypertrophied and macrophages are increased in number

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39
Q

collection of immune cells in nonlymphoid tissue (tertiary lymphoid organs) are usually seen in what kind of lymphadenitits?

A

chronic nonspecific lymphdenitis. (example H pylori –> peyer’s patches)

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40
Q

_ is reactive condition marked by cytopenias and signs and symptoms of systemic inflammation

A

hemophagocytic lymphohistiocytosis (HLH)

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41
Q

HLH is caused by

A

systemic activation of macrophages and CD8 T cells –> cytokine storm –> shock-like presentation

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42
Q

which form of HLH is more severe?

A

familial form.. needs hematopoietic stem transplant

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43
Q

what is the treatment for HLH?

A

immunosuppressive drugs and mild chemo

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44
Q

survival rate o HLH without treatment

A

less then 2 months. with treatment 1/2 live with significant sequelae such as renal damage.

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45
Q

what s/s are associated with a severely enlarged spleen?

A

Dragging sensation in LUQ and pressure on stomach, and discomfort after eating

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46
Q

what lab findings are also associated with hypersplenism?

A
  • anemia
  • leukopenia
  • thrombocytopenia
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47
Q

Morphology of an enlarged spleen

A

Gross: enlarged and soft
Micro: acute congestion of red pulp –> may efface lymphoid follicles; neutrophils, plasma cells, sometimes eosinophils in red and white pulps

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48
Q

Congestive splenomegaly results from

A

chronic venous outflow obstruction leading to splenic or portal HTN. Less commonly it can be due to right-sided cardiac issues

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49
Q

morphology of congestive splenomegaly

A
  • enlarged (1000-5000gm); firm, capsule is thickened and fibrous
  • Micro: collagen deposition in BM –> dilated rigit walls sinusoids –> prolonged flow and exposure to macrophages –> excessive destruction —> hypertension
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50
Q

Splenic infarcts are usually occlusion of major artery or it’s branches by emboli arriving from _

A

heart

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51
Q

Differentiate between bland vs septic infarcts

A 
Bland infarcts (emboli coming from heart ) --> pale, wedge shaped subcapuslar 
- Septic infarcts --> suppurative necrosis
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52
Q

Malignancies of white cells fall under what broad categories?

A

Lymphoid neoplasm (tumors of B, T and NK cells)

  • Myeloid neoplasm ( AML, myelodysplastic syndrome, CML)
  • Histiocytoses (proliferation of macrophages and DC’s)
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53
Q

What is langerhans cell histiocytoses?

A

Immature dendritic cells

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54
Q

In etiologic and pathogenetic factors in white cell neoplasia, what is the most common pathogenetic factor?

A

chromosomal translocation

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55
Q

The most important pathogenetic cause of acute leukemias is _

A

oncoproteins that block normal maturation, and arrest differentiation of lymphoid or myeloid cells

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56
Q

what are the three major pathogenetic factors that leading to hematologic malignancies?

A
  1. Pro-growth mutation (tyrosine kinase mutation, MYC translocation)
  2. Pro-survival mutation (BCL2 translocation)
  3. Mutations in transcription factors that influence self-renewal (MLL translocation, PML-RARA fusion gene)
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57
Q

Proto-oncogenes are activated most commonly in which type of hematologic neoplasms?

A

Lymphoid

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58
Q

What inherited genetic factors puts one at an increased risk of hematologic malignancies?

A
  • Bloom syndrome
  • Fanconi anemia
  • ataxia telangiectasis
  • Down syndrome
  • NF I
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59
Q

What viruses are associated with hematologic malignancies?

A
  • HTLV1 (adult T cell leukemia/lymphoma)
  • EBV (brkitt lymphoma, Hodgkin lymphoma, B cell lymphoma)
  • Kaposi sarcoma herpesvirus/HHV8 ( B cell lymphoma)
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60
Q

What factors causing chronic inflammation is associated with hematologic malignancies?

A
  • H hypoli ( gastric B cell lymphomas)
  • Gluten-sensitivity enteropathy (T cell lymphomas)
  • Breast implants (T cell lymphomas)
  • HIV ( B cell lymphomas)
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61
Q

Smoking is a common risk factor for which hematologic malignancy?

A

AML

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62
Q

_ is defined as neoplasm that present with widespread involvement of bone marrow and usuallly peripheral blood

A

Leukemia

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63
Q

_ is defined as proliferation that arises as discrete tissue masses

A

lymphoma

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64
Q

Lymphoid Neoplasms are classified into _

A
  1. Hodgkin lymphoma
  2. Non-hodgkin lymphoma
  3. Plasma cell neoplasm (Multiple myeloma)
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65
Q

Most NHL and almost all HL presents as enlarged nontender lymph nodes greater than

A

2cm

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66
Q

_ causes bony destruction of skeleton and often presents with pain due to pathologic fractures

A

Multiple myeloma

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67
Q

In contrast to normal immune responses, population of lymphocytes derived from malignant progenitor share _

A

same antigen receptor gene configuration and sequence and synthesize identical antigen receptors proteins (either Igs or T cell receptors)

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68
Q

85-90% of all lymphoid neoplasm are of _ cell origin

A

B

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69
Q

Neoplastic B and T cells tend to recapitulate the bahaviior of their normal counterparts, except which malignancy?

A

Hodgkin’s lymphoma and marginal zone B cell lymphomas. HL are restricted to one group of lymph nodes; and marginal zone B cell lymphomas are often restricted to sites of chronic inflammation

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70
Q

Acute lymphoblasticc leukemia/lymphomas (ALL) are composed of what kind of cells?

A

immature B (pre-B) or T (pre T), referred to as lymphoblastss

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71
Q

85% of B-ALL occur in what patient population?

A

childhood

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72
Q

T-ALL are less common and are seen in what patient population?

A

Adolescent male as thymic lymhomas

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73
Q

ALL is due to chromosomal aberration that dysregulate _ factors

A

Transcription

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74
Q

70% of T-ALL are due to gain of function mutation in

A

NOTCH1

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75
Q

B-ALL is due to loss of function mutation in genes required for B cell development such as _

A

PAX5, E2A, EBF or balanced t(12;21) involving ETV6 and RUNX1

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76
Q

ALL requires multiple mutations for oncogenesis. Common comlementary mutation include:

A

increased tyrosine kinase activity and RAS signaling

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77
Q

90% of ALL have numerical or structural chromosomal changes, of which most common is _

A

hyperploidy ( >50 chromosomes)

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78
Q

Morphology of ALL

A
  • In leukemic presentation: marrow is hypercellular and packed with lymphoblasts
  • Histo: scant basophilic cytoplasm and somewhat larger nuclei; rapidly growing tumor look like starry night
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79
Q

Distinguish ALL from AML

A
  • Compared to myeloblast, lymphoblast have more condensed chromatin, less conspicuous nuclei and smaller amounts of cytoplasm and usually lacks granules
  • Lymphoblast is negative for myeloperoxidase; and positive for Acid-Schiff
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80
Q

In immunophenotyping what are the markers for B-ALL

A

CD19; TF TAX5 and CD10 (except in very immature B-ALL); late B-ALL express CD10, CD19, and CD20 and cytoplasmic IgM

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81
Q

In immunophenotyping what are the markers for T-ALL

A

CD1, CD2, CD5, CD7

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82
Q

Symptoms of ALL

A
  • abrupt onset after first symptom
  • Symptoms related to depression of marrow function (fatiue due to anemia, fever, infection, bleeding)
  • Mass effects: bone pain, lymphadenopathy, splenomegaly, hepatomegaly; testicular enlargement; and T-ALL complication is related to compression of large vessels and airways in mediastinum)
  • CNS: HA, vomitting, nerve palsies
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83
Q

Prognosis of ALL in kids vs adults

A
  • in kids 90% complete remission with aggressive chemo.

- 35-40% remission in adults

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84
Q

Factors associated with worse prognosis of ALL

A
  • age <2 associated with MLL gene
  • presentation in adolescence or adulthood
  • peripheral blood blast count >100,000
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85
Q

Factor associated with favorable prognosis of ALL

A
  • age 2-10
  • low WBC
  • hyperdiploidy
  • Trisomy of chromosome 4, 7 , 10
  • Presence of t(12;21)
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86
Q

Chronic lymphocytic leukemia (CLL) presents as lymphocytosis, Absolute lymphocytes greater than _

A

5000

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87
Q

What is the most common leukemia of adults in the western world?

A

CLL

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88
Q

demographic of CLL

A

average age 60 with 2:1 male dominance

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89
Q

In the pathogenesis of CLL, deletion of what are most common?

A

13q14.3; 11p; 17p

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90
Q

which trisomy is common in CLL/SLL

A

12q

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91
Q

In CLL tumors with what pursue a more aggressive course?

A

unmutated Ig segments

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92
Q

Gain of function mutation in what gene is implicated in 10-18% of CLL

A

NOTCH1

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93
Q

Morphologically, presence of what is pathognomonic for CLL/SLL

A

proliferation centers (admixed aggregates of mostly small lymphocytes and some larger activated lymphocytes)

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94
Q

How do chronic lymphocytic leukemia and small lymphocytic lymphoma differ?

A

differ in the degree of peripheral blood lymphocytosis

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95
Q

what are smudge cells?

A

In morphology of CLL/SLL, referring to small round lymphocytes with scant cytoplasm that been be disrupted in the process of making smears.

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96
Q

Immunophenotype of CLL/SLL

A

tumor cells express the pan B-cell markers: CD19, CD20 as well as CD23, and CD5

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97
Q

Clinical features of CLL/SLL

A
  • nonspecific (easy fatigability, wt loss, anorexia)
  • generalized lymphadenopathy and hepatosplenomegaly
  • variable leukocyte count
  • small monoclonal Ig spike in some pts
  • disruptions of normal immune function
  • hypogammaglobulinemia –> infection
  • hemolytic anemia, thrombocytopenia in some
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98
Q

Overall median survival rate of CLL/SLL

A

4-6 yrs; in those with low tumor burden survival rate is more than 10 yrs

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99
Q

factors that correlate with worse prognosis of CLL/SLL

A
  1. presence of deletion of 11q and 17q
  2. lack of somatic hypermutation
  3. expression of ZAP-70
  4. presence of NOTCH1 mutation
  5. capacity to transform into more aggressive tumor such as large B cell lymphoma (Richter syndrome)
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100
Q

Typical treatment fo CLL/SLL

A

chemo and immunotherapy against CD20

- hematopoietic stem cell transplantation in young pts

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101
Q

_ is clonal proliferation of incompetent B cells

A

CLL

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102
Q

A pt with CLL presents with wt loss, fever, night sweats, cachexia and lyphadenopathy. what is the most likely cause?

A

Richter syndrome/transformation

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103
Q

THe most common form of indolent NHL in the US

A

follicular lymphoma

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104
Q

Follicular lymphoma arises from 1 and is strongly associated with chromosomal translocation involving 2

A
  1. germinal center B cell

2. BCL2

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105
Q

_ is defined as small-size B cell proliferation in the follicles

A

Follicular lymphoma

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106
Q

The main pathogenetic cause of follicular lymphoma

A

(14;18) translocation that juxtaposes the IGH locus on chromosome 14 and BCL2 locus on chromosome 18 –> overexpression of BCL2 –> antagonizes apoptosis and promote survival of follicular lymphoma cells

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107
Q

In 90% of follicular lymphoma, epigenetic abnormalities is almost implicated, particularly mutation in _ gene

A

MLL2

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108
Q

Morphology of follicular lymphoma

A
  • nodular or nodular and diffuse growth pattern in lymph node
  • presence of small cells with irregular or cleaved nuclear contours and scant cytoplasm referred to as centrocytes
  • presence of larger cells with open nuclear chromatin many nucleoli and modest cytoplasm, referred to as centroblats
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109
Q

Immunophenotype of follicular lymphoma

A
  • resemble normal germinal center B cells, expressing Cd19, CD20, CD10, surface Ig, and BCL6 (normal is BCL6 negative)
  • CD5 is NOT expressed unlike CLL/SLL and mantle cell lymphoma
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110
Q

Clinical features of follicular lymphoma

A
  • painless generalized lyphadenopathy

- extranodal sites involvement is uncommon

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111
Q

Prognosis of follicular lymphoma

A
  • incurable
  • indolent course, waxes and wanes
  • Survival median 7-9 yrs; aggressive therapy does not improve
  • Histologic transformation to diffuse large B cell lymphoma in 30-50%; median survival after transformation is 1 yr
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112
Q

_ is large-size B cell proliferation

A

Diffuse Large B-cell lymphoma (DLBCL)

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113
Q

Most common subtype of NHL

A

DLBCL

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114
Q

Demographics of DLBCL

A

males, 60s, but can occur in young adults and kids too

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115
Q

In the pathogenesis of DLBCL, frequent pathogenic event is dysregulation of _

A

BCL6 - needed for normal germinal center formation

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116
Q

In 30% of DLBCL there are various translocation that have in common a breakpoint in BCL6 at chromosome

A

3q27

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117
Q

10-20% of DLBCL are associated with what translocation?

A

14;18 –> overexpression of BCL2

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118
Q

5% of DLBCL are associated with translocation involving

A

MYC

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119
Q

Distinct morphology of DLBCL

A

large cell size and a diffuse pattern of growth

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120
Q

Immunophenotype of DLBCL

A

CD19 and CD20 and variable expression of germinal center B cell markers such as CD10 and BCL6

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121
Q

two special subtypes of DLBCL associated with viral infections

A
  1. Immunodificiency-associated large B cell lymphoma (common with advanced HIV infection and allogeneic bone marrow transplant. Neoplastic B cells are usually infected with EBV
  2. Primary effusion lymphoma (commonly in pts with advanced HIV); tumor cells are often anaplastic and fail to express surface B or T cell markers but have clonal IgH gene rearrangements . usually infected with KSHV/HHV8
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122
Q

Clinical features of DLBCL

A
  • typically presents as a rapidly enlarging mass at a nodal or extranodal site
  • waldeyer ring, oropharyngeal lymphoid tissue that includes tonsils and adenoids are commonly involved
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123
Q

Prognosis of DLBCL

A
  • Very aggressive with poor prognosis without treatment

- with intensive combo of chemo –> 60-80% complete remission and 40-50% cured

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124
Q

DLBCL with what translocation have a worse prognosis

A

MYC

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125
Q

_ is intermediate-size B cell proliferation

A

Burkitt lymphoma ( form of NHL)

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126
Q

Burkitt lymphoma exists in what three catregory

A
  1. African burkett lymphoma (endemic)
  2. sporadic (nonendemic)
  3. subset of aggressive lymphomas occuring in HIV infected
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127
Q

All forms of Burkitt lymphoma are highly associated with what translocation?

A

8;14 translocation: approximates the Ig heavy chain locus (14) with c-myc (8) –> increased levels of c-myc drives cell growth

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128
Q

Essentially all endemic burkitt lymphomas are latently infected with _

A

EBV, which also present in about 25% of HIV associated tumor 15-20% of sporadic cases

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129
Q

Morphology of Burkitt lymphoma

A

tumors exhibits a high mitottic index and contains numerous apoptoic cells –> starry night pattern

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130
Q

Immunophenotype of Burkitt lymphoma

A

Burkitt is tumor of mature B cells that express surface igM, CD19, CD20, CD10 and BCL6
- Negative for BCL2

131
Q

Clinical features of Burkitt’s lymphoma

A
  • both endemic and sporadic forms found in kids and young adults
  • most have extranodal sites
  • endemic forms presents as mass on mandible ad shows a unusual predilection for abd viscera, esp kidney, ovaries and adre
132
Q

Plasma cell neoplasms almost always secrete which immunoglobulin?

A

Monoclonal Ig or Ig fragment

133
Q

Most common and deadly form of plasma cell neoplasm is

A

Multiple myeloma

134
Q

A monoclonal Ig identified in the blood is referred to as

A

M component, in reference ot myeloma

135
Q

Neoplastic plasma cells along with complete Igs also synthesize excess amounts of _

A

light chains

136
Q

Pts with plasma cell tumors, the level of free _ in the blood is used as a marker since it’s usually elevated and is markedly skewed toward one type at the expense of the other.

A

Light chain (kappa vs. lambda)

137
Q

What are Bence -Jones proteins?

A

Free light chains, which are small enough, excreted out in urine. Seen in Plasma cell neoplasm such as multiple myeloma

138
Q

What terms describes the abnormal Igs associated with plasma cell neoplasms?

A
  • moonoclonal gammaopathy
  • dysproteinemia
  • paraproteinemia
139
Q

the abnormal proteins associated with plasma cell neoplasm can be seen in multiple myeloma where it usually presents as tumourous masses scattered throughout which body system?

A

skeletal system

140
Q

What is solitary myeloma?

A

aka plasmacytoma, an infrequent variant of multiple myeloma that present as a single mass in bone or soft tissue

141
Q

What is smoldering myeloma?

A

A variant form of myeloma defined by a lack of symptoms and a high plasma M component

142
Q

What is Waldenstom macroglobulinemia

A

A manifestation of the abnormal Igs seen in plasma cell neoplasm, leads to this syndrome in which high level of IgM leads to symptoms related to hyperviscosity of blood. Occurs in older adults, most commonly in association with lymphoplasmacytic lymphoma

143
Q

In plasma cell neoplasm, the abnormal Igs proteins (termed monoclonal gammopathy, dysproteinemia, and paraproteinemia) can present in which clinicopathogic entities?

A
  1. Multiple Myeloma
  2. Waldenstrom macroglobulinemia
  3. Heavy-chain disease
  4. Primary or immunocyte-associated amyloidosis
  5. Monoclonal gammopathy of undetermined significance (MGUS)
144
Q

What is heavy-chain disease?

A

rare monoclonal gammopathy that is seen in many disorders including lymphoplasmacytic lymphoma and an unusual small bowel marginal zone lymphoma that occurs in malnourished populations.
- Common feature: synthesis and secretion of free heavy chain fragments

145
Q

Primary or immunocyte-associated amyloidosis results from monoclonal proliferation of _

A

plasma cells secreting light chains (usually lambda isotype) that are deposited in amyloid

146
Q

What is monoclonal gammopathy of undetermined significance?

A

pts with plasma cell neoplasm w/o S/S who have small to moderate large M components in their blood. Common in older pts with a constant rate of transformation to symptomatic monoclonal gammopathies most often MM

147
Q

_ is defined as plasma cell neoplasm commonly associated with lytic bone lesions, hypercalcemia, renal failure, and acquired immunne abnormalities

A

Multiple Myeloma (MM)

148
Q

Demographic of multiple myeloma

A

Common in:

  • Western part of the world
  • Male
  • older adults (65-70)
  • African descent
149
Q

MM is associated with frequent rearrangement iinvolving the _ locus and various proto-oncogenes

A

IgH

150
Q

What are the common translocation involved in MM?

A

Ig heavy-chain gene on chromosome 14q32 with cyclin D1 genes on 11q13 and D3 on 6p21

151
Q

Deletion of what has a poorer outcome in MM?

A

17p that involve TP53

152
Q

Late stage, highly aggressive forms of MM are associated with acquisition of rearrnagemnts involving what gene?

A

MYC

153
Q

Deep sequencing of myeloma genomes identified frequent mutaiton involving which signaling pathway that supports that MM is due to B-cell surivival and proliferation

A

NF-kB

154
Q

The proliferation and survival of myeloma cells in MM are dependent on notably which cytokine?

A

IL6, pts with high levels of IL6 in serum has poor prognosis

155
Q

What mediates the bone destruction as seen in MM?

A

Factors produced by neoplastic cells:

  1. especially MIP1a which upregulates expression of receptor activator of NF-kB ligand (RANKL) –> activates osteoclasts;
  2. factors modulating Wnt pathway inhibits osteoblast function. Together increase in bone resorption, which leads to hypercalcemia and pathologic fractures
156
Q

Morphology of MM: presents as destructive plasma cell tumors involving what bones?

A

axial skeleton starting from my medullary cavity and erode outward

157
Q

The bone lesions of MM radiographically appear as _

A

punched out defects usually 1-4 cm in diameter

158
Q

Hislogolically, the plasma cell seen in MM can appear as _

A
  • normal appearing, plasmablasts with vesicular nuclear chromatin and a prominent single nucleolus OR
  • bizarre multinulceated cells
159
Q

Features seen in cytology of MM

A
  • Flame cells with fiery red cytoplasm
  • Mott cells with multiple grapelike cytoplasmic droplets
  • cells containing variety of inclusions such as fibrils, cyrstalline rods, and globules which are referred to as Russell bodies (if cytoplasmic) or Dutcher bodies (if nuclear)
160
Q

In MM, common blood smear finding of peripheral blood

A
  • High levels of M proteins causing RBC to stick together –> rouleaux formation
161
Q

What is myeloma kidney?

A

A clinical finding of MM where Bence Jones proteins are excreted in kidney and contribute to renal disease

162
Q

Immunophenotype of MM

A

CD138

CD56

163
Q

The clinical features of MM stems from what three factors?

A
  1. plasma cell growth in tissues esp bones –> pathologic fractures and chronic pain; hyercalcemia –> neurological manifestation (confusion, weakness, lethergy, constipation, polyuria)
  2. Production of excessive Igs with abnormal physicochemical properties –> recurrent bacterial infection; renal insufficiency (bence jones proteinuria) and prone of amyloidosis
  3. Suppression of normal humoral immunity
164
Q

Significant lab findings of MM

A
  • Increased levels of Igs in blood (>3gm/dL); commonly IgG followed by IgA
  • light chains (bence-jones proteins in urine (>6mg/dL)
  • free light chains and serum M proteins
165
Q

Definitive diagnosis of MM

A
  • radiographic finding
  • Lab finding
  • Bone marrow examination
166
Q

Prognosis of MM

A

4-7 yrs with treatments

167
Q

what factors are associated with good prognosis of MM

A

Translocation involving cyclin D1

168
Q

More aggressive and poor prognosis of MM are associated with

A

deletion of 13q, 17p and t(4;14)

169
Q

Extraosseous lesion of solitary myeloma (plasmacytoma) are seen in what locations?

A

lungs, oronasopharynx or nasal sinuses

170
Q

Prognosis of solitary myeloma (plasmacytoma)

A

progresses to MM with 10-20 years

- extraosseous plasmacytomas involving upper respiratory tract are cured by local resection

171
Q

Prognosis of smoldering myeloma

A

progresses to MM over 15 year period

172
Q

_ is the most common plasma cell dyscrasia

A

monoclonal gammopathy of uncertain significance (MGUS)

173
Q

About 1% of MGUS pts develop symptomatic plasma cell neoplasm, commonly _

A

multiple myeloma. MGUS is considered an early stage of MM, thus periodic asessment of serum M component and Bence Jones proteinuria is warranted

174
Q

_ is a B cell neoplasm of older adults that usually presents in 6th or 7th decade and has a resemblance to CLL/SLL, but with substantial fraction of the tumor cells undergoing differentiation to plasma cells

A

Lymphoplasmacytic lymphoma

175
Q

In lymphoplasmacytic lymphoma, the common plasma cell component secreted is 1 and often sufficient enough to cause hyperviscosity syndrome known as 2

A
  1. monoclonal IgM,

2. Waldenstrom macroglobulinemia

176
Q

Virtually all cases of lymphoplasmacytic lymphoma are associated with acquired mutations in 1 which encodes an adaptor protein involved in signaling events that activates 2 and augment signaling downstream of B cell receptor complex.

A
  1. MYD88

2. NF-kB

177
Q

Morphological/histological findings of lymphoplasmacytic lymphoma

A
  • marrow contains lymphocytes, plasma cells, plasmacytoid lymphocytes and sometimes mast cell hyperplasia
  • Acid-schiff-positive includsion containg Ig are seen in cytoplasm (russel bodies) or the nucleus (Dutcher bodies)
  • At diagnosis, tumor has usually disseminated to lymph nodes, spleen, and liver
178
Q

Immunophenotypic markers of lymphoplasmacytic lymphoma

A

Lymphoid component express B cell markers: CD20 and surface Ig
Plasma cell component secretes the same Ig and usually IgM.

179
Q

Clinical signs and symptoms of Lymphoplasmacytic lymphoma

A
  • nonspecific (weakness, fatigue, wt loss)
  • lymphadenopathy, hepatomegaly and splenomegaly
  • anemia
  • autoimmune hemolysis caused by cold agglutinins
  • pts with IgM secreting tumors have hyperviscosity syndrome which involves: visual impairment, neurologic problems, bleeding, cryoglobulinemia
180
Q

Prognosis of lymphoplasmacytic lymphoma

A
  • incurable progressive disease

- median survival is 4 yrs

181
Q

_ is a type of non-hodgkin’s lymphoma defined as small B cell proliferation of the area surrounding the follicular zone–the tumor resemble normal mantle zone B cells that surround germinal centers

A

Mantle cell lymphoma.

182
Q

Pathogenesis of Mantle cell lymphoma

A

t(11;14) involving IgH locus on chromosome 14 and cyclin D1 locus on chromosome 11 –> overexpression of cyclin D1 –> promotes G1 to S phase progression

183
Q

Morphology/histology of mantle cell lymphoma

A

proliferation consists of a homogenous population of small lymphocytes with irregular to occasionally deeply clefted (cleaved) nuclear contours

184
Q

Frequent site of extranodal involvement of mantle cell lymphoma

A
  • bone marrow
  • spleen
  • liver
  • gut
  • occasionally: mucosa of small and large bowel
185
Q

Immunophenotype of mantle cell lymphoma

A
  • high levels of Cyclin D1
  • Most express CD19, CD20
  • moderate level of surface Ig, esp IgM and D
  • usually CD5+ and CD23- thus helps to distinguish from CLL/SLL
186
Q

Clinical features of Mantle cell lymphoma

A

Painless lymphadenopathy

  • symptoms related to spleen involvement
  • poor prognosis (median survival 3-4yrs)
187
Q

_ is defined as a type of NHL of small heterogenous group of B cell proliferation that arise in lymph nodes margin, spleen, and extranodal tissues such as mucosa and are associated with chronic inflammatory disorders of autoimmune or infectious etiology (Sjogren, Hashimoto thyroiditis, H pylori)

A

Marginal zone lymhoma

188
Q

Pathogenetics of marginal zone lymphoma

A

Chromosomal translocations (11;18); (14;18); or (1;14). All upregulate BCL10 or MALT1 –> activates NF-kB –> promote growth and survival of B cells

189
Q

_ is defined as indolent leukemia of mature B cells with infiltration of bone marrow, common among middle aged man and associated with autoimmune conditions

A

Hairy cell leukemia (HCL)

190
Q

Pathogenetics of HCL

A

activating point mutations in serine/threonine kinase BRAF

191
Q

Histologic findings of HCL

A

Fine hair like projections. On routine peripheral blood smears hairy cells are oblong, reniform nuclei and moderate amount of pale blue cytoplasm with threadlike or bleblike extensions

192
Q

Immunophenotype of HCL

A

express pan B cell markers CD19, CD20, surface Ig (usually IgG) and certain relatively distinctive markers, such as CD11c, CD25, CD103 and annexin A1

193
Q

Clinical features of HCL

A
  • Splenomegaly
  • Hepatomegaly
  • lymphadenopathy rarely
  • Pancytopenia
  • infections
194
Q

The disease course of HCL is unusual among other cancers, how?

A

HCL is exceptionally sensitive to gentle chemo and produce long lasting remissions but oftem relapse after 5 or more years, yet generaly responds well with the same treatment. Overall prognosis is excellent

195
Q

HCL that have failed conventionally chemo have excellent response to what directed therapy?

A

BRAF inhibitors

196
Q

Peripheral T-cell lymphomas, unspecified largely a wastebasket category for tumors that do not fit any WHO with no morphologic feature thati s pathognomonic, but certain findings are characteristics. Such as _

A
  • tumors cells diffusely efface lyph nodes and are composed of pleomorphic mixture of variably sized malignant T cells
  • Infiltrates of reactive cells are common (e.g eosinophils, macrophages)
  • Have mature T cell phenotype; express pan T cell markers (CD2, CD3, CD5)
197
Q

Clinical findings of peripheral T cell lymphomas unspecified

A
  • generalized lymphadenopathy
  • eosinophilia,
  • pruritus
  • fever
  • wt loss
  • comparably worse prognosis than aggressive mature B cell neoplasm
198
Q

Anaplastic large-cell lymphoma (ALK positive) is defined by the presence of rearrangements in the 1 gene on chromosome 2

A

ALK
2p23

Creates a fusion protein that triggers RAS and JAK/STAT pathway

199
Q

Histological feature of anaplastic large-cell lymphoma

A

Large anaplastic cells some containing horseshoe-shaped nuclei and voluminous cytoplasm (hallmark cells)
- tumor cells cluster about venules and infiltrates lymphoid sinuses mimicking metastatic carcinoma

200
Q

T-cell lymphomas with ALK rearrangements tend to occur in what age group and involve what tissue?

A

kids or young adults and involve soft tissues with good prognosis

201
Q

Markers for ALK+ anaplastic large cell lymphoma

A

CD30

202
Q

Adult T cell leukemia/lymphoma is of _ T cells and only observed in adults infected by what virus?

A

CD4+

HTLV-1

203
Q

Common findings of adult T cell leukemia

A
  • skin lesions
  • generalized
  • lymphodenopathy
  • hepatosplenomegaly,
  • peripheral blood lymphocytosis and hypercalcemia
204
Q

Histological findings of adult T cell leukemia/lymphoma

A
  • multilobated nuclei (cloverleaf or flower cells)
205
Q

Pathogenesis of Adult T cell leukemia/lymphoma

A

HTLV1 provirus plays the critical role in pathogenesis. It encodes Tax that is a activator of NK-kB and enhaces lymphocyte growth and survival

206
Q

Clinical course and prognosis of adult T cell leukemia/lymphoma

A

Rapidly progressive disease that is fatal within months to 1 year even with aggressive chemo.
- less commonly there’s only skin involvement and has a more indolent course like mycosis fungoides

207
Q

Both _ and _ are different manifestation of a tumor of CD4+ T helper cells on the skin.

A

Mycosis fungoides

Sezary syndrome

208
Q

Mycosis fungoides progress through what three stages?

A
  1. an inflammatory premycotic phase
  2. plaque phase
  3. tumor phase
209
Q

Histological feature of epidermis and upper dermis of Mycosis fungoides

A

infiltration by neoplastic T cells with cerebriform appearance

210
Q

Characteristic findings on skin of sezary syndrome

A

generlaized exfoliative erythroderma with sezary cells with characteristic cerebriform nuclei

211
Q

Immunophenotypic marker of Mycosis fungoides/sezary syndrome

A

Tumor cells express adhesion molecule cutaneous leukocyte antigen (CLA) and chemokine receptors CCR4 and CCR10

212
Q

Prognosis of Mycosis fungoides/sezary syndrome

A

indolent tumors with 8-9 years survival.

213
Q

Large granular lymphocyti leukemia have acquired mutation in the transcriptio factor _, and occurs in both T and NK cells

A

STAT3

214
Q

Histology of large granular lymphocytic leukemia

A

tumor cells are large lymphocytes with abundant blue cytoplasm and few coarse azurophilic granules seen in peripheral blood smears.

215
Q

Dominant clinical feature of large granular lymphocytic leukkemia

A

Neutropenia and anemia

Rarely: pure red cell aplasia

216
Q

what is Felty syndrome?

A

A triad of rheumatoid arthritis, splenomgealy and neutropenia as seen in pts with large granular lymphocytic leukemia

217
Q

_ is a NHL that presents most commonly as a destructive nasopharyngeal mass and less commonly in testis and skin. Tumor cells infiltrate/ invades small vessels leading to ischemic necrosis, and large azurophilic granules can be seen in touch preparations

A

Extranodal NK/T cell lymphoma

218
Q

Extranodal NK/T cell lymphoma is HIGHLY associated with what virus

A

EBV

219
Q

Prognosis of extranodal NK/T cells lymphomas

A
  • highly aggressive but responds well to radiation but resistant to chemo.
  • poor prognosis with advanced disease
220
Q

_ is defined as B cell malignancy originating in lymphatic system commonly due to EBV infection and Reed-Sternberg cells

A

Hodgkin lymphoma

221
Q

Differentiate between HL and NHL

A

HL: localized to single axial group of nodes; orderly spread by continuity; mesenteric nodes and waldeyer ring; extranodal presentation rare

NHL: multiple peripheral nodes; noncontinuous spread; waldeyer ring and mesenteric nodes; extranodal presentation common

222
Q

The reed-sternberg cells as seen in HL are derived from _

A

germinal centers or postgerminal centers of B cells

223
Q

The 5 WHO classification of HL

A
  1. Nodular sclerosis
  2. mixed cellularity
  3. Lymphocyte-rich
  4. Lymphocyte depletion
  5. Lymphocyte predominance

1-4 are considered classical forms of HL with Reed-sternberg cells having a similar immunophenotype

224
Q

Activation of what transcription factor is a common event in classical HL?

A

NF-kB

225
Q

In HL, activation of NF-kB is thought occur in what ways?

A
  • EBV infection
  • EBV+ tumor cells expressing LMP1 which transmit signals that upregulate NF-kB
  • Activation of NF-kB due to loss of function mutation in IkB or A20 (aka TNFAIP3)
  • activation of NF-kB rescues crippled germinal center B cells that cannot express Igs from apoptosis –> acquisition of mutation and production of Reed-Stermberg cells
226
Q

Reed-Sternberg cells are positive for which markers?

A

CD15 and CD30

227
Q

Histologically describe what Reed-Sternberg cells look like

A

large cells w/ multiple nuclei or a single nucleus with multiple nuclear lobes, each with a large inclusion-like nucleolus about the size of a small lymphocyte

228
Q

Nodular sclerosis type of HL are the most common type and is characterized by presence of 1 Reed-Sternberg cells and the deposition of collagen in bands that divide involved lymph nodes into circumscribed nodules

A
  1. Lacunar variant
229
Q

Reed-Sternberg cells ni the classical HL are positive for 1, 2, and 3, and negative for 4

A
  1. PAX5
  2. CD15
  3. CD30
  4. Other B cell markers, T cell markers, and CD45
230
Q

This type of HL occur equally in males and females with propensity to involve lower cervical, supraclavicular and mediastinal lymph nodes of adolescents or young adults. Has excellent prognosis. Not associated with EBV

A

Nodular sclerosis type

231
Q

In about 70% of cases this type of HL have plenty of mononuclear variants and Reed-sternberg cells that are infected with EBV.

A

Mixed-cellularity type

232
Q

In this type of HL, the Reed-sternberg cells are infected with EBV in over 90% of cases, occurs common in the older adults, in HIV+, and in nonindustrialized countries. Prognosis is somewhat less favorable than the other types

A

Lymphocyte depletion HL

233
Q

In this type of HL, Reed sternberg cells are usually difficult to find and instead contains L&H (lymphocytic and histiocytic) variants, which have a multilobed nucleus resembling a popcorn kernal (popcorn cell)

A

Lymphocyte predominance HL

234
Q

In contrast to Reed Sternberg cells found in classicail forms of HL, L&H variants express what markers?

A

B cell markers typical of germinal center B cells such as CD20, BCL6 and are usually negative for CD15, CD30

235
Q

Clinical features of HL

A
  • commonly presents as painless lymphadenopathy
  • Pts with nodular sclerosis or lymphocyte predominance types tend to have stage I-II and are free of symptoms
  • pts with disseminated disease (stages III-IV) or the mixed-celluarity or lymphocyte depletion subtypes are more likely to have constitutional symptoms like fever, night sweats, weight loss etc.
236
Q

Pattern of spread of HL

A

nodal disease first then splenic disease hepatic disease and finally involvement of marrow and other tissues

237
Q

_ antibodies have produced excellent response in pts with HL that has failed conventional treatments

A

Anti-CD30

238
Q

The three broad category of myeloid neoplasm include

A
  1. AML
  2. Mylodysplastic syndromes
  3. Myeloproliferative disorders
239
Q

_ is a tumor of hematopoietic progenitors caused by acquired oncogenic mutations that impede differentiation, leading to accumulation of immature myloid blasts

A

Acute myeloid leukemia (AML)

240
Q

AML are categorized in to four categories based on _

A
  1. those associated with particular genetic aberrations
  2. Those arising after a myelodysplastic disorder (MDS) with MDS like features
  3. Therapy-related AML
  4. AML not otherwised specified, classified based on degree of differentiation and lineage of leukemic blasts
241
Q

Most common pathogenetic cause of AML

A

t(8;21) and inv(16) –> disrupts RUNX1 and CBFB genes, respectively –> creates a chimeric genes encoding proteins that interfere with function of RUNX1/CBF1b and block maturation of myeloid cells
- mutation that lead to activation of growth factor signaling pathways collaborate with the transcription factors aberration

242
Q

_ is a subtype of AML with t(15;17) that disrupts retinoic acid receptor (RAR) required for myeloblast maturation and is associated with DIC and presence of Auer rods (peroxidase positive eosinophilic cytoplasmic inclusions)

A

Acute promyelocytic leukemia (APML)

243
Q

Which subtype of AML is associated with Down syndrome

A

Acute megakaryoblastic leukemia

244
Q

Which subtype of AML infiltrates the gums of the mouth?

A

acute monocytic leukemia

245
Q

diagnosis of AML is based on presence of at least 20% _ in the bone marrow

A

myloid blasts

246
Q

Depending on the AML type the myeloid blasts have different morphologic features. Describe the two common myloid blasts seen

A
  1. Myeloblasts - 2-4 nucleoli, voluminous cytoplasm containing fine, azurophilic peroxidase-positive granules or distinctive red staining, peroxidase positive needle like structures called Auer rods
  2. Monoblasts: folded or lobulated nuclei, lack auer rods and does not express peroxidase but can be IDed by staining for non-specific esterase
247
Q

in certain type of AML, what’s meant by aleukemic leukemia

A

Absence of myeloid blast in the blood. Usually there’s greater than 100k blasts in the blood

248
Q

Immununophenotype for AML

A

stain for myeloid-specific antigen

249
Q

AML arising de novo in younger adults are commonly associated with which chromosomal translocation

A

t(8;21), inv(16); and t(15;17)

250
Q

AML following myelodysplastic syndromes often have deletion or monosomies of which chromosomes?

A

5 and 7 and usually lacks translocation

251
Q

AML occuring after treatment with topoisomerase II inhibitors are associated with translocation involving what gene?

A

MLL gene on 11q23

252
Q

Clinical findings/features of AML

A
  • symptoms related to anemia, neutropenia, and thrombocytopenia, most notably fatigue, fever, and spontaneous mucosal and cutaneous bleeding, cutnaous petchiae, ecchymoses, serosal hemorrhage into body cavity/viscera
  • Pts with APML produce procagulatns and can produce DIC
  • neutropenia –> infection (frequently opportunistic, e.g. fungal, pseudomoas, etc)
  • tumors with monocytic differentiation infiltrate skin (leukemia cutis) and gingiva
253
Q

which AML type have the best prognosis?

A

AML with t(15;17): treated with all-trans retinoic acid and arsenic salts

254
Q

which AML types have the worst prognosis?

A

AML following MDS or genotoxic therapy

255
Q

_ refers to a group of clonal stem cell disorders characterized by maturation defects that are associated ith ineffective hematopoiesis and a high risk of transformation to AML

A

Myelodysplastic syndromes (MDS)

256
Q

In MDS, what change occurs in the bone marrow?

A

Bone marrow is partly or wholly replaced by clonal progeny of a neoplastic multipotent stem cell –> peripheral blood cytopenias

257
Q

All forms of MDS can transform to AML, but transformation occurs with highest frequency and most rapidly in _

A

radiation therapy-MDS (t-MDS)

258
Q

In the pathogenesis of MDS, the commonly mutated genes are lumped into what three category?

A
  1. Epigenetic factors
  2. RNA splicing factors
  3. Transcription Factors
259
Q

Both primary MDS and t-MDS are associated with chromosomal abnormalities including _

A
  • monosomies 5 and 7
  • deletion of q, 7q and 20 q
  • trisomy 8
260
Q

Characteristic histological finding of MDS

A
  • disordered differentiation affecting erythroid, granulocytic, monocytic and megakaryocytic lineages to varying degrees
261
Q

what are the characteristic histologic finding of the erythroid lineage effects as seen in MDS

A
  • ringed sideroblasts (erythorblast with iron-laden mitochondria )
  • Megablastoid maturation ( as seen in vit B12 or folate def)
  • Nuclear budding abnormalities –> misshapen nuclei w/ polypoid outlines
262
Q

What are the characteristic histologic findgins of granulocytic lineage effects as seen in MDS?

A
  • Neutrophils with decreased numbers of secondary granules, toxic granulations or Dohle bodies
  • Pseudo-Pelger-Huet cells (neutrophils with only two nuclear lobes)
263
Q

What are the characteristic histologic findgins of megakaryocytic lineage effects as seen in MDS?

A
  • single nuclear lobes or multiple separate nuclei (pawn bll megakaryocytes)
264
Q

Clinical features of MDS

A
  • peaks at 70 years
  • discovered incidentally and if symptomatic presents as weakness, infections, hemorrhages all due to pencytopneia
  • higher blast count, more severe cytopenias and presence of multiple clonal chromosomal abnormalities have worse prognosis
  • median survival in primary MDS 9-29 months
  • 10-40% progress to AML
265
Q

In myeloproliferative disorders mutated constitutively activated _ or other aberrations in signaling pathways leads to growth factor independence

A

Tyrosine kinase

266
Q

In myeloproliferative disorder because tyrosine kinase mutation do not impair differentiation the most common conseequence is increase in _

A

one or more mature blood elements

267
Q

Most myeloproliferative disorder originate in

A

multipotent myeloid progenitors

268
Q

Common features of myeloproliferative disorders include

A
  1. increased proliferative drive in the marrow
  2. homing of hematopoietic stem cells to non-marrow sites, causing extramedullary hematopoiesis
  3. Variable transformation to a spent phase characterized by marrow fibrosis and peripheral cytopenia
  4. Variable transformation to acute leukemia
269
Q

_ is a neoplasm of pluripotent hematopoietic stem cells leading to preferential proliferation of granulocytic progenitors. It’s distincgished from other MPD by presence of chimeric, constitutively active BCR-ABL tyrosine kinase

A

Chronic myeloid leukemia (CML)

270
Q

In more than 90% of CML, BCR-ABL fusion gene is generated by _

A

reciprocal t(9;22) translocation designated the Philadelphia chromosome

271
Q

Explain the pathogenesis of CML

A

t(9;22) –> BCR-ABL fusion gene –> fusion proteins w/ constitutively active tyrosine kinase activity. BCR porption provide dimerization domain leading to activation of ABL kinase which then phosphorylates downstream targets to drive proliferation and survival

272
Q

Morphology of CML

A
  • marrow is hypercellular comprising maturing granulocytic precursors
  • peripheral blood shows leukocytosis (>100k)
  • marked splenomegaly –> focal infarction
273
Q

S/S of CML

A

Peaks at 50-60 yrs of age, insidiuous onset

  • B symptoms (fever, weight loss, fatigue)
  • Splenomegaly (LUG discomfort, early satiety
274
Q

Clinical course of CML

A
  • after a variable stable phase period of about 3 yrs, 50% enter accelerated phase (worsening anemia, thrombocytopenia, increased basophilia, and refractoriness to tx); new clonal cytogenetic abnormalities like trisomy 8, isochromsome 17q or duplication of philadelphia chromosome may appear
  • within 6-12 months accelerated phase terminates in acute leukemia (blast crisis)
  • 70% of pts blasts have morphologic and cytochemical features of myeloblasts; in 30% blast are of pre B cell origin
275
Q

Treatment of CML

A
  • curable in 75% w/ bone marrow transplant durign stable phase
  • imatinib decrease BCR-ABL positive cells and decrease risk of transformation to accelerated phase and blast crisis; once acclerated phase or blast crisis is reached CML becomes resistant to kinase inhibitor therapy
276
Q

_ is a type of myeloproliferative disorder characterized by increased marrow production of erythrocytes, granulocytes and platelets. But absolute RBC mass is responsile for most clinical symptoms

A

Polycythemia vera (PCV)

277
Q

PCV is strongly associated with activating point mutation in _

A

JAK2 tyrosine kinase that participates in JAK/STAT signaling pathways –> constitutively active JAK2 signaling and thus does not need erythropoietin and other growth factors to drive growth

278
Q

Mutation in Jak2 results in _ substitution at residue 617

A

valine to phenylalanine. this renders hematopoietic cell lines growth factor independent

279
Q

Morphology of PCV

A
  • hypercellular marrow involving all three lineages; 10% have increased marrow reticulin fibers
  • peripheral blood shows basophilia and abnormaly large platelets
  • late disease –> spent phase –> marrow fibrosis —> extramedullary hematopoiesis in spleen and liver –> organomegaly
280
Q

Clinical features of PCV

A
  • appear insidiously usually late middle age
  • erythroytosis –> plethoric and cyanotic due to vascular stagnation and deoxygenation, headache, dizziness and HTN are common
  • Basophilia w/ histamine release –> peptic ulcer risk, and inense pruritus
  • high cell turnover –> hyperuricemia–> gout
  • Platelet dysfunction –> risk of bleeding and thrombotic events
281
Q

_ is often associated with activating point mutation in JAK2 or MPL, a receptor tyrosine kinase that is normally activated by thrombopoietin. Most other cases have mutation in calreticulin

A

Essential thrombocytosis (ET)

282
Q

ET is an MPD arising in multipotent stem cells, but the increased proliferation and production is largely confined to _ elements

A

megakaryocytic

283
Q

Bone marrow finding and peripheral blood finding of ET

A

Marrow: cellularity mildly elevated but megakaryocytes markedly increaed and inclde abnormally large forms
Peripheral blood smears: thrombocytosis and abnromally large platelets and mild leukocytosis

284
Q

Clinical manifestation of ET are mainly due to

A

thrombosis and hemorrhage.

285
Q

A characteristic symptom of ET

A

erythromelalgia - throbbing and burning of hands and feet caused by occlusion of small arterioles by platelet aggregates

286
Q

Prognosis and course of ET

A

indolent course; long asymptomatic periods punctuated by thrombotic or hemorrhagic crises.
- median survival time is 12-15 yrs

287
Q

_ is characterized by development of obliterative marrow fibrosis leading to diminished hematopoiesis, cytopenias and extramedually hematopoiesis (splenomegaly)

A

primary myelofibrosis

288
Q

In primary myelofibrosis, 50-60% have activating mutation in _ and 1-5% have activating mutations in _

A

JAK2

MPL

289
Q

The main pathologic feature of primary myelofibrosis is

A

extensive deposition of collagen in marrow by non-neoplastic fibroblasts, probably due to inappropriate release of fibrogenic factors from neoplastic megakaryocytes, particularly PDGF and TGF-b

290
Q

In primary myelofibrosis, nucleated erythroid progenitors and early granulocytes are inappropriate release from fibrotic marrow and sites of extramedullary hematopoiesis; their appearance in circulation is termed _

A

leukoerythroblastosis

291
Q

In Primary myelofibrosis, characteristic histologic findings of peripheral blood

A

tear-drop erythrocytes, increased basophils and abnormally large platelets
- normochromic, normocytic anemia is common

292
Q

S/S of primary myelofibrosis

A
  • Splenomegaly: secondary to extramedullary hematopoiesis
  • Bleeding: megakaryocytes are dysfunctional
  • Thrombosis: platelets can rupture which stimulate coaulation
  • Anemia
  • hyperuricemia
293
Q

Prognosis of primary myelofibrosis

A
  • median survival 3-5 yrs

- cause of death include infection, thrombotic episodes or bleeding, and transformation to AML

294
Q

Langerhan cell histiocytoses are monoclonal proliferation of _

A

immature dendritic cell population

295
Q

Characteristic markers of langerhan cell histiocytoses

A

HLA-DR, S100, and CD1a

296
Q

In EM of langerhan cell histiocytosis, cytoplasmic structures called _ are seen which are pentalaminar tubules resembling tennis racquets and contains langerin protein

A

Birbeck granules

297
Q

Langerhan histiocytoses presents as what clinicopathilogic entities:

A
  1. Multifocal multisystem langerhans cell histiocytosis ( Letterer-Siwe disease occurs before are 2): aggressive and systemic disorder in which Langerhans infiltrate and proliferate in skin, spleen, liver, lung, and bone marrow; anemia and destructive bone lesion are seen
  2. Unifocal and multifoal unisystem langerhans cell histiocytosis (eosinophilic granuloma)
  3. Pulmonary Langerhans cell histiocytosis, seen in adult smokers
298
Q

pathogenetic cause of langerhans cell histiocytosis

A
  • commonly BRAF mutation

- less commonly mutations in TP53, RAS and tyrosine kinase MET

299
Q

Unifocal and multifocal unisystem langerhans cell histiocytosis usually affects 1 as an erosive, expanding accumulation of langerhan cells within calvarium, ribs, or femur; also in skin, lungs, or stomach.

A
  1. Skeleton
300
Q

S/S of Unifocal and multifocal unisystem langerhans cell histiocytosis

A
  • painless or painful lesions on skeleton, or mucosa, skin or lungs
  • pathologic fractures
  • involvement of posterior hypothalamus causesdiabetes insipidus
  • Hand-Schuller-Christian syndrome (triad of calvarial bone defects, diabetes, and exopthalmos)
301
Q

Four major functions of spleen that impact disease states:

A
  1. phagocytosis of blood cells and particulate matter: If RBC cannot be deformed due to disease as it needs to pass through sinusoids of spleen, it gets phagocytosed
  2. Antibody production
  3. Hematopoiesis
  4. Sequestration of formed blood elements
302
Q

Hypersplenism is characterized by

A

A syndrome due to enlargement of spleen causing leukopenia, thrombocytopneia and anemia

303
Q

Common infectious cause of splenomegaly

A
  • Mono
  • nonspecific blood-borne infections
  • TB
  • Typhoid fever
  • Bruellosis
  • CMV
  • Syphilis
  • Malaria
  • Histo, toxo
  • kala azar
  • Schistossomiasis
  • Leishmaniasis
  • Echinococcosis
304
Q

Lymphohematogenous disorders leading to Splenomegaly

A
  • HL
  • NHL
  • MM
  • MPD
  • Hemolytic anemias
305
Q

Immunologic-inflammatory conditios disorders leading to Splenomegaly

A
  • RA

- SLE

306
Q

Storage diseases disorders leading to Splenomegaly

A
  • Gaucher disease
  • Niemann-Pick
  • Mucopolysaccharidoses
307
Q

Morphology of spleen as seen in nonspecific acute splenitis

A
  • Caused by blood-borne infection and cytokine induced proliferation
  • Spleen is red and strememly soft
  • red pulp congestion w/lymphoid follicle effacement
308
Q

Common cause of congestive splenomegaly

A
  • systemic congestion due to right-sided HF
  • intrahepatic derangement of portal venous drainage (due to cirrhosis)
  • Extrahepatic portal vein obstruction
309
Q

Splenic infarcts are usually bland infarcts characterized as _

A

pale, wedge-shaped and subcapsular in location.

310
Q

Septic infarcts of spleen is usually due to

A

infectious endocarditis

311
Q

Neoplastic involvement of spleen is seen in _ tumors and cause splenomegaly.

A

myeloid and lymphoid

312
Q

Benign tumors of spleen includes

A
  • fibromas
  • osteomas
  • chondromas,
  • lymphangiomas
  • hemangiomas
313
Q

asplenia is rare but is commonly associated with _

A

Other congenital abnormalities such as situs inversus and cardiac malformation

314
Q

Most common congenital anomalies of spleen

A

accessory spleen which can occur anywhere in the abd cavity

315
Q

Splenic rupture is usually due to

A

blunt trauma to a spleen that previously made fragile by an underlying conditions such as infectious mono, malaria, typhoid fever, neoplasms anad etc

316
Q

Thymic hypoplasia or aplasia is sene in _ 1_ syndrome and is associated with other development defect as part of the _ 2_deletion syndrome

A
  1. DiGeorge

2. 22q11

317
Q

Thymic cysts usually have little clinical significance, but needs to worked up why?

A

they can herald an adjacent thymic neolasm, esp lymphoma or thymoma

318
Q

Thymic hyperplasia refers to appearance of reactive _ cells lymphoid follicles within thymus, and is seen in chronic inflammatory and immunologic states particularly 2

A
  1. B cells

2. Myasthenia gravis

319
Q

Thymomas are neoplasms derived from _

A

thymic epithelial cells

320
Q

Gross apperance of thymomas

A

loblated, firm, gray white mass up to 15-20cm; can have cystic necrosis and calcifications

321
Q

Microscopic findings of noninvasive thymomas

A
  • Noninvasive thymomas are composed of medullary (spindled) and/or cortical (plump with rounded vesicular nuclei) epithelial cells, oftten with a sparsed thymocyte infiltrate
322
Q

Microscopic findings of invasive thymomas

A

exhibit cortical-type epithelial cells and more numerous thymocytes

323
Q

Microscopic findings of thymic carcinoma

A
  • Fleshy, invasive masses that are commonly squamous cell carcinomas; and second most common variant is lmphoepithelioma-like carcinoma, resembling nasopharyngeal carcinoma and commonly contains monoclonal EBV genomes
324
Q

Clinical features of thymomas

A
  • symptoms usually stem from impingement on mediastinal structures
  • some present with myasthenia gravis
  • associated with other paraneoplastic syndromes such as acqired hypogammaglobulinemia, pure RBC aplasia, Graves disease, pernicous anemia, dermatomyositis polymyositis, and Cushing syndrome
  • good prognosis; 90% 5yr survival

Heme and Lymph Midterm (7 decks)

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