Chapter 13: Disorders of White Blood Cells Flashcards

1
Q

what are multipotent progenitors?

A

they’re like HSC’s, but are more proliferative and have a lesser capacity for self renewal

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2
Q

What are tumors of hematopoietic origin often associated with?

A

mutations that block progenitor cell maturation or abrogate their growth factor dependence

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3
Q

What are the 2 branches of disorders of WBC’s?

A

prolferative disorders

leukopenias

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4
Q

Leukopenia

A
  • reduced WBC count
  • usually from reduced neutrophils
  • Neutropenia and agranulocytosis are things under it
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5
Q

Neutropenia

A

reduction in the number of neutrophils in blood

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6
Q

Agraulocytosis

A

clinically significant reduction in neutrophils

-has serious consequence of making individuals susceptible to bacterial and fungal infections

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7
Q

What is neutropenia caused by?

A
  • inadequate or ineffective granulopoiesis

- increased destruction ofr sequestration of neutrophils in the periphery

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8
Q

In what kind of situation does inadequate granulopoiesis observed?

A
  • suppression of hematopoietic stem cells
  • suppression of committed granulocytic precursors
  • disease states with ineffective hematopoiesis
  • rare congenital conditions
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9
Q

When does accelerated destruction or sequestration of neutophils happen?

A
  • immunologically mediated injury to neutrophils
  • splenomegaly
  • increased peripheral utilization
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10
Q

What is the most common cause of agranulocytosis?

A

drug toxicity

-cancer treatment

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11
Q

how will the bone marrow look if there’s destruction of neutrophils in the periphery?

A

hypercellular due to a compensatory increase in granulocytic precursors

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12
Q

If there’s an infection, that causes agranulocytosis, what will that look like?

A
  • necrotizing lesions of the gingiva, floor of mouth, pharynx… oral cavity
  • gray to green-black necrotic membranes
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13
Q

What is the neutropenic patient at particularly high risk for?

A

deep infections caused by Candida and Aspergillus

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14
Q

Clinical features of leukopenia

A
  • serious infections most likely when neutrophil count <500

- give full spectrum abx

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15
Q

How is neutropenia treated?

A

with G-CSF

-stimulates production of granulocytes from marrow precursors

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16
Q

Leukocytosis

A

increase in the number of WBC’s in the blood

-common with inflammatory states

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17
Q

What does IL-5 stimulate?

A

eosinophil production

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18
Q

What does G-CSF stimulate?

A

neutrophilia

-lots of neutrophils

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19
Q

In sepsis or severe inflammatory disorders, what morphologic changes do we see in neutrophils?

A

Dohle bodies and cytoplasmic vacuoles

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20
Q

What are Dohle bodies?

A

patches of dilated ER that appear as sky-blue cytoplasmic “puddles”

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21
Q

What will result in large numbers of activated lymphocytes in children that might look like neoplastic lymphoid cells?

A

acute viral infections

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22
Q

What else might appear in severe infections?

A

a lot of immature granulocytes, mimicking a myeloid leukemia

leukemoid rxn

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23
Q

What are the 3 kinds of lymphadenitis that were discussed?

A

Acute nonespecific Lymphadenitis
Chronic nonspecific lympadenitis
Hemophagocytic lymphohistiocytosis

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24
Q

Acute nonspecific lymphadenitis

A
  • watch out for this in the mesentery… can mimick appendicitis
  • nodes are swollen gray-red, and engorged
  • reacitve germinal centers
  • endothelial cells lining the sinuses undergo hyperplasia
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25
Q

Chronic nonspecific lymphadenitis

A

follicular hyperplasia
paracortical hyperplasia
sinus histiocytosis

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26
Q

What are some features favoring a reactive (nonneoplastic) hyperplasia?

A
  • preservation of lymph node architectur
  • marked variation in the shape and sizie of the follicles
  • presence of frequent mitotic figures, phagocytic macs, and recognizeable light and dark zones
  • all of these tend to be absent from neoplastic follicles
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27
Q

What is paracortical hyperplasia caused by?

A

stimuli that trigger T-cell -mediated immune responses

-i.e. acute viral infections

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28
Q

What is sinus histiocytosis

A
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29
Q

Are lymph nodes in chronic rxns tender?

A

nope

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30
Q

what region of the body ins chronic lymphadenitis common in?

A

inguinal and axillary nodes

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31
Q

Where else do collections of immune cells show up in chronic immune rxns?

A

in nonlymphoid tissues

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32
Q

What is Hemophagocytic lymphohistiocytosis (HLH)

A

reactive condition marked by cytopenias and signs and symptoms of systemic inflammation related to macrophage activation
-that’s why it is sometimes called macrophage activation syndrome

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33
Q

What is a common feature of all forms of HLH?

A

systemic activation of macs and CD8+ cytotoxic T-cells

-shock like picture… cytokine storm

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34
Q

What is the most common trigger for HLH?

A

infection

-particularly with the EBV

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35
Q

What are the familial forms of HLH associated with?

A

mutations that impact the ability of cytoxic T cells and NK to properly form or deploy cytoxic granules….
-doesn’t really make sense

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36
Q

How does HLH present clinically?

A
  • acute febrile illness
  • splenomegaly and hepatomegaly
  • very high levels of plasma ferritin and soluble IL-2 receptor (means severe inflammation)
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37
Q

How do tx HLH?

A

immunosuppressive drugs and “mild” chemotherapy

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38
Q

What are the 3 kinds of Neoplastic proliferations of WBC’s we talked about?

A
  • lympoid neoplasms
  • myeloid neoplasms
  • histiocytoses
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39
Q

What is most common chromosomal abnormality with white cell neoplasms?

A

translocations

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40
Q

What 3 viruses have been implicated as causative agents in particular lymphomas?

A

HTLV-1
EBV
Kaposi sarcom/HHV-8

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41
Q

what is KSHV associated with>?

A

malignant effusion often in the pleural cavity

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42
Q

What is the most common plasma cell neoplasm?

A

multiple myeloma

-causes bony destruction of the skeleton and often present with pain due to pathologic fractures

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43
Q

What is required for diagnosis of lymphoid neoplasia?

A

histologic examination of lymph nodes or other involved tissues

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44
Q

Are most lymphoid neoplasms B or T cell related?

A

B cell origin!

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45
Q

Are lymphomas usually disseminated at the time of diagnosis?

A

yes, unless they are hodgkin… those are restricted to a group of lymphnodes
-or unless they are marginal zone B-cell lymphomas, whcih are often restricted to sites of chronic inflammation

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46
Q

Precursor B and Tcell neoplasms

A

Acute lymphoblastic leukemia (ALL)

  • composed of immature B or T cells (lymphoblasts)
  • 85% are B-ALLs: childhood acute leukemias
  • T-ALLs are thymic lymphomas in adolescent males
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47
Q

What is the most common cancer of children?

A

ALL

  • acute lymphoblastic leukemia
  • hispanics have the highest incidence rate
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48
Q

If we see a T-ALL, what mutation will probably be there?

A

GOF mutation in NOTCH1

-diverese chromosomal translocations

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49
Q

If there’s B-ALL, what kinds of mutations are there?

A

LOF mutations

  • PAX5, E2A, EBF
  • diverse chromosomal translocations: t(12;21) involving RUNX1 and ETV6 present in 25%*****
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50
Q

What chromosomal changes are common in ALL’s

A

hyperploidy (>50 chromosomes)

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51
Q

How does the bone marrow look in leukemic presentations?

A

hypercellular and packed with lymphoblasts
-mediastinal thymic masses with T-ALL’s
-

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52
Q

What does the tumor cell cytoplasm look like in both B-ALL and T-ALL?

A

scant basophilic cytoplasma

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53
Q

How are lymphoblasts different from myeloblasts?

A

lymphblasts have more condesnsed chromatin, less conspicuous nucleoli (smaller), and smaller amounts of cytoplasm that usually lacks granules

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54
Q

are lymphoblasts MPO positive or negative?

A

negative

-also contain periodic acid-Schiff-positive cytoplasmic material

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55
Q

For immunostaining, what willl we see in pre-B and pre-T lymphoblasts?

A

95%

-TdT

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56
Q

Staining for B-ALLs

A

CD19
PAX5
CD10
CD 20 and IgM heavy chain if mature

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57
Q

Staining for T-ALLs

A

CD1,2,5, and 7

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58
Q

Clinical features of ALL’s?

A

abrupt stormy onset

  • depression of marrow
  • CNS stuff like headache, vomiting, nerve palsies resulting from meningeal spread
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59
Q

Prognosis of ALL’s

A

-children: awesome! 95%.. but it’s still the leading cause of cnacer deaths in children

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60
Q

What is associated with a worse prognosis for ALL’s?

A
  • younger than 2 years
  • present in adolescence or adulthood
  • peripheral blood blast counts greater than 100,000
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61
Q

What are markers of favorable prognosis for ALLs

A
  • age b/w 2-10
  • low WBC count
  • hperdiploidy
  • trisomy of chormosomes 4,7,and 10
  • presence of a t(12;21)
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62
Q

Which mutation makes that BRC-ABL tyrosine kinase?

A

t(9;22)

  • it shows up in CML too! but it’s 210 kDa and less tyrosine activity there
  • in B-ALL, it’s 190 kDa and stronger tyrosine kinase activity
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63
Q

What are the peripheral B-cell neoplasms that we need to worry about?

A

Chronic lymphocytic leukemia

Small lymphocytic lymphoma

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64
Q

How do CML and SLL differ

A

only in the degree of peripheral blood lymphocytosis

-CLL is more (>5000 lymphocytes)

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65
Q

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

A

CLL

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66
Q

Are chromosomal translocations a thing with CLL and SLL?

A

no, that’s why they’re kinda weird

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67
Q

What are the most common genetic anomalies in CLL/SLL?

A

deletions of 13q14.3, 11q, and 17p, and trisomy 12q

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68
Q

What will CLL/SLL tumors that pursue an aggressive course have?

A

unmutated Ig segments

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69
Q

how do the lymph noedes look in peripheral B-cell neoplasms?

A

diffusely effaced

  • proliferation enters: they’re just larger activated lymphocytes that often gather in loose aggregates…
  • smudge cells
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70
Q

What is the distinctive immunophenotype for CLL/SLL?

A

CD19, 20

*CD23 and CD5

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71
Q

clinical presentation of CLL/SLL?

A
  • generalized lymphadenopathy and hepatosplenomegaly

- disrupts normal immune function through uncertain mechanisms

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72
Q

Things that mean worse outcome for CLL/CLL?

A
  • del 11q and 17p
  • no somatic hypermutation
  • expression of ZAP-70
  • presence of NOTCH1 mutations
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73
Q

What does the CLL/SLL transform into that is much worse?

A

Diffuse large B-cell lymphoma

-also called Richter syndrome

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74
Q

Follicular lymphoma

A

most common form of indolent NHL in the US

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75
Q

Chromosomal translocations of what are associated with follicular lymphoma?

A

BCL2

  • the hallmark t(14;18)
  • 90% of follicular lymphomas
  • IGH locus goes to 18, BCL2 locus goes to 14
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76
Q

does follicular lymphoma have apoptotic cells?

A

no!

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77
Q

What other gene has been identified as being mutated in 90% of follicular lymphoma cases as well?

A

MLL2

-histone methyl transferase

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78
Q

Morphology of follicular cell lymphoma?

A

2 cell types: small cells… centrocytes and larger cells…. centroblasts

  • the small cleaved cells are in the majority
  • Bone marrow involvement happens
  • form aof paratrabecular lymphoid aggregates*
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79
Q

immunophenotype of follicular lymphoma

A

CD19, 20, 10, and surface Ig and BCL6

-UNLIKE CLL/SLL, CD5 IS NOT EXPRESSED

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80
Q

clinical features of follicular lymphoma?

A

painless generalized lymphadenopathy

  • incurable, but indolent waxing and waning course
  • histologic transformation happens 30-50%… most commonly to diffuse large B-cell lymphomas
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81
Q

Diffuse large B-cell lymphoma (DLBCL)

A
  • the most common form of NHL!
  • 60 years
  • dysregulation of BCL6
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82
Q

Morphology of DLBCL

A
  • large cell csize
  • diffuse pattern of growth
  • round or oval nucleus
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83
Q

Immunophenotype of DLBCL

A

CD19, 20, 10, BCL6, most have surface Ig

84
Q

Immunodeficiency-associated Large B-cell lymphoma

A
  • occurs in setting of severe t-cell immunodeficiency
  • EBV
  • restore T cells and may lead to regression
85
Q

Primary effusion lymphoma

A
  • malignant pleural or ascitic effusion
  • HIV infection
  • KSHV/HHV-8
  • tumor cells fail to express surface b or t cell markers
  • clonal IgH gene rearrangements are there though
86
Q

Clinical features of DLBCL

A
  • rapidly enlarging mass at a nodal or extranodal site
  • can arise anywhere in body, but Waldeyer ring (oropharyngeal lymphoid tissue) is involved commonly
  • rapidly fatal without treatment
  • MYC translocations have a worse prognosis
87
Q

Burkitt lymphoma

A
  • highly associated with translocations of the MYC gene
  • fastest growing human tumor
  • t(8;14)
88
Q

What chromosome is the MYC gene on?

A

8

89
Q

What are all endemic burkitt lymphomas latently infected with

A

EBV

-infection precedes transformation

90
Q

Morphology of Burkitt lymphoma

A
  • high mitotic index… lots of apoptotic cells
  • phagocytes have the “starry sky” pattern
  • royal blue cytoplasm containing clear cytoplasmic vacuoles
91
Q

Immunophenotype of Burkitt

A
  • tumor of mature B-cells, sooooo

- IgM, CD19, 20, 10, and BCL6

92
Q

Unlike other tumors of germinal center origin, what does Burkitt lymphoma always FAIL to express?

A

the protein BCL2

93
Q

Clinical feature of Burkitt lymphoma

A
  • extranodal sites
  • endemic kind in mandible
  • sporadic gets the ileocecum and peritoneum
  • very aggressive but responds well to intensive chemotherapy
94
Q

what’s another name for plasma cell tumor?

A

dryscrasia

95
Q

what is an M component?

A

monoclonal antibody found in the blood

-reference to myeloma

96
Q

what do neoplastic plasma cells often synthesize?

A

excess light chains along with complete Igs

-so, the level of free light chains is usually elevated and is markedly skewed toward one light chain

97
Q

When the light chains forma plasma cell neoplasm are excreted in the urine, what are they referred to as then?

A

Bence-Jones proteins

98
Q

What is the most important plasma cell neoplasm?

A

Multiple myeloma

99
Q

What is Waldenstom macroglobulinemia?

A

-when high levels of IgM lead to symptoms related to hyperviscosity of the blood

100
Q

Multiple myeloma

A

plasma cell neoplasm commonly associated with lytic bone lesions, hypercalcemia, renal failure, and acquired immune abnormalities

101
Q

pathogenesis of multiple myeloma

A

rearrangement of IgH locus

  • Cyclin D1 of chrom 11
  • del 17p involving TP53 is bad
  • IL-6 will be there (also bad)…
  • MIP1a upregulates RANKL by bone marrow… turns on the osteoclasts
  • hypercalcemia happens
102
Q

Morhpology of multiple myeloma

A

destructive plasma cell tumores involving the axial skeleton

  • punched-out defects
  • flame cells, mott cell
  • fibrils, crystalline rods, globules
  • russell bodies (cytoplasmic)
  • dutcher bodies (if nuclear)
  • high level of M proteins causes red cells to stick to each other in linear arrays= ROULEAUX FORMATION
  • plasma cell leukemia
  • bence jones proteins excreted in kidney…. gives rise to myeloma kidney
103
Q

Immunophenotype of mutliple myeloma

A

CD138
Syndecan-1
CD56

104
Q

clinical features of multiple myeloma

A
  • hypercalcemia: confusion and weakness
  • recurrent bacterial infections: abnormal Ig’s
  • bence-jones proteinuria: toxic to renal tubular epithelia cells
  • most common M protein is actually IgG
  • translocation involving cyclin D1 are good
  • deletion of 13q, 17p, and t(4;14) are all bad and aggressive…
105
Q

Most common cause of death with multiple myeloma?

A

infections

106
Q

what is a solitary myeloma (Plasmacytoa)

A

solitary lesion of bone or soft tissue

107
Q

what does a plasmacytoma inevitably progress to?

A

multiple myeloma

108
Q

what is smoldering myeloma

A

the middle gorund between multiple myeloma and monoclonal gammopathy of uncertain significance (MGUS)

  • has all of the lab values for multiple myeloma (lots of plasma cells in marrow and serum M protein >3
  • but the patients are asymptomatic
  • 75% progress to multiple myeloma over a 15 year period
109
Q

Monoclonal gammopathy of uncertain significance (MGUS)

A

most common plasma cell dyscrasia

-pts are asymptomatic and the serum M ptn is <3

110
Q

Lymphoplasmacytic lymphoma

A

B-cell neoplasm of older adults

  • substantial fraction of tumor cells undermgo terminal diff to plasma cells… unlike CLL/SLL
  • IgM is around… hyperviscosity syndrome
  • unlike multiple myeloma, complications from secretion of free light chains are rare and there is no bone destruction
111
Q

What is that hyperviscosity syndrom known as?

A

waldenstrom macroglobulinemia

112
Q

What mutation does lymphoblastic lymphoma have?

A

MYD88

113
Q

Morphology of lymphoblastic lymphoma

A

marrow has lymphocytes

-russell bodies: PAS inclusions containing Ig are frequently seen in the cytoplasm or nucleus (Dutcher bodies)

114
Q

immunophenotype of lymphoplasmacytic lymphoma

A

CD20 and surace Ig (usually IgM)

115
Q

clinical features of lumphoplasmacytic lymphoma

A
  • lymphadenopathy, hepatomegaly, and splenomegaly
  • anemia caused by marrow infiltration is common
  • cold agglutinins
116
Q

What will happen with someone with and IgM secreting tumors?

A

hyperviscosity syndrome

117
Q

What is hyperviscosity syndrome characterized by?

A
  • visual impairment
  • neuologic problems
  • bleeding
  • cryoglobulinemia: Raynaud phenomenon and urticaria
118
Q

What do virtually all mantle cell lymphomas have?

A

t(11;14) translocation involving the IgH locus on thromosome 14 and the cyclin D1 locus on chromosome 11 that leads to overexpression of cyclin D1

119
Q

What does the up regulation of cyclin D1 result in?

A

G1-S phase progression

120
Q

morphology of mantle cell lymphoma

A

-homogeneous population of small lymphocytes with irregular to occasionally deeply clefted (cleaved) nuclear contours

121
Q

What distinguished mantle cell lymphoma from follicular lymphoma and CLL/SLL

A

follicular lymphoma: large cells resembling centroblasts are absent
CLL/SLL: proliferation centers are absent (in the mantle cell lymphoma they are)

122
Q

Immunophenotype of mantle cell lymphoma

A
  • high levels of cyclin D1
  • CD5+ and CD23- (makes it different form CLL and SLL)
  • IgH genes lack somatic hypermutation, supporting an origin from a naive B cell
123
Q

clinical features of Mantle cell lymphoma

A
  • most common presentation is PAINLESS LYMPHADENOPATHY
  • prognosisi is poor
  • not curable
124
Q

Marginal zone lymphomas

A
  • extranodal sites
  • B-cell tumors
  • 3 weird things: 1.) often arise within tissues involved by chroninc inflammatory disorders of AI or infectious etiology
    2. ) they remain localized for prolonged periods, spreading systemically only late in their course
    3. ) may regress if the inciting agent (H. Pylori) is eradicated
125
Q

What are the translocations with marginal zone lymphomas and what proteins do they up regulate?

A

11;18
14;18
1;14
-upregulate function of BCL10 or MALT1

126
Q

Hairy cell Leukemia

A

-think middle aged white males

127
Q

pathogenesis of hairy cell leukemia

A
  • activating pt mutations in the serine/threonine kinase BRAF
  • Val to Glu substitution at residue 600 (also found in langerhans cell histiocytosis
128
Q

immunophenotype of hairy cell leukemia

A

CD19
CD20
surgace Ig (G)
CD11c, 25, and 103 and annexin A1

129
Q

Morphology of hair cell leukemia

A
  • fine hairlike projections
  • white pulp is obliterated and red pulp has beefy red gross appearance
  • hepatic portal triads also involved frequently
130
Q

clinical features of hairy cell leukemia

A
  • splenomegaly
  • pancytopenia
  • sensitive to “gentle” chemotherapeutic regimens
  • overall prognosis is excellent
131
Q

Peripheral T-Cell lymphoma, Unspecified

A

-efface lymp nodes diffusely and are typically composed of a pleomorphic mixture of variably sized malignant T cells

132
Q

what are all T-cell lymphomas erived from?

A

Mature T cells

133
Q

What do T cell lymphomas express then?

A

CD2, 3, 5, and aB or gd TCRs

134
Q

Anaplastic large cell lymphoma (ALK positive)

A

uncommon

  • presence of rearrangments of ALK gene on chromosome 2p23
  • ALK fusion ptns
  • horshoe shaped nucleii (hallmark cells
  • children or young adults
135
Q

how is the prognosis of T cell lymphomas with ALK rearrangements

A

very good

-tumors lacking the ALK rearrangements occur in older adults and have a substantially wore prognosis

136
Q

Adult T cell leukemia/lymphoma

A

-only in adults infected by HTLV-1

137
Q

What protein does HTLV-1 make?

A

Tax

-potent activator of NFkB

138
Q

Mycosis Fungoides and Sezary syndrome

A
  • different manifestations of a tumor of CD4+ helper T cells that HOME TO THE SKIN
  • mycosis fungoides is skin; T cells have the cerebriform appearance
  • Sezary syndrome: skin involvement is manifested as generalized exfoliative erythroderma
139
Q

What do the tumor cells of Sezary syndrome express?

A

CLA
CCR4 and 10
-these contribute to the homing of normal CD4+ T cells to the skin

140
Q

Large granular lymphocytic leukemia

A
  • rare
  • adults
  • STAT3
  • azurophilic granules
  • T-cell: CD3+
  • NK-cell: CD3- and CD56+
  • neutropenia and anemia*
  • T cell tumors more indolent
  • NK cells more aggressive
141
Q

Extranodal NK/T-Cell lymphoma

A
  • rare in US
  • destructive nasopharyngeal mass
  • ischemic necrosis
  • large azurophilic granules
  • highly associated with EBV
  • highly aggressive
  • but respond welll to chemo
  • CD3 negative and no TCR’s
142
Q

What kind of cells are in a Hodgkin lymphoma?

A

Reed-Sternberg cells

-they release factors that induce a bunch of cells to come Party

143
Q

What are the 5 different types of HL?

A
  • nodular sclerosis (most common)
  • Mixed cellularity
  • lymphocyte-rich
  • lymphocyte depletion
  • lymphocyte predominance (RS cell has B cell immunophenotype)
144
Q

Activation of what TF is a common event in classical HL?

A

NFkB

145
Q

What do EBV+ tumor cells express?

A

latent membrane protein-1 (LMP1)

146
Q

What else do we find reed sternberg cells in?

A

infectious mononucleosis

147
Q

What do Reed Sternberg cells look like?

A

large
multiple nuclei or single nucleus with multiple lobes
-mononuclear variants have single nucleus with large inclusion-like nucleolus

148
Q

What is characteristic of the lymphocyte predominance subtype of HL?

A

Lymphohistiocytic variants (L and H cells) with polypoid nuclei, inconcpicuous nucleoli, and moderately abundant cytoplasm

149
Q

Nodular sclerosis type of HL

A

most common form

  • lacunar variant RS cells
  • deposition of collagen in bands that divide involved lymph nodes into circumscribed nodules
  • PAX5, CD15, CD30
  • excellent prognosis
  • no EBV
150
Q

Mixed Cellularity type of HL

A
  • 2nd most common
  • RS cells and mononuclear variants
  • YES EBV***
  • males.. older
  • night sweats and weight loss
  • good prognosis
151
Q

Lymphocyte-rich type of HL

A
  • uncommon
  • reactive lymphocytes make up the majority of the cellular infiltrate
  • very good to excellent prognosis
152
Q

Lymphocyte depletion type of HL

A
  • least common type
  • paucity of lymphocytes
  • lots of RS cells
  • watch out, you have to immunophenotype it…
  • most tumors suspected of being lymphocy depletion HL actually prove to be large-cell NHLs
  • The RS cells are infected with EBV in over 90% of cases**
153
Q

Lymphocyte predominance type of HL

A
  • uncommon
  • nonclassical
  • L&H cells (lymphocytic and histiocytic): multilobed nucleus resembling a popcorn kernel
  • these L&H variants express B-cell markers typical of germinal-center B cells (CD20, BCL6)
  • negative for CD15 and CD30
  • nodular pattern of growth due to expanded B cell follicles
  • males <35 with cervical or axillary LAD
  • excellent prognosis
154
Q

how does HL usually present?

A

Painless lymphadenopathy

155
Q

What are the different myeloid neoplasms that we have to worry about?

A

Acute Myeloid leukemia
Myelodysplastic syndromes
myeloproliferative disorders

156
Q

what is a common featur of myeloid neoplasms

A

an origin from hematopoietic progenitor cells

157
Q

what is an acute myeloid leukemia?

A

accumulation of immature myeloid forms in the bone marrow

-suppresses normal hematopoiesis

158
Q

what is myelodysplastic syndromes?

A

defective maturation of myeloid progenitors gives rise to ineffective hematopoiesis, leading to cytopenias

159
Q

what is myeloproliferative disorders?

A

increased production of one or more types of blood cells

160
Q

AML

A
  • the accumulation of immature myeloid blasts in the marrow
  • causes marrow failure
  • anemia, thrombocytopenia, and neutropenia
  • disruption of genes encodings TFs required for normal myeloid idfferentiation
161
Q

What are the 2 most common chromosomal rearrangements for AML?

A

t(8;21)… disrupts RUNX1
inv(16)… disrupts CBFB
-blocks maturation of myeloid progenitors

162
Q

is PML-RARa fusion prn sufficient to cause AML?

A

no

-it needs to be combined with activated FLT3 to induce AML in mice

163
Q

What is needed for the diagnosis of AML?

A

20% myeloid blasts in the bone marrow

164
Q

What doe the myeloblasts look like?

A
  • peroxidase + azurophilic granules

- Auer rods (especially with t(15;17) which is APL)

165
Q

What do monoblasts have?

A

folded or lobulated nuclei

  • lack auer rods
  • nonspecific esterase-positive
166
Q

What CD marker will the myeloid blasts have?

A

CD34, it means that they are multipotent stem cells

  • they DO NOT express CD64 which means they’re mature myeloid cells
  • they also express CD33, means immature myeloid cell
  • do not express CD15, means mature myeloid cell
167
Q

clinical features of AML?

A
  • anemia, neutropenia, and thrombocytopenia

- infections in oral cavity, skin, lungs, etc… with pseudomonas

168
Q

Which kind of AML has the best prognosis?

A

t(15;17)

-8’21 and inv16 is good too

169
Q

which AML is the really bad one to have?

A

-AMLs that follow MDS or genotoxic therapy

170
Q

Myelodysplastic Syndromes (MDS)

A

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

171
Q

What is the kind of MDS that almost always transforms to AML?

A

t-MDS (from radiation therapy)

172
Q

what is the most characteristic finding in MDS?

A

disordered differentiation affecting the erythroid, granulocytic, monocytic, and megakaryocytic lineages to varying degrees

173
Q

What is seen with erythrocyte MDS?

A

-ring sideroblasts
-megaloblastoid maturation (like vit B12 deficiency)
-nuclear budding abnormalities
-

174
Q

What do the neutrophils in MDS look like?

A

Pseudo-Pelger-Guet cells

-neutrophils with only two nuclear lobes

175
Q

What do Megakaryocytes in MDS look like?

A

single nuclear lobes or multiple separate nuclei (pawn ball megakaryocytes)

176
Q

Clinical features of MDS?

A
  • older adults
  • pancytopenia, so bleeding
  • outlook for t-MDS is terrible
177
Q

Mutation in CML

A

BCR-ABL fusion gene

178
Q

Mutation in Polycythemia Vera

A

JAK2 pt mutations

179
Q

Mutation is Essential thrombocythemia

A

JAK2

180
Q

Mutation in primary myelofibrosis

A

JAK2

181
Q

Mutation is systemic mastocytosis

A

KIT

182
Q

Mutation ins chronic eosinophilic leukemia

A

-FIP1L1-PDGFRA fusion gene is the common one

183
Q

mutation for stem cell leukemia

A

Various FGFR1 fusion genes

184
Q

Myelproliferative disorders common pathogenic feature

A

presence of mutated, contitutively activated tyr kinases or other acquired aberrations
-lead to growth factor independence

185
Q

Chronic Myelogenous Leukemia (CML)

A
  • BCR-ABL gene
  • BCR from 22
  • ABL from 9
  • THIS IS THE FUCKING PHILADELPHIA CHROMOSOME
186
Q

What is the cell of origin in CML?

A

Pluripotent hematopoietic stem cell

187
Q

Clinical features of CML

A
  • adults usually
  • insidious
  • BRC-ABL
  • accelerated phase… turns quickly into what looks like Acute leukemia
  • it’s called a blast crisis
188
Q

What lineage are most of the cells in a blast crisis?

A

myeloid origin

-makes sense because it’s from a pluripotent stem cell with both myeloid and lymphoid potential

189
Q

Polycythemia Vera

A
  • strongly associated with active point mutation in the try kinase JAK2
  • the increase in red cells is what is responsible for most of the symptoms
190
Q

morphology of PCV?

A
  • hypercellular marrow
  • increase in RBC progenitors is subtle and usually accompanied by an increase in granulocytic precursors and megakaryocytes as well
  • late in course, it goes to spent phase characterized by extensice marrow fibrosis that displaces hematopoietic cells
  • extramedullary heamtooiesis in spleen and liver…. prominent organomegaly
191
Q

clinical features of PCV?

A
  • uncommon
  • abnormal blood flow and platlet function lead to increased risk of both major bleed and thrombotic episodes (DVTs, MI, or stroke)
  • can get into hepatic veins (budd-chiari syndrom)
  • chronic bleeding….. iron deficiency…. suppresses erythropoiesis… owers the hematocrit to normal range
192
Q

Without tx, what happens to ppl with PCV?

A

death from bleeding or thrombosis within months of diagnosis

193
Q

Essential Thrombocytosis

A

JAK2 point mutation (50%)
MPL (5-10%)… normally activated by thrombopoietin
-thrombopoietin-independent
-dysfunction of platlets…. PCV-like symptoms
characteristic symptom is erythromelalgia

194
Q

What is erythromelalgia?

A

a throbbing and burning of hands and ffet caused by occlusion of small arterioles by platelet aggregates

195
Q

Primary Myelofibrosis

A
  • hallmark is the development of obliterative marrow fibrosis
  • JAK2 mutation sin 50-60%
  • Chief pathologic feature is the extensive deposition of collagen in the marrow by non-neoplastic fibroblasts
196
Q

Morphology of primary myelofibrosis

A

early, marrow is hypercellular

  • megaaryocytes are large, dysplastic, and abnormally clustered
  • with progression, marrow becomes more hypocellular and diffusely fibrotic
  • fibrolitc obliteration of bone marrow space leads to extensive extramedullary hematopoiesis.. mostly in spleen
  • teardrop-shaped red cells
197
Q

Clinical features of Primary myelofibrosis

A
  • less common than PCV and ET
  • older than 60
  • sensation of fullness in the left upper quadrant
198
Q

Langerhans Cell Histiocytosis

A
  • histiocytosis: proliferative disorder of dendritic cells or macrophages
  • most common mutation is Val-Glu substitution at residue 600 in BRAF
199
Q

What other entity was BRAF messed up in?

A

hairy cell leukemia

-present in 55-60% of cases of Langerhans Cell histiocytosis

200
Q

What is characteristic of Langerhans cell histiocytosis?

A

Birbeck granules i the cytoplasm

201
Q

What doe the birbeck granules look like?

A

tennis rackets!!!!

-contain the protein langerin

202
Q

What else do the tumor cells express in langerhans cell histiocytosis?

A

HLAD-DR, S-100, and CD1a

203
Q

Multifocal multisystem Langerhans cell histiocytosis (Letterer-Siwe disease)

A
  • b4 2 years of age
  • cutaneous lesions resembling a seborrheic eruption
  • caused by infiltrates of langerhans cells over the front and back of the trunk and on the scalp
  • rapidly fatal if untreated
204
Q

Unifocal and multifocal unisystem Langerhans cell histiocytosis (eosinophilic granuloma)

A
  • unifocal: skeletal system in older children and adults
  • multifocal: young children, multiple erosive bony masses that sometimes expand into adjacent soft tissue
  • involvement of posterior pituitary stalk leads to diabetes insipidus in 50%
  • Hand-Schuller-Christian triad
205
Q

What is the Hand-Schuller-Christian triad?

A

calvarial bone defects
diabetes insipidus
exophthalmos
-happens in eosinophilic granulomas

206
Q

Pulmonary langerhans cell histiocytosis

A
  • adult smokers
  • may regress spontaneously upon cessation of smoking
  • 40% associated with BRAF mutations
207
Q

What factor contributes to the homing of neoplastic langerhans cells?

A

aberrant expression of chemokine receptors