Ch 13 Leukemia/Lymphoma Flashcards
1
Q
leukierythroblastosis
A
abnormal release of immature precursors into peripheral blood
2
Q
when is inadequate or ineffetive granulopoiesis observed
A
suppression of hematopoietic stem cells, suppression of committed granulocytic precursors via drug exposure, ineffective hematopoiesis, congenital conditions
3
Q
examples of suppression of hematopoietic stem cells
A
aplastic anemia, infiltrative marrow disorders
4
Q
examples of ineffective hematopoiesis
A
megaloblastic anemias and myelodysplastic syndromes-defective precursors die in marrow
5
Q
accelerated removal or destruction of neutrophils occurs with
A
immuologically mediated injury, splenomegaly, increased peripheral utilization
6
Q
most common cause of agranulocytosis
A
drug toxicity
7
Q
neutropenia caused by chlorpromazine and related phenothiazines results from
A
toxic effect on granulocytic precursors in bone marrow
8
Q
agranulocytosis following administration of aminopyrine, thiouracil, and certain sulfonamides stems from
A
antibody-mediated destruction of mature neutrophils through mechaisms similar to those in drug-induced immunohemolytic anemias
9
Q
hypercellular bone marrow
A
compensatory due to high destruction in periphery; ineffective granulopoiesis
10
Q
what is a neutropenic patient at particularly high risk for
A
deep fungal infections caused by Candida and Aspergillus
11
Q
toxic granules
A
coarser and darker than normal neutrophilic granules; represent abnormal azurophilic (primary) granules
12
Q
Dohle bodies
A
patches of dilated endoplasmic reticulum that appear as sky blue cytoplasmic ‘puddles’
13
Q
neutrophilic leukocytosis causes
A
acute bacterial infections; sterile inflammation (MI, burns)
14
Q
eosinophilic leukocytosis causes
A
allergic disorders; skin diseases; parasitic infections; drug rxns; certain malignancies; collagen vascular disorders and some vasculitides; atheroembolic disease transiently
15
Q
Basophilic leukocytosis causes
A
rare; myeloproliferative disease
16
Q
monocytosis leukocytosis causes
A
chronic infections, bacterial endocarditis, riskettsiosis, malaria, collagen vascular disease, IBS
17
Q
lymphocytosis leukocytosis causes
A
accompanies monocytosis in many disorders associated with chronic immunological stimulation; viral infections; bordetella pertussis infection
18
Q
morphology of lymphadenitis
A
nodes swollen, gray-red, and engorged; prominence of reactive germinal centers with numerous mitotic centers
19
Q
follicular hyperplasia of nodes (chronic)
A
due to stimuli that activate humoral immune responses; large oblong germinal centers surrounded by a collar of small restinf naïve B cells
20
Q
germinal centers in follicular hyperplasia
A
1) dark zone containing proliferating blastlike B cells
2) light zone composed of B cells with irregular or cleaved nuclear contours
21
Q
tingible-body macrophages
A
interspersed btwn germinal B centers and form an inconspicuous network of antigen-presenting follicular dendritic cells and macrophages; contain nuclear debris of B cells that underwent apoptosis
22
Q
causes of follicular hyperplasia
A
RA, toxoplasmosis, early HIV infection
23
Q
Paracortical hyperplasia of nodes
A
stimuli that trigger T cell-mediated immune responses like acute viral infections
24
Q
T-cells in paracortical hyperplasia
A
activated T cells 3-4 times size of resting lymphocytes, several prominent nucleoli, and moderate amounts of pale cytoplasm
25
sinus histiocytosis (aka reticular hyperplasia)
increase in number and size of cells that line lymphatic sinusoids; may be prominent in nodes draining cancers like breast
26
lymphotoxin
cytokine required for formation of normal Peyer's patches; involved in establishment of extranodal inflammation-induced collections of lymphoid cells
27
lymphoid neoplasms
diverse group of tumors of B, T, and NK-cell origin
28
Myeloid neoplasms
arise from early hematopoietic progenitors
29
3 categories of myeloid neoplasms
acute myeloid leukemias, myelodysplastic syndromes, and chronic myeloproliferative disorders
30
acute myeloid leukemias
immature progenitor cells accumulate in bone marrow
31
myelodysplastic syndromes
associated with ineffective hematopoisis and resultant peripheral blood cytopenias
32
chronic myeloproliferative disorders
increased production of one or more terminally differentiated myeloid elements usually leading to elevated peripheral blood counts
33
histiocytes
uncommon proliferative lesions of macrophages and dendritic cells; ex Langerhan cells-immature dendritic
34
MALToma genetic aberrations
MALT1 or BCL10 gene=bind one another in protein complex that regulates NF-kB
35
BCL6
encodes transcription factor expressed in germinal center B cells-germinal B cells can't form without; must be turned off for germinal B cells to mature into memory or plasma cells
36
what occurs once B cell has antigen stimulation
enter germinal centers and upregulate activation-induced cytosine deaminase (AID)
37
AID fxn
specialized DNA-modifying enzyme essential for 2 types of Ig gene modifications: class switching and somatic hypermutation
38
EBV cancer assocaition
subset of Burkett lymphoma; 30-40% Hodgkin lymphoma, many B-cell lymphomas in setting of T-cell immunodeficiency, and rare NK-cell lymphomas
39
HHV8 cancer associations
Kaposi sarcoma, unusual B-cell lymphoma that presents as malignant effusion often in pleural cavity
40
gluten-sensitive cancer assocaition
T-cell lymphomas
41
H pylori cancer association
B-cell lymphomas
42
most common plasma cell neoplasm and presentation
multiple myeloma-causes bony destruction of skeleton and often presents as pain due to pathologic fractures
43
5 broad categories of lymphoid neoplasms used by WHO
1) precursor B-cell neoplasms
2) peripheral B-cell neoplasms
3) precursor T-cell neoplasms
4) peripheral T cell and NK-cell neoplasms
5) Hadgkin lymphoma
44
Acute lymphoblastic Leukemia/lymphomas (ALLs)
neoplasms of immature B or T cells; 85% are B-ALLs as childhood acute leukemias
45
what occurs in 55-70% of all T-ALLs
mediastinal thymic masses-also more likely to be associated with lymphadenopathy and splenomegaly
46
B- and T-ALL morphology
tumor cells have scant basophilic cytoplasm and nuclei somewhat larger than those of small lymphocytes; nuclear chromatin delicate and finely stippled-nucleoli absent/inconspicuous; high mitotic rate
47
differentiating ALL from AML
lymphoblasts have more condensed chromatin, less conspicuous nuclei, and smaller amounts of cytoplasm that usually lacks granules; diffinitive differentiation must be done with stains on antibodies specific for B and T cell antigens
48
histochemical stains
lymphblasts are myeloperoxidase-neg and often contain periodic acid-Schiff pos cytoplasmic material
49
what is positive in more than 95% of B and T-ALLs
immunostaining for terminal TdT (specialized DNA polymerase expressed only in B and T pre-lymphblasts)
50
B-ALLs usually express
pan B-cell marker B19 and transcription factor PAX5 and CD10 (CD10 neg in very immature B cells)
51
more mature B-ALLs express ("late pre-B")
CD10, CD19, CD20, and cytoplasmic IgM heavy chain
52
most cases of T-ALLs express
CD1, CD2, CD5, CD7
53
late pre-T cell tumors express
CD3, CD4, and CD8
54
70% T-ALLs have what genetic gain-of fxn mutation
NOTCH1
55
loss of fxn mutations in B-ALLs
PAX5, E2A, and EBF, or balanced (12;21) involving genes TEL and AML1
56
clinical characteristics of ALLs
abrupt stormy onset within days to few weeks of first symptoms; depression of marrow fxn; mass effects caused by neoplastic infiltration; CNS manifestations due to meningeal spread
57
pediatric ALL prognosis
95% obtain complete remission with aggressive chemo and 75-85% are cured; only 35-40% adults cured
58
what indicates worse prognosis with ALLs
age under 2 (translocations involving MLL gene); adolescence or adulthood; peripheral blood blasts >100,000; philadelphia chromosome (9;22)
59
favorable indicators of ALL prognosis
age 2-10; low white cell count; hyperploidy; trisomy of 4, 7, and 10; (12;21)
60
Chronic lymphocytic leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
differ only in degree of peripheral blood lymphocytosis; chronic is >4000 per mm^3
61
CLL and SLL morphology
lymph nodes diffusely effaced by infiltrate of predominately small lymphocytes 6-12 um with round to slightly irregular nuclei (condensed chromatin and scant cytoplasm)
62
proliferation centers of CLL/SLL
larger activated lymphocytes that often gather in loose aggregates = pathognomonic for CLL/SLL
63
immunophenotype of CLL/SLL
pan B-cell markers CD19 and 20 as well as CD23 and 5; low-level expression of surface Ig typical
64
where is growth of CLL/SLL
largely confined to proliferation centers-receive critical cues from microenvironment
65
leukocyte count in CLL/SLL
highly variable-leukopenia can be seen with SLL marrow displacement and counts in excess of 200,000 sometimes seen in CLL with heavy tumor burdens
66
CLL/SLL and immune fxn
disrupts normal fxn via uncertain mechanisms; hypogammaglobulinemia common
67
what correlates with worse outcomes for CLL/SLL
deletions of 11q and 17p; lack somatic hypermutation; expression of ZAP-70
68
ZAP-70
protein that augments signal produced by Ig receptor
69
Richer syndrome
CLL prolymphocytic transformation or transformation to diffuse large B-cell lymphoma (5-10% patients)
70
prolymphocytes
large cells with single prominent, centrally placed nucleolus
71
Follicular lymphoma
tumor arises from germinal center B cells and is strongly associated with chromosomal translocations involving BCL2
72
2 principle cell types in follicular lymphoma
1) small cells with irregular or cleaved nuclear contours and scant cytoplasm (centrocytes) 2) larger cells with open nuclear chromatin, several nucleoli, and modest amount of cytoplasm (centroblasts)
73
other sites involved in follicular lymphom
peripheral blood 10%, bone marrow 85%-paratrabecular lymphoid aggregates, splenic white pulp and hepatic portal triads
74
neoplastic cells in follicular lymphoma express
CD19, CD20, CD10, surface Ig, BCL6; CD5 NOT expressed; BCL2 in more than 90%
75
translocation in follicular lymphoma
(14;18) that juxtaposes IgH locus on chromosome 14 and BCL2 locus on chromosome 18
76
presentation of follicular lymphoma clinically
painless, generalized lymphadenopathy; incurable-waxing and waning course
77
histologic transformation of follicular lymphomas
30-50% occurance; usually to diffuse large B-cell lymphoma; survival less than 1 year
78
Diffuse large B-cell lymphoma (DLBCL)
most common NHL; relatively large cell size and diffuse pattern of growth
79
what do DLBCL express
CD19, CD20, variable expression of germinal center B-cell markers like CD10 and BCL6; most have surface Ig
80
BCL6
DNA-binding zinc finger transcriptional repressor that is required for the fomration of normal germinal centers; can suppress p53
81
immunodeficiency-associated large B-cell lymphomas
severe T-cell immunodeficiency; neoplastic B cells usually infected with EBV
82
primary effusion lymphoma
malignant pleural or ascitis effusion-mostly with HIV or elderly; anaplastic in appaearance and fail to express surface B or T-cell markers, clonal IgH rearrangements; HHV8 infected
83
presentation of DLBCL
rapidly enlarging mass at nodal or extranodal site, virtually anywhere in body; bone marrow involvement usually late in course
84
outcome of DLBCL
rapidly fatal without treatment; wth chemo 60-80% complete remission with 40-50% cured
85
Burkitt lymphoma morphology
diffuse infiltrate of intermediate-sized lymphoid cells with round/oval nuclei, coarse chromatin, several nucleoli, and moderate cytoplasm; high mitotic index with numerous apoptotic cells
86
immunophenotype of Burkitt lymphoma
mature B cells that express IgM, CD19, 20, 10, and BCL6; fails to express BCL2
87
translocations in Burkitt lymphoma
c-MYC gene on chromosome 8
88
endemic burkitt lymphoma common presentation
mass involving madible and shows unusual predilection for abdominal viscera, especially kidneys, ovaries, and adrenals
89
sporadic burkitt lymphoma common presentation
mass involving ileocecum and peritoneum; involvement of bone marrow and peripheral blood uncommon
90
M component
monoclonal Ig identified in blood-in reference to myeloma
91
Bence-Jones proteins
free light chains small enough to be excreted in urine
92
what are associated with monoclonal gammopathies
1) multiple myeloma
2) Waldenstrom macroglobulinemia
3) heavy-chain disease
4) primary or immunocyte-associated amyloidosis
5) monoclonal gammopathy of undetermined significance (MGUS)
93
multiple myeloma
presents as tumorous masses scattered throughout skeletal system
94
Waldenstrom macroglobulinemia
high IgM lead to symptoms related to hyperviscocity of blood; usually in older adults with lymphoplasmacytic lymphoma
95
Heavy-chain disease
rare; associated with lymphoplastic lymphoma and unusual small bowel marginal zone lymphoma in malnourished populations; synthesis and secretion of free heavy-chain segments
96
Primary or immunocyte-associated amyloidosis
monoclonal proliferation of plasma cells secreting light chains deposited as amyloid; some due to overt multiple myeloma
97
multiple myeloma molecular specs
Ig genes in myeloma cells show evidence of somatic hypermutation; post-germinal center B cell that homes to bone marrow and differentiates into plasma cell
98
what cytokines is the proliferation and survival of myeloma cells dependent on
IL-6
99
MIP1alpha
myeloma-derived; up-regulates expression of receptor activator NF-kB ligand (RANKL) by bone marrow stromal cells, thus activating osteoclasts
100
common translocation in multiple myeloma
FGFR (chromosome 4-cellular proliferation) and cell cycle regulatory genes cyclin D1 (chromosome 11) and cyclin D3 (chromosome 6); among others
101
where do multiple myeloma lesions begin
in medullary cavity, erode cancellous bone, and progressively destroy bone cortex
102
appearance of bone lesions in multiple myeloma
punched-out defects usually 1-4 cm and grossly consist of soft, gelatinous, red tumor masses
103
cell variants in multiple myeloma
flame cells, plasmablasts, Mott cells (multiple grapelike cytoplasmic droplets), other inclusions like fibrils, crystalline rods and globules
104
Russell bodies (cytoplasmic) or Dutcher bodies (nuclear)
globular inclusions
105
rouleaux formation
red cells in peripheral blood stick to one another in linear arrays on smears
106
myeloma kidney
bence jones proteins excreted and contribute to this in multiple myeloma-toxic to renal tubular epithelial cells
107
hypercalcemia from multiple myeloma can cause
neurologic manifestations-confusion, weakness, lethargy, constipation, polyuria; contributes to renal dysfunction
108
most common Ig in multiple myeloma
IgG 55%, IgA 25%; 1% nonsecretory
109
marrow involvement in multiple myeloma causes
normocytic and chromatic anemia, sometimes accompanied by moderate leukopenia and thrombocytopenia
110
proteasome inhibitors as treatment in multiple mueloma
induce cell death by exacerbating inherent tendency of misfolded proteins
111
solitary myeloma (plasmacytoma)
inevitably progresses to multiple myeloma-can take 10-20 yrs or longer; upper respiratory tract can be cured by recestion
112
smoldering myeloma
middle ground btwn multiple myeloma and monoclonal gammoathy of uncertain significance; plasma cells 10-30% marrow cellularity, serum M protein elevated, patients asymptomatic; 75% progress to multiple myeloma over 15 yrs
113
monoclonal gammopathy of uncertain significance (MGUS)
most common plasma cell dyscrasia; patients asymptomatic and serum M protein <3gm/dL; ~1% dvlp symptomatic plasma cell neoplasm per year
114
lymphoplasmic lymphoma
B-cell neoplasm of older adults; bears special resemblance to CLL/SLL-differs due to small fraction of tumor cells undergo terminal differentiation into plasma cells (usually monoclonal IgM)
115
what does hyperviscosity due to IgM in lymphplasmic lymphoma cause
Walden-Strom macroglobulinemia: visual impairment associated with venous congestion, neurologic problems, bleeding, cryglobulinemia
116
immunophenotype of lymphoplasmacytic lymphoma
B cell markers like CD20 and surface Ig; plasma cell component secretes same Ig that is expressed on surface of lymphoid cells; usually lack translocations
117
clinical presentation of lymphoplasmacytic lymphoma
nonspecific; half have lymphadenopathy, hepatomegaly, splenomegaly; anemia caused by marrow infiltration common; 10% autoimmune hemolysis caused by cold agglutinins
118
cryglobulinemia
results from precipitation of macroglobulins at low temps-produces symptoms like Raynaud phenomenon and cold uticaria
119
lymphoplasmacytic lymphoma prognosis
incurable progressive disease. Median survival 4 yrs
120
Mantle cell lymphoma demographics
uncommon; 5th to 6th decades; male predominance; tumor cells resemble normal matle zone B cells that surround germinal center
121
what distinguishes mantle cell lymphoma from follicular and CLL/SLL
large cells resembling centroblasts and proliferation centers are absent
122
what form of lymphoma is most likely to have involvement of the small bowel or colon with polyp-like lesions (lymphomatoid polyposis)
mantle cell lymphoma
123
immunophenotype of mantle cell lymphoma
high levels of cyclin D1; most also express CD19, 20 and moderately high levels of surface Ig; usually CD5+ and CD23- (helps distinguish from CLL/SLL)
124
what causes cyclin D1 overexpression in mantle cell lymphoma
(11;14) translocation involving IgH locus (14) and cyclin D1 locus (11); promotes G1 to S phase progression
125
mantle cell lymphoma prognosis
poor-median survival 3-4 yrs; not currently curable
126
marginal zone lymphomas
heterogeneous group of B-cell tumors that arise within lymph nodes, spleen, or extranodal tissues (eg MALTomas); most of memory B-cell origin
127
Hairy cell leukemia
rare, distinctive B-cell neoplasm; middle-age white males
128
morphology of hairy cell leukemia
leukemic cells have hairlike projections that are best recognized under phase-contrast microscope
129
hairy cell leukemia and aspirations
generally cannot be aspirated since enmeshed in ECM composed of reticulin fibers
130
splenic red pulp in hairy cell leukemia
heavily infiltrated leading to obliteration of white pulp and beefy red gross appearance; hepatic portal triads also involved frequently
131
immunophenotype of hairy cell leukemia
pan B-cell markers CD19 and 20, surface Ig (usually IgG), and certain relatively distinctive markers like CD11c, CD25, and CD103; somatic hypermutation (post-germinal center memory B-cell origin)
132
clinical manifestation of hairy cell leukemia
infiltation of bone marrow, liver, and spleen; massive splenomegaly; 1/3 present with infection
133
prognosis of hairy cell leukemia
excellent; sensitive to 'gentle' chemo drugs
134
peripheral T-cell lymphoma, unspecified
tumors efface lymph nodes diffusely; typically composed of pleomorphic mixture of variably sized malignant T cells; prominent infiltrate of reactive cells; brisk neoangiogenesis may also be seen
135
immunotype of peripheral T-cell lymphoma, unspecified
CD2, 3, 5, and either aB or gd T-cell receptors; some express CD4 or 8
136
prognosis of peripheral T-cell lymphoma, unspecified
cures have been reported, but prognosis significantly worse than comparable aggressive mature B-cell neoplasms
137
Anaplastic Large-cell lymphoma (ALK positive)
uncommon; rearrangements in ALK gene (chromosome 2)-fusion gene with constitutively active tyrosine kinases (trigger pathways like Jak/STAT); tend to occur in children or young adults; frequently involve soft tissues
138
hallmark cells of Anaplastic Large-cell lymphoma
horseshoe-shaped nuclei and columinous cytoplasm; often cluster around cenules and infiltrate lymphoid sinuses (mimicking metastatic carcinoma)
139
what is a reliable indicator of ALK gene rearrangement
detection of ALK protein in tumor cells, as it is not expressed in normal lymphocytes
140
prognosis of Anaplastic Large-cell lymphoma
good; cure rate 75% with chemo
141
Adult T-cell leukemia/lymphoma
neoplasm of CD4+ T cells; infection with HTLV-1; endemic in Hapan, west africa, caribbean basin
142
common findings of Adult T-cell leukemia/lymphoma
skin lesions, generalized lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, and hypercalcemia
143
appearance of tumore cells in Adult T-cell leukemia/lymphoma
varies, but multilobed nuclei (cloverleaf or flower cells) frequently observed
144
HTLV-1 and tumor pathogenesis
encodes a protein Tax, that is a potent activator of NF-kB, which enhances lymphocyte growth and survival
145
presentation/prognosis of Adult T-cell leukemia/lymphoma
present with rapidly progressive disease fatal within months to 1 yr despite aggressive chemo; sometimes only invades skin
146
Mycosis Fungoides/Sezary syndrome
manifestations of CD4+ tumor cells that home to skin; 3 somewhat distinct stages (premycotic, plaque, and tumor phases); indolent course survival 8-9 yrs
147
sezary syndrome
skin involvement is manifested as generalized exfoliative erythroderma-skin lesions rarely progress to tumefaction
148
what do tumor cells of Mycosis Fungoides express
adhesion molecule CLA and chemokine receptors CCR4 and CCR10-contribute to homing to skin
149
Large granular lymphcytic leukemia
T and NK cell variants; mainly in adults; tumor cells large lymphocytes with abundant blue cytoplasm and few course azurophilic granules
150
T cell and NK cell variants in Large granular lymphcytic leukemia
T cell: Cd3+; NK cell: CD3- and CD56+
151
prognosis of Large granular lymphcytic leukemia
T cell origin indolent and NK variants more aggressive
152
extranodal NK/T-cell lymphoma
destructive nasopharyngeal mass is most common presentation; infiltrate surrounds and invades small vessels leading to extensive ishemic necrosis; associated with EBV
153
prognosis of extranodal NK/T-cell lymphoma
highly aggressive-respond well to radiation, resistant to chemo; poor prognosis with advanced disease
154
Hodkin lymphoma (HL) progression
arises in single node/chain of nodes and spreads first to anatomically contiguous lymphoid tissues
155
Reed-Sternberg cells
neoplastic giant cells; seen in HL; release factors that induce accumulation of reactive lymphocytes, macrophages, and granulocytes (make up >90% tumor cellularity); derived from germinal center or post-germinal center B cells
156
5 subtypes of HL
1) nodular sclerosis
2) mixed cellularity
3) lymphcyte-rich
4) lymphocyte depletion
5) lymphocyte predominance;
First 4 reed-sternberg cells have similar immunophenotype=classical HL
157
morphology of Reed-sternberg cells
>45 um with multiple nuclei or single nucleus with multiple nuclear lobes-each with large inclusion-like nucleolus about size of small lymphocyte; abundant cytoplasm
158
lacunar cells
seen in noduar sclerosis subtype; more delicate, folded, or multilobate nuclei and abundant pale cytoplasm often disrupted during cutting of sections (leaves empty hole = lacuna)
159
diagnosis of HL
identification of Reed-Sternberg cells in a typical prominent background of non-neoplastic inflammatory cells
160
nodular sclerosis type of HL
most common 65-70%; lacunar variant and deposition of collagen in bands that divide involved lymph nodes into circumscribed nodules' associated with EBV; excellent prognosis
161
immunophenotype of Reed-sternberg cells in nodular sclerosis type of HL
PAX5 (B-cell transcription factor), CD15, CD30, neg for other B cell markers, t-cell markers, and CD45
162
Mixed cellularity type of HL
20-25% cases; involved nodes diffusely effaced by heterogeneous cellular infiltrate; EBV 70%
163
Lymphocyte-rich type of HL
uncommon-reactive lymphocytes make up vast majority of cellular infiltrate; nodes usually diffusely effaced, but vague nodularity due to presence of residual B-cell follicles sometimes seen; EBV 40%
164
lymphocyte depletion type of HL
least common 90%; less favorable outcome
165
why is immunotypeing in lymphocyte depletion type important
most tumors suspected to be this type actually prove to be large cell NHLs
166
lymphocyte predominance type of HL
uncommon nonclassical variant ~5%; effaced by nodular infiltrate of small lymphocytes admixed with variable # macrophages; L&H variants instead of Reed-sternberg cells
167
L&H (lymphocytic and histocytic) variants
multilobed nucleus resembling popcorn kernal; express B-cell markers typical of germinal-center B cells (CD20, BCL 6, neg for CD15 and 30); no EBV association
168
EBV and NF-kB
express latent membrane protein 1 (LMP-1) that transmits signals that upregulate NF-kB
169
example of cross talk of Reed-sternberg cells with surrounding reactive cells
T cells express ligands that activate CD30 and CD40 receptors found on Reed-sternberg cells-produce signals that up-regulate NF-kB
170
alkylating chemotherapeutics increase risk for
AML and myelodysplasia
171
myeloid neoplasms
heterogeneous group with origin from hematopoietic progenitor cells; primarily involve marrow and lesser degree secondary hematopoietic organs
172
3 broad categories of myeloid neoplasms
Acute Myeloid leukemias, myelodysplastic syndromes, and myeloproliferative disorders
173
Acute Myeloid leukemia
accumulation of immature myeloid forms in bone marrow suppresses normal hematopoiesis
174
myelodysplastic syndromes
ineffective hematopoiesis leads to cytopenias
175
myeloproliferative disorders
usually increased production of one or more types of blood cells
176
Acute Myeloid leukemia specs
tumor of hematopoietic progenitors caused by aquired oncogenic mutations that impede differentiation, leading to accumulation of immature myeloid blasts in marrow; occurs at all ages-rises throughout life
177
4 subdivisions of AML
particular genetic abberations, arising after myelodysplastic disorder or with MDS-features, therapy -related AML, wastebasket category=lack other features
178
diagnosis of AML
presence of at least 20% myeloid blasts in bone marrow
179
myeloblasts in AML morphology
delicate nuclear chromatin, 2-4 nucleoli, and more voluminous cytoplasm than lymphoblasts; Auer rods in cytoplasm
180
Auer rods
distinctive needle-like azurophilic granules
181
Monoblasts in AML
folded/lobulated nuclei, lack auer rods, and are nonspecific esterase-positive
182
number of leukemic cells in blood in AML
highly variable; blasts may be >10000/mm^3 but are <10000 in half ppl; occasionally blasts absent from blood
183
AMLs arising de novo in younger adults are associated with
balanced chromosomal translocations (8;21), inv(6), and (15;17)
184
AMLs following MDS or exposure to DNA damaging agents
deletions or monosomies involving chromosomes 5 and 7 and usually lack translocations
185
AML occuring after treatment with topisomerase II inhibitors
translocations involving MLL gene on chromosome 11
186
AML in elderly
bad' aberrations like deletions of schomosomes 5 and 7
187
what do (8;21) and inv(16) disrupt in AML
CBF1-alpha and CBF1-Beta genes; encode polypeptides that bind one another to form a transcription factor required for normal hematopoiesis
188
t(15;17) in acute promyelocytic leukemia
creates fusion gene that encodes part of retinoic acid receptor-alpha (RARa) fused to protein called PML; results in inhibition of granulocytic maturation
189
FLT3
receptor tyrosine kinase that transmites signals that increase cellular proliferation and survival; commonly occurs with t(15;17), also with NPM (nucleophosmin) and c-KIT mutations
190
ATRA (all-trans retinoic acid)
bonds PML-RARa fusion protein and antagonizes inhibitory effect
191
clinical presentation of AML
fatigue, fever, spontaneous mucosal and cutaneous bleeding (similar to ALL)
192
good prognostic indicators in AML
(8; 21) or inv(6); absence of c-KIT mutations
193
Myelodysplastic syndromes (MDS) specs
clonal stem cell disorders characterized by maturation defects associated with ineffective hematopoiesis and high risl of transformation into AML
194
MDS chromosomal aberration associations
monosomies 5 and 7, deletions of 5, 7, and 20, and trisomy 8
195
marrow in MDS
usually hypercellular at diagnosis, sometimes normocellular or less commonnly hypocellular; disordered differentiation affecting erythroid, granulocytic, monocytic, and megakaryocytic lineages
196
erythroid series in MDS
ringed sideroblasts (iron-laden mitochondria); megaloblastoid maturation-resembles B12 and folate deficiencies; nuclear budding abnormalities
197
neutrophils in MDS
decreased secondary granules, toxic granulations, and/or Dohle bodies; pseudo-pelger-huet cells
198
pseudo-pelger-huet cells
neutrophils with only 2 nuclear lobes
199
pawn ball megakaryocytes
single nuclear lobes or multiple separate nuclei
200
myeloid blasts in MDS
may be increased, but <10% leukocytes in blood
201
myeloproliferative disorders specs
presence of mutated, constitutively activated tyrosine kinases; GF independent proliferation and survival of marrow progenitors; don not impair differentiaton=increase production of one or more mature blood elements
202
Chronic Myeloid leukemia (CML)
presence of chimeric BCR-ABL gene derived from portions of 22 (BCR) and 9 (ABL); 90% philadelphia chromosome
203
morphology of CML
marrow markedly hypercellular-increased #maturing granulocytic precursors; megakaryocytes increased with small, dysplastic forms; scattered macrophages with abundant wrinkled, green-blue cytoplasm; increased deposition of reticulin
204
blood in CML
leukocytosis often over 100,000 cells/mm^3: predominately neutrophils, band forms, metamyelocytes, myelocytes, eosinophils, and basophils; blasts <10% blood cells; platelets increased
205
imatinib
BCR-ABL inhibitor; diminishes BCR-ABL pos cells in marrow and elsewhere, but does not extinguish hematopoietic stem cell
206
polycythemia vera (PCV)
increased marrow production of RBCs, granulocytes, and platelets; RBC increase responsible for most symptoms; activating point mutations in tyrosine kinase JAK2
207
2 mutated copies of JAK2 in PCV leads to
higher WBC counts, more significant splenomegaly, symptomatic pruritis, and greater rate of progression to the spent phase
208
morphology of marrow in PCV
hypercellular, but residual fat usually present; moderate to marked increase in reticulin fibers in 10%
209
why does intense pruritis and peptic ulceration occur in PCV
release of histamine from basophils
210
what does high cell turnover cause in PCV
hyperuricemia-gout in 5-10% cases
211
huge consequences of PCV
bleeding or thrombosis
212
spent phase of PCV
obliterative fibrosis in marrow and extensive extramedullary hematopoiesis, especially spleen
213
essential thrombocytosis (ET)
point mutations in JAK2 (50%) or MPL (5-10%); elevated platelets, absence of polycythemia and marrow fibrosis
214
MPL
receptor tyrosine kinase that is normally activated by thrombopoietin
215
what must be excluded before diagnosis of ET when JAK2 or MPL intact
reactive thrombocytosis (inflammatory disorders and iron deficiency)
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bone marrow in ET
cellularity only mildly increased; megakaryocytes increased and include abnormally large forms
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peripheral smears in ET
abnormally large platelets, often accompanied by mild leukocytosis
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erythromelalgia
throbbing and burning of hands and feet caused by occlusion of small arterioles by platelet aggregates; seen in PCV and ET
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primary myelofibrosis
dvlp obliterative marrow fibrosis; cytopenias and extensive neoplastic extramedullary hematopoiesis; histologically similar to spent phase of other myeloproliferative diseases
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molecular pathogenesis of primary myelofibrosis
JAK 2 (50-60%), activating MPL (1-5%)
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cause of primary myeloofibrosis
fibrogenic factors released from neoplastic megakaryocytes causing ectensive deposition of collagen by non-neoplastic fibroblasts
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what factors from megakaryocytes may be cause for fibrosis in primary myelofibrosis
PDGF and TBF-B
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Primary mylofibrosis vs PCV and ET
nor clear whether truly distinct or merely reflects unusually rapid progression to spent phase
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osteosclerosis
fibrotic marrow space converted into bone
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histiocytosis
umbrella' designation for variety of proliferative disorders of dendritic cells or macrophages
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Langerhans cell histiocytosis
abundant, often vacuolated cytoplasm and vesicular nuclei containing linear grooves or folds; presence of Birbeck granules in cytoplasm
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birbeck granules
pentalaminar tubules, often with dilated terminal end producing a tennis racket-like appearance, which contain protein langerin
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what do langerhan cell histiocytes express
HLA-DR, S-100, and CD1a
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clinicopathological entities of langerhan cell histoicytes
1) multifocal multisystem (letterer-siwe disease)
2) unifocal and multifocal unisystem (eosinophilic granuloma)
3) pulmonary
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multifocal multisystem (letterer-siwe disease)
before 2 yrs age, occasionally adults; cutaneous lesions resembling seborrheic eruption; rapidly fatal, intensive chemo 50% survive 5 years
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unifocal and multifocal unisystem (eosinophilic granuloma)
eosinophils usually prominent infiltrate; arises in medullary cavity of bones (calvarium, ribs, femur)
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unifocal lesions
commonly affect skeletal system in older children/adults; may heal spontaneously or cured by excision/irradiation
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multifical unisystem disease
young children; present with multiple erosive bony masses that sometimes expand into adjacent soft tissue; posterior pit involvement 50%
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HandSchuller-Christian triad
calvarial bone defects, diabetes insipidus, and exophthalmos
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Pulmonary Langerhans cell histiocytosis
adult smokers; may regress spontaneously on smoking cessation; polyclonal population of langerhan cells-reactive hyperplasia rather than true neoplasm
