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
2
Q
What are tumors of hematopoietic origin often associated with?
A
mutations that block progenitor cell maturation or abrogate their growth factor dependence
3
Q
What are the 2 branches of disorders of WBC’s?
A
prolferative disorders
leukopenias
4
Q
Leukopenia
A
- reduced WBC count
- usually from reduced neutrophils
- Neutropenia and agranulocytosis are things under it
5
Q
Neutropenia
A
reduction in the number of neutrophils in blood
6
Q
Agraulocytosis
A
clinically significant reduction in neutrophils
-has serious consequence of making individuals susceptible to bacterial and fungal infections
7
Q
What is neutropenia caused by?
A
- inadequate or ineffective granulopoiesis
- increased destruction ofr sequestration of neutrophils in the periphery
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
9
Q
When does accelerated destruction or sequestration of neutophils happen?
A
- immunologically mediated injury to neutrophils
- splenomegaly
- increased peripheral utilization
10
Q
What is the most common cause of agranulocytosis?
A
drug toxicity
-cancer treatment
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
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
13
Q
What is the neutropenic patient at particularly high risk for?
A
deep infections caused by Candida and Aspergillus
14
Q
Clinical features of leukopenia
A
- serious infections most likely when neutrophil count <500
- give full spectrum abx
15
Q
How is neutropenia treated?
A
with G-CSF
-stimulates production of granulocytes from marrow precursors
16
Q
Leukocytosis
A
increase in the number of WBC’s in the blood
-common with inflammatory states
17
Q
What does IL-5 stimulate?
A
eosinophil production
18
Q
What does G-CSF stimulate?
A
neutrophilia
-lots of neutrophils
19
Q
In sepsis or severe inflammatory disorders, what morphologic changes do we see in neutrophils?
A
Dohle bodies and cytoplasmic vacuoles
20
Q
What are Dohle bodies?
A
patches of dilated ER that appear as sky-blue cytoplasmic “puddles”
21
Q
What will result in large numbers of activated lymphocytes in children that might look like neoplastic lymphoid cells?
A
acute viral infections
22
Q
What else might appear in severe infections?
A
a lot of immature granulocytes, mimicking a myeloid leukemia
leukemoid rxn
23
Q
What are the 3 kinds of lymphadenitis that were discussed?
A
Acute nonespecific Lymphadenitis
Chronic nonspecific lympadenitis
Hemophagocytic lymphohistiocytosis
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
25
Chronic nonspecific lymphadenitis
follicular hyperplasia
paracortical hyperplasia
sinus histiocytosis
26
What are some features favoring a reactive (nonneoplastic) hyperplasia?
- 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
27
What is paracortical hyperplasia caused by?
stimuli that trigger T-cell -mediated immune responses
| -i.e. acute viral infections
28
What is sinus histiocytosis
increase in the number and size of the cells that line lymphatic sinusoids
-
29
Are lymph nodes in chronic rxns tender?
nope
30
what region of the body ins chronic lymphadenitis common in?
inguinal and axillary nodes
31
Where else do collections of immune cells show up in chronic immune rxns?
in nonlymphoid tissues
32
What is Hemophagocytic lymphohistiocytosis (HLH)
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
33
What is a common feature of all forms of HLH?
systemic activation of macs and CD8+ cytotoxic T-cells
| -shock like picture... cytokine storm
34
What is the most common trigger for HLH?
infection
| -particularly with the EBV
35
What are the familial forms of HLH associated with?
mutations that impact the ability of cytoxic T cells and NK to properly form or deploy cytoxic granules....
-doesn't really make sense
36
How does HLH present clinically?
- acute febrile illness
- splenomegaly and hepatomegaly
- very high levels of plasma ferritin and soluble IL-2 receptor (means severe inflammation)
37
How do tx HLH?
immunosuppressive drugs and "mild" chemotherapy
38
What are the 3 kinds of Neoplastic proliferations of WBC's we talked about?
- lympoid neoplasms
- myeloid neoplasms
- histiocytoses
39
What is most common chromosomal abnormality with white cell neoplasms?
translocations
40
What 3 viruses have been implicated as causative agents in particular lymphomas?
HTLV-1
EBV
Kaposi sarcom/HHV-8
41
what is KSHV associated with>?
malignant effusion often in the pleural cavity
42
What is the most common plasma cell neoplasm?
multiple myeloma
| -causes bony destruction of the skeleton and often present with pain due to pathologic fractures
43
What is required for diagnosis of lymphoid neoplasia?
histologic examination of lymph nodes or other involved tissues
44
Are most lymphoid neoplasms B or T cell related?
B cell origin!
45
Are lymphomas usually disseminated at the time of diagnosis?
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
46
Precursor B and Tcell neoplasms
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
47
What is the most common cancer of children?
ALL
- acute lymphoblastic leukemia
- hispanics have the highest incidence rate
48
If we see a T-ALL, what mutation will probably be there?
GOF mutation in NOTCH1
| -diverese chromosomal translocations
49
If there's B-ALL, what kinds of mutations are there?
LOF mutations
- PAX5, E2A, EBF
- diverse chromosomal translocations: t(12;21) involving RUNX1 and ETV6 present in 25%*****
50
What chromosomal changes are common in ALL's
hyperploidy (>50 chromosomes)
51
How does the bone marrow look in leukemic presentations?
hypercellular and packed with lymphoblasts
-mediastinal thymic masses with T-ALL's
-
52
What does the tumor cell cytoplasm look like in both B-ALL and T-ALL?
scant basophilic cytoplasma
53
How are lymphoblasts different from myeloblasts?
lymphblasts have more condesnsed chromatin, less conspicuous nucleoli (smaller), and smaller amounts of cytoplasm that usually lacks granules
54
are lymphoblasts MPO positive or negative?
negative
| -also contain periodic acid-Schiff-positive cytoplasmic material
55
For immunostaining, what willl we see in pre-B and pre-T lymphoblasts?
95%
| -TdT
56
Staining for B-ALLs
CD19
PAX5
CD10
CD 20 and IgM heavy chain if mature
57
Staining for T-ALLs
CD1,2,5, and 7
58
Clinical features of ALL's?
abrupt stormy onset
- depression of marrow
- CNS stuff like headache, vomiting, nerve palsies resulting from meningeal spread
59
Prognosis of ALL's
-children: awesome! 95%.. but it's still the leading cause of cnacer deaths in children
60
What is associated with a worse prognosis for ALL's?
- younger than 2 years
- present in adolescence or adulthood
- peripheral blood blast counts greater than 100,000
61
What are markers of favorable prognosis for ALLs
- age b/w 2-10
- low WBC count
- hperdiploidy
- trisomy of chormosomes 4,7,and 10
- presence of a t(12;21)
62
Which mutation makes that BRC-ABL tyrosine kinase?
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
63
What are the peripheral B-cell neoplasms that we need to worry about?
Chronic lymphocytic leukemia
| Small lymphocytic lymphoma
64
How do CML and SLL differ
only in the degree of peripheral blood lymphocytosis
| -CLL is more (>5000 lymphocytes)
65
What is the most common leukemia of adults in the western world?
CLL
66
Are chromosomal translocations a thing with CLL and SLL?
no, that's why they're kinda weird
67
What are the most common genetic anomalies in CLL/SLL?
deletions of 13q14.3, 11q, and 17p, and trisomy 12q
68
What will CLL/SLL tumors that pursue an aggressive course have?
unmutated Ig segments
69
how do the lymph noedes look in peripheral B-cell neoplasms?
diffusely effaced
- ***proliferation enters***: they're just larger activated lymphocytes that often gather in loose aggregates...
- smudge cells
70
What is the distinctive immunophenotype for CLL/SLL?
CD19, 20
| *CD23 and CD5
71
clinical presentation of CLL/SLL?
- generalized lymphadenopathy and hepatosplenomegaly
| - disrupts normal immune function through uncertain mechanisms
72
Things that mean worse outcome for CLL/CLL?
- del 11q and 17p
- no somatic hypermutation
- expression of ZAP-70
- presence of NOTCH1 mutations
73
What does the CLL/SLL transform into that is much worse?
Diffuse large B-cell lymphoma
| -also called Richter syndrome
74
Follicular lymphoma
most common form of indolent NHL in the US
75
Chromosomal translocations of what are associated with follicular lymphoma?
BCL2
- the hallmark t(14;18)
- 90% of follicular lymphomas
- IGH locus goes to 18, BCL2 locus goes to 14
76
does follicular lymphoma have apoptotic cells?
no!
77
What other gene has been identified as being mutated in 90% of follicular lymphoma cases as well?
MLL2
| -histone methyl transferase
78
Morphology of follicular cell lymphoma?
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******
79
immunophenotype of follicular lymphoma
CD19, 20, 10, and surface Ig and BCL6
| -UNLIKE CLL/SLL, CD5 IS NOT EXPRESSED
80
clinical features of follicular lymphoma?
painless generalized lymphadenopathy
- incurable, but indolent waxing and waning course
- histologic transformation happens 30-50%... most commonly to diffuse large B-cell lymphomas
81
Diffuse large B-cell lymphoma (DLBCL)
- the most common form of NHL!
- 60 years
- dysregulation of BCL6
82
Morphology of DLBCL
- large cell csize
- diffuse pattern of growth
- round or oval nucleus
83
Immunophenotype of DLBCL
CD19, 20, 10, BCL6, most have surface Ig
84
Immunodeficiency-associated Large B-cell lymphoma
- occurs in setting of severe t-cell immunodeficiency
- EBV
- restore T cells and may lead to regression
85
Primary effusion lymphoma
- 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
Clinical features of DLBCL
- 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
Burkitt lymphoma
- highly associated with translocations of the MYC gene
- fastest growing human tumor
- t(8;14)
88
What chromosome is the MYC gene on?
8
89
What are all endemic burkitt lymphomas latently infected with
EBV
| -infection precedes transformation
90
Morphology of Burkitt lymphoma
- high mitotic index... lots of apoptotic cells
- phagocytes have the "starry sky" pattern
- royal blue cytoplasm containing clear cytoplasmic vacuoles
91
Immunophenotype of Burkitt
- tumor of mature B-cells, sooooo
| - IgM, CD19, 20, 10, and BCL6
92
Unlike other tumors of germinal center origin, what does Burkitt lymphoma always FAIL to express?
the protein BCL2
93
Clinical feature of Burkitt lymphoma
- extranodal sites
- endemic kind in mandible
- sporadic gets the ileocecum and peritoneum
- very aggressive but responds well to intensive chemotherapy
94
what's another name for plasma cell tumor?
dryscrasia
95
what is an M component?
monoclonal antibody found in the blood
| -reference to myeloma
96
what do neoplastic plasma cells often synthesize?
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
When the light chains forma plasma cell neoplasm are excreted in the urine, what are they referred to as then?
Bence-Jones proteins
98
What is the most important plasma cell neoplasm?
Multiple myeloma
99
What is Waldenstom macroglobulinemia?
-when high levels of IgM lead to symptoms related to hyperviscosity of the blood
100
Multiple myeloma
plasma cell neoplasm commonly associated with lytic bone lesions, hypercalcemia, renal failure, and acquired immune abnormalities
101
pathogenesis of multiple myeloma
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
Morhpology of multiple myeloma
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
Immunophenotype of mutliple myeloma
CD138
Syndecan-1
CD56
104
clinical features of multiple myeloma
- 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
Most common cause of death with multiple myeloma?
infections
106
what is a solitary myeloma (Plasmacytoa)
solitary lesion of bone or soft tissue
107
what does a plasmacytoma inevitably progress to?
multiple myeloma
108
what is smoldering myeloma
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
Monoclonal gammopathy of uncertain significance (MGUS)
most common plasma cell dyscrasia
| -pts are asymptomatic and the serum M ptn is <3
110
Lymphoplasmacytic lymphoma
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
What is that hyperviscosity syndrom known as?
waldenstrom macroglobulinemia
112
What mutation does lymphoblastic lymphoma have?
MYD88
113
Morphology of lymphoblastic lymphoma
marrow has lymphocytes
| -russell bodies: PAS inclusions containing Ig are frequently seen in the cytoplasm or nucleus (Dutcher bodies)
114
immunophenotype of lymphoplasmacytic lymphoma
CD20 and surace Ig (usually IgM)
115
clinical features of lumphoplasmacytic lymphoma
- lymphadenopathy, hepatomegaly, and splenomegaly
- anemia caused by marrow infiltration is common
- cold agglutinins
116
What will happen with someone with and IgM secreting tumors?
hyperviscosity syndrome
117
What is hyperviscosity syndrome characterized by?
- visual impairment
- neuologic problems
- bleeding
- cryoglobulinemia: Raynaud phenomenon and urticaria
118
What do virtually all mantle cell lymphomas have?
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
What does the up regulation of cyclin D1 result in?
G1-S phase progression
120
morphology of mantle cell lymphoma
-homogeneous population of small lymphocytes with irregular to occasionally deeply clefted (cleaved) nuclear contours
121
What distinguished mantle cell lymphoma from follicular lymphoma and CLL/SLL
follicular lymphoma: large cells resembling centroblasts are absent
CLL/SLL: proliferation centers are absent (in the mantle cell lymphoma they are)
122
Immunophenotype of mantle cell lymphoma
- 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
clinical features of Mantle cell lymphoma
- most common presentation is PAINLESS LYMPHADENOPATHY
- prognosisi is poor
- not curable
124
Marginal zone lymphomas
- 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
What are the translocations with marginal zone lymphomas and what proteins do they up regulate?
11;18
14;18
1;14
-upregulate function of BCL10 or MALT1
126
Hairy cell Leukemia
-think middle aged white males
127
pathogenesis of hairy cell leukemia
- activating pt mutations in the serine/threonine kinase BRAF
- Val to Glu substitution at residue 600 (also found in langerhans cell histiocytosis
128
immunophenotype of hairy cell leukemia
CD19
CD20
surgace Ig (G)
CD11c, 25, and 103 and annexin A1
129
Morphology of hair cell leukemia
- fine hairlike projections
- white pulp is obliterated and red pulp has beefy red gross appearance
- hepatic portal triads also involved frequently
130
clinical features of hairy cell leukemia
- splenomegaly
- pancytopenia
- sensitive to "gentle" chemotherapeutic regimens
- overall prognosis is excellent
131
Peripheral T-Cell lymphoma, Unspecified
-efface lymp nodes diffusely and are typically composed of a pleomorphic mixture of variably sized malignant T cells
132
what are all T-cell lymphomas erived from?
Mature T cells
133
What do T cell lymphomas express then?
CD2, 3, 5, and aB or gd TCRs
134
Anaplastic large cell lymphoma (ALK positive)
uncommon
- presence of rearrangments of ALK gene on chromosome 2p23
- ALK fusion ptns
- horshoe shaped nucleii (hallmark cells
- children or young adults
135
how is the prognosis of T cell lymphomas with ALK rearrangements
very good
| -tumors lacking the ALK rearrangements occur in older adults and have a substantially wore prognosis
136
Adult T cell leukemia/lymphoma
-only in adults infected by HTLV-1
137
What protein does HTLV-1 make?
Tax
| -potent activator of NFkB
138
Mycosis Fungoides and Sezary syndrome
- 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
What do the tumor cells of Sezary syndrome express?
CLA
CCR4 and 10
-these contribute to the homing of normal CD4+ T cells to the skin
140
Large granular lymphocytic leukemia
- 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
Extranodal NK/T-Cell lymphoma
- 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
What kind of cells are in a Hodgkin lymphoma?
Reed-Sternberg cells
| -they release factors that induce a bunch of cells to come Party
143
What are the 5 different types of HL?
- nodular sclerosis (most common)
- Mixed cellularity
- lymphocyte-rich
- lymphocyte depletion
- lymphocyte predominance (RS cell has B cell immunophenotype)
144
Activation of what TF is a common event in classical HL?
NFkB
145
What do EBV+ tumor cells express?
latent membrane protein-1 (LMP1)
146
What else do we find reed sternberg cells in?
infectious mononucleosis
147
What do Reed Sternberg cells look like?
large
multiple nuclei or single nucleus with multiple lobes
-mononuclear variants have single nucleus with large inclusion-like nucleolus
148
What is characteristic of the lymphocyte predominance subtype of HL?
Lymphohistiocytic variants (L and H cells) with polypoid nuclei, inconcpicuous nucleoli, and moderately abundant cytoplasm
149
Nodular sclerosis type of HL
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
Mixed Cellularity type of HL
- 2nd most common
- RS cells and mononuclear variants
- YES EBV***
- males.. older
- night sweats and weight loss
- good prognosis
151
Lymphocyte-rich type of HL
- uncommon
- reactive lymphocytes make up the majority of the cellular infiltrate
- very good to excellent prognosis
152
Lymphocyte depletion type of HL
- 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
Lymphocyte predominance type of HL
- 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
how does HL usually present?
Painless lymphadenopathy
155
What are the different myeloid neoplasms that we have to worry about?
Acute Myeloid leukemia
Myelodysplastic syndromes
myeloproliferative disorders
156
what is a common featur of myeloid neoplasms
an origin from hematopoietic progenitor cells
157
what is an acute myeloid leukemia?
accumulation of immature myeloid forms in the bone marrow
| -suppresses normal hematopoiesis
158
what is myelodysplastic syndromes?
defective maturation of myeloid progenitors gives rise to ineffective hematopoiesis, leading to cytopenias
159
what is myeloproliferative disorders?
increased production of one or more types of blood cells
160
AML
- 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
What are the 2 most common chromosomal rearrangements for AML?
t(8;21)... disrupts RUNX1
inv(16)... disrupts CBFB
-blocks maturation of myeloid progenitors
162
is PML-RARa fusion prn sufficient to cause AML?
no
| -it needs to be combined with activated FLT3 to induce AML in mice
163
What is needed for the diagnosis of AML?
20% myeloid blasts in the bone marrow
164
What doe the myeloblasts look like?
- peroxidase + azurophilic granules
| - Auer rods (especially with t(15;17) which is APL)
165
What do monoblasts have?
folded or lobulated nuclei
- lack auer rods
- nonspecific esterase-positive
166
What CD marker will the myeloid blasts have?
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
clinical features of AML?
- anemia, neutropenia, and thrombocytopenia
| - infections in oral cavity, skin, lungs, etc... with pseudomonas
168
Which kind of AML has the best prognosis?
t(15;17)
| -8'21 and inv16 is good too
169
which AML is the really bad one to have?
-AMLs that follow MDS or genotoxic therapy
170
Myelodysplastic Syndromes (MDS)
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
What is the kind of MDS that almost always transforms to AML?
t-MDS (from radiation therapy)
172
what is the most characteristic finding in MDS?
disordered differentiation affecting the erythroid, granulocytic, monocytic, and megakaryocytic lineages to varying degrees
173
What is seen with erythrocyte MDS?
-ring sideroblasts
-megaloblastoid maturation (like vit B12 deficiency)
-nuclear budding abnormalities
-
174
What do the neutrophils in MDS look like?
Pseudo-Pelger-Guet cells
| -neutrophils with only two nuclear lobes
175
What do Megakaryocytes in MDS look like?
single nuclear lobes or multiple separate nuclei (pawn ball megakaryocytes)
176
Clinical features of MDS?
- older adults
- pancytopenia, so bleeding
- outlook for t-MDS is terrible
177
Mutation in CML
BCR-ABL fusion gene
178
Mutation in Polycythemia Vera
JAK2 pt mutations
179
Mutation is Essential thrombocythemia
JAK2
180
Mutation in primary myelofibrosis
JAK2
181
Mutation is systemic mastocytosis
KIT
182
Mutation ins chronic eosinophilic leukemia
-FIP1L1-PDGFRA fusion gene is the common one
183
mutation for stem cell leukemia
Various FGFR1 fusion genes
184
Myelproliferative disorders common pathogenic feature
presence of mutated, contitutively activated tyr kinases or other acquired aberrations
-lead to growth factor independence
185
Chronic Myelogenous Leukemia (CML)
- BCR-ABL gene
- BCR from 22
- ABL from 9
- THIS IS THE FUCKING PHILADELPHIA CHROMOSOME
186
What is the cell of origin in CML?
Pluripotent hematopoietic stem cell
187
Clinical features of CML
- adults usually
- insidious
- BRC-ABL
- accelerated phase... turns quickly into what looks like Acute leukemia
- it's called a blast crisis
188
What lineage are most of the cells in a blast crisis?
myeloid origin
| -makes sense because it's from a pluripotent stem cell with both myeloid and lymphoid potential
189
Polycythemia Vera
- 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
morphology of PCV?
- 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
clinical features of PCV?
- 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
Without tx, what happens to ppl with PCV?
death from bleeding or thrombosis within months of diagnosis
193
Essential Thrombocytosis
JAK2 point mutation (50%)
MPL (5-10%)... normally activated by thrombopoietin
-thrombopoietin-independent
-dysfunction of platlets.... PCV-like symptoms
*characteristic symptom is erythromelalgia*
194
What is erythromelalgia?
a throbbing and burning of hands and ffet caused by occlusion of small arterioles by platelet aggregates
195
Primary Myelofibrosis
- 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
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Morphology of primary myelofibrosis
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
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Clinical features of Primary myelofibrosis
- less common than PCV and ET
- older than 60
- sensation of fullness in the left upper quadrant
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Langerhans Cell Histiocytosis
- histiocytosis: proliferative disorder of dendritic cells or macrophages
- most common mutation is Val-Glu substitution at residue 600 in BRAF
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What other entity was BRAF messed up in?
hairy cell leukemia
| -present in 55-60% of cases of Langerhans Cell histiocytosis
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What is characteristic of Langerhans cell histiocytosis?
Birbeck granules i the cytoplasm
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What doe the birbeck granules look like?
tennis rackets!!!!
| -contain the protein langerin
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What else do the tumor cells express in langerhans cell histiocytosis?
HLAD-DR, S-100, and CD1a
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Multifocal multisystem Langerhans cell histiocytosis (Letterer-Siwe disease)
- 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
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Unifocal and multifocal unisystem Langerhans cell histiocytosis (eosinophilic granuloma)
- 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
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What is the Hand-Schuller-Christian triad?
calvarial bone defects
diabetes insipidus
exophthalmos
-happens in eosinophilic granulomas
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Pulmonary langerhans cell histiocytosis
- adult smokers
- may regress spontaneously upon cessation of smoking
- 40% associated with BRAF mutations
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What factor contributes to the homing of neoplastic langerhans cells?
aberrant expression of chemokine receptors
