Ch 13 Flashcards
1
Q
Blood cell progenitors first appear during _ weeks of embryonic development in _
A
3rd week,
Yolk sac
2
Q
Definitive hematopoietic stem cells first arises where?
A
aorta/gonad/mesonephros regions
3
Q
By 3rd month hematopoietic stem cell (HSC) migrates to what organ?
A
Liver and becomes the chief site of blood cell formation until shortly before birth
4
Q
By what month does HSC shift location to bone marrow?
A
4th
5
Q
until puberty hematopoietically active marrow is found where? what about after puberty?
A
Until puberty found throughout skeleton. After puberty it becomes restricted to axial skeleton (bones of head and trunk)
6
Q
To maintain hematopoiesis, what two properties are essential of HSC? explain explain what the properties mean
A
- pluripotency - ability of single HSC to general ALL mature blood cells
- Capacity for self-renewal - during cell division, one daughter cell retains self-renewal characteristic
7
Q
Marrow response to short-term physiologic needs is regulated by hematopoietic growth factors through effects on which cells?
A
committed progenitor cells such as CFU-G, CFU-M, CFU-eo, CFU-b, CFU-Mg, BFU-E
8
Q
In maintaining growth and differentiation of blood cells, which growth factors act on receptors located on VERY early progenitor cells? which ones act on committed progenitor cells?
A
Early: KIT ligand, and FLT3-land
Committed: EPO, GM-CSF, G-CSF, and thrombopoietin
9
Q
Where are hematopoietic cells located in the bone marrow?
A
within interstitium
10
Q
what is leukoerythroblastosis?
A
abnormal release of immature precursor into peripheral blood. usually due to disease
11
Q
what is the best way to assess morphology of hematopoietic cells?
A
Marrow aspirate smears - helps to differentiate between mature and precursors
12
Q
best modality for estimating marrow activity
A
bone marrow biopsy - cells to get ratio of hematopoietic cells vs fat cells
13
Q
what is the normal ratio of fat cells to hematopoietic cells?
A
normal 1:1
hypoplastic: increased fat cells ratio
Hyperplastic (cancer): increased hematopoietic cells ratio
14
Q
what is the difference between neutropenia and agranulocytosis?
A
Neutropenia is reduced number of neutrophils in blood. Agranulocytosis is severe clinically significant reduction of leukocytes, esp neutrophils, putting pt at risk of bacterial and fungal infections
15
Q
Common cause of neutropenia
A
1) inadeqaute or ineffective granulopoiesis (aplastic anemia, suppression of precursors with drugs, congenital disorders such as Kostman syndrome)
2) Increased destruction (immune mediated such as SLE, splenomegaly, increased peripheral utilization)
3) idiopathic (LGL leukopenia)
16
Q
with Neutropenia and granulocytosis, how does the marrow respond?
A
Neutropenia –> marrow hypercellularity
Agranulocytosis –> marrow hypocellularity (usually cuz of drugs)
17
Q
Main clinical feature of neutropenia and agranulocytosis
A
related to infection: malaise, chills, fevers, weakness, fatigability
18
Q
Serious infections are likely with neutrophils below what level?
A
500
19
Q
Main treatment in pts with neutropenia/agranulocytosis
A
- braod-specturm abx to prevent infections
- in case of mylosuppressive chemo treat with G-CSF
20
Q
Factors that influence of leukocytosis
A
- size of myeloid and lymphoid precursor and storage cell pools
- rate of release
- proportion of cells struck to endothelial cells
- rate of extravasation into tissue
21
Q
Common cause of increased production in the marrow leading to leukocytosis
A
- chronic infection or inflammation; paraneopastic, myloproliferative disorders
22
Q
common causes of increased release from marrow stores leading to leukocytosis
A
- endotoxemia
- infection
- hypoxia
23
Q
common cause of decreased margination leading to leukocytosis
A
- exercise
- catecholamines
24
Q
common cause of decreased extravasation into tissues leading to leukocytosis
A
glucocorticoids
25
During acute infection what leads to egress of mature leukocytes from marrow pool?
TNF and IL1
IL5 --> eosinophils
G-CSF--> neutrophils
26
Common cause of neutrophilic leukocytosis
- acute bacterial infection, esp pyogenic organism
27
common cause of eosinophilic leukocytosis
- allergic disorders such as asthma, hay fever, parasites, malignancies
28
Common cause of basophilic leukocytosis
- rare but indicative of myeloproliferative diseases (e.g. CML)
29
Common cause of Lymphocytosis
- accompanies monocytosis and seen in chronic immunologic stmulation (TB, viral infection; Bordetella pertussis
30
Common cause of monocytosis
- chronic infection (TB), bacterial endocardittis, rickettsiosis, malaria, autoimmune disorders (SLE),; IBD
31
In sepsis or severe inflammatory disorders, what morphological changes in neutrophils are seen
- toxic granulation: cells are coarser and darker (represents abnormal azurophilic (primary) granules)
- Dohle bodies: patches of dilated ER that appears sky blue cytoplasmic puddles
- Cytoplasmic vacuoles
32
Usually it's easy to distinguish from reactive and neoplastic leukocytoses. In what situation does it become uncertain?
1. acute viral infection, esp in kids where theres increased number of lymphocytes
2. severe infection leading to immature granulocytes in blood mimicking myeloid leukemia (Leukemoid reaction)
33
Morphology of nonspecific lymphadenitis
- nodes are swollen, grey red, engorged
- large reactive germinal center with many mitotic figures
- with pyogenic infection: neutrophils are prominent
34
In chronic nonspecific lymphadenitis, follicular hyperplasia is seen with activation of what kind of immune response?
humoral
35
what is tingible body macrophages?
found in germinal center of follicular hyperplasia in chronic nonspecific lymphadinitis. They represents DC and macrophages that are interspersed among B cells
36
What features favor reactive (nonneoplastic) vs hyperplasia of neoplasm?
- presevation of lymph nodes architecture
- marked variation in shape and size of follicles
- presence of frequent mitotic figures, phaogcytic macrophages and recognizable light and dark zones
37
Paracortical hyperplasia of lymph nodes are seen in what kind of response?
T cell triggered response such as viral infection
38
what is sinus histiocytosis?
increased number of size of cells that line lymphatic sinusoids, common in lymph nodes draining cancers such as breast cancer.
- linings of lymphatic cells are marked hypertrophied and macrophages are increased in number
39
collection of immune cells in nonlymphoid tissue (tertiary lymphoid organs) are usually seen in what kind of lymphadenitits?
chronic nonspecific lymphdenitis. (example H pylori --> peyer's patches)
40
_ is reactive condition marked by cytopenias and signs and symptoms of systemic inflammation
hemophagocytic lymphohistiocytosis (HLH)
41
HLH is caused by
systemic activation of macrophages and CD8 T cells --> cytokine storm --> shock-like presentation
42
which form of HLH is more severe?
familial form.. needs hematopoietic stem transplant
43
what is the treatment for HLH?
immunosuppressive drugs and mild chemo
44
survival rate o HLH without treatment
less then 2 months. with treatment 1/2 live with significant sequelae such as renal damage.
45
what s/s are associated with a severely enlarged spleen?
Dragging sensation in LUQ and pressure on stomach, and discomfort after eating
46
what lab findings are also associated with hypersplenism?
- anemia
- leukopenia
- thrombocytopenia
47
Morphology of an enlarged spleen
Gross: enlarged and soft
Micro: acute congestion of red pulp --> may efface lymphoid follicles; neutrophils, plasma cells, sometimes eosinophils in red and white pulps
48
Congestive splenomegaly results from
chronic venous outflow obstruction leading to splenic or portal HTN. Less commonly it can be due to right-sided cardiac issues
49
morphology of congestive splenomegaly
- enlarged (1000-5000gm); firm, capsule is thickened and fibrous
- Micro: collagen deposition in BM --> dilated rigit walls sinusoids --> prolonged flow and exposure to macrophages --> excessive destruction ---> hypertension
50
Splenic infarcts are usually occlusion of major artery or it's branches by emboli arriving from _
heart
51
Differentiate between bland vs septic infarcts
```
Bland infarcts (emboli coming from heart ) --> pale, wedge shaped subcapuslar
- Septic infarcts --> suppurative necrosis
```
52
Malignancies of white cells fall under what broad categories?
Lymphoid neoplasm (tumors of B, T and NK cells)
- Myeloid neoplasm ( AML, myelodysplastic syndrome, CML)
- Histiocytoses (proliferation of macrophages and DC's)
53
What is langerhans cell histiocytoses?
Immature dendritic cells
54
In etiologic and pathogenetic factors in white cell neoplasia, what is the most common pathogenetic factor?
chromosomal translocation
55
The most important pathogenetic cause of acute leukemias is _
oncoproteins that block normal maturation, and arrest differentiation of lymphoid or myeloid cells
56
what are the three major pathogenetic factors that leading to hematologic malignancies?
1. Pro-growth mutation (tyrosine kinase mutation, MYC translocation)
2. Pro-survival mutation (BCL2 translocation)
3. Mutations in transcription factors that influence self-renewal (MLL translocation, PML-RARA fusion gene)
57
Proto-oncogenes are activated most commonly in which type of hematologic neoplasms?
Lymphoid
58
What inherited genetic factors puts one at an increased risk of hematologic malignancies?
- Bloom syndrome
- Fanconi anemia
- ataxia telangiectasis
- Down syndrome
- NF I
59
What viruses are associated with hematologic malignancies?
- HTLV1 (adult T cell leukemia/lymphoma)
- EBV (brkitt lymphoma, Hodgkin lymphoma, B cell lymphoma)
- Kaposi sarcoma herpesvirus/HHV8 ( B cell lymphoma)
60
What factors causing chronic inflammation is associated with hematologic malignancies?
- H hypoli ( gastric B cell lymphomas)
- Gluten-sensitivity enteropathy (T cell lymphomas)
- Breast implants (T cell lymphomas)
- HIV ( B cell lymphomas)
61
Smoking is a common risk factor for which hematologic malignancy?
AML
62
_ is defined as neoplasm that present with widespread involvement of bone marrow and usuallly peripheral blood
Leukemia
63
_ is defined as proliferation that arises as discrete tissue masses
lymphoma
64
Lymphoid Neoplasms are classified into _
1. Hodgkin lymphoma
2. Non-hodgkin lymphoma
3. Plasma cell neoplasm (Multiple myeloma)
65
Most NHL and almost all HL presents as enlarged nontender lymph nodes greater than
2cm
66
_ causes bony destruction of skeleton and often presents with pain due to pathologic fractures
Multiple myeloma
67
In contrast to normal immune responses, population of lymphocytes derived from malignant progenitor share _
same antigen receptor gene configuration and sequence and synthesize identical antigen receptors proteins (either Igs or T cell receptors)
68
85-90% of all lymphoid neoplasm are of _ cell origin
B
69
Neoplastic B and T cells tend to recapitulate the bahaviior of their normal counterparts, except which malignancy?
Hodgkin's lymphoma and marginal zone B cell lymphomas. HL are restricted to one group of lymph nodes; and marginal zone B cell lymphomas are often restricted to sites of chronic inflammation
70
Acute lymphoblasticc leukemia/lymphomas (ALL) are composed of what kind of cells?
immature B (pre-B) or T (pre T), referred to as lymphoblastss
71
85% of B-ALL occur in what patient population?
childhood
72
T-ALL are less common and are seen in what patient population?
Adolescent male as thymic lymhomas
73
ALL is due to chromosomal aberration that dysregulate _ factors
Transcription
74
70% of T-ALL are due to gain of function mutation in
NOTCH1
75
B-ALL is due to loss of function mutation in genes required for B cell development such as _
PAX5, E2A, EBF or balanced t(12;21) involving ETV6 and RUNX1
76
ALL requires multiple mutations for oncogenesis. Common comlementary mutation include:
increased tyrosine kinase activity and RAS signaling
77
90% of ALL have numerical or structural chromosomal changes, of which most common is _
hyperploidy ( >50 chromosomes)
78
Morphology of ALL
- In leukemic presentation: marrow is hypercellular and packed with lymphoblasts
- Histo: scant basophilic cytoplasm and somewhat larger nuclei; rapidly growing tumor look like starry night
79
Distinguish ALL from AML
- Compared to myeloblast, lymphoblast have more condensed chromatin, less conspicuous nuclei and smaller amounts of cytoplasm and usually lacks granules
- Lymphoblast is negative for myeloperoxidase; and positive for Acid-Schiff
80
In immunophenotyping what are the markers for B-ALL
CD19; TF TAX5 and CD10 (except in very immature B-ALL); late B-ALL express CD10, CD19, and CD20 and cytoplasmic IgM
81
In immunophenotyping what are the markers for T-ALL
CD1, CD2, CD5, CD7
82
Symptoms of ALL
- abrupt onset after first symptom
- Symptoms related to depression of marrow function (fatiue due to anemia, fever, infection, bleeding)
- Mass effects: bone pain, lymphadenopathy, splenomegaly, hepatomegaly; testicular enlargement; and T-ALL complication is related to compression of large vessels and airways in mediastinum)
- CNS: HA, vomitting, nerve palsies
83
Prognosis of ALL in kids vs adults
- in kids 90% complete remission with aggressive chemo.
| - 35-40% remission in adults
84
Factors associated with worse prognosis of ALL
- age <2 associated with MLL gene
- presentation in adolescence or adulthood
- peripheral blood blast count >100,000
85
Factor associated with favorable prognosis of ALL
- age 2-10
- low WBC
- hyperdiploidy
- Trisomy of chromosome 4, 7 , 10
- Presence of t(12;21)
86
Chronic lymphocytic leukemia (CLL) presents as lymphocytosis, Absolute lymphocytes greater than _
5000
87
What is the most common leukemia of adults in the western world?
CLL
88
demographic of CLL
average age 60 with 2:1 male dominance
89
In the pathogenesis of CLL, deletion of what are most common?
13q14.3; 11p; 17p
90
which trisomy is common in CLL/SLL
12q
91
In CLL tumors with what pursue a more aggressive course?
unmutated Ig segments
92
Gain of function mutation in what gene is implicated in 10-18% of CLL
NOTCH1
93
Morphologically, presence of what is pathognomonic for CLL/SLL
proliferation centers (admixed aggregates of mostly small lymphocytes and some larger activated lymphocytes)
94
How do chronic lymphocytic leukemia and small lymphocytic lymphoma differ?
differ in the degree of peripheral blood lymphocytosis
95
what are smudge cells?
In morphology of CLL/SLL, referring to small round lymphocytes with scant cytoplasm that been be disrupted in the process of making smears.
96
Immunophenotype of CLL/SLL
tumor cells express the pan B-cell markers: CD19, CD20 as well as CD23, and CD5
97
Clinical features of CLL/SLL
- nonspecific (easy fatigability, wt loss, anorexia)
- generalized lymphadenopathy and hepatosplenomegaly
- variable leukocyte count
- small monoclonal Ig spike in some pts
- disruptions of normal immune function
- hypogammaglobulinemia --> infection
- hemolytic anemia, thrombocytopenia in some
98
Overall median survival rate of CLL/SLL
4-6 yrs; in those with low tumor burden survival rate is more than 10 yrs
99
factors that correlate with worse prognosis of CLL/SLL
1. presence of deletion of 11q and 17q
2. lack of somatic hypermutation
3. expression of ZAP-70
4. presence of NOTCH1 mutation
5. capacity to transform into more aggressive tumor such as large B cell lymphoma (Richter syndrome)
100
Typical treatment fo CLL/SLL
chemo and immunotherapy against CD20
| - hematopoietic stem cell transplantation in young pts
101
_ is clonal proliferation of incompetent B cells
CLL
102
A pt with CLL presents with wt loss, fever, night sweats, cachexia and lyphadenopathy. what is the most likely cause?
Richter syndrome/transformation
103
THe most common form of indolent NHL in the US
follicular lymphoma
104
Follicular lymphoma arises from _1_ and is strongly associated with chromosomal translocation involving _2_
1. germinal center B cell
| 2. BCL2
105
_ is defined as small-size B cell proliferation in the follicles
Follicular lymphoma
106
The main pathogenetic cause of follicular lymphoma
(14;18) translocation that juxtaposes the IGH locus on chromosome 14 and BCL2 locus on chromosome 18 --> overexpression of BCL2 --> antagonizes apoptosis and promote survival of follicular lymphoma cells
107
In 90% of follicular lymphoma, epigenetic abnormalities is almost implicated, particularly mutation in _ gene
MLL2
108
Morphology of follicular lymphoma
- nodular or nodular and diffuse growth pattern in lymph node
- presence of small cells with irregular or cleaved nuclear contours and scant cytoplasm referred to as centrocytes
- presence of larger cells with open nuclear chromatin many nucleoli and modest cytoplasm, referred to as centroblats
109
Immunophenotype of follicular lymphoma
- resemble normal germinal center B cells, expressing Cd19, CD20, CD10, surface Ig, and BCL6 (normal is BCL6 negative)
- CD5 is NOT expressed unlike CLL/SLL and mantle cell lymphoma
110
Clinical features of follicular lymphoma
- painless generalized lyphadenopathy
| - extranodal sites involvement is uncommon
111
Prognosis of follicular lymphoma
- incurable
- indolent course, waxes and wanes
- Survival median 7-9 yrs; aggressive therapy does not improve
- Histologic transformation to diffuse large B cell lymphoma in 30-50%; median survival after transformation is 1 yr
112
_ is large-size B cell proliferation
Diffuse Large B-cell lymphoma (DLBCL)
113
Most common subtype of NHL
DLBCL
114
Demographics of DLBCL
males, 60s, but can occur in young adults and kids too
115
In the pathogenesis of DLBCL, frequent pathogenic event is dysregulation of _
BCL6 - needed for normal germinal center formation
116
In 30% of DLBCL there are various translocation that have in common a breakpoint in BCL6 at chromosome
3q27
117
10-20% of DLBCL are associated with what translocation?
14;18 --> overexpression of BCL2
118
5% of DLBCL are associated with translocation involving
MYC
119
Distinct morphology of DLBCL
large cell size and a diffuse pattern of growth
120
Immunophenotype of DLBCL
CD19 and CD20 and variable expression of germinal center B cell markers such as CD10 and BCL6
121
two special subtypes of DLBCL associated with viral infections
1. Immunodificiency-associated large B cell lymphoma (common with advanced HIV infection and allogeneic bone marrow transplant. Neoplastic B cells are usually infected with EBV
2. Primary effusion lymphoma (commonly in pts with advanced HIV); tumor cells are often anaplastic and fail to express surface B or T cell markers but have clonal IgH gene rearrangements . usually infected with KSHV/HHV8
122
Clinical features of DLBCL
- typically presents as a rapidly enlarging mass at a nodal or extranodal site
- waldeyer ring, oropharyngeal lymphoid tissue that includes tonsils and adenoids are commonly involved
123
Prognosis of DLBCL
- Very aggressive with poor prognosis without treatment
| - with intensive combo of chemo --> 60-80% complete remission and 40-50% cured
124
DLBCL with what translocation have a worse prognosis
MYC
125
_ is intermediate-size B cell proliferation
Burkitt lymphoma ( form of NHL)
126
Burkitt lymphoma exists in what three catregory
1. African burkett lymphoma (endemic)
2. sporadic (nonendemic)
3. subset of aggressive lymphomas occuring in HIV infected
127
All forms of Burkitt lymphoma are highly associated with what translocation?
8;14 translocation: approximates the Ig heavy chain locus (14) with c-myc (8) --> increased levels of c-myc drives cell growth
128
Essentially all endemic burkitt lymphomas are latently infected with _
EBV, which also present in about 25% of HIV associated tumor 15-20% of sporadic cases
129
Morphology of Burkitt lymphoma
tumors exhibits a high mitottic index and contains numerous apoptoic cells --> starry night pattern
130
Immunophenotype of Burkitt lymphoma
Burkitt is tumor of mature B cells that express surface igM, CD19, CD20, CD10 and BCL6
- Negative for BCL2
131
Clinical features of Burkitt's lymphoma
- both endemic and sporadic forms found in kids and young adults
- most have extranodal sites
- endemic forms presents as mass on mandible ad shows a unusual predilection for abd viscera, esp kidney, ovaries and adre
132
Plasma cell neoplasms almost always secrete which immunoglobulin?
Monoclonal Ig or Ig fragment
133
Most common and deadly form of plasma cell neoplasm is
Multiple myeloma
134
A monoclonal Ig identified in the blood is referred to as
M component, in reference ot myeloma
135
Neoplastic plasma cells along with complete Igs also synthesize excess amounts of _
light chains
136
Pts with plasma cell tumors, the level of free _ in the blood is used as a marker since it's usually elevated and is markedly skewed toward one type at the expense of the other.
Light chain (kappa vs. lambda)
137
What are Bence -Jones proteins?
Free light chains, which are small enough, excreted out in urine. Seen in Plasma cell neoplasm such as multiple myeloma
138
What terms describes the abnormal Igs associated with plasma cell neoplasms?
- moonoclonal gammaopathy
- dysproteinemia
- paraproteinemia
139
the abnormal proteins associated with plasma cell neoplasm can be seen in multiple myeloma where it usually presents as tumourous masses scattered throughout which body system?
skeletal system
140
What is solitary myeloma?
aka plasmacytoma, an infrequent variant of multiple myeloma that present as a single mass in bone or soft tissue
141
What is smoldering myeloma?
A variant form of myeloma defined by a lack of symptoms and a high plasma M component
142
What is Waldenstom macroglobulinemia
A manifestation of the abnormal Igs seen in plasma cell neoplasm, leads to this syndrome in which high level of IgM leads to symptoms related to hyperviscosity of blood. Occurs in older adults, most commonly in association with lymphoplasmacytic lymphoma
143
In plasma cell neoplasm, the abnormal Igs proteins (termed monoclonal gammopathy, dysproteinemia, and paraproteinemia) can present in which clinicopathogic entities?
1. Multiple Myeloma
2. Waldenstrom macroglobulinemia
3. Heavy-chain disease
4. Primary or immunocyte-associated amyloidosis
5. Monoclonal gammopathy of undetermined significance (MGUS)
144
What is heavy-chain disease?
rare monoclonal gammopathy that is seen in many disorders including lymphoplasmacytic lymphoma and an unusual small bowel marginal zone lymphoma that occurs in malnourished populations.
- Common feature: synthesis and secretion of free heavy chain fragments
145
Primary or immunocyte-associated amyloidosis results from monoclonal proliferation of _
plasma cells secreting light chains (usually lambda isotype) that are deposited in amyloid
146
What is monoclonal gammopathy of undetermined significance?
pts with plasma cell neoplasm w/o S/S who have small to moderate large M components in their blood. Common in older pts with a constant rate of transformation to symptomatic monoclonal gammopathies most often MM
147
_ is defined as plasma cell neoplasm commonly associated with lytic bone lesions, hypercalcemia, renal failure, and acquired immunne abnormalities
Multiple Myeloma (MM)
148
Demographic of multiple myeloma
Common in:
- Western part of the world
- Male
- older adults (65-70)
- African descent
149
MM is associated with frequent rearrangement iinvolving the _ locus and various proto-oncogenes
IgH
150
What are the common translocation involved in MM?
Ig heavy-chain gene on chromosome 14q32 with cyclin D1 genes on 11q13 and D3 on 6p21
151
Deletion of what has a poorer outcome in MM?
17p that involve TP53
152
Late stage, highly aggressive forms of MM are associated with acquisition of rearrnagemnts involving what gene?
MYC
153
Deep sequencing of myeloma genomes identified frequent mutaiton involving which signaling pathway that supports that MM is due to B-cell surivival and proliferation
NF-kB
154
The proliferation and survival of myeloma cells in MM are dependent on notably which cytokine?
IL6, pts with high levels of IL6 in serum has poor prognosis
155
What mediates the bone destruction as seen in MM?
Factors produced by neoplastic cells:
1. especially MIP1a which upregulates expression of receptor activator of NF-kB ligand (RANKL) --> activates osteoclasts;
2. factors modulating Wnt pathway inhibits osteoblast function. Together increase in bone resorption, which leads to hypercalcemia and pathologic fractures
156
Morphology of MM: presents as destructive plasma cell tumors involving what bones?
axial skeleton starting from my medullary cavity and erode outward
157
The bone lesions of MM radiographically appear as _
punched out defects usually 1-4 cm in diameter
158
Hislogolically, the plasma cell seen in MM can appear as _
- normal appearing, plasmablasts with vesicular nuclear chromatin and a prominent single nucleolus OR
- bizarre multinulceated cells
159
Features seen in cytology of MM
- Flame cells with fiery red cytoplasm
- Mott cells with multiple grapelike cytoplasmic droplets
- cells containing variety of inclusions such as fibrils, cyrstalline rods, and globules which are referred to as Russell bodies (if cytoplasmic) or Dutcher bodies (if nuclear)
160
In MM, common blood smear finding of peripheral blood
- High levels of M proteins causing RBC to stick together --> rouleaux formation
161
What is myeloma kidney?
A clinical finding of MM where Bence Jones proteins are excreted in kidney and contribute to renal disease
162
Immunophenotype of MM
CD138
| CD56
163
The clinical features of MM stems from what three factors?
1. plasma cell growth in tissues esp bones --> pathologic fractures and chronic pain; hyercalcemia --> neurological manifestation (confusion, weakness, lethergy, constipation, polyuria)
2. Production of excessive Igs with abnormal physicochemical properties --> recurrent bacterial infection; renal insufficiency (bence jones proteinuria) and prone of amyloidosis
3. Suppression of normal humoral immunity
164
Significant lab findings of MM
- Increased levels of Igs in blood (>3gm/dL); commonly IgG followed by IgA
- light chains (bence-jones proteins in urine (>6mg/dL)
- free light chains and serum M proteins
165
Definitive diagnosis of MM
- radiographic finding
- Lab finding
- Bone marrow examination
166
Prognosis of MM
4-7 yrs with treatments
167
what factors are associated with good prognosis of MM
Translocation involving cyclin D1
168
More aggressive and poor prognosis of MM are associated with
deletion of 13q, 17p and t(4;14)
169
Extraosseous lesion of solitary myeloma (plasmacytoma) are seen in what locations?
lungs, oronasopharynx or nasal sinuses
170
Prognosis of solitary myeloma (plasmacytoma)
progresses to MM with 10-20 years
| - extraosseous plasmacytomas involving upper respiratory tract are cured by local resection
171
Prognosis of smoldering myeloma
progresses to MM over 15 year period
172
_ is the most common plasma cell dyscrasia
monoclonal gammopathy of uncertain significance (MGUS)
173
About 1% of MGUS pts develop symptomatic plasma cell neoplasm, commonly _
multiple myeloma. MGUS is considered an early stage of MM, thus periodic asessment of serum M component and Bence Jones proteinuria is warranted
174
_ is a B cell neoplasm of older adults that usually presents in 6th or 7th decade and has a resemblance to CLL/SLL, but with substantial fraction of the tumor cells undergoing differentiation to plasma cells
Lymphoplasmacytic lymphoma
175
In lymphoplasmacytic lymphoma, the common plasma cell component secreted is _1_ and often sufficient enough to cause hyperviscosity syndrome known as _2_
1. monoclonal IgM,
| 2. Waldenstrom macroglobulinemia
176
Virtually all cases of lymphoplasmacytic lymphoma are associated with acquired mutations in _1_ which encodes an adaptor protein involved in signaling events that activates _2_ and augment signaling downstream of B cell receptor complex.
1. MYD88
| 2. NF-kB
177
Morphological/histological findings of lymphoplasmacytic lymphoma
- marrow contains lymphocytes, plasma cells, plasmacytoid lymphocytes and sometimes mast cell hyperplasia
- Acid-schiff-positive includsion containg Ig are seen in cytoplasm (russel bodies) or the nucleus (Dutcher bodies)
- At diagnosis, tumor has usually disseminated to lymph nodes, spleen, and liver
178
Immunophenotypic markers of lymphoplasmacytic lymphoma
Lymphoid component express B cell markers: CD20 and surface Ig
Plasma cell component secretes the same Ig and usually IgM.
179
Clinical signs and symptoms of Lymphoplasmacytic lymphoma
- nonspecific (weakness, fatigue, wt loss)
- lymphadenopathy, hepatomegaly and splenomegaly
- anemia
- autoimmune hemolysis caused by cold agglutinins
- pts with IgM secreting tumors have hyperviscosity syndrome which involves: visual impairment, neurologic problems, bleeding, cryoglobulinemia
180
Prognosis of lymphoplasmacytic lymphoma
- incurable progressive disease
| - median survival is 4 yrs
181
_ is a type of non-hodgkin's lymphoma defined as small B cell proliferation of the area surrounding the follicular zone--the tumor resemble normal mantle zone B cells that surround germinal centers
Mantle cell lymphoma.
182
Pathogenesis of Mantle cell lymphoma
t(11;14) involving IgH locus on chromosome 14 and cyclin D1 locus on chromosome 11 --> overexpression of cyclin D1 --> promotes G1 to S phase progression
183
Morphology/histology of mantle cell lymphoma
proliferation consists of a homogenous population of small lymphocytes with irregular to occasionally deeply clefted (cleaved) nuclear contours
184
Frequent site of extranodal involvement of mantle cell lymphoma
- bone marrow
- spleen
- liver
- gut
- occasionally: mucosa of small and large bowel
185
Immunophenotype of mantle cell lymphoma
- high levels of Cyclin D1
- Most express CD19, CD20
- moderate level of surface Ig, esp IgM and D
- usually CD5+ and CD23- thus helps to distinguish from CLL/SLL
186
Clinical features of Mantle cell lymphoma
Painless lymphadenopathy
- symptoms related to spleen involvement
- poor prognosis (median survival 3-4yrs)
187
_ is defined as a type of NHL of small heterogenous group of B cell proliferation that arise in lymph nodes margin, spleen, and extranodal tissues such as mucosa and are associated with chronic inflammatory disorders of autoimmune or infectious etiology (Sjogren, Hashimoto thyroiditis, H pylori)
Marginal zone lymhoma
188
Pathogenetics of marginal zone lymphoma
Chromosomal translocations (11;18); (14;18); or (1;14). All upregulate BCL10 or MALT1 --> activates NF-kB --> promote growth and survival of B cells
189
_ is defined as indolent leukemia of mature B cells with infiltration of bone marrow, common among middle aged man and associated with autoimmune conditions
Hairy cell leukemia (HCL)
190
Pathogenetics of HCL
activating point mutations in serine/threonine kinase BRAF
191
Histologic findings of HCL
Fine hair like projections. On routine peripheral blood smears hairy cells are oblong, reniform nuclei and moderate amount of pale blue cytoplasm with threadlike or bleblike extensions
192
Immunophenotype of HCL
express pan B cell markers CD19, CD20, surface Ig (usually IgG) and certain relatively distinctive markers, such as CD11c, CD25, CD103 and annexin A1
193
Clinical features of HCL
- Splenomegaly
- Hepatomegaly
- lymphadenopathy rarely
- Pancytopenia
- infections
194
The disease course of HCL is unusual among other cancers, how?
HCL is exceptionally sensitive to gentle chemo and produce long lasting remissions but oftem relapse after 5 or more years, yet generaly responds well with the same treatment. Overall prognosis is excellent
195
HCL that have failed conventionally chemo have excellent response to what directed therapy?
BRAF inhibitors
196
Peripheral T-cell lymphomas, unspecified largely a wastebasket category for tumors that do not fit any WHO with no morphologic feature thati s pathognomonic, but certain findings are characteristics. Such as _
- tumors cells diffusely efface lyph nodes and are composed of pleomorphic mixture of variably sized malignant T cells
- Infiltrates of reactive cells are common (e.g eosinophils, macrophages)
- Have mature T cell phenotype; express pan T cell markers (CD2, CD3, CD5)
197
Clinical findings of peripheral T cell lymphomas unspecified
- generalized lymphadenopathy
- eosinophilia,
- pruritus
- fever
- wt loss
- comparably worse prognosis than aggressive mature B cell neoplasm
198
Anaplastic large-cell lymphoma (ALK positive) is defined by the presence of rearrangements in the _1_ gene on chromosome _2_
ALK
2p23
Creates a fusion protein that triggers RAS and JAK/STAT pathway
199
Histological feature of anaplastic large-cell lymphoma
Large anaplastic cells some containing horseshoe-shaped nuclei and voluminous cytoplasm (hallmark cells)
- tumor cells cluster about venules and infiltrates lymphoid sinuses mimicking metastatic carcinoma
200
T-cell lymphomas with ALK rearrangements tend to occur in what age group and involve what tissue?
kids or young adults and involve soft tissues with good prognosis
201
Markers for ALK+ anaplastic large cell lymphoma
CD30
202
Adult T cell leukemia/lymphoma is of _ T cells and only observed in adults infected by what virus?
CD4+
| HTLV-1
203
Common findings of adult T cell leukemia
- skin lesions
- generalized
- lymphodenopathy
- hepatosplenomegaly,
- peripheral blood lymphocytosis and hypercalcemia
204
Histological findings of adult T cell leukemia/lymphoma
- multilobated nuclei (cloverleaf or flower cells)
205
Pathogenesis of Adult T cell leukemia/lymphoma
HTLV1 provirus plays the critical role in pathogenesis. It encodes Tax that is a activator of NK-kB and enhaces lymphocyte growth and survival
206
Clinical course and prognosis of adult T cell leukemia/lymphoma
Rapidly progressive disease that is fatal within months to 1 year even with aggressive chemo.
- less commonly there's only skin involvement and has a more indolent course like mycosis fungoides
207
Both _ and _ are different manifestation of a tumor of CD4+ T helper cells on the skin.
Mycosis fungoides
| Sezary syndrome
208
Mycosis fungoides progress through what three stages?
1. an inflammatory premycotic phase
2. plaque phase
3. tumor phase
209
Histological feature of epidermis and upper dermis of Mycosis fungoides
infiltration by neoplastic T cells with cerebriform appearance
210
Characteristic findings on skin of sezary syndrome
generlaized exfoliative erythroderma with sezary cells with characteristic cerebriform nuclei
211
Immunophenotypic marker of Mycosis fungoides/sezary syndrome
Tumor cells express adhesion molecule cutaneous leukocyte antigen (CLA) and chemokine receptors CCR4 and CCR10
212
Prognosis of Mycosis fungoides/sezary syndrome
indolent tumors with 8-9 years survival.
213
Large granular lymphocyti leukemia have acquired mutation in the transcriptio factor _, and occurs in both T and NK cells
STAT3
214
Histology of large granular lymphocytic leukemia
tumor cells are large lymphocytes with abundant blue cytoplasm and few coarse azurophilic granules seen in peripheral blood smears.
215
Dominant clinical feature of large granular lymphocytic leukkemia
Neutropenia and anemia
Rarely: pure red cell aplasia
216
what is Felty syndrome?
A triad of rheumatoid arthritis, splenomgealy and neutropenia as seen in pts with large granular lymphocytic leukemia
217
_ is a NHL that presents most commonly as a destructive nasopharyngeal mass and less commonly in testis and skin. Tumor cells infiltrate/ invades small vessels leading to ischemic necrosis, and large azurophilic granules can be seen in touch preparations
Extranodal NK/T cell lymphoma
218
Extranodal NK/T cell lymphoma is HIGHLY associated with what virus
EBV
219
Prognosis of extranodal NK/T cells lymphomas
- highly aggressive but responds well to radiation but resistant to chemo.
- poor prognosis with advanced disease
220
_ is defined as B cell malignancy originating in lymphatic system commonly due to EBV infection and Reed-Sternberg cells
Hodgkin lymphoma
221
Differentiate between HL and NHL
HL: localized to single axial group of nodes; orderly spread by continuity; mesenteric nodes and waldeyer ring; extranodal presentation rare
NHL: multiple peripheral nodes; noncontinuous spread; waldeyer ring and mesenteric nodes; extranodal presentation common
222
The reed-sternberg cells as seen in HL are derived from _
germinal centers or postgerminal centers of B cells
223
The 5 WHO classification of HL
1. Nodular sclerosis
2. mixed cellularity
3. Lymphocyte-rich
4. Lymphocyte depletion
5. Lymphocyte predominance
1-4 are considered classical forms of HL with Reed-sternberg cells having a similar immunophenotype
224
Activation of what transcription factor is a common event in classical HL?
NF-kB
225
In HL, activation of NF-kB is thought occur in what ways?
- EBV infection
- EBV+ tumor cells expressing LMP1 which transmit signals that upregulate NF-kB
- Activation of NF-kB due to loss of function mutation in IkB or A20 (aka TNFAIP3)
- activation of NF-kB rescues crippled germinal center B cells that cannot express Igs from apoptosis --> acquisition of mutation and production of Reed-Stermberg cells
226
Reed-Sternberg cells are positive for which markers?
CD15 and CD30
227
Histologically describe what Reed-Sternberg cells look like
large cells w/ multiple nuclei or a single nucleus with multiple nuclear lobes, each with a large inclusion-like nucleolus about the size of a small lymphocyte
228
Nodular sclerosis type of HL are the most common type and is characterized by presence of _1_ Reed-Sternberg cells and the deposition of collagen in bands that divide involved lymph nodes into circumscribed nodules
1. Lacunar variant
229
Reed-Sternberg cells ni the classical HL are positive for _1_, _2_, and _3_, and negative for _4_
1. PAX5
2. CD15
3. CD30
4. Other B cell markers, T cell markers, and CD45
230
This type of HL occur equally in males and females with propensity to involve lower cervical, supraclavicular and mediastinal lymph nodes of adolescents or young adults. Has excellent prognosis. Not associated with EBV
Nodular sclerosis type
231
In about 70% of cases this type of HL have plenty of mononuclear variants and Reed-sternberg cells that are infected with EBV.
Mixed-cellularity type
232
In this type of HL, the Reed-sternberg cells are infected with EBV in over 90% of cases, occurs common in the older adults, in HIV+, and in nonindustrialized countries. Prognosis is somewhat less favorable than the other types
Lymphocyte depletion HL
233
In this type of HL, Reed sternberg cells are usually difficult to find and instead contains L&H (lymphocytic and histiocytic) variants, which have a multilobed nucleus resembling a popcorn kernal (popcorn cell)
Lymphocyte predominance HL
234
In contrast to Reed Sternberg cells found in classicail forms of HL, L&H variants express what markers?
B cell markers typical of germinal center B cells such as CD20, BCL6 and are usually negative for CD15, CD30
235
Clinical features of HL
- commonly presents as painless lymphadenopathy
- Pts with nodular sclerosis or lymphocyte predominance types tend to have stage I-II and are free of symptoms
- pts with disseminated disease (stages III-IV) or the mixed-celluarity or lymphocyte depletion subtypes are more likely to have constitutional symptoms like fever, night sweats, weight loss etc.
236
Pattern of spread of HL
nodal disease first then splenic disease hepatic disease and finally involvement of marrow and other tissues
237
_ antibodies have produced excellent response in pts with HL that has failed conventional treatments
Anti-CD30
238
The three broad category of myeloid neoplasm include
1. AML
2. Mylodysplastic syndromes
3. Myeloproliferative disorders
239
_ is a tumor of hematopoietic progenitors caused by acquired oncogenic mutations that impede differentiation, leading to accumulation of immature myloid blasts
Acute myeloid leukemia (AML)
240
AML are categorized in to four categories based on _
1. those associated with particular genetic aberrations
2. Those arising after a myelodysplastic disorder (MDS) with MDS like features
3. Therapy-related AML
4. AML not otherwised specified, classified based on degree of differentiation and lineage of leukemic blasts
241
Most common pathogenetic cause of AML
t(8;21) and inv(16) --> disrupts RUNX1 and CBFB genes, respectively --> creates a chimeric genes encoding proteins that interfere with function of RUNX1/CBF1b and block maturation of myeloid cells
- mutation that lead to activation of growth factor signaling pathways collaborate with the transcription factors aberration
242
_ is a subtype of AML with t(15;17) that disrupts retinoic acid receptor (RAR) required for myeloblast maturation and is associated with DIC and presence of Auer rods (peroxidase positive eosinophilic cytoplasmic inclusions)
Acute promyelocytic leukemia (APML)
243
Which subtype of AML is associated with Down syndrome
Acute megakaryoblastic leukemia
244
Which subtype of AML infiltrates the gums of the mouth?
acute monocytic leukemia
245
diagnosis of AML is based on presence of at least 20% _ in the bone marrow
myloid blasts
246
Depending on the AML type the myeloid blasts have different morphologic features. Describe the two common myloid blasts seen
1. Myeloblasts - 2-4 nucleoli, voluminous cytoplasm containing fine, azurophilic peroxidase-positive granules or distinctive red staining, peroxidase positive needle like structures called Auer rods
2. Monoblasts: folded or lobulated nuclei, lack auer rods and does not express peroxidase but can be IDed by staining for non-specific esterase
247
in certain type of AML, what's meant by aleukemic leukemia
Absence of myeloid blast in the blood. Usually there's greater than 100k blasts in the blood
248
Immununophenotype for AML
stain for myeloid-specific antigen
249
AML arising de novo in younger adults are commonly associated with which chromosomal translocation
t(8;21), inv(16); and t(15;17)
250
AML following myelodysplastic syndromes often have deletion or monosomies of which chromosomes?
5 and 7 and usually lacks translocation
251
AML occuring after treatment with topoisomerase II inhibitors are associated with translocation involving what gene?
MLL gene on 11q23
252
Clinical findings/features of AML
- symptoms related to anemia, neutropenia, and thrombocytopenia, most notably fatigue, fever, and spontaneous mucosal and cutaneous bleeding, cutnaous petchiae, ecchymoses, serosal hemorrhage into body cavity/viscera
- Pts with APML produce procagulatns and can produce DIC
- neutropenia --> infection (frequently opportunistic, e.g. fungal, pseudomoas, etc)
- tumors with monocytic differentiation infiltrate skin (leukemia cutis) and gingiva
253
which AML type have the best prognosis?
AML with t(15;17): treated with all-trans retinoic acid and arsenic salts
254
which AML types have the worst prognosis?
AML following MDS or genotoxic therapy
255
_ refers to a group of clonal stem cell disorders characterized by maturation defects that are associated ith ineffective hematopoiesis and a high risk of transformation to AML
Myelodysplastic syndromes (MDS)
256
In MDS, what change occurs in the bone marrow?
Bone marrow is partly or wholly replaced by clonal progeny of a neoplastic multipotent stem cell --> peripheral blood cytopenias
257
All forms of MDS can transform to AML, but transformation occurs with highest frequency and most rapidly in _
radiation therapy-MDS (t-MDS)
258
In the pathogenesis of MDS, the commonly mutated genes are lumped into what three category?
1. Epigenetic factors
2. RNA splicing factors
3. Transcription Factors
259
Both primary MDS and t-MDS are associated with chromosomal abnormalities including _
- monosomies 5 and 7
- deletion of q, 7q and 20 q
- trisomy 8
260
Characteristic histological finding of MDS
- disordered differentiation affecting erythroid, granulocytic, monocytic and megakaryocytic lineages to varying degrees
261
what are the characteristic histologic finding of the erythroid lineage effects as seen in MDS
- ringed sideroblasts (erythorblast with iron-laden mitochondria )
- Megablastoid maturation ( as seen in vit B12 or folate def)
- Nuclear budding abnormalities --> misshapen nuclei w/ polypoid outlines
262
What are the characteristic histologic findgins of granulocytic lineage effects as seen in MDS?
- Neutrophils with decreased numbers of secondary granules, toxic granulations or Dohle bodies
- Pseudo-Pelger-Huet cells (neutrophils with only two nuclear lobes)
263
What are the characteristic histologic findgins of megakaryocytic lineage effects as seen in MDS?
- single nuclear lobes or multiple separate nuclei (pawn bll megakaryocytes)
264
Clinical features of MDS
- peaks at 70 years
- discovered incidentally and if symptomatic presents as weakness, infections, hemorrhages all due to pencytopneia
- higher blast count, more severe cytopenias and presence of multiple clonal chromosomal abnormalities have worse prognosis
- median survival in primary MDS 9-29 months
- 10-40% progress to AML
265
In myeloproliferative disorders mutated constitutively activated _ or other aberrations in signaling pathways leads to growth factor independence
Tyrosine kinase
266
In myeloproliferative disorder because tyrosine kinase mutation do not impair differentiation the most common conseequence is increase in _
one or more mature blood elements
267
Most myeloproliferative disorder originate in
multipotent myeloid progenitors
268
Common features of myeloproliferative disorders include
1. increased proliferative drive in the marrow
2. homing of hematopoietic stem cells to non-marrow sites, causing extramedullary hematopoiesis
3. Variable transformation to a spent phase characterized by marrow fibrosis and peripheral cytopenia
4. Variable transformation to acute leukemia
269
_ is a neoplasm of pluripotent hematopoietic stem cells leading to preferential proliferation of granulocytic progenitors. It's distincgished from other MPD by presence of chimeric, constitutively active BCR-ABL tyrosine kinase
Chronic myeloid leukemia (CML)
270
In more than 90% of CML, BCR-ABL fusion gene is generated by _
reciprocal t(9;22) translocation designated the Philadelphia chromosome
271
Explain the pathogenesis of CML
t(9;22) --> BCR-ABL fusion gene --> fusion proteins w/ constitutively active tyrosine kinase activity. BCR porption provide dimerization domain leading to activation of ABL kinase which then phosphorylates downstream targets to drive proliferation and survival
272
Morphology of CML
- marrow is hypercellular comprising maturing granulocytic precursors
- peripheral blood shows leukocytosis (>100k)
- marked splenomegaly --> focal infarction
273
S/S of CML
Peaks at 50-60 yrs of age, insidiuous onset
- B symptoms (fever, weight loss, fatigue)
- Splenomegaly (LUG discomfort, early satiety
274
Clinical course of CML
- after a variable stable phase period of about 3 yrs, 50% enter accelerated phase (worsening anemia, thrombocytopenia, increased basophilia, and refractoriness to tx); new clonal cytogenetic abnormalities like trisomy 8, isochromsome 17q or duplication of philadelphia chromosome may appear
- within 6-12 months accelerated phase terminates in acute leukemia (blast crisis)
- 70% of pts blasts have morphologic and cytochemical features of myeloblasts; in 30% blast are of pre B cell origin
275
Treatment of CML
- curable in 75% w/ bone marrow transplant durign stable phase
- imatinib decrease BCR-ABL positive cells and decrease risk of transformation to accelerated phase and blast crisis; once acclerated phase or blast crisis is reached CML becomes resistant to kinase inhibitor therapy
276
_ is a type of myeloproliferative disorder characterized by increased marrow production of erythrocytes, granulocytes and platelets. But absolute RBC mass is responsile for most clinical symptoms
Polycythemia vera (PCV)
277
PCV is strongly associated with activating point mutation in _
JAK2 tyrosine kinase that participates in JAK/STAT signaling pathways --> constitutively active JAK2 signaling and thus does not need erythropoietin and other growth factors to drive growth
278
Mutation in Jak2 results in _ substitution at residue 617
valine to phenylalanine. this renders hematopoietic cell lines growth factor independent
279
Morphology of PCV
- hypercellular marrow involving all three lineages; 10% have increased marrow reticulin fibers
- peripheral blood shows basophilia and abnormaly large platelets
- late disease --> spent phase --> marrow fibrosis ---> extramedullary hematopoiesis in spleen and liver --> organomegaly
280
Clinical features of PCV
- appear insidiously usually late middle age
- erythroytosis --> plethoric and cyanotic due to vascular stagnation and deoxygenation, headache, dizziness and HTN are common
- Basophilia w/ histamine release --> peptic ulcer risk, and inense pruritus
- high cell turnover --> hyperuricemia--> gout
- Platelet dysfunction --> risk of bleeding and thrombotic events
281
_ is often associated with activating point mutation in JAK2 or MPL, a receptor tyrosine kinase that is normally activated by thrombopoietin. Most other cases have mutation in calreticulin
Essential thrombocytosis (ET)
282
ET is an MPD arising in multipotent stem cells, but the increased proliferation and production is largely confined to _ elements
megakaryocytic
283
Bone marrow finding and peripheral blood finding of ET
Marrow: cellularity mildly elevated but megakaryocytes markedly increaed and inclde abnormally large forms
Peripheral blood smears: thrombocytosis and abnromally large platelets and mild leukocytosis
284
Clinical manifestation of ET are mainly due to
thrombosis and hemorrhage.
285
A characteristic symptom of ET
erythromelalgia - throbbing and burning of hands and feet caused by occlusion of small arterioles by platelet aggregates
286
Prognosis and course of ET
indolent course; long asymptomatic periods punctuated by thrombotic or hemorrhagic crises.
- median survival time is 12-15 yrs
287
_ is characterized by development of obliterative marrow fibrosis leading to diminished hematopoiesis, cytopenias and extramedually hematopoiesis (splenomegaly)
primary myelofibrosis
288
In primary myelofibrosis, 50-60% have activating mutation in _ and 1-5% have activating mutations in _
JAK2
| MPL
289
The main pathologic feature of primary myelofibrosis is
extensive deposition of collagen in marrow by non-neoplastic fibroblasts, probably due to inappropriate release of fibrogenic factors from neoplastic megakaryocytes, particularly PDGF and TGF-b
290
In primary myelofibrosis, nucleated erythroid progenitors and early granulocytes are inappropriate release from fibrotic marrow and sites of extramedullary hematopoiesis; their appearance in circulation is termed _
leukoerythroblastosis
291
In Primary myelofibrosis, characteristic histologic findings of peripheral blood
tear-drop erythrocytes, increased basophils and abnormally large platelets
- normochromic, normocytic anemia is common
292
S/S of primary myelofibrosis
- Splenomegaly: secondary to extramedullary hematopoiesis
- Bleeding: megakaryocytes are dysfunctional
- Thrombosis: platelets can rupture which stimulate coaulation
- Anemia
- hyperuricemia
293
Prognosis of primary myelofibrosis
- median survival 3-5 yrs
| - cause of death include infection, thrombotic episodes or bleeding, and transformation to AML
294
Langerhan cell histiocytoses are monoclonal proliferation of _
immature dendritic cell population
295
Characteristic markers of langerhan cell histiocytoses
HLA-DR, S100, and CD1a
296
In EM of langerhan cell histiocytosis, cytoplasmic structures called _ are seen which are pentalaminar tubules resembling tennis racquets and contains langerin protein
Birbeck granules
297
Langerhan histiocytoses presents as what clinicopathilogic entities:
1. Multifocal multisystem langerhans cell histiocytosis ( Letterer-Siwe disease occurs before are 2): aggressive and systemic disorder in which Langerhans infiltrate and proliferate in skin, spleen, liver, lung, and bone marrow; anemia and destructive bone lesion are seen
2. Unifocal and multifoal unisystem langerhans cell histiocytosis (eosinophilic granuloma)
3. Pulmonary Langerhans cell histiocytosis, seen in adult smokers
298
pathogenetic cause of langerhans cell histiocytosis
- commonly BRAF mutation
| - less commonly mutations in TP53, RAS and tyrosine kinase MET
299
Unifocal and multifocal unisystem langerhans cell histiocytosis usually affects _1_ as an erosive, expanding accumulation of langerhan cells within calvarium, ribs, or femur; also in skin, lungs, or stomach.
1. Skeleton
300
S/S of Unifocal and multifocal unisystem langerhans cell histiocytosis
- painless or painful lesions on skeleton, or mucosa, skin or lungs
- pathologic fractures
- involvement of posterior hypothalamus causesdiabetes insipidus
- Hand-Schuller-Christian syndrome (triad of calvarial bone defects, diabetes, and exopthalmos)
301
Four major functions of spleen that impact disease states:
1. phagocytosis of blood cells and particulate matter: If RBC cannot be deformed due to disease as it needs to pass through sinusoids of spleen, it gets phagocytosed
2. Antibody production
3. Hematopoiesis
4. Sequestration of formed blood elements
302
Hypersplenism is characterized by
A syndrome due to enlargement of spleen causing leukopenia, thrombocytopneia and anemia
303
Common infectious cause of splenomegaly
- Mono
- nonspecific blood-borne infections
- TB
- Typhoid fever
- Bruellosis
- CMV
- Syphilis
- Malaria
- Histo, toxo
- kala azar
- Schistossomiasis
- Leishmaniasis
- Echinococcosis
304
Lymphohematogenous disorders leading to Splenomegaly
- HL
- NHL
- MM
- MPD
- Hemolytic anemias
305
Immunologic-inflammatory conditios disorders leading to Splenomegaly
- RA
| - SLE
306
Storage diseases disorders leading to Splenomegaly
- Gaucher disease
- Niemann-Pick
- Mucopolysaccharidoses
307
Morphology of spleen as seen in nonspecific acute splenitis
- Caused by blood-borne infection and cytokine induced proliferation
- Spleen is red and strememly soft
- red pulp congestion w/lymphoid follicle effacement
308
Common cause of congestive splenomegaly
- systemic congestion due to right-sided HF
- intrahepatic derangement of portal venous drainage (due to cirrhosis)
- Extrahepatic portal vein obstruction
309
Splenic infarcts are usually bland infarcts characterized as _
pale, wedge-shaped and subcapsular in location.
310
Septic infarcts of spleen is usually due to
infectious endocarditis
311
Neoplastic involvement of spleen is seen in _ tumors and cause splenomegaly.
myeloid and lymphoid
312
Benign tumors of spleen includes
- fibromas
- osteomas
- chondromas,
- lymphangiomas
- hemangiomas
313
asplenia is rare but is commonly associated with _
Other congenital abnormalities such as situs inversus and cardiac malformation
314
Most common congenital anomalies of spleen
accessory spleen which can occur anywhere in the abd cavity
315
Splenic rupture is usually due to
blunt trauma to a spleen that previously made fragile by an underlying conditions such as infectious mono, malaria, typhoid fever, neoplasms anad etc
316
Thymic hypoplasia or aplasia is sene in _ 1_ syndrome and is associated with other development defect as part of the _ 2_deletion syndrome
1. DiGeorge
| 2. 22q11
317
Thymic cysts usually have little clinical significance, but needs to worked up why?
they can herald an adjacent thymic neolasm, esp lymphoma or thymoma
318
Thymic hyperplasia refers to appearance of reactive _ cells lymphoid follicles within thymus, and is seen in chronic inflammatory and immunologic states particularly _2_
1. B cells
| 2. Myasthenia gravis
319
Thymomas are neoplasms derived from _
thymic epithelial cells
320
Gross apperance of thymomas
loblated, firm, gray white mass up to 15-20cm; can have cystic necrosis and calcifications
321
Microscopic findings of noninvasive thymomas
- Noninvasive thymomas are composed of medullary (spindled) and/or cortical (plump with rounded vesicular nuclei) epithelial cells, oftten with a sparsed thymocyte infiltrate
322
Microscopic findings of invasive thymomas
exhibit cortical-type epithelial cells and more numerous thymocytes
323
Microscopic findings of thymic carcinoma
- Fleshy, invasive masses that are commonly squamous cell carcinomas; and second most common variant is lmphoepithelioma-like carcinoma, resembling nasopharyngeal carcinoma and commonly contains monoclonal EBV genomes
324
Clinical features of thymomas
- symptoms usually stem from impingement on mediastinal structures
- some present with myasthenia gravis
- associated with other paraneoplastic syndromes such as acqired hypogammaglobulinemia, pure RBC aplasia, Graves disease, pernicous anemia, dermatomyositis polymyositis, and Cushing syndrome
- good prognosis; 90% 5yr survival
