Chapter 13: Disorders of White Blood Cells Flashcards
what are multipotent progenitors?
they’re like HSC’s, but are more proliferative and have a lesser capacity for self renewal
What are tumors of hematopoietic origin often associated with?
mutations that block progenitor cell maturation or abrogate their growth factor dependence
What are the 2 branches of disorders of WBC’s?
prolferative disorders
leukopenias
Leukopenia
- reduced WBC count
- usually from reduced neutrophils
- Neutropenia and agranulocytosis are things under it
Neutropenia
reduction in the number of neutrophils in blood
Agraulocytosis
clinically significant reduction in neutrophils
-has serious consequence of making individuals susceptible to bacterial and fungal infections
What is neutropenia caused by?
- inadequate or ineffective granulopoiesis
- increased destruction ofr sequestration of neutrophils in the periphery
In what kind of situation does inadequate granulopoiesis observed?
- suppression of hematopoietic stem cells
- suppression of committed granulocytic precursors
- disease states with ineffective hematopoiesis
- rare congenital conditions
When does accelerated destruction or sequestration of neutophils happen?
- immunologically mediated injury to neutrophils
- splenomegaly
- increased peripheral utilization
What is the most common cause of agranulocytosis?
drug toxicity
-cancer treatment
how will the bone marrow look if there’s destruction of neutrophils in the periphery?
hypercellular due to a compensatory increase in granulocytic precursors
If there’s an infection, that causes agranulocytosis, what will that look like?
- necrotizing lesions of the gingiva, floor of mouth, pharynx… oral cavity
- gray to green-black necrotic membranes
What is the neutropenic patient at particularly high risk for?
deep infections caused by Candida and Aspergillus
Clinical features of leukopenia
- serious infections most likely when neutrophil count <500
- give full spectrum abx
How is neutropenia treated?
with G-CSF
-stimulates production of granulocytes from marrow precursors
Leukocytosis
increase in the number of WBC’s in the blood
-common with inflammatory states
What does IL-5 stimulate?
eosinophil production
What does G-CSF stimulate?
neutrophilia
-lots of neutrophils
In sepsis or severe inflammatory disorders, what morphologic changes do we see in neutrophils?
Dohle bodies and cytoplasmic vacuoles
What are Dohle bodies?
patches of dilated ER that appear as sky-blue cytoplasmic “puddles”
What will result in large numbers of activated lymphocytes in children that might look like neoplastic lymphoid cells?
acute viral infections
What else might appear in severe infections?
a lot of immature granulocytes, mimicking a myeloid leukemia
leukemoid rxn
What are the 3 kinds of lymphadenitis that were discussed?
Acute nonespecific Lymphadenitis
Chronic nonspecific lympadenitis
Hemophagocytic lymphohistiocytosis
Acute nonspecific lymphadenitis
- 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
Chronic nonspecific lymphadenitis
follicular hyperplasia
paracortical hyperplasia
sinus histiocytosis
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
What is paracortical hyperplasia caused by?
stimuli that trigger T-cell -mediated immune responses
-i.e. acute viral infections
What is sinus histiocytosis
Are lymph nodes in chronic rxns tender?
nope
what region of the body ins chronic lymphadenitis common in?
inguinal and axillary nodes
Where else do collections of immune cells show up in chronic immune rxns?
in nonlymphoid tissues
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
What is a common feature of all forms of HLH?
systemic activation of macs and CD8+ cytotoxic T-cells
-shock like picture… cytokine storm
What is the most common trigger for HLH?
infection
-particularly with the EBV
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
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)
How do tx HLH?
immunosuppressive drugs and “mild” chemotherapy
What are the 3 kinds of Neoplastic proliferations of WBC’s we talked about?
- lympoid neoplasms
- myeloid neoplasms
- histiocytoses
What is most common chromosomal abnormality with white cell neoplasms?
translocations
What 3 viruses have been implicated as causative agents in particular lymphomas?
HTLV-1
EBV
Kaposi sarcom/HHV-8
what is KSHV associated with>?
malignant effusion often in the pleural cavity
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
What is required for diagnosis of lymphoid neoplasia?
histologic examination of lymph nodes or other involved tissues
Are most lymphoid neoplasms B or T cell related?
B cell origin!
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
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
What is the most common cancer of children?
ALL
- acute lymphoblastic leukemia
- hispanics have the highest incidence rate
If we see a T-ALL, what mutation will probably be there?
GOF mutation in NOTCH1
-diverese chromosomal translocations
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%*****
What chromosomal changes are common in ALL’s
hyperploidy (>50 chromosomes)
How does the bone marrow look in leukemic presentations?
hypercellular and packed with lymphoblasts
-mediastinal thymic masses with T-ALL’s
-
What does the tumor cell cytoplasm look like in both B-ALL and T-ALL?
scant basophilic cytoplasma
How are lymphoblasts different from myeloblasts?
lymphblasts have more condesnsed chromatin, less conspicuous nucleoli (smaller), and smaller amounts of cytoplasm that usually lacks granules
are lymphoblasts MPO positive or negative?
negative
-also contain periodic acid-Schiff-positive cytoplasmic material
For immunostaining, what willl we see in pre-B and pre-T lymphoblasts?
95%
-TdT
Staining for B-ALLs
CD19
PAX5
CD10
CD 20 and IgM heavy chain if mature
Staining for T-ALLs
CD1,2,5, and 7
Clinical features of ALL’s?
abrupt stormy onset
- depression of marrow
- CNS stuff like headache, vomiting, nerve palsies resulting from meningeal spread
Prognosis of ALL’s
-children: awesome! 95%.. but it’s still the leading cause of cnacer deaths in children
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
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)
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
What are the peripheral B-cell neoplasms that we need to worry about?
Chronic lymphocytic leukemia
Small lymphocytic lymphoma
How do CML and SLL differ
only in the degree of peripheral blood lymphocytosis
-CLL is more (>5000 lymphocytes)
What is the most common leukemia of adults in the western world?
CLL
Are chromosomal translocations a thing with CLL and SLL?
no, that’s why they’re kinda weird
What are the most common genetic anomalies in CLL/SLL?
deletions of 13q14.3, 11q, and 17p, and trisomy 12q
What will CLL/SLL tumors that pursue an aggressive course have?
unmutated Ig segments
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
What is the distinctive immunophenotype for CLL/SLL?
CD19, 20
*CD23 and CD5
clinical presentation of CLL/SLL?
- generalized lymphadenopathy and hepatosplenomegaly
- disrupts normal immune function through uncertain mechanisms
Things that mean worse outcome for CLL/CLL?
- del 11q and 17p
- no somatic hypermutation
- expression of ZAP-70
- presence of NOTCH1 mutations
What does the CLL/SLL transform into that is much worse?
Diffuse large B-cell lymphoma
-also called Richter syndrome
Follicular lymphoma
most common form of indolent NHL in the US
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
does follicular lymphoma have apoptotic cells?
no!
What other gene has been identified as being mutated in 90% of follicular lymphoma cases as well?
MLL2
-histone methyl transferase
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*
immunophenotype of follicular lymphoma
CD19, 20, 10, and surface Ig and BCL6
-UNLIKE CLL/SLL, CD5 IS NOT EXPRESSED
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
Diffuse large B-cell lymphoma (DLBCL)
- the most common form of NHL!
- 60 years
- dysregulation of BCL6
Morphology of DLBCL
- large cell csize
- diffuse pattern of growth
- round or oval nucleus