CH6 - White Blood Cell Disorders Flashcards
What does hematopoetic CD34+ stem cells produce?
Both
Myeloid Stem Cells
and
Lymphoid Stem Cells
What do myeloid stem cells produce?
Erythroblast
Myeloblast
Monoblast
Megakaryoblast
What does erythroblast produce?
RBCs
What does myeloblast produce?
Neutrophils
Basophils
Eosinophils
What does monoblast produce?
Monocytes
What does megakaryoblast produce?
Megakaryocytes->
Platelets
What does lymphoid stem cells produce?
B lymphoblast
and
T Lymphoblast
What does B lymphoblast produce?
Naïve Bcells
What do Naïve B cells produce?
Plasma cells
What does T lymphoblast produce?
Naïve Tcells
What does Naïve T cells produce?
CD8+
and
CD4+
T cells
How does hematopoiesis occur?
via
stepwise differentiation
of
CD34+ HSCs
in Bone Marrow
What happens to hematopoetic stem cells?
Cells mature and are released from the bone marrow into blood
What is the normal white blood cell (WBC) count?
it is approximately 5-10 K/mL³
What is a low WBC count? What is it called?
< 5 K
called
Leukopenia
What is a high WBC count? What is it called?
> 10 K
called
leukocytosis
What is a low or high WBC count usually due to?
↓ or ↑
in
ONE
particular cell lineage
What is neutropenia?
↓ circulating neutrophils
What are some of the causes of neutropenia?
1) Drug toxicity
(chemo drugs interfere with rapidly dividing cells like Neutrophils)
2) severe infection ->
Neutrophils go to tissue site of infection
How can drug toxicity lead to neutropenia?
e.g., chemotherapy with alkylating agents, interfere with rapidly dividing tumor cells
BUT ALSO
Hematopoietic progenitor cells in bone marrow ->
↓ production of WBCs, especially neutrophils = b/c they are the most abundant
Chemo patients are commonly Neutropenic
so treat ith GM-CSF/G-CSF
How does severe infection lead to neutropenia?
e.g., gram-negative sepsis leads to increased movement of neutrophils into tissues resulting in decreased circulating neutrophils.
What is GM-CSF or G-CSF?
granulocyte monocyte stimulating factor
and
granulocyte stimulating factor
used to boost neutrophil count -> ↓ the risk of infection
What is lymphopenia?
Low number of circulating lymphocytes (B & T cells)
What are the some of the causes of lymphopenia?
1) Immunodeficiency
2) High Cortisol state
3) Aautoimmune destruction
4) Whole body Radiation
What are some examples of immunodeficiency that lead to lymphopenia?
DiGeorge syndrome (Failure to form 3rd and 4th Pharyngeal pouch)-> No Thymus -> T cells don’t develop properly
or
HIV -> Destruction of CD4 TH cells
How does a High Cortisol state lead to lymphopenia?
induce apoptosis in lymphocytes
Exogenous corticosteroids or Cushing syndrome
What is an example of autoimmune destruction leading to lymphopenia?
SLE (Systemic lupus erythematosus) -> Can produce Ab’s against any blood cell line
How can whole body radiation lead to lymphopenia?
Lymphocytes are most sensitive cell to radiation
lymphopenia is the earliest change to emerge after whole body radiation
What are the different types of leukocytosis?
1) neutrophilic leukocytosis
2) monocytosis
3) Eosinophilia
4) Basophilia
5) Lymphocytic leukocytosis
What does neutrophilic leukocytosis refer to?
High number of circulating neutrophils
What are the causes of neutrophilic leukocytosis?
2 Primary Forces driving Acute Inflammation
1) Bacterial infection
2) tissue necrosis
+
3) High cortisol state
How does Bacterial infection or tissue necrosis lead to neutrophilic leukocytosis?
Induces bone marrow to produce and release as many granulocytes/neutrophils as possible, including immature forms (left shift = ↓ Fc Receptors (CD16) -> decreased ability to bind Abs that have opsonized bacteria)
+
release marginated pool
(also happens with cortisol surge)
When immature neutrophils are released into the blood, how are they characterized?
by decreased Fc receptors (CD16)
What is the marker for the decreased Fc receptor?
CD16
Why are Fc receptors important?
They help the neutrophil to recognize immunoglobulin which is going to act as an opsonin for phagocytosis
How does high cortisol state lead to neutrophilic leukocytosis?
impairs leukocyte adhesion ->
release of marginated pool of neutrophils
What does monocytosis refer to?
increased circulating monocytes
What are the causes of monocytosis?
Chronic Inflammatory states
(e.g., autoimmune and infections)
and
Malignancy
What does eosinophilia refer to?
increased circulating eosinophils
What are the causes of eosinophilia?
1) allergic reactions (type I hypersensitivity)
2) parasitic infections
and
3) Hodgkin lymphoma (due to ↑ IL-5)
What is eosinophilia driven by?
↑ eosinophil chemotactic factor (IL-5)
What does basophilia refer to?
↑ circulating basophils
What is basophilia classically seen in?
CML (Chronic Myeloid Leukemia)
What does lymphocytic leukocytosis refer to?
↑ circulating lymphocytes
What are the causes of lymphocytic leukocytosis?
1) Viral infection
2) Bordetella pertussis
How does viral infections lead to lymphocytic leukocytosis?
b/c CD8+ T Cells handle viral infections and are called to the site of infection
How does Bordetella pertussis infection lead to lymphocytic leukocytosis?
This bacteria is an exception b/c it
produces Lymphocytosis-Promoting Factor->
blocks circulating lymphocytes from leaving the blood to enter the lymph node
Normally, lymphocytes made in BM-> blood-> enter lymph node to make Ab’s or to be stimulated to fight infection.
If they can’t enter lymph node, they are stuck in blood
What is infectious mononucleosis?
most commonly due to
EBV infection -> lymphocytic leukocytosis comprised of reactive CD8+ T cells (normal response to viral infection)
CMV is less common cause
How is EBV transmitted?
by saliva (kissing disease)
classically affects teenagers
What does EBV primarily infect?
- Oropharynx-> pharyngitis
- Liver-> hepatitis with hepatomegaly and elevated liver enzymes
- B cells
CD8+ T-cell response to EBV infection leads to what?
1) Generalized LAD (Lymphadenopathy) because of CD8+ Tcells hyperplasia/expansion in the paracortex of lymph nodes
2) Splenomegaly because Tcells in PALS (Periarterial lymphatic sheath) of white pulp undergo hyperplasia/expansion
3) High WBC count with atypical lymphocytes (reactive CD8+ T cells) in the blood
How does the CD8+ T cell response lead to generalized lymphadenopathy (LAD)?
It is due to T-cell hyperplasia in the lymph node paracortex
How does CD8+ T cell response lead to splenomegaly?
It is due to T-cell hyperplasia in the periarterial lymphatic sheath (PALS) of the Spleen’s white pulp
What are the major components of the spleen?
Red pulp (blood) - looks red
and
White pulp (Lymphocytes) - looks blue
Tcells grow and expand around Arteries of white pulp
(called PALS - (periarterial lymphatic sheaths)
What are the Atypical Lymphocytes in Mononucleosis?
They are just reactive CD8+ Tcells
which have a massive nucleus (much bigger than normal = size of RBC)
Abundant blue cytoplasm (more than normal)
Originally were thought to be monocytes-> hence the name mononucelosis
What is used for screening of IM?
The monospot test
What does the monospot test do?
Detects IgM antibodies that cross-react with horse or sheep red blood cells (heterophile antibodies)
hetero = other (animals RBCs)
Phile - like (these IgM Ab’s react against them)
When would the monospot test turn positive?
Usually turns positive within 1 week after infection
What would a negative monospot test suggest?
CMV as a possible cause of Infectious Mononucleosis
How is a definitive diagnosis for Infectious Mononucleosis made?
serologic testing for the EBV viral capsid antigen
What are the complications of EBV?
1) increased risk for splenic rupture b/c splenomegaly can cause the capsule of spleen to rupture (advise avoiding contact sports for 1 year)
2) Rash if exposed to Penicillin
3) Dormancy of virus in the B cells it attacks->
recurrence of infectious mononucleosis and potentially developing B cell lymphoma (especially if immunodeficiency develops e.g. HIV)
What are patients told who have an increased risk for splenic rupture?
patients are generally advised to avoid contact sports for one year.
When might a rash develop as a complication of EBV?
if exposed to ampicillin
With EBV complications, why is there a risk of recurrence and B cell lymphoma?
Dormancy of virus in B cells leads to increased risk for both recurrence and B-cell lymphoma, especially if immunodeficiency (e.g., HIV) develops.
What is acute leukemia?
Neoplastic proliferation of blasts
Accumulation of >20% blasts in BM
(Normal: 1-2%)
What is the acute presentation for acute leukemia?
Anemia (fatigue)
Thrombocytopenia (bleeding)
Neutropenia (infection)
What is the reason for the acute presentation of acute leukemia?
Increased blasts crowd-out normal hematopoiesis
In acute leukemia, why is there a high WBC count?
Neoplastic blasts enter bloodstream ->
High WBC count
Describe blasts
Large - bigger than RBC’s
Immature cells: Very little cytoplasm
often Punched out nucleoli
What is acute leukemia subdivided into?
Acute Lymphoblastic Leukemia (ALL)
or
Acute Myelogenous Leukemia (AML)
The subdivision of acute leukemia is based on what?
phenotype of the blasts (Markers)
b/c histology inconclusive
What is acute lymphoblastic leukemia?
Neoplastic accumulation of lymphoblasts (> 20%) in BM
Why is TdT useful in characterizing lymphoblasts?
B/c TdT is a DNA polymerase
EXPRESSED in the Nucleus of Lymphoblasts
and
ABSENT in myeloid blasts and mature lymphocytes
TdT is a DNA Polymerase that adds N-nucleotides to the V, D, and J exons of the TCR and BCR genes during antibody gene recombination, enabling the phenomenon of junctional diversity
Why is MPO useful in characterizing lymphoblasts?
How is it detected?
Myeloperoxidase is only expressed in Myeloblasts
Detected by:
1) Chemical study to determine MPO is in cell cytoplasm
2) view AUER RODS under microscope b/c MPO can crystalize inside of cells in the form of Auer rods
AML (Acute Myeloid Leukemia)
*It is an enzyme that produces hypochlorous acid (HOCl) bleach from hydrogen peroxide (H2O2) and chloride anion (Cl−) during neutrophil’s respiratory burst
Neutrophil verdoperoxidase has green heme pigment giving secretions rich in neutrophils, such as pus and some forms of mucus a greenish color
Acute lymphoblastic leukemia most commonly arises in whom?
children
What syndrome is associated with ALL?
At what age does ALL arise?
Down syndrome
(usually after 5 y.o.)
Acute lymphoblastic leukemia is subclassified into?
What is basis of classification?
B-ALL
and
T-ALL
based on surface markers
*B/c Lymphoblast differentiates into
1) B-Lymphoblast -> B-cell
and
2) T-Lymphoblast -> T-cell
so neoplastic proliferation of either one -> ALL
both express TdT in nucleus but their surface markers will be different
What is the most common type of ALL?
B-ALL
What is B-ALL usually characterized by?
lymphoblasts (TdT+) that express
CD10
CD19
CD20
What is the treatment for B-ALL?
Excellent response to chemotherapy
requires prophylaxis (i.e. direct injection) into scrotum and CSF
b/c chemo can’t cross BBB or Blood Testicle Barrier
What is the prognosis B-ALL
and how is it determined?
Generally good
based on cytogenetic abnormalities
Which B-ALL has a good prognosis and is more commonly seen in children?
t(12;21)
Most common, and commonly seen in kids
Which B-ALL has a poor prognosis and in what population is it seen?
t(9;22)
Philadelphia chromosome (Ph+ ALL)
poor prognosis; more commonly seen in adults
This translocation is much more common with CML but B-ALL also possible
What is T-ALL characterized by?
lymphoblasts (TdT+) that express markers from
CD2 - CD8
Blasts do not express CD10
How does T-ALL usually present?
T is the menmonic
mediastinal (Thymic) mass
Usually in Teenagers
called Acute Lymphoblastic Lymphoma because the malignant cells form a mass
and not just lymphoblasts floating in blood
What is acute myeloid leukemia?
Neoplastic accumulation of myeloblasts (> 20%) in BM
How are myeloblasts usually characterized?
by positive cytoplasmic staining for myeloperoxidase (MPO)
via
1) Chemical stain
or
2) visually see as Auer Rods
So Auer Rods in blasts = AML
What may be seen in the characterization of myeloblasts?
Crystal aggregates of MPO = Auer rods
In whom does acute myeloid leukemia most commonly arise?
older adults (average age is 50-60 years)
What is the subclassification of AML based on?
From highest to lowest priority
1) Cytogenetic abnormalities
2) Lineage of myeloblasts
3) Surface markers
What are the high-yield subtypes?
Acute Promyelocytic Leukemia
Acute Monocytic Leukemia
Acute Megakaryoblastic Leukemia
What is acute promyelocytic leukemia characterized by?
t(15;17)
Translocation of the retinoic acid receptor (RAR) on chromosome 17 to chromosome 15
What is the effect of RAR disruption in Acute Promyelocytic Anemia?
Disruption of RAR disrupts ability of Promyelocytes to mature ->
Accumulation of Promyelocytes (blasts) accumulate
How does acute promyelocytic leukemia lead to ↑ risk for DIC?
The accumulating promyelocytes contain many Auer rods ->
which can activate coag cascade ->
↑ risk of DIC
BECAUSE of DIC,
Acute Promyelocytic Anemia
is a MEDICAL EMERGENCY
What is the treatment for acute promyelocytic leukemia?
with all-trans retinoic acid (ATRA, a vitamin A derivative)
How does ATRA work?
It binds the altered receptor and causes the promyeolcytes (blasts) to mature (and eventually die)
What is acute monocytic leukemia?
Proliferation of monoblasts;
usually lack MPO
b/c Monoblasts are typically MPO-negative and promonocytes are MPO variable . MPO is expressed later in differentiation into Macrophage
* has no distinctive cytogenetic abnormality, so classification based on lineage (monoblast)
In acute monocytic leukemia what do blasts characteristically do?
infiltrate gums
What is acute megakaryoblastic leukemia?
Proliferation of megakaryoblasts;
lack MPO, because platelets obviously not involved in oxygen-dependent killing
What is acute megakaryoblastic leukemia associated with?
Down syndrome
usually arises before the age of 5
by contrast Down syndrome associated with ALL
AFTER age of 5
How else can Acute Myeloid Leukemia arise?
From pre-existing dysplasia = myelodysplastic syndromes
especially with prior exposure to alkylating agents or radiotherapy
What do myelodysplastic syndromes usually present with?
cytopenias b/c the blasts are dysplastic they have abnormal maturation
and
therefore get stuck in bone marrow = hypercellular bone marrow
BM Biopsy will show increased blasts < 20%. If number were to increase to >20% it would then be classified as Acute Myeloid Leukemia NOT Dysplastic syndrome
With myelodysplastic syndromes resulting in acute myeloid dysplastic syndrome what do most patients die from?
Most patients die from infection or bleeding because of cytopenias, though some progress to acute myeloid leukemia.
What is chronic leukemia?
Neoplastic proliferation of
MATURE circulating lymphocytes
(B-cells or T-cells)
What is chronic leukemia characterized by?
High WBC count
Describe the onset of chronic leukemia?
Insidious onset
Often Asymptomatic
Can live a long time with this disease
Usually seen in older adults
What is chronic lymphocytic leukemia?
Neoplastic proliferation of naive B cells
Co-express
CD5
(abnormally expressed; normally on T-cells)
and
CD20
What is the prototypic/classic Chronic Leukemia?
CLL
Chronic Lymphocytic Leukemia
It is a proliferation of Naive Bcells that just left BM
Co-express CD5 (normally expressed on T-cell) and CD20
What is the most common leukemia overall?
Chronic lymphocytic leukemia (CLL)
NOT SURE THIS IS TRUE
In CLL what is seen on the blood smear?
↑ lymphocytes
and
↑ smudge cells (big cells that look like someone smashed a normal lymphocyte with their finger)
Small Lymphocytic Lymphoma
When Chronic Lymphocytic Leukemia (CLL) spreads to lymph nodes-> generalized lymphadenopathy
Because now a mass in the lymph node, Called Lymphoma NOT Leukemia
What are the complications of CLL?
1) Hypogammaglobulinemia - these neoplastic Bcells never develop into Ig producing Plasma Cells. As they take over as the dominant Bcell, normal infection response with maturation to Ig producing Plasma cell happens less and less -> death from infection
2) autoimmune hemolytic anemia b/c if these neoplastic B-cells actually make Ig, it is not against an infectious agent, but against patient’s own RBC’s
3) Richter transformation - Transformation from small lymphocytic lymphoma to diffuse large B-cell Lymphoma
What is the most common of death in CLL?
infection
What is Richter transformation?
transformation of small lymphocytic lymphoma ->
diffuse large B-cell lymphoma
b/c
one of the neoplastic B-cells of CLL (now residing in a lymph node or spleen) acquires more mutations, transforming into a rapidly growing aggressive tumor->
instead of just general lymphadenopathy patient presents with a single
enlarging lymph node or spleen as aggressive neoplastic cell proliferates at unprecedented rate
What is Richter transformation marked clinically by?
an single enlarging lymph node or spleen
What is Hairy cell leukemia?
Neoplastic proliferation of mature B cell
What characterizes hairy cell leukemia?
hairy cytoplasmic processes
What stain would you do to confirm hairy cell leukemia cells?
tartrate-resistant acid phosphatase (TRAP) stain
as TRAP expression is abnormally increased in
Hairy Cell Leukemia
What are the clinical features for hairy cell leukemia?
Splenomegaly involving Red Pulp
Dry tap on bone marrow aspiration b/c BM is often fibrosed in these patients
Absence of Lymphadenopathy
Why is there splenomegaly in hairy cell leukemia?
Due to accumulation of hairy cells in RED pulp (expansion in chronic leukemias would normally be expected to happen in white pulp - but in Hairy leukemias happens in Red Pulp)
In chronic leukemia, neoplastic lymphoid cells go to lymphoid tissues (lymph nodes and spleen) and proliferate there. In hairy cell Leukemia’s they are “TRAP”ped in the Red Pulp and Bone Marrow, so no lymphadenopathy, fibrosis of BM, and Splenomegaly in Red Pulp not white
Why is there a dry tap on bone marrow aspiration in hairy cell leukemia?
due to marrow fibrosis
How is lymphadenopathy related to hair cell leukemia?
Lymphadenopathy is usually absent b/c unlike other CLL’s, the Hairy cell B-cells don’t go to lymph nodes or Splenic White Pulp, but instead to Splenic Red Pulp
What drug is used in the treatment of hairy cell leukemia?
2-CDA (cladribine) is a Adenosine Deaminase Inhibitor
How does hair cell leukemia respond to cladribine?
excellent response
How does cladribine work?
Its an adenosine deaminase inhibitor,
Neplastic cell divides rapidly requiring tons of DNA synthesis
Adenosine Deaminase is part of Purine Degredation Pathway
cladribine causes adenosine accumulation to toxic levels in neoplastic B cells
What is Adult T cell Leukemia Lymphoma?
ATLL = Neoplastic proliferation of mature CD4+ T cells
What is adult T cell leukemia associated with?
Associated with HTLV-I (Human T cell Leukemia Virus -1)
Where is ATLL associated with HTLV-1 most commonly seen in?
Japan and the Caribbean
What are the clinical features for ATLL?
1) Rash = skin infiltration is common for Tcell Leukemia’s
(think of Type 4 hypersensitivity involving Tcells and skin)
2) Generalized lymphadenopathy with hepatosplenomegaly - b/cmature lymphocytes go to lymph nodes and spleen
3) Lytic (punched-out) bone lesions with hypercalcemia
(don’t think Multiple Myeloma if Also Rash present)
What is mycosis fungoides?
Neoplastic proliferation of mature CD4+ T cells that
1) Infiltrate the skin (because mature CD4+ T cells always like to go to skin)
2) Produce localized skin rash OR plaques OR nodules throughout the body
Biopsy would reveal accumulation of neoplastic CD4+ T cells in epidermis (Patitrier microabscesses)
What are Patitrier microabscesses?
Aggregation of neoplastic CD4+ T-cells in the epidermis as seen mycosis fungoides
Sezary syndrome
When neoplastic CD4+ T-cells of mycosis fungoides spread to involve the blood
On Blood smear you will see Sezary cells
What are Sezary cells?
Characteristic CD4+ T-cells of mycosis fungoides with cerebriform nuclei (nucleus looks like bunch of folds in the brain)
What would you see on blood smear in mycosis fungoides?
Sezary cells
What are myeloproliferative disorders/myelodysplastic syndrome?
Neoplastic proliferation of MATURE cells of myeloid lineage ->
HIGH WBC count (b/c increased production of all myeloid lineages including GRANULOCYTES (Neutrophils, Eosinophils, Basophils, Mast Cells) which are part of WBC count together with lymphocytes) with Hypercellular marrow
Disease of late adulthood (average age is 50-60 years)
What does myeloproliferative disorders result in?
high WBC count with hypercellular bone marrow
How are myeloproliferative disorders characterized?
Cells of EVERY myeloid lineage is increased;
However, classified based on the DOMINANT myeloid cell produced
What are the complications for myeloproliferative disorders?
1) Increased risk for hyperuricemia and gout due to high turnover of cells (e.g. in Polycythemia Vera, tons of RBC’s produced. In RBC maturation, nucleus is removed. The DNA from expelled nucleus goes through Purine degradation pathway -> end product is uric acid->hyperuricemia->gout )
2) Progression to marrow fibrosis (aka spent phase or burnt-out phase)
3) Transformation to acute leukemia - Accumulation of mutations causes proliferation of myeloid cell in Blast phase -> Acute Leukemia
What is chronic myeloid leukemia?
Neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors;
In chronic myeloid leukemia what cells are characteristically increased?
basophils
What is chronic myeloid leukemia driven by?
driven by t(9:22) - Philadelphia chromosome - which generates a BCR-ABL fusion protein with increased tyrosine kinase activity
What is the first line treatment for chronic myeloid leukemia?
imatinib,
What does imatinib do?
It blocks tyrosine kinase activity
How is splenomegaly related to chronic myeloid leukemia?
Splenomegaly is common, enlarging spleen suggests accelerated phase of disease;
In chronic myeloid leukemia what usually follows after splenomegaly?
transformation to acute leukemia
What can chronic myeloid leukemia transform to?
AML in 2/3 of cases or ALL in 1/3 of cases since mutation is in a pluripotent stem cell,
What is a leukemoid reaction?
Reactive neutrophilic leukocytosis
How is CML distinguished from a leukemoid reaction (reactive neutrophilic leukocytosis)?
Negative LAP stain, inc basophils, t(9;22)
What is a LAP stain?
leukocyte alkaline phosphatase (LAP) stain
How is a LAP stain related to a leukemoid reaction?
granulocytes in a leukemoid reaction are LAP positive
Why are basophils useful in determining the difference between a leukemoid reaction and CML?
Basophils are increased in CML and are absent with a leukemoid reaction
How is t(9;22) useful in determining the difference between a leukemoid reaction and CML?
It is present in CML and absent in leukemoid reaction
What is polycythemia vera?
Neoplastic proliferation of mature myeloid cells, especially RBCs
In polycythemia vera, in addition to the RBC increase what are also increased?
Granulocytes and platelets are also increased
What mutation is associated with polycythemia vera?
JAK2 kinase mutation
What are the clinical symptoms for polycythemia vera due to?
they are mostly due to hyperviscosity of blood
What are the clinical symptoms for polycythemia vera?
- Blurry vision and headache 2. Increased risk of venous thrombosis (e.g., hepatic vein, portal vein, and dural sinus) 3. Flushed face due to congestion (plethora) 4. Itching, especially after bathing (due to histamine release from increased mast cells)
What is plethora in relation to PV?
One of the clinical symptoms; flushed face due to congestion
Why is there itching in PV?
Itching, especially after bathing due to histamine release from increased mast cells
What is the treatment for PV?
phlebotomy;
What is the second-line therapy for PV?
hydroxyurea.
What happens to a patient with PV who goes intreated?
Without treatment, death usually occurs within one year.
How can PV be distinguished from reactive polycythemia?
- In PV, erythropoietin (EPO) levels are decreased, and Sao, is normal. 2. In reactive polycythemia due to high altitude or lung disease, SaO2 is low, and EPO is increased. 3. In reactive polycythemia due to ectopic EPO production from renal cell carcinoma, EPO is high, and Sao2 is normal.
What are the EPO and SaO2 levels in PV?
EPO is decreased and SaO2 is normal
What are the EPO and SaO2 levels in reactive polycythemia due to high altitude or lung disease?
EPO is increased and SaO2 is low
What are the EPO and SaO2 levels in reactive polycythemia due to renal cell carcinoma?
EPO is high, SaO2 is normal
What is essential thrombocythemia?
Neoplastic proliferation of mature myeloid cells, especially platelets
In ET, in addition to the platelets what else is increased?
RBCs and granulocytes are also increased.
What is mutation is ET associated with?
JAK2 kinase mutation
What do the symptoms of ET result from?
they are related to an increased risk of bleeding and/or thrombosis.
What do the symptoms of ET rarely progresses to?
marrow fibrosis or acute leukemia
In ET what is there no significant risk for?
hyperuricemia or gout
What is myelofibrosis?
It is neoplastic proliferation of mature myeloid cells, especially megakaryocytes
What mutation is associated with myelofibrosis?
JAK2 kinase mutation in 50% of cases
In myelofibrosis, what causes marrow fibrosis?
Megakaryocytes produce excess platelet-derived growth factor (PDGF) causing marrow fibrosis
What are the clinical features for myelofibrosis?
1) splenomegaly 2) leukoerythroblastic smear 3) Increased risk of infection, thrombosis, and bleeding
In myelofibrosis what is splenomegaly due to?
extramedullary hematopoiesis
In myelofibrosis what is the leukoerythroblastic smear?
It’s tear-drop RBCs, nucleated RBCs, and immature granulocytes
What is lymphadenopathy (LAD)?
it refers to enlarged lymph nodes
Painful LAD is usually seen in what?
lymph nodes that are draining a region of acute infection (acute lymphadenitis)
Painless LAD can be seen with what?
chronic inflammation (chronic lymphadenitis), metastatic carcinoma, or lymphoma.
In inflammation, lymph node enlargement is due to what?
hyperplasia of particular regions of the lymph node
What is follicular hyperplasia seen with?
(B-cell region) rheumatoid arthritis and early stages of HIV infection, for example.
What is paracortex hyperplasia seen with?
(T-cell region) viral infections (e.g., infectious mononucleosis).
What is involved with hyperplasia of sinus histiocytes?
It is seen in lymph nodes that are draining a tissue with cancer.
What is lymphoma?
Neoplastic proliferation of lymphoid cells that forms a mass; may arise in a lymph node or in extranodal tissue
What is lymphoma divided into?
non-Hodgkin lymphoma (NHL 60%) and Hodgkin lymphoma (HL 40%)
NHL further classified based on what?
cell type (e.g., B versus T), cell size, pattern of cell growth, expression of surface markers, and cytogenetic translocations, - small, intermediate and large B cells
What are some examples of small B cells?
follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma (i.e.. CLL cells that involve tissue)
What are some examples of intermediate-sized B cells
Burkitt lymphoma
What are some examples of large B cells
diffuse large B-cell lymphoma
What is the overall frequency for NHL?
60%
What is the overall frequency for HL?
40%
What are the malignant cells of NHL?
Lymphoid cells
What are the malignant cells of HL?
Reed-Sternberg cells
What is the composition of mass for NHL?
lymphoid cells
What is the composition of mass of HL?
Predominantly reactive cells (inflammatory cells and fibrosis)
How does NHL present clinically?
Painless lymphadenopathy, usually arises in late adulthood
How does HL present clinically?
Painless lymphadenopathy occasionally with ‘B’ symptoms, usually arises in young adults
What is the spread of NHL?
Diffuse: often extranodal
What is the spread of HL?
Contiguous; rarely extra nodal
Do you use staging in NHL?
Limited importance
Do you use staging in HL?
Guides therapy; radiation is the mainstay of treatment.
Is there a Leukemic phase in lymphoma?
Occurs in NHL but not in HL
What is follicular lymphoma?
Neoplastic proliferation of small B cells (CD20+) that form follicle-like nodules
How does follicular lymphoma present clinically?
in late adulthood with painless lymph adenopathy
What is follicular lymphoma driven by?
t(14;18)
How does t(14:18) result in follicular lymphoma?
BCL2 on chromosome 18 translocates to the Ig heavy chain locus on chromosome 14 this results in overexpression of Bcl2, which inhibits apoptosis
What is the treatment for follicular lymphoma?
is reserved for patients who are symptomatic and involves low-dose chemotherapy or rituximab (anti-CD20 antibody).
What does follicular lymphoma progress to and how does it present?
diffuse large B-cell lymphoma which is an important complication and presents as an enlarging lymph node
How is follicular lymphoma distinguished from reactive follicular hyperplasia?
1) disruption of normal lymph node architecture (maintained in follicular hyperplasia) 2) Lack of tangible body macrophages in germinal centers (tangible body macrophages are present in follicular hyperplasia) 3) Bcl2 expression in follicles (not expressed in follicular hyperplasia) 4) Monoclonality (follicular hyperplasia is polyclonal)
What is mantle cell lymphoma?
Neoplastic proliferation of small B cells (CD20+) that expands the mantle zone
How does mantle cell lymphoma present clinically?
presents in late adulthood with painless lymph adenopathy
What is mantle cell lymphoma driven by?
t(ll;14)
How does t(11;14) result in mantle cell lymphoma?
1) Cydin D1 gene on chromosome 11 translocates to Ig heavy chain locus on chromosome 14. 2) Overexpression of cydin Dl promotes Gl/S transition in the cell cycle, facilitating neoplastic proliferation
What is marginal zone lymphoma?
Neoplastic proliferation of small B cells (CD 20+) that expands the marginal zone
What is marginal zone lymphoma associated with?
chronic inflammatory states such as Hashimoto thyroiditis, Sjogren syndrome, and H pylori gastritis
What is the marginal zone formed by?
post-germinal center B cells.
What is MALToma?
it is marginal zone lymphoma in mucosal sites.
How might Gastric MALToma regress
with treatment of H Pylori,
What is burkitt lymphoma?
Neoplastic proliferation of intermediate-sized B cells (CD20+);
What is butkitt lymphoma associated with?
EBV
How does burkitt lymphoma classically present?
as an extranodal mass in a child or young adult
What is specific about the african form of burkitts lymphoma?
usually involves the jaw
What does the sporadic form of Burkitts lymphoma usually involve?
the abdomen
What is Burkitt lymphoma driven by?
Driven by translocations of c-myc (chromosome 8)
What is the most common translocation for Burkitts lymphoma?
t(8;14) is most common,
In Burkitts lymphoma what does t(8:14) result in?
translocation of c-myc to the Ig heavy chain locus on chromosome 14.
What does overexpression of c-myc oncogene do?
promotes cell growth
How is Burkitts lymphoma characterized?
by high mitotic index and ‘starry-sky’ appearance on microscopy
What is diffuse large B-cell lymphoma?
Neoplastic proliferation of large B cells (CD20+) that grow diffusely in sheets
What is the most common form of non-hodgkins lymphoma?
Diffuse large B-cell lymphoma
Describe diffuse large B-Cell lymphoma clinically?
Clinically aggressive (high-grade)
How does diffuse large B-cell lymphoma arise?
either sporadically or from transformation of a low-grade lymphoma (e.g., follicular lymphoma)
How does diffuse large B-cell lymphoma present?
Presents in late adulthood as an enlarging lymph node or an extranodal mass
What is Hodgkins Lymphoma?
Neoplastic proliferation of Reed-Slernberg (RS) cells,
What are Reed-Slernberg cells?
large B cells with multilobed nuclei and prominent nucleoli (‘owl-eyed nuclei’);
Hodgkins lymphoma is classically positive for what?
CD15 and CD30
What do RS cells secrete?
cytokines.
What are the symptoms for HL
Occasionally results in ‘B’ symptoms (fever, chills, and night sweats)
In HL what do the RS cells attract?
reactive lymphocytes, plasma cells, macrophages, and eosinophils
What may the RS cells in HL lead to?
fibrosis
What makes up a bulk of the tumor and form the basis for classification of HL?
Reactive inflammatory cells
What are the subtypes of reactive inflammatory cells in HL?
Include 1. Nodular sclerosis 2. Lymphocyte-rich 3. Mixed cellularity 4. Lymphocyte-depleted
What is the most common subtype of HL?
Nodular sclerosis (70% of all cases),
What is the classic presentation for nodular sclerosis?
it is an enlarging cervical or mediastinal lymph node in a young adult, usually female
Dsecribe the lymph node in nodular sclerosis?
It is divided by bands of sclerosis; RS cells are present in lake-like spaces (lacunar cells),
What are lacunar cells?
Lake like spaces in the lymph node where the RS cells are present
What type of HL has the best prognosis of all types?
Lymphocyte-rich
In HL mixed cellularity is often associated with what?
abundant eosinophils (RS cells produce IL-5).
What is the most aggressive HL type and in whom is it usually seen?
Lymphocyte-depleted is the most aggressive of all types; usually seen in the elderly and HIV-positive individuals
What are the plasma cell disorders?
Dyscrasias: 1) multiple myeloma 2) MGUS 3) Waldenstrom Macroglobulinemia
What is multiple myeloma?
Malignant proliferation of plasma cells in the bone marrow
Whis the most common primary malignancy of bone?
metastatic cancer,
What is the most common malignant lesion of bone overall?
Multiple myeloma
In multiple myeloma what is usually present?
High serum IL-6 is sometimes present; stimulates plasma cell growth and immunoglobulin production
What are the clinical features for multiple myeloma?
1) Bone pain with hypercalcemia 2) Elevated serum protein 3) increased risk of infection 4) Rouleaux formation of RBC’s on blood smears 5) Primary AL amyloidosis 6) Proteinuria
Why is there bone pain with hypercalcemia in multiple myeloma?
Neoplastic plasma cells activate the RANK receptor on osteoclasts, leading to bone destruction.
With multiple myeloma what might you see on x-ray?
Lytic, ‘punched-out’ skeletal lesions are seen on x-ray, especially in the vertebrae and skull; increased risk for fracture
Why is there elevated serum protein in multiple myeloma?
Neoplastic plasma cells produce immunoglobulin;
In multiple myeloma, what is seen on electrophoresis?
M spike is present on serum protein electrophoresis (SPEP), most commonly due to monoclonal IgG or IgA
In multiple myeloma why is there increased risk of infection?
Monoclonal antibody lacks antigenic diversity
What is the most common cause of death in multiple myeloma?
infection
Why is there rouleaux formation of RBCs on blood smear?
increased serum protein decreases charge between RBCs
Why is there primary AL amyloidosis in multiple myeloma?
Free light chains circulate in serum and deposit in tissues.
Why is there proteinuria in multiple myeloma? What does this increase the risk for?
Free light chain is excreted in the urine as Bence Jones protein; deposition in kidney tubules leads to risk for renal failure (myeloma kidney).
What is monoclonalgammopathy of undetermined significance?
Increased serum protein with M spike on SPEP; other features of multiple myeloma are absent (no lytic bone lesions, hypercalcemia, AL amyloid, or Bence Jones proteinuria)
MGUS is common in what group of people?
elderly (seen in 5% of 70-year-old individuals);
What are the odds of a patient with MGUS developing multiple myeloma?
1% of patients with MGUS develop multiple myeloma each year.
What is Waldenstrom macroglobulinemia?
B-cell lymphoma with monoclonal IgM production
What are the clinical features for waldenstrom macroglobulinemia?
1) Generalized lymphadenopathy, lytic bone lesions are absent 2) Increased serum protein with M spike (comprised of IgM) 3) Visual and neurologic deficits (e.g., retinal hemorrhage or stroke) IgM (large pentamer) causes serum hyperviscosity. 4) Bleeding
Why is there bleeding in waldenstrom macroglobulinemia?
Viscous serum results in defective platelet aggregation
What are the complications for waldenstrom macroglobulinemia treated with?
plasmapheresis, which removes IgM from the serum
What are langerhans cells?
specialized dendritic cells found predominantly in the skin.
What are langerhans cells derived from?
bone marrow monocytes
What do langerhans cells present?
Present antigen to naive T cells
What is langerhans cell histiocytosis?
it is a neoplastic proliferation of Langerhans cells
What is seen on electron microscopy in langerhan cell histiocytosis?
Characteristic Birbeck (tennis racket) granules are seen on electron microscopy;
What is langerhan cell histiocytosis immunochemistry?
cells are CDla+ and S100+
What is Letterer-Siwe disease?
Malignant proliferation of Langerhans cells
What is the classic presentation of Letterer-Siwe?
it is a skin rash and cystic skeletal defects in an infant (< 2 years old).
Can Letterer-Siwe be fatal?
Multiple organs may be involved; rapidly fatal
What is eosinophilic granuloma?
Benign proliferation of Langerhans cells in bone
What is the classic presentation for eosinophilic granuloma?
it is a pathologic fracture in an adolescent; skin is not involved
What does biopsy of eosinophilic granuloma show?
Langerhans cells with mixed inflammatory cells, including numerous eosinophils
What is Hand-Schuller-Christian disease?
Malignant proliferation of Langerhans cells
What is the classic presentation of Hand-Schuller-Christian disease?
it is scalp rash, lytic skull defects, diabetes insipidus, and exophthalmos in a child.
