White Blood Cell Pathology

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Back 1

Know that

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What CD#+ are Hematopoietic Stem cells?

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CD34+

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What is normal WBC count?

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5-10K

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Leukopenia

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Low WBC count (<5K)

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Leukocytosis

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A high WBC count (>10K)

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Leukopenia and/or Leukocytosis usually happens due to one cell lineage (eg. RBC, T-cell, or netrophils) being too high or too low.

TRUE OR FALSE?

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TRUE.

Know that.

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Neutropenia

What is it?

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Decreased number of circulating neutrophils

(a form of leukopenia)

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Neutropenia:

Common causes?

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Drug toxicity (some chemo agents damage stem cells resulting in decreased WBC especially neutrophils)

Severe infection (the neutrophil goes to tissues, thus decreased in circulation) (eg. severe gram negative sepsis)

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Neutropenia

Treatment?

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GM-CSF (granulocyte-macrophage colony stimulating hormone)

G-CSF

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Lymphopenia

What is it?

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Decreased number of circulating lympocytes

(a form of Leukopenia)

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Lymphopenia

Common causes?

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Immunodeficient (eg. HIV, Digeorge)
High cortisol state (induce apoptosis of lympocytes)
Autoimmune destruction (SLE)
Whole body radiation

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What cell is most sensitive to radiation?

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Lymphocytes

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Neutrophilic leukocytosis

What is it?

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Increased circulating neutrophils

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Neutophilic leukocytosis

Common causes?

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Bacterial infection/tissue necrosis - due to increased inflammation

High cortisol state (marginated pool of neutrophils released)

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What is considered the marginal pool of neutrophils?

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These are the neutrophils adhesing to the bv and just stay attached. High levels of cortisol releases it into the blood vessel (increasing the count)

Neutrophil Leukocytosis

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Pt. with bacterial infection has both leukopenia and leukocytosis (neutrophils mainly).

Explain that

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TIME-DEPENDENT

early infections usually leukocytosis. As it progresses and becomes severe (deadly, septic shock like), then it is leukopenia (low neutrophil count)

WEIRD

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Leukocytosis during bacterial infection

Left shift or right? Why?

Immature cells have more or less FC receptors?*

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Immature forms (left shift) due to more neutorphils produced quickly.

Immature cells have LESS FC receptors (CD16)

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What CD are FC receptors?

Are they increased or decreased in immature neutrophils during bacterial infection (leukocytosis)

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CD16

DECREASED FC receptors**

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Monocytosis

What is it?
Common causes?

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Increased circulating monocytes

Common causes:
-Chronic inflammation (autoimmune and infections)
-malignancy

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Eosinophila

What is it?
Common causes?

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Increased circulating eosinophils

Common causes:
Allergic rxns (type I)
Parasitic infections
Hodgkin lymphoma*

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In Hodkin's lymphoma you have an increased or decreased Esophilia?

MOA? (hint: why cytokine)

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INCREASED Eosinophila

HL produces IL-5 which increases eosinophils

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Basophila

What is it?
Common causes?

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Increased circulating basophils

Common causes:
Chronic Myeloid Leukemia**

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Lymphocytic leukocytosis

What is it?
Common causes?

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increased circulating lymphocytes

Common causes
-Viral infections (T-Cell hyperplasia)
-Bordetella pertussis infection (Exception to the rule)

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What organism mainly causes Infectious Mononucleosis?
What is a less common cause?

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EBV infection = most common cause of mono

CMV = less common cause

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How is EBV transmitted?
What age group is it common in?

(hint: you already know about mono!)

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"Kissing disease"
Spread via saliva

Common in teenagers

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Common symptoms of Infectious mono?

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Fever, malaise, sore throat, swollen/enlarged lymph nodes, BIG spleen

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What 3 things does EBV primarily infect?

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Throat
Liver - resulting in hepatitis with hepatomegaly
B cells

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What cells of the immune system primarily respond to EBV infection?

(hint: all viruses cause this cell to be activated)

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CD8+ T-cells

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CD8+ T cell response leads to??

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Generalized lymphadenpathy due to T-cell hyperplasia in lymph nodes

Splenomegaly due to T-cell hyperplasia in the spleen

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Where in the spleen is the T-cell hyplerplasia occuring?

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Periarterial lymphatic sheath (PALS)*

(if you don't know what that is, review Spleen histology; FLashcard coming soon near you!)

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Normal Spleen Histology?

Red Pulp vs. White Pulp?

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Red Pulp: BV mainly (hence red)

White pulp (actually blue): site of B and T cells

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Where is the Periarterial lymphatic sheath?
What is happening here?

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This is the outside area of the white pulp.

T-cell proliferation occurs here

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Normal Lymph node histology:

Find Cortex, paracortex, medulla (and figure out what grows where)

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Cortex: B- cells
Paracortex: T-cells

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What disease is this?

What cell does it represent?

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Mono

Atypical lympocyte (CD8+ T cell)

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Monospot test screening or definative diagnosis?

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Screen test for mono

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What are heterophile antibodies? Who produces them? What test detects them?

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These are weird ABs made against the horse or sheep blood cells when someone is infected with mono.

Monospot test detects them

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IgM antibodies against sheep/horse RBC are called?

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Heterophile antibodies

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14 yr male pt. has had a fever and has been feeling weak for few days. History suggests a new girlfriend. Physicial exam reveals enlarged posterior cervical lymph nodes, normal size liver, but enlarged spleen. You suggest mono and do a monotest, but it comes back negative. What do you think he has?

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CMV infection (also causing mono --- same symptoms just caused by different virus).

(whenever you suspect mono but test comes back negative, think CMV!)

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How do you make a definite diagnosis of EBV?

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Serologic studies looking for EBV antigens

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What are some complications associated with Mono?

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Increased risk of splenic rupture (b/c it is big)*

Recurrence and B-cell lymphoma (if immunodeficient) b/c the virus stays dormant in the B-cells it infects

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Acute Leukemia

What is it?

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Neoplastic proliferation of the blasts;
defined as accumulation of >20% of blasts in the BM

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How does Acute leukemia cause anemia, thrombocytopenia and neutropenia?

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Increased blasts "crowd out" normal hematopoiesis resulting in decreased production of everything

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Why do you get high WBC in acute leukemia?

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B/c the Blasts (neoplastic) enter blood stream

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What do the neoplastic blast cells look like?

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Blasts are large, immature cells, often with punched out nucleoli

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Two divisions of Acute leukemia?

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Divisions based on whether it is the myleoid linage or lympocytic linage

AML and ALL

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Acute Lymphoblastic leukemia (ALL)

What is it?

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Neoplastic accumulation of lympoblasts (>20%) in the bone marrow

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What marker is used to detect ALL?

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TdT, a DNA polymerase**

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ALL is commonly associated with what disease?
What age?

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Down syndrome

Usually AFTER age 5

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2 subdivisions of ALL?

ALL common in what age group?

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B-ALL and T-ALL

usually children

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Most common type of ALL?

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B-ALL

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B-ALL is usually characterized by TdT+ lymphoblasts that express CD__, CD__ and CD___

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CD10, 19, 20

(hint: For B-cells, CD are greater then 10)

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Prognosis of B-ALL is based on?

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Cytogenetic abnormalities

t(12;21) has good prognosis; more common in children
t(9;22) has poor prognosis; adults (philadelphia chromosome)

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T-ALL is characterized by TdT+ lymphoblasts that express CD__, CD__, etc. markers

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Markers ranging from Cd2-CD8

(hint: For T cells, CD are less then 10)

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T-ALL cause a mediastinal mass hence another name is acute lympoblastic LYMPHOMA

T/F?

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TRUE

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Acute Myeloid Leukemia (AML)

What is it?

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Neoplastic accumulation of myeloblasts (>20%) in the BM

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AML common in what age group?

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Usually elderly (~55)

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AML is characterized by positive cytoplasmic staining for?

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MPO**

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When you stain for Myeloperoxidase (MPO) in AML, crystal aggregates might form. What are these called?

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Auer rods

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AML subtypes?

(hint: there are many; know the high yield ones -- 3)

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Acute promyelocytic leukemia
Acute monocytic leukemia
Acute megakaryoblastic leukemia

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Acute Promyelocytic leukemia

What is it?
MOA (what genetic abnormality)*

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A subtype of AML

t(15;17) which involves translocation of retinoic acid receptor on chom 17 to chrom 15**

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RAR disruption blocks maturation of myloid and promyelocyte accumulate

What disease is this? What genetic abnormality?

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Acute promyolocytic leukemia (form of AML)

t(15;17) of RAR (needed for maturation)

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What emergency risk are you at for in pt. with Acute promyelocytic leukemia? Why?*

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Dissemented Intravascular Coagulation*

APL has many auer rods which increase risk of DIC

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Tx of APL?

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ATRA (vitamin A derivative)

Binds to altered receptor and causes the blasts to mature (and die) --> lets the RAR do its function

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Acute monocytic leukemia

What is it?
Common place to infiltrate?*

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Proliferation of monoblasts (form of AML)

Infiltrates gums* (swelling)

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Acute megakaryoblastic leukemia

What is it?
Associated with what? at what age?

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Proliferation of megakaryoblasts (form of AML)

Associated with Downs BEFORE age 5

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What two blood cancers associated with Downs?

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Acute megakaryoblastic leukemia (form of AML) = BEFORE age 5

ALL = AFTER age 5

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What is chronic leukemia?

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Neoplastic proliferation of mature circulating lymphocytes;

usually takes a long time to occur (thus usually adults)

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Chronic lymphocytic leukemia (CLL)

What is it?

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Neoplastic proliferatoin of naive B-cells that co-express CD5 and CD20

(weird b/c low numbers usually T-cell associated)

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What is the most common leukemia overall?

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Chronic Lymphocytic Leukemia

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What disease is this?
How do you know?

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Chronic Lymphocytic Leukemia

SMUDGE CELL**

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Complications of CLL?

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Hypogammaglobulenima - the B cells don't become plasma cells (increased risk of infection)

Autoimmune hemolytic anemia - if they do become plasma cells, the AB are stupid

Transformation to diffuse large B-cell lymphoma

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Richter transformation

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CLL turning into diffuse large B-cell lymphoma

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Hairy Cell Leukemia
What is it?

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Neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes

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What is this?

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hair cell leukemia

(The hairy process is what the arrow is pointing at)

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In hairy cell Leukemia, what are the cells positive for?

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Tartrate resistant acid phosphatase

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2 clinical features of Hairy Cell leukemia

(hint: spleen and BM)

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Splenomegaly and "dry" tap on BM aspiration (due to marrow fibrosis)

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Why do you get splenomegaly in Hairy Cell Leukemia (this is weird)

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Due to accumulation of hairy cells in the red pulp (instead of white)

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General features of Chronic leukemia regarding lymph nodes and spleen?

Explain why hairy cell leukemia is an exception

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Splenomegaly (generally WHITE pulp hyperplasia)

Enlarged lymph nodes

In Hairy cell, you have no lymph node enlargement and it is the RED pulp

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Treatment for Hairy cell leukemia?

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2-CDA (Cladribine) - adenosine deaminase inhibitor (adenosine will accumulate and cells will die)

Excellent response

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Adult T-Cell Leukemia/Lymphoma (ATLL)

What is it?
Associated with what in what areas of the world?

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Neoplastic proliferation of mature CD4+ T cells (like to go to skin).

Associated with HTLV-1 infection; most commonly seen in Japan and Caribean**

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Clinical features of Adult T-Cell Leukemia/Lymphoma (ATLL)

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lymphadenopathy, hepatosplenomegly (two things associated with any CL), lytic bone lesions with hypercalcemia

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A person with punched-out lesion and you think there is some blood cancer. What is your DDx?

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ATLL and Multiple Mylemona

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Mycosis Fungoides

What is it?

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Neoplastic proliferation of mature CD4+ T cells (like ATLL) but it has distinctive characteristics

(spreads to blood)

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Clinical features of Mycosis Fungoides

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Localized skin rash, plaques and nodules (b/c CD4 T cells accumulate in skin);

Also goes into blood stream

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Pautrier microabcesses

What is it? seen in what disease?

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Neoplastic cells in epidermis = Pautrier microabscesses

Seen in Mycosis Fungoides

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If the neoplastic CD4 T-cells in Mycosis Fungoides spread to blood stream, what is the disease called?

What are the characteristic cells in blood smear?

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Sezary syndrome

Sezary cells (bunch of lobes in the nucleus)

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Myeloproliferative Disorders

What is it?

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Neoplastic proliferation of mature cells of the myeloid lineage (eg. too many RBC or platelets)

Old age usually

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What cells are usually incresaed in Myeloproliferative Disorders?

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All cells of the myeloid lineage are increased (eg. RBC, neutrophils, Platelets, monocytes).

However we name it based on the dominating one.

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Complications associated with Myeloproliferative Disorders

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Increased risk of hyperurecemia and gout due to high turnover

Progress to marrow fibrosis or transformation to acute leukemia

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Name some Myeloproliferative disorders

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Chronic Myeloid Leukemia (granulocytes-basophils)
Polycythemia Vera (RBCs)
Essential Thrombocythemia (platelets)
Myelofibrosis (MK)

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Chronic Myeloid Leukemia (CML)

What is it?

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Neoplastic proliferation of mature myeloid cells, especially granulocytes (mainly basophils**)

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What is this?

Back 92

Chronic Myeloid Leukemia

Lots of lympocytes (those big huge things), especially basophils usually

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What genetic abnormality is associated with CML?

(hint: city)

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Philadelpha chromosome: t(9;22)

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What does the Philadelphia chromosome t(9;22) translocation lead to?

(hint: some kind of fusion)

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BCL-ABL fusion protein

This increases tyrosine kinase activity (increased GROWTH)

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What can be a complication of CML?

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Can advance to AML or ALL

(Note: if you are confused as to why it can turn into ALL --> it is b/c the error is in the FIRST step of hemapotosis)

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How can you differentiate CML from leukemoid reaction (eg. lots of lymphocytes) during infection and stuff?

(random list, be familiar with)

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-Negative Leukocyte Alkaline Phosphatase stain in CML (+ in leukoemoid rxn)

-Increased basophils in CML

-Philadelpha chromosome

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Polycythemia Vera

What is it?

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Neoplastic proliferation of mature myeloid cells, especially RBCs

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What mutation do you have in Polycythemia vera?

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JAK2 Kinase mutation

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Clinical features of Polycythemia Vera

(all caused by what?)

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All symptoms caused by blood being viscous (too many RBCs)

Blurry vision headache
Increased risk of Venous thrombososis
Flushed face due to congestion
Itching (due to increased mast cells)

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Tx. of Polycythemia Vera

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Phelobotomy

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If you don't treat a pt. with Polycyhtemia Vera, what happens?

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Pt. dies within an yr

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How do you differentiate b/w Polycythemia Vera and reactive polycythemia (increased RBC due to some weird stimulus)?

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In PV, Erythropoietin levels are decreased (negative feedback)

And O2 saturation should be normal (duh --- why would that change)

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Essential Thrombocythemia

What is it?

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Neoplastic proliferation of mature myeloid cells, especially platelets

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What is this?

Back 104

Essential Thrombocythemia (ET)

little dots = platelets

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What mutation is associated with Thrombocythemia?

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JAK2 kinase mutation (just like Polychtemia Vera---RBC)

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Symptoms of Essential Thrombocythemia?

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Either too much bleeding or too much clotting

All depending on if the extra platelets are working (clots) or are defective (leading to bleed)

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Most Myeloproliferative Disorders have potential complications of hyperurecemia, marrow fibrosis, and acute leukemia transformation EXCEPT?

Back 107

Essential Thrombocyhthemia

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Myelofibrosis

What is it?

Back 108

Neoplastic proliferation of mature myeloid cells, especialy megakaryocytes

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What do megakaryotes produce that leads to marrow fibrosis?

Back 109

produce excess platelet-derived growth factor causing marrow fibrosis (hence the name)

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Why do you have increased risk of infection, thrombosis, bleeding and splenomegaly in Myelofibrosis?

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Due to the excess fibrosis, the BM sucks at making everything. Spleen (and other places) take over, but just aren't good enough :(

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Notice that long RBC.

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Tear drop cells of Myelofibrosis (the BM sucks at making them right)

Would also see immature granulocytes and immature RBC (with nuclues) b/c Spleen doesn't check whether they mature or not (its stupid)

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What is Lymphoma and what is it sub-divided into?

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Neoplastic proliferatoin of lyphoid cells that form a mass;

Divided into non-Hodgkin (60%) and Hodgkin lymphoma

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Non-hodgkin is further divided into what?

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Divided based on many things (one being size and type of cell---B or T)

Small B cells (Follicular, Mantle, Marginal), Intermediate (burkitt), Large B cells

There are many many more but those are the high yields (mainly B)

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Where is the Follicle?
Where is the Mantle zone?
Where would the marginal zone be (if it was there)?

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Follicle is inside the Mantle zone (pink)
Mantle zone is labeled (duh)
Marginal zone would be OUTside of the mantle zone

Front 115

Follicular Lymphoma

What is it?

Back 115

Neoplastic proliferation of small B-Cells (CD20+) that form follicle-like nodules

(lots of follicles - little circle things)

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What genetic abnormality lead to Follicular lymphoma?

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t(14;18) trans-location

BCL on chromosome 18 translocated to the Ig heavy chain locus on chromosome 14 (highly expressed)

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Increased expressoin of BCL2 in Follicular lymphoma leads to what?

Back 117

Inhibits apoptosis, hence the tumor

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How do you differentiate Follicular lymphoma from follicular hyperplasia?

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Lymphoma disrupts normal lymph node structure (spreads everywhere)

Lack of tingible body macrophages in lymphoma

BcL2 expression in lymphoma

Monoclonality in the lymphoma (

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What are tingibile body macrophages?

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These are just MC which are present in hyperplasia and stuff to clean out the dead cells.

In lymphoma the cells don't die, thus NO MC present.

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What is Mantle Cell Lymphoma?

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Neoplastic proliferation of small (CD20) that expands the mantle zone (right outside the follicle)

"adjacent to follicle"

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What genetic abnormality drives Mantle Cell Lymphoma?

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t(11;14) trans-location

Cyclin D1 gene on 11 goes to Ig heavy chain locus on chromosome 14.

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What is the role of cyclin D1? What happens if it is overexpressed (as the case with mantle Cell lymphoma)

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Cyclin D1 promotes G1/S transition

overexpression leads to cancer (uncontrolled growth!)

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What is Marginal Zone lymphoma

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Neoplastic proliferation of small B cells (CD20+) that expands the marginal zone

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What is Marginal Zone lymphoma associated with?

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Associated with chronic inflammatory states

Eg. Hahimoto thyroiditis, Sjogren syndrome, H. pylory gastritis

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What is MALToma

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Marginal zone lymphona in mucosal sites

(usually associated with H.pylori)

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What is Burkitt Lymphoma?

Associated with what virus?

Back 126

Neoplastic proliferation of intermediate-sized B cells (CD20+);

associated with EBV

Front 127

Compared to other Non-Hodgkin lymphomas, who (age group) does Burkitt's present in?

Back 127

usually in kids (other ones usually adults)

Front 128

What are the two forms of Burkitt's lymphoma?

Back 128

African form usually involves jaw

Sporadic form usually involves abdomen

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What genetic abnormality is associated with Burkitt's lymphoma?

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t(8;14)

c-myc on chromosome translocated to chromosome 14 (Ig heavy chain); hence heavily expressed, leading to cell growth

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Starry-sky apperance in what disease?

Back 130

Burkitt's lympoma

sky = blue = proliferating B cells
starry = white = MC cleaning it up

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What is Diffuse Large B-Cell lymphoma?

Aggressive or NBD?

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Neoplastic proliferation of large B-cells (CD20) that grow diffusely

Clinically agressive (high grade)

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What is the most common form of Non-hodgkin lymphoma?

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Diffuse Large- Bell Lymphoma

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How does Diffuse Large B-cell lymphoma arise?

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Like most, it can come sporadicly.

Or it can come from some low grade lymphoma (eg. follicular)