What are 4 causes of lymphopenia?
1. immunodeficiency (HIV, DiGeorge)
2. High cortisol state (exogenous corticosteroids, Cushing syndrome)
3. Autoimmune destruction (SLE--Abs against blood cells)
4. Whole body radiation
How does a high cortisol state lead to lymphopenia?
corticosteroids induce apoptosis of lymphocytes
Infectious mononucleosis is caused by infection with what pathogen?
less commonly, CMV
What is infectious mononucleosis?
EBV infection that results in a lymphocytic leukocytosis comprised of reactive CD8+ T cells
How is EBV transmitted?
What cells/structures does EBV primarily infect?
1. oropharynx (--> pharyngitis)
2. liver (--> hepatitis, hepatomegaly, inc. liver enzymes)
3. B cells
The CD8+ T cell response to EBV infection leads to what clinical manifestations?
1. Generalized lymphadenopathy (multiple nodes, due to T-cell hyperplasia in the lymph nodes paracortex)
2. Splenomegaly (T cell hyperplasia in the periarteriolar lymphocyte sheath)
3. High WBC count with atypical lymphocytes (reactive CD8+ T cells)
What test is used for screening in a person suspected to have mononucleosis?
The monospot test
What does the monospot test detect?
IgM antibodies that cross react with horse or sheep RBCs (heterophile antibodies)
usually turns positive within one week after infection
What does a negative monospot test suggest?
1. The patient does not have infectious mononucleosis
2. CMV (instead of EBV) might be the cause of the IM
3. We tested too early, and the test is giving us a false negative.
How do you make a definitive diagnosis for infectious mononucleosis?
Serologic testing for the EBV viral capsid antigen
What are 3 complications of EBV infectious mononucleosis?
1. inc. risk of splenic rupture (patients advised to avoid contact sports for one year)
2. Rash if exposed to ampicillin
3. Dormancy of virus in B cells --> inc. risk of recurrence and B cell lymphoma, esp. if immunodeficiency develops.
What is acute lymphoblastic leukemia?
A neoplastic proliferation of lymphoblasts (>20%) in the bone marrow.
In which demographic does acute lymphoblastic leukemia most commonly arise?
It is associated with Down Syndrome (usually arises after the age of 5)
Into what broad groups can ALL (acute lymphoblastic leukemia) be subclassified?
B-ALL and T-ALL
B-ALL is most common
What is the characteristic histologic marker for lymphoblasts?
positive nuclear staining for TdT, a DNA polymerase
What cell markers are used to characterize B-ALL
--positive nuclear staining for TdT
--CD10, CD19, and CD20
Upon what information is the prognosis for B-ALL usually made?
The prognosis is typically based on cytogenic abnormalities:
--t(12;21) has a good prognosis (more common in children)
t(9;22) has a poor prognosis (more common in adults)
What cell markers characterize T-ALL?
positive nuclear staining for TdT
Myeloblasts are usually characterized by positive staining for what?
MPO can form crystal aggregates calles Auer rods.
What is chronic lymphocytic leukemia (CLL)?
A neoplastic proliferation of naive B cells that co-express CD5 and CD20.
These cells enter the blood stream and lymph nodes
What is seen on PBS in chronic lymphocytic leukemia?
Increased #s of lymphocytes and smudge cells
What are 3 complications of chronic lymphocytic leukemia?
2. Autoimmune hemolytic anemia
3. Transformation to diffuse large B-cell lymphoma
If chronic lymphoblastic leukemia involves a proliferation of naive B cells, why do w see complications of hypogammaglobulinemia and immune hemolytic anemia?
Normally, B cells will mature to become immunoglobin-producing plasma cells. However the neoplastic B cells in chronic lymphocytic leukemia do not produce Ig. When they do, they often do a bad job, and end up producing antibodies against the patient's own RBCs --> autoimmune hemolytic anemia.
Clinically, what marks the transition from chronic lymphocytic leukemia to diffuse large B-cell lymphoma?
An enlarging lymph node or an enlarging spleen
What is adult T-Cell Leukemia/lymphoma?
A neoplastic proliferation of mature CD4+ T cells
It is associated with HTLV-1
What are the clinical feature of adult T Cell Leukemia/lymphoma?
1. rash (skin infiltration)
2. generalized lymphadenopathy with hepatosplenomeglay
3. lytic (punched-out) bone lesions with hypercalcemia
What is Mycosis fungoides?
A neoplastic proliferation of mature CD4+ T cells that infiltrate the skin, producing localized skin rash, plaques and nodules.
Cells can spread to the blood, producing Sezary syndrome
What is Sezary syndrome?
Associated with mycosis fungoides.
The neoplastic proliferation of CD4+ t cells that infiltrate the skin in this disease can spread to the blood, producing Sezary syndrome.
In this syndrome, characteristic lymphocytes with cerebriform nuclei (sezary cells) can be seen on PBS.
What is the main root cause of the clinical symptoms in polycythemia vera?
clinical symptoms are mostly due to hyperviscosity of the blood.
What are 4 clinical symptoms of polycythemia vera?
1. blurry vision and headache
2. increased risk of venous thrombosis
3. flushed face due to congestion
4. Itching, especially after bathing (due to histamine release from increased mast cells)
Are the the first and second line treatments for plycythemia vera?
What is Essential Thrombocythemia (ET)?
A neoplastic proliferation of mature myeloid cells, especially platelets.
(granulocytes and RBCs are also increased)
With what mutation is Essential Thrombocythemia associated?
What is myelofibrosis?
A neoplastic proliferation of mature myeloid cells, especially megakaryocytes.
With what mutation is myelofibrosis associated?
Why does an increased in megakaryocytes in myelofibrosis lead to marrow fibrosis?
The megakaryocytes produce excess platelet-derived growth factor (PDGF), which causes marrow fibrosis
List the clinical features of myelofibrosis
1. splenomegaly (due to extramedullary hematopoiesis)
2. Increased risk of infection, thrombosis and bleeding
What would you see on PBS in myelofibrosis?
What is lymphoma?
--A neoplastic proliferation of lymphoid cells that form a mass.
--May arise in a lymph node or in extranodal tissue.
--Divided into Hodgkin and non-Hodgkin lymphoma.
non-Hodgkin lymphoma is classified based upon cell type, cell size, pattern of cell growth, expression of cell surface markers, and cytogeneic translocations. Name 4 small B cell lymphomas
1. follicular lymphoma
2. mantle cell lymphoma
3. marginal zone lymhoma
4. small lymphocytic lymphoma
Based upon size, what type of lymphoma is Burkitt Lymphoma?
Intermediate-size B cell lymphoma.
What is follicular lymphoma?
A neoplastic proliferation of small B cells (CD20+) that form follicle-like nodules
What cytogenetic abnormality drives follicular lymphoma?
BCL-2 on chromosome 18 translocates to Ig heavy chaing locus on chromosome 14.
This results in overexpression of BCL-2, which inhibits apoptosis
What is the treatment for follicular lymphoma?
Rituximab (anti-CD20 antibody) or chemotherapy
How can you distinguish follicular lymphoma from reactive follicular hyperplasia? (4)
1. disruption of normal lymph node architecture
2. lack of tingible body macrophages in germinal centers
3. Bcl-2 expression in follicles
(reactive hyperplasia is polyclonal, does not express Bcl-2, has tingible body macrophages, and maintains normal node architecture)
What is mantle cell lymphoma?
A neoplastic proliferation of small B-cells (CD20+) that expands the mantle zone.
What cytogenetic abnormality drives the production of mantle cell lymphoma?
The cyclin D1 gene on chromosome 11 translocates to the Ig heavy chain locus on chromosome 14.
Overexpression of cyclin D1 promotes G1/S transition in the cell cycle, leading to (neoplastic) proliferation
What is marginal zonelymphoma?
A neoplastic proliferation of small B cells (CD20+) that expand the marginal zone in a lymph node.
With what diseases is marginal zone lymphoma associated?
Marginal zone lymphoma is associated with chronic inflammatory states, including:
--H. pylori gastritis
What is Burkitt lymphoma?
neoplastic proliferationof intermediate-sized B Cells (CD20+)
It is associated with EBV
With what infeciton is Burkitt lymphoma associated?
What cytogenetic abnormality drives the formation of Burkitt lymphoma?
results in the translocation of the c-myc gene on chromosome 8 to the Ig heavy chain locus on chromosome 14.
Overexpression of the c-myc oncogene promotes cell growth.
How does Burkitt lymphoma appear on microscopy?
Characterized by a high mitotic index and 'starry sky' appearance.
What are the two forms of Burkitt lymphoma?
1. African form usually involves the jaw
2. Sporadic form usually involves the abdomen
What is multiple myeloma?
Malignant proliferation of plasma cells in the bone marrow.
An increase in what cytokine is often associated with multiple myeloma?
IL-6 stimulates plasma cell growth and immunoglobulin production.
What is the classic PBS finding in multiple myeloma?
Rouleaux formation of RBCs.
Increased serum protein (immunoglobulins) decreases charge between the RBCs, causing them to stack on each other like poker chips.
What might you see on x-ray in multiple myeloma?
Punched-out lesions, especially in the vertebrae and skull.
(neoplastic plasma cells activate RANK receptor on osteoclasts, leading to bone destruction, bone pain, and hypercalcemia)
Name 6 clinical features of multiple myeloma
1. bone pain
3. elevated serum protein
4. increased risk of infection
5. primary AL amyloidosis
Why do we see elevated serum protein in multiple myeloma?
The neoplastic plasma cells produce immunoglobulin.
An M spike is present on serum protein electrophoresis (SPEP), most commonly due to IgG or IgA.
Why are patients with mutliple myeloma at increased risk of infection?
In mutliple myeloma, neoplastic plasma cells produce immunoglobulin. However, these immunoglobulins lack antigenic diversity