White Blood Cell disorders Flashcards
What is the CD marker of hematopoietic stem cells?
CD34+
What is the value of a normal WBC? Leukopenia? Leukocytosis?
Normal = 5,000 - 10,000
Leukopenia < 5,000
Leukocytosis > 10,000
What are the causes of neutropenia? What are the treatments?
Neutropenia can be caused by drugs that damage the hematopoietic stem cells or severe infection (e.g. sepsis) that increases the movement of neutrophils out of the blood and into the tissues. Neutropenia can be treated with GM-CSF or G-CSF
What are the causes of eosinophilia? basophilia?
eosinophilia - allergic reactions, parasitic infections, Hodgekin lymphoma
basophilia - chronic myeloid leukemia
What disease does EBV cause? What organs does it primarily infect? What happens to the T cells in an EBV infection? What test can distinguish between CMV and EBV? A rash can develop if exposed to which antibiotic?
EBV causes infectious mononucleosis. It infects the oropharynx (pharyngitis), liver (hepatitis) and B cells. T cells undergo hyperplasia and cause swollen lymph nodes and splenomegaly. Lymphocytic leukocytosis with atypical lymphocytes. The monospot is used for differentiating between EBV and CMV. The test detects IgM antibodies that cross-react with horse and sheep RBCs (heterophile antibodies). As rash can develop if exposed to ampicillin.
What is the pathogenesis of acute leukemia? Chronic leukemia?
Acute leukemia - neoplastic proliferation of blasts (lymphoblast or myeloid blast) such that >20% blasts in the bone marrow.
Chronic leukemia - neoplastic proliferation of mature lymphocytes
What are the histological characteristics of acute leukemia?
blasts are large, immature cells with punched out nucleoli
What are the two main subdivisions of acute leukemia? How are they distinguished?
Acute leukemia is either acute myelogenous leukemia (AML) if the proliferating blasts are myeloid blasts or acute lymphoblastic leukemia (ALL) if the proliferating blasts are lymphoblasts. Histologically, ALL can be distinguished from AML because it will stain positive for TdT, a DNA polymerase, but TdT is absent in myeloid blasts and mature lymphocytes. AML will stain positive for myeloperoxidase (MPO) and crystal aggregates of MPO can form Auer rods.
What are the two main types of acute lymphoblastic leukemia? How can they be distinguished? How do these patients present?
B-ALL (pre-B cell lymphoblastic leukemia)- proliferation of B lymphoblasts marked by CD10, CD19 and CD20
T-ALL (pre-T cell lymphoblastic leukemia) - proliferation of T lymphoblasts marked by CD2-CD8
Most patients present with bone marrow failure and pancytopenia caused by extensive marrow replacement by leukemic cells
What translocations are common in a B lymphoblast acute lymphoblastic leukemia (B-ALL)?
T(12;21) good prognosis; more common in children
t(9,22) bad prognosis; more common in adults; Philadelphia chromosome
How does a T lymphoblast acute lymphoblastic leukemia (T-ALL) usually present?
In teenagers with a thymic mass
What are the four main types of chronic leukemia?
Chronic lymphocytic leukemia (CLL) (also called small lymphocytic leukemia), Hairy cell leukemia, Adult T cell leukemia/lymphoma (ATLL), mycosis fungoides
What cells are proliferating in chronic lymphocytic leukemia (CLL)? What are its histological characteristics? What are some of the complications of CLL?
Neoplastic proliferation of naive B cells that co-express CD5 and CD20 (B cells usually do NOT express CD5). Histologically there are increased lymphocytes and smudge cells. Complications include increased risk of infection due to hypogammaglobulinemia (these B cells don’t produce antibodies), autoimmune hemolytic anemia (the antibodies that the B cells DO manage to produce are dysfunctional) and transformation to a B cell lymphoma
What cells are proliferating in hairy cell leukemia? What are its histological characteristics? What are accompanying signs and symptoms? What is the treatment?
Neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes. These cells will have CD11c and CD103 on their surface and will be positive for TRAP (tartrate resistant acid phosphatase). Clinical features are splenomegaly due to accumulation of hairy cells in the RED PULP, marrow infiltration/fibrosis, and absence of lymphadenopathy and leukocytosis. Treatment with 2-CDA has been very effective to kill B cells. 2-CDA is an adenosine deaminase inhibitor. Backup of the purine degradation pathway causes adenosine to accumulate to toxic levels in B and T cells (causes SCID).
What cells are proliferating in Adult-T cell leukemia/lymphoma? What type of infection is it associated with? What are the accompanying signs and symptoms?
Neoplastic proliferation of mature CD4+ T cells. ATLL is associated with the HTLV virus which is especially common in Japan and the Caribbean. The clinical features of this disease are lytic bone lesions with hypercalcemia, skin rash and generalized lymphadenopathy with hepatosplenomegaly.
What cells are proliferating in mycosis fungoides? Where in the body do these cells initially go? What are the accompanying signs and symptoms? What are aggregates of these cells called? Where in the body do these cells secondarily go?
Neoplastic proliferation of mature CD4+ T cells. T cells go to the skin and form plaques, nodules and rashes. Aggregates of these proliferating CD4+ T cells in the epidermis are called Pautrier microabscesses. These neoplastic cells can spread into the blood and cause Sezary syndrome which is characterized by cerebriform nuclei in the lymphocytes.
What cells types are proliferating in myeloproliferative disorders? What are the types of myeloproliferative disorders? Which mature cell of myeloid lineage is predominant in each disorder? (although all myeloid cells will be elevated) What mutations are common in these disorders?
Neoplastic proliferation of myeloid progenitors that retain the capacity for terminal differentiation (as opposed to AML where the immature myeloid blasts cannot terminally differentiate).
chronic myeloid leukemia (CML) - granulocytes (neutrophils, eosinophils, basophils)
polycythemia vera - RBCs
essential thrombocythemia - platelets
myelofibrosis - megakaryocytes
Mutated tyrosine kinases: The BCR-ABL fusion protein is common in CML. Mutations in the JAK2 kinase are common in PV, ET and MF.
What cell types are proliferating in multiple myeloma? What do these cells secrete and how does it lead to the clinical signs and symptoms?
Multiple myeloma is a neoplastic proliferation of plasma cells. These plasma cells secrete two products:
1) Osteoclast activating factor that stimulates the RANK receptor on osteoclasts and stimulates break down of bone.
- hypercalcemia
- lytic, “punched out” lesion on bone
- The most common lesions are in the skull and vertebrae so this disease often presents with severe back pain or pathological fractures.
2) monoclonal immunoglobulin (usually IgG or IgA).
- Causes elevated serum protein levels and an M spike on serum protein electrophoresis (SPEP).
- The increased serum protein decreases the charge between RBCs so they form small aggregates called Rouleaux formation of RBCs
- Decreases antigenic diversity of the immune system increases risk of infection.
3) kappa or lambda light chain (paraproteins)
- primary AL amyloidosis due to excess free light chains (paraproteins)
- proteinuria due to excess free light chains (paraproteins) being excreted in the urine as Bence-Jones proteins
- renal failure (myeloma kidney) due to deposition of free light chains (paraproteins) in the kidney tubule
How does multiple myeloma differ from monoclonal gammopathy of undetermined significance (MGUS)?
MGUS is when there is an M spike on serum protein plasmaphoresis (SPEP) but no other signs or symptoms of multiple myeloma. About 1% of patients with MGUS will develop multiple myeloma per year.
What is the pathogenesis of Waldenstrom macroglobulinema? What are the clinical signs and symptoms?
Waldenstrom macroglobulinema is a B cell lymphoma that produces IgM antibodies. Because of the increased number of antibodies, there will be an M spike on SPEP. The excess IgM will make the blood more viscous because IgM is a large molecule. Hyperviscosity increases risk of stroke or other neurological deficits and increase risk of bleeding due to impaired platelet aggregation.
What are Langerhans cells? What is a neoplastic proliferation of Langerhans cells called? What are the histological hallmarks of this disease? What are the types of neoplastic proliferation of Langerhans cells and what are the clinical signs and symptoms?
Langerhans cells are specialized macrophages/dendritic cells in the skin.
A neoplastic proliferation of Langerhans cells is called Langerhans cell histiocytosis.
Characteristic Birbeck (tennis racket) granules are seen histologically.
Types of LCH:
Letterer-Siwe disease - malignant proliferation with a skin rash and cystic skeletal defects in infants 5 y/o
What type of leukemia is Chronic Myeloid (myelogenous) Leukemia? What types of cell are proliferating? What translocation drives this disease? What leukemias can CML transform into and why? What are the clinical findings? How is CML distinguished from a leukemoid reaction?
CML is a myeloproliferative disorder because myeloid progenitors that retain the capacity for terminal differentiation are proliferating out of control (as opposed to AML where the immature myeloid blasts cannot terminally differentiate). In this case the mature myeloid cells are mainly granulocytes (neutrophils, basophils and eosinophils). This is one of the few diseases where the basophil count is elevated. The t(9:22) translocation (Philadelphia chromosome) causes this disease by creating a fusion protein, BCR-ABL, which is a constitutively active tyrosine kinase that speeds up the cell cycle. Because the translocation is in the hematopoietic stem cell, CML can transform into AML or ALL. CML presents with extreme splenomegaly CML can be distinguished from a leukemoid reaction by:
CML is negative for leukocyte alkaline phosphatase (LAP) stain while LR is positive for LAP stain. CML has increased basophil count while LR has normal basophil count. The t(9:22) translocation is not present in LR.
What type of leukemia is polycythemia vera? What types of cells are proliferating? What are the clinical signs and symptoms? What is the treatment? How can polycythemia vera be distinguished from reactive polycythemia?
Polycythemia vera is a myeloproliferative disorder because myeloid progenitors that retain the capacity for terminal differentiation are proliferating out of control (as opposed to AML where the immature myeloid blasts cannot terminally differentiate). In this case, the mature myeloid cells are mainly RBCs. The clinical signs are signs of hyper viscosity of blood: blurry vision, headache, increased risk of venous thrombosis, flushed face (plethora) itching especially after bathing. The treatment is phlebotomy, and then hydroxyurea if needed.
PV - EPO levels are decreased, SaO2 is normal
RP due to altitude or lung disease - EPO levels are increased, SaO2 is low
RP due to ectopic EPO production from renal cell carcinoma - EPO levels are increased, SaO2 is normal
What type of leukemia is essential thrombocythemia? What types of cells are proliferating? What are the clinical signs and symptoms?
Essential thrombocythemia is a myeloproliferative disorder because myeloid progenitors that retain the capacity for terminal differentiation are proliferating out of control (as opposed to AML where the immature myeloid blasts cannot terminally differentiate). In ET, platelets are proliferating and symptoms are related to an increased risk of thrombosis or bleeding.
What type of leukemia is myelofibrosis? What type of cells are proliferating? What are the histological hallmarks of this disease?
Myelofibrosis is a myeloproliferative disorder because myeloid progenitors that retain the capacity for terminal differentiation are proliferating out of control (as opposed to AML where the immature myeloid blasts cannot terminally differentiate). In MF, megakaryocytes are proliferating. Histologically, RBCs have nuclei, RBCs are in a tear-drop shape and granulocytes are immature.
What are the etiologies of painful lymphadenopathy (swollen lymph nodes) and painless lymphadenopathy?
painful LAD - draining a region of acute infection
painless LAD - chronic inflammation, lymphoma, metastatic carcinoma
What are the Non-Hodgkin lymphomas of small B cells? Intermediate B cells? Large B cells?
Small B cell NHL - follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, small lymphocytic lymphoma
Intermediate sized B cell NHL - Burkitt Lymphoma
Large sized B cell NHL - diffuse large B cell lymphoma
What cells are proliferating in follicular lymphoma? What is the pathogenesis of follicular lymphoma? How can you distinguish follicular lymphoma from reactive follicular hyperplasia in an acute infection?
In follicular lymphoma, small, CD20+ B cells proliferate and form nodules. This disease is driven by the t(14:18) translocation which moves the Bcl2 gene to the Ig heavy chain location. Distinguishing between reactive follicular hyperplasia and follicular lymphoma:
FL disrupts normal lymph node architecture while RFH does not.
Tingible body macrophages in germinal centers are present in RFH but not in FL.
FL is a monoclonal proliferation while RFH is a polyclonal proliferation.
Bcl2 is expressed in the follicles in FL but not in RFH
What cells are proliferating in mantle cell lymphoma? What is the pathogenesis of mantle cell lymphoma?
In mantle cell lymphoma, small CD20+ B cells are proliferating and expanding the mantle zone of the follicles. It is driven by the t(11:14) translocation which moves the Cyclin D gene to the Ig heavy chain location.
What cells are proliferating in marginal zone lymphoma? What lymphoid tissues does it typically arise in? What other diseases is it associated with?
In marginal zone lymphoma, small CD20+ B cells proliferate and expand the marginal zone of the follicles. It commonly arises in mucosal-associated lymphoid tissues (MALT) near the salivary glands, stomach, intestines and lungs. It is associated with chronic inflammatory states such as Hashimoto’s thyroiditis, Sjogren’s syndrome, and H pylori gastritis. In the case of H pylori gastric MALT lymphoma, antibiotic treatment of H pylori leads to regression of the tumor cells
What cells are proliferating in Burkitt lymphoma? What virus is it associated with? How does it usually present? What is the pathogenesis? What are its histological hallmarks?
In Burkitt lymphoma, intermediate sized CD20+ B cells proliferate. Associated with EBV. It usually presents as an extra nodal mass in the jaw in Africans. It is driven by a t(8:14) translocation that moves the c-myc gene to the Ig heavy chain location. The mitotic rate for this tumor is so high that tumor cells often die and are cleaned up by macrophages. These macrophages are often surrounded by a clear space so they create a “starry sky” appearance.
What cells are proliferating in Hodgkin’s lymphoma? What is the pathogenesis of Hodgkin’s lymphoma? What are the histological characteristics of Hodgkin’s lymphoma? What are the subtypes?
In Hodgkin’s lymphoma the proliferating cell are Reed-Sternberg cells. These cells secrete cytokines that attract inflammatory cells including lymphocytes, plasma cells, macrophages and eosinophils. This is one of the few diseases with an elevated eosinophil count. The bulk of the tumor is made of these reactive inflammatory cells, NOT the Reed-Sternberg cells. Histologically, RS cells are large B cells with multi lobed nuclei and prominent nucleoli (“owl-eyed” nuclei). These B cells are usually CD15+ and CD30+. The subtypes of Hodgkin’s lymphoma are based on the type of reactive inflammatory cells: Nodular sclerosis, lymphocyte-rich, mixed cell, lymphocyte-depleted.
Which lymphomas/leukemias are most common in children? In adults? What is the most common type of lymphoma
Children - acute lymphoblastic leukemias
Adults - non-Hodgkin lymphomas
Most common lymphoma - diffuse large B cell lymphoma
What type of lymphoma is Diffuse Large B-cell lymphoma? What is its pathogenesis?
DLBL is a heterogenous group of mature B cell tumors that have large B cells and an aggressive clinical behavior. One third arise from follicular lymphoma and carry the t(14:18) translocation. One third are associated with translocations or mutations of the BCL6 gene.
What mutations are associated with AMLs?
t(15:17) translocation which ruses the retinoid acid receptor alpha (RARA) gene on chrom 17 with the PML gene on chrom 15. The fusion protein blocks myeloid differentiation. Can be treated with retinoid acid, a vitamin A analogue.
t(8:21) and inv(16)
What diseases is the Philadelphia chromosome associated with?
t(9:22) is associated with CML and ALL
