WBC Disorders Flashcards
Hematopoietic stem cells have what CD marker?
CD34+
Hematopoietic CD34+ stem cells differentiate into Myeloid or Lymphoid stem cells. What cells are included in the myeloid lineage?
Erythroblasts —> RBCs
Myeloblasts —> Neutrophils, basophils, eosinophils (granulocytes)
Monoblasts —> monocytes —> macrophages
Megakaryoblasts —> megakaryocytes
Hematopoietic CD34+ stem cells differentiate into Myeloid or Lymphoid stem cells. What cells are included in the lymphoid lineage?
B lymphoblasts —> naive B cells —> plasma cells
T lymphoblasts —> naive T cells —> CD8+ T cells, CD4+ T cells
Neutropenia is a decrease in circulating neutrophils. What are 2 classic scenarios in which this is seen?
Drug toxicity — classic example is chemotherapy (tx with GM-CSF or G-CSF; used to boost neutrophil count)
Severe infection
Immunodeficiency states, high cortisol states, autoimmune destruction, and whole body radiation are scenarios associated with leukopenia of what type of cell?
Lymphopenia
[Immunodeficiency example is DiGeorge syndrome. High cortisol induces apoptosis of circulating lymphocytes. Autoimmune example is SLE —> antibodies against cells in blood]
What is the most sensitive cell in the body to radiation exposure, aka which cells are the first to exhibit damage?
Lymphocytes
Neutrophilic leukocytosis is associated with bacterial infection, tissue necrosis, and a ______ cortisol state
High
[cortisol causes demargination]
In the setting of bacterial infection, an increase in immature neutrophils is released from the bone marrow in a phenomenon called left-shift. These immature neutrophils will have a decreased expression of _________, evidenced by low expression of CD_____. This indicates that they are less effective at fighting infection
Fc receptors; CD16+
In what 2 conditions might you see a monocytosis?
Chronic inflammatory state
Malignancy
3 clinical scenarios associated with eosinophilia include allergic reaction, parasitic infections, and _______ lymphoma due to an increase in ______ production
Hodgkin; IL-5
For all practical purposes, the one scenario in which you will see basophilia is ______
CML
Lymphocytic leukocytosis is classically associated with viral infections in which the primary cell fighting infection is CD8+ T cells. Most bacterial infections are associated with neutrophilia moreso than lymphocytic leukocytosis. The one bacteria that is an exception to this is _____ ____, which secretes lymphocytosis-promoting factor, which prevents lymphocytes from entering lymph nodes (thus they remain high in the blood)
Bordetella pertussis
Infectious mononucleosis is an EBV infection that results in a lymphocytic leukocytosis comprised of reactive _______ cells. CMV is a less common cause.
EBV primarily infects 3 tissues: ______, ______, and _____
CD8+ T cells
Oropharynx; liver; B cells
In response to mononucleosis infection, CD8+ T cells cause generalized LAD, splenomegaly, and high white count with atypical lymphocytes (large nucleus, abundant blue cytoplasm, look like monocytes).
Which areas of the lymph nodes and spleen are enlarged?
Lymph nodes = paracortex expansion
Spleen = periarterial lymphatic sheath (aka PALS - part of white pulp)
The monospot test is used for screening for mononucleosis. It detects ____________ and usually turns positive within _____ after infection. Definitive diagnosis is made by testing for ____________
A negative monospot test suggests _____ as the cause.
IgM heterophile antibodies; 1 week; EBV viral capsid antigen
CMV
Complications of infectious mononucleosis include increased risk for splenic rupture, rash if exposed to ________, and dormancy of virus in _______
Penicillin; B cells
[increased risk later on of B cell lymphoma due to latency in B cells]
Acute leukemia is a neoplastic proliferation of blasts, defined as an accumulation of >20% blasts in the bone marrow. Blasts “crowd-out” normal hematopoeisis, resulting in “acute” presentation with anemia, thrombocytopenia, or neutropenia. Blasts usually enter the blood resulting in a high WBC. How do blasts appear on blood smear?
Large, immature cells, often with punched out nucleoli
If blasts are identified on peripheral smear indicating an acute leukemia, they may be of either myeloid or lymphoid origin.
If they are of myeloid origin, it is called AML. Myeloid blasts will stain positive for _______ enzyme in the cytoplasm, which may be detected in 2 ways: one is to do a chemical study, and the other is to view the cell under a microscope as _____ ______, which may be visualized as crystallized structures.
If they are of lymphoid origin, it is called ALL. Lymphoid blasts will stain positive for ______ in the ______, which is a compound found NOT found in mature lymphoid cells or myeloblasts.
MPO+; auer rods
TdT+ (DNA polymerase); nucleus
ALL can be subclassified into B-ALL or T-ALL, and this is based on surface markers (since both have tdt+). Which one is more common: B-ALL or T-ALL?
B-ALL
In B-ALL, lymphoblasts classically express what 3 cell markers?
CD10
CD19
CD20
B-ALL has an excellent response to chemotherapy, but requires what additional component of treatment?
Prophylaxis to scrotum and CSF (direct injection of chemo to those areas) — because chemotherapy does not cross those barriers
The prognosis for B-ALL is generally good, and is based on cytogenetic abnormalities (in this case translocations).
________ has a good prognosis — this is the type most are familiar with and is more commonly seen in kids.
________ has a poor prognosis and is more commonly seen in adults.
t(12;21)
t(9;22) — Ph+ (philadelphia chromosome)
T-ALL is identified based on lymphoblasts that express markers ranging from ____-_____.
CD2-CD8
T/F: T-ALL cells express CD10
False — CD10 is found on cells of B-ALL
How does T-ALL present clinically?
Presents as a mediastinal (thymic) mass in a teenager
Remember that this means it is referred to as Acute Lymphoblastic LYMPHOMA (not leukemia) since it is presenting as a solid mass
AML is a neoplastic proliferation of myeloblasts. Myeloblasts are characterized by staining for MPO. Crystal aggregates of MPO may be seen as Auer rods.
Is AML more common in children, adolescents, or older adults?
Older adults — average age is 50-60 years
AML can be subclassified in 3 ways: by cytogenetic abnormalities, by lineage of myeloblasts, or by surface markers. The predominant mechanism is by cytogenic abnormalities.
A classic type of AML is Acute Promyelocytic Leukemia, which is characterized by a _______ translocation. This results in disruption of the ______ receptor, leading to accumulation of promyelocytes.
Promyelocytes contain numerous Auer rods, which can activate the coagulation cascade, increasing the risk of ______.
t(15;17); Retinoic acid (RAR)
DIC
What is the treatment for acute promyelocytic leukemia and what does it do?
All-trans retinoic acid (ATRA) — causes the blasts to mature into neutrophils
AML can be subclassified in 3 ways: by cytogenetic abnormalities, by lineage of myeloblasts, or by surface markers. If there are no recurring cytogenic abnormalities, the lineage of myeloblasts is used to classify.
What type of leukemia, classified based on lineage, is characterized by a lack of MPO, and blasts that characteristically infiltrate the gums?
Acute monocytic leukemia
AML can be subclassified in 3 ways: by cytogenetic abnormalities, by lineage of myeloblasts, or by surface markers. If there are no recurring cytogenic abnormalities, the lineage of myeloblasts is used to classify.
What type of leukemia, classified based on lineage, is characterized by a lack of MPO and is associated with Down syndrome (before the age of 5)
Acute megakaryoblastic leukemia
Patients with Down syndrome are at increased risk for acute leukemia. What type of leukemia do they typically develop before the age of 5 vs. after the age of 5?
Before the age of 5 = Acute megakaryoblastic leukemia
After the age of 5 = Acute lymphoblastic leukemia
AML may also arise from pre-existing dysplasia, particularly seen with prior exposure to ________ or _________, resulting in a myelodysplastic syndrome.
While myelodysplastic syndrome may progress to acute leukemia, most patients with myelodysplastic syndromes die from ____ or ____
Alkylating agents; radiotherapy
Infection; bleeding
Define myelodysplastic syndrome
Cytopenia with hypercellular bone marrow — abnormal maturation with increased blasts (<20%)
[if it reaches the point of >20% blasts, it has progressed to acute leukemia]
A chronic leukemia is a neoplastic proliferation of mature circulating lymphocytes, characterized by a high WBC count. This usually insidious in onset and seen in older adults.
The prototypic chronic leukemia is CLL, which is a neoplastic proliferation of ______ B-cells. These cells co-express _____ and _____. It may be identified based on increased lymphocytes and _____ cells seen on blood smear
Naive; CD5; CD20; smudge
CLL may progress to cause generalized lymphadenopathy, at which point it may be called small lymphocytic lymphoma. What are the complications of CLL regarding immunoglobulin levels, anemia, and transformation?
Hypogammaglobulinemia (common cause of death is infection)
Autoimmune hemolytic anemia
Transformation to diffuse large B-cell lymphoma (presents with enlarging lymph node or enlarging spleen)
Hairy cell leukemia is a neoplastic proliferation of ______ B cells characterized by hairy cytoplasmic processes. These cells are positive for _______ enzyme.
Mature; TRAP (tartrate-resistant acid phosphatase)
Splenomegaly involving the RED pulp, absence of lymphadenopathy, and “dry tap” on bone marrow aspiration are indicative of what WBC disorder?
Hairy cell leukemia
Hairy cell leukemia has an excellent response to what treatment? Why is it effective?
2-CDA
This is an adenosine deaminase inhibitor, so it causes accumulation of adenosine to toxic levels in neoplastic B cells [adenosine deaminase is part of purine degradation pathway]
Adult T-cell leukemia/lymphoma (ATLL) is a neoplastic proliferation of mature _______ cells. It is associated with the virus _______, which is particularly seen in Japan and the Caribbean.
Clinical features of ATLL are rash, generalized LAD with HSM, and lytic bone lesions with _____calcemia
CD4+ T cells; HTLV-1
Hypercalcemia
[Don’t immediately assume multiple myeloma if there are lytic bone lesions! If rash is present it is more likely to be ATLL!!]
______ ______ is a neoplastic proliferation of mature CD4+ T cells that infiltrate skin, producing rash, plaques, or nodules. Aggregates of neoplastic T-cells in the epidermis are called ______ ______.
Theses cells can also spread to the blood in a phenomenon called _______ syndrome. This is characterized by lymphocytes with _______ nuclei on blood smear
Mycosis fungoides; Pautrier microabscesses
Sezary; cerebriform
In a myeloproliferative disorder, there is neoplastic proliferation of ALL of the mature cells of the myeloid lineage. The disorder is then named for whichever cells is PREDOMINANT. Overall, these are diseases of late adulthood that result in high WBC count with hypercellular bone marrow.
What are the 3 primary complications associated with myeloproliferative disorders?
Hyperuricemia and gout (high cell turnover)
Progression to marrow fibrosis
Transformation to acute leukemia
Chronic myeloid leukemia is a neoplastic proliferation of mature myeloid cells, especially ___________. Of these, the _________ are characteristically increased.
CML is driven by a ______ translocation, resulting in BCR-ABL fusion with increased ______ ______ activity. First line treatment is _______, which blocks this activity
Granulocytes; basophils
t(9;22); tyrosine kinase; imatinib
In CML, an actively enlarging ______ suggests accelerated phase of the disease, and transformation to acute leukemia usually follows shortly thereafter
Transformation of CML into an acute leukemia can result in ______ (2/3 of the time) or ______ (1/3 of the time). This is because the original mutation is in a pluripotent stem cell
Spleen
AML; ALL
How is CML distinguished from a leukemoid reaction?
CML granulocytes are leukocyte alkaline phosphatase negative
CML is associated with increased basophils
CML granulocytes exhibit t(9;22)
______ ______ is a neoplastic proliferation of mature myeloid cells, especially RBCs (although granulocytes and platelets are also increased). It is associated with a __________ mutation.
Polycythemia vera; JAK2 kinase
Clinical symptoms of polycythemia vera include blurry vision and headache, icnreased risk of venous thrombosis, flushed face due to congestion, and itching after bathing. What is a classic presentation of venous thrombosis in these patients?
Budd chiari syndrome
[PV is the most common cause!!!]
First line treatment for polycythemia vera is _______. Second line treatment is ________. Without treatment, death usually occurs within 1 year
Phlebotomy; hydroxyurea
How is polycythemia vera distinguished from reactive polycythemia?
In PV, SaO2 is normal and EPO is decreased
In reactive polycythemia due to lung disease, SaO2 is low and EPO is increased
In reactive polycythemia due to ectopic EPO production (e.g., renal cell carcinoma), EPO is high and SaO2 is normal
______ ______ is a neoplastic proliferation of mature myeloid cells, especially platelets. RBCs and granulocytes are also increased. It is associated with a _____ mutation
Essential thrombocythemia; JAK2 kinase
Symptoms of essential thrombocythemia include increased risk of bleeding and/or thrombosis.
T/F: essential thrombocythemia rarely progresses to marrow fibrosis or acute leukemia, and there is NO significant risk for hyperuricemia or gout
True
_______ is a neoplastic proliferation of mature myeloid cells, especially megakaryocytes. It is associated with a ______ mutation
Myelofibrosis; JAK2 kinase
Megakaryocytes produce excess ______ which results in marrow fibrosis. Clinical features include splenomegaly due to _______ ________ resulting in an leukoerythroblastic smear (including nucleated RBCs, small immature leukocytes, etc). These pts are at an increased risk of infection, thrombosis, and bleeding. Since much of the bone marrow is overtaken by fibrosis, _____ cells may be seen on peripheral smear
PDGF; extramedullary hematopoeisis
Teardrop (make this shape when squeezing through narrowed marrow spaces)
In inflammation, enlargement of LNs is due to hyperplasia in certain regions. Which area of the lymph node undergoes hyperplasia in the setting of rheumatoid arthritis and early HIV?
Follicles
In inflammation, enlargement of LNs is due to hyperplasia in certain regions. Which area of the lymph node undergoes hyperplasia in the setting of viral infection?
Paracortex
In inflammation, enlargement of LNs is due to hyperplasia in certain regions. Which area of the lymph node undergoes hyperplasia when it is draining a tissue with cancer?
Sinus histiocytes
Lymphoma is a neoplastic proliferation of lymphoid cells that forms a MASS. It may arise in a LN or in extranodal tissue. Lymphoma can be divided into NHL (60%) and HL (40%). NHLs can be further classified based on cell type, cell size, pattern of growth, expression of surface markers, or cytogenetic translocations. What are the 3 key NHL lymphomas that can affect the cortex of the LN, composed of small well-differentiated B cells?
Follicular lymphoma
Mantle cell lymphoma
Marginal zone lymphoma
Follicular lymphoma is a neoplastic proliferation of small CD____ B cells that make follicle-like nodules. It clinically presents in late adulthood with PAINLESS LAD.
Follicular lymphoma is driven by translocation ________, resulting in ______ translocating to the _______ locus, leading to inhibition of apoptosis
CD20+
t(14;18); BCL2; Ig heavy chain
[BCL2 on chromosome 18 translocates to Ig heavy chain locus on chromosome 14, resulting in overexpression of Bcl2, which inhibits apoptosis]
Patients with follicular lymphoma are typically asymptomatic for long periods of time, and treatment is reserved for patients who are symptomatic. This treatment is low-dose chemotherapy, or _______ which is an anti-CD20 antibody.
The primary complication of follicular lymphoma is progression to __________, which presents as an enlarging LN
Rituximab
Diffuse large B-cell lymphoma
How is follicular lymphoma distinguished from follicular hyperplasia?
Disruption of normal LN architecture
Lack of tingible body macrophages in the germinal center
Expression of Bcl2 in follicles
Monoclonality
[tingible body macrophages are macrophages undergoing apoptosis after clearing cells that have failed somatic hypermutation in healthy LN. Also in normal LNs you would want to turn Bcl2 OFF because you want apoptosis of those cells]
Mantle cell lymphoma is a neoplastic proliferation of small CD____ B cells that expand the mantle zone (the region IMMEDIATELY adjacent to the ______). This clinically presents in late adulthood with PAINLESS LAD.
This tumor is driven by a ______ translocation, in which case _____ translocates to the _______ locus on its respective chromosome
CD20+; follicle
t(11;14); cyclin D1; Ig heavy chain locus
In mantle cell lymphoma, the t(11;14) translocation results in cyclin D1 on chromosome 11 translocating to the Ig heavy chain locus on chromosome 14. The resulting overexpression of cyclin D1 has what effect?
The resulting overexpression of cyclin D1 promotes G1/S transition in the cell cycle
[cyclin D1 phosphorylates regulators required for this transition]
A marginal zone lymphoma is a neoplastic proliferation of small B-cells (again CD20+) that expand the marginal zone, which is the region outside of the _____
Mantle
Of the NHL types follicular, mantle, and marginal, which one is associated with chronic inflammatory states (e.g., Hashimoto’s thyroiditis, Sjogren syndrome, H.pylori gastritis) and is formed by post-germinal center B-cells?
Marginal zone lymphoma
[remember this because the marginal zone is only present when there is inflammation!]
A MALToma is a ______ ______ lymphoma in mucosal sites (e.g., stomach). A gastric MALToma may regress with treatment of H.pylori
Marginal zone
Neoplastic intermediate-sized B cell lymphoma (CD20+) associated with EBV
Burkitt lymphoma
Burkitt lymphoma classically presents as an extranodal mass in a child or young adult. What is the difference in presentation between the African form and the Sporadic form?
African form usually involves the jaw
Sporadic form usually involves the abdomen
Burkitt lymphoma is driven by translocations of nuclear regulator _____ which is present on chromosome 8. The most common translocation is _______, resulting in translocation onto the Ig heavy chain locus. The resulting overexpression promotes cell growth; it is characterized by a high mitotic rate and “starry sky” appearance
c-myc; t(8;14)
Most common form of NHL
DLBCL
Neoplastic large B-cells (CD20+) that grow diffusely in sheets; very clinically aggressive
DLBCL
DLBCLs can arise sporadically or from transformation of ______ lymphoma. It presents in late adulthood as an enlarging LN or extranodal mass.
Follicular
Hodgkins lymphoma is characterized by a neoplastic proliferation of large _____ cells, called Reed-Sternberg cells, which have multilobed nuclei and prominent nucleoli. These cells are positive for ____ and ____
B cells; CD15+; CD30+
[Notice that although these are B cells, they don’t have CD20]
Reed sternberg cells secrete _______, which occasionally results in B symptoms (_____, _____, and _____), attraction of reactive lymphocytes, plasma, cells, macrophages, and eosinophils, and eventually may lead to FIBROSIS
Cytokines
Fevers, chills, night sweats
[note that the bulk of the tumor is actually reactive cells called in by these cytokines, not the reed sternberg cells themselves]
The bulk of Hodgkins lymphomas are made up of reactive inflammatory cells called in by the cytokines secreted by RS cells. This forms the basis for classification. What are the 4 subtypes and which one is most common?
Nodular sclerosis (70% of cases - most common)
Lymphocyte-rich
Mixed cellularity
Lymphocyte-depleted
Subtype of HL that presents with enlarging cervical neck or mediastinal LN in a young female. On biopsy the LN is divided by broad bands of fibrosis and the RS cells are present in lake-like spaces (lacunar cells)
Nodular sclerosis HL
Subtype of HL with the worst prognosis, seen in elderly and HIV+ individuals
Lymphocyte depleted HL
Subtype of HL with the best prognosis
Lymphocyte-rich HL
Subtype of HL associated with abundent eosinophils being called in by IL-5 secreted by RS cells
Mixed cellularity
Most common primary malignancy of bone; characterized by malignant proliferation of plasma cells in bone marrow
Multiple myeloma
In multiple myeloma, high serum _____ is sometimes present, which is an important growth factor for plasma cells
IL-6
In multiple myeloma, neoplastic plasma cells activate the _____ receptor on _________.
This results in lytic ‘punched-out’ lesions seen on x-ray, especially in the ______ and _______. Clinical presentation involves bone pain with hypercalcemia and an increased risk of fracture
RANK; osteoclasts
Vertebrae; skull
In multiple myeloma, plasma cells also produce immunoglobulin, resulting in elevated serum ______.
This results in the finding of ______ on serum protein electrophoresis (SPEP), most commonly due to monoclonal ____, but can also be _____
Protein
M spike; IgG; IgA
[note that M spike does NOT mean IgM]
The most common cause of death in multiple myeloma is infection. Why are pts with multiple myeloma at increased risk of infection if they have such a high production of immunoglobulin?
The monoclonal antibody being produced lacks antigenic diversity
In multiple myeloma, the increased serum protein decreases the charge between RBCs. This change manifests as what finding on blood smear?
Rouleaux formation
Multiple myeloma may result in ______________ due to the free light chain that is circulating in serum depositing in tissues
Primary AL amyloidosis
What effect does multiple myeloma have on the kidney?
Free light chain is excreted in urine as Bence Jones proteins
Deposition in kidney tubules leads to risk for renal failure (myeloma kidney)
An elderly patient’s lab results include increased serum protein with M spike on SPEP. On further investigation, there are no lytic bone lesions, hypercalcemia, AL amyloid, or Bence-Jones proteinuria. What is your diagnosis?
Monoclonal gammopathy of undetermined significance (MGUS)
[Common in the elderly — seen in 5% of 70 year old individuals. Only 1% of pts with MGUS develop multiple myeloma each year]
B-cell lymphoma with monoclonal IgM production that presents with generalized LAD, increased serum protein with M spike composed of IgM, visual and neurologic deficits (e.g., retinal hemorrhage or stroke), and bleeding
Waldenstrom Macroglobulinemia
[called MACROglobulinemia because IgM is a pentamer — very large! Acute complications are treated with plasmapheresis which removes IgM from the serum]
Langerhans cells are specialized dendritic cells found predominantly in the skin. They are derived from bone marrow _______. They function to present antigen to naive T cells.
Monocytes
Langerhans cell histiocytosis is a neoplastic proliferation of Langerhans cells with characteristic ______ granules seen on EM.
Cells are positive for _____ and _____ on immunohistochemistry
Birbeck (tennis racket)
CD1a+; S100+
Malignant proliferation of Langerhans cells in which the classic presentation is skin rash and cystic skeletal defects in an infant <2 years old. Multiple organs may be involved and the disease is rapidly fatal
Letterer-Siwe disease
[2 names = infants <2]
Benign proliferation of Langerhans cells in the bone in which classic presentation is pathologic fracture in an adolescent and the skin is NOT involved. Biopsy shows Langerhans cells with mixed inflammatory cells, including eosinophils
Eosinophilic granuloma
Malignant proliferation of Langerhans cells in which the classic presentation is scalp rash, lytic skin defects, diabetes insipidus, and exophthalmos in a child
Hand-Schuller-Christian disease
[3 names = child >3]
