WBC Disorders Flashcards
Leukopenia and leukocytosis basic principles
A. Hematopoiesis occurs via a stepwise maturation of CD34+ hematopoietic stem cells
(Fig. 6.1). B. Cells mature and are released from the bone marrow into the blood. C. A normal white blood cell (WBC) count is approximately 5-10 K/µL.
1. A low WBC count(< 5 K) is called leukopenia. 2. A high WBC count (> 10 K) is called leukocytosis. 3. A low or high WBC count is usually due to a decrease or increase in one
particular cell lineage.
Leukopenia: neutropenia and causes
Neutropenia refers to a decreased number of circulating neutrophils. Causes include
1. Drug toxicity (e.g., chemotherapy with alkylating agents) - Damage to stem cells
results in decreased production of WBCs, especially neutrophils. 2. Severe infection (e.g., gram-negative sepsis) - Increased movement of
neutrophils into tissues results in decreased circulating neutrophils. 3. As a treatment, GM-CSF or G-CSF may be used to boost granulocyte production,
thereby decreasing risk of infection in neutropenic patients.
Leukopenia: lymphopenia and causes
Lymphopenia refers to a decreased number of circulating lymphocytes. Causes
include
1. Immunodeficiency (e.g., DiGeorge syndrome or HIV) 2. High cortisol state (e.g., exogenous corticosteroids or Cushing syndrome)-
induces apoptosis of lymphocytes 3. Autoimmune destruction (e.g., systemic lupus erythematosus) 4. Whole body radiation - Lymphocytes are highly sensitive to radiation;
lymphopenia is the earliest change to emerge after whole body radiation.
Leukocytosis: Neutrophilic
A. Neutrophilic leukocytosis refers to increased circulating neutrophils. Causes include
1. Bacterial infection or tissue necrosis - induces release of marginated pool and
bone marrow neutrophils, including immature forms (left shift); immature cells
are characterized by decreased Fe receptors (CD16).
2. High cortisol state - impairs leukocyte adhesion, leading to release of
marginated pool of neutrophils
Monocytosis
Monocytosis refers to increased circulating monocytes. Causes include chronic
inflammatory states (e.g., autoimmune and infectious) and malignancy.
Eosinophilia
Eosinophilia refers to increased circulating eosinophils. Causes include allergic
reactions (type I hypersensitivity), parasitic infections, and Hodgkin lymphoma.
Eosinophilia is driven by increased eosinophil chemotactic factor.
Basophilia
Basophilia refers to increased circulating basophils; classically seen in chronic
myeloid leukemia
Lymphocytic leukocytosis
E. Lymphocytic leukocytosis refers to increased circulating lymphocytes. Causes
include
1. Viral infections - T lymphocytes undergo hyperplasia in response to virally
infected cells. 2. Bordete lla pertussis infection - Bacteria produce lymphocytosis-promoting
factor, which blocks circulating lymphocytes from leaving the blood to enter the
lymph node.
INFECTIOUS MONONUCLEOSIS (IM)
EBV infection that results in a lymphocytic leukocytosis comprised of reactive CD8+
T cells; CMV is a less common cause.
1. EBV is transmitted by saliva (“kissing disease”); classically affects teenagers
B. EBV primarily infects
1. Oropharynx, resulting in pharyngitis
2. Liver, resulting in hepatitis with hepatomegaly and elevated liver enzymes
3. B cells C. CD8+ T-cell response leads to
1. Generalized lymphadenopathy (LAD) due to T-cell hyperplasia in the lymph node
paracortex 2. Splenomegaly due to T-cell hyperplasia in the periarterial lymphatic sheath
(PALS) 3. High WBC count with atypical lymphocytes (reactive CD8+ T cells) in the blood
(Fig. 6.2)
Testing for Mono
D. The monospot test is used for screening.
1. Detects IgM antibodies that cross-react with horse or sheep red blood cells
(heterophile antibodies) 2. Usually turns positive within 1 week after infection 3. A negative monospot test suggests CMV as a possible cause of IM. 4. Definitive diagnosis is made by serologic testing for the EBV viral capsid antigen.
Complications of mono
E. Complications
1. Increased risk for splenic rupture (Fig. 6.3); patients are generally advised to
avoid contact sports for one month. 2. Rash if exposed to ampicillin 3. Dormancy of virus in B cells leads to increased risk for both recurrence and
B-cell lymphoma, especially if immunodeficiency (e.g., HIV) develops.
Acute Leukemia basics
A. Neoplastic proliferation of blasts; defined as the accumulation of > 20% blasts in the bone marrow.
B. Increased blasts “crowd-out” normal hematopoiesis, resulting in an “acute”
presentation with anemia (fatigue), thrombocytopenia (bleeding), or neutropenia
(infection).
C. Blasts usually enter the blood stream, resulting in a high WBC count.
1. Blasts are large, immature cells, often with punched out nucleoli
D. Acute leukemia is subdivided into acute lymphoblastic leukemia (ALL) or acute
myelogenous leukemia (AML) based on the phenotype of the blasts.
ACUTE LYMPHOBLASTIC LEUKEMIA
A. Neoplastic accumulation of lymphoblasts ( > 20%) in the bone marrow
1. Lymphoblasts are characterized by positive nuclear staining for TdT, a DNA
polymerase. 2. TdT is absent in myeloid blasts and mature lymphocytes.
B. Most commonly arises in children; associated with Down syndrome (usually arises
after the age of 5 years)
C. Subclassified into B-ALL and T-ALL based on surface markers
B-ALL
B-ALL is the most common type of ALL.
1. Usually characterized by lymphoblasts (TdT+) that express CD10, CD19, and
CD20. 2. Excellent response to chemotherapy; requires prophylaxis to scrotum and CSF
(Fig. 6.5) 3. Prognosis is based on cytogenetic abnormalities.
i. t(12;21) has a good prognosis; more commonly seen in children
ii. t(9;22) has a poor prognosis; more commonly seen in adults (Philadelphia+
ALL)
T-ALL
T-ALL is characterized by lymphoblasts (TdT+) that express markers ranging from
CD2 to CD8 (e.g., CD3, CD4, CD7). The blasts do not express CD10.
Usually presents in teenagers as a mediastinal (thymic) mass (called acute
lymphoblastic lymphoma because the malignant cells form a mass)
ACUTE MYELOID LEUKEMIA
A. Neoplastic accumulation of immature myeloid cells (> 20%) in the bone marrow
B. Myeloblasts are usually characterized by positive cytoplasmic staining for
myeloperoxidase (MPO). 1. Crystal aggregates of MPO may be seen as Auer rods (Fig. 6.6).
C. Most commonly arises in older adults (average age is 50-60 years)
D. Subclassification based on cytogenetic abnormalities, lineage of immature myeloid
cells, and surface markers.
AML may also arise from pre-existing dysplasia (myelodysplastic syndromes),
especially with prior exposure to alkylating agents or radiotherapy.
1. Myelodysplastic syndromes usually present with cytopenias, hypercellular bone
marrow, abnormal maturation of cells, and increased blasts(< 20%). 2. Most patients die from infection or bleeding, though some progress to acute
leukemia.
Acute promyelocytic leukemia (APL)
Acute myeloid leukemia
Characterized by t(15;17), which involves translocation of the retinoic acid
receptor (RAR) on chromosome 17 to chromosome 15; RAR disruption blocks maturation and promyelocytes (blasts) accumulate.
ii. Abnormal promyelocytes contain numerous primary granules that increase
the risk for DIC. iii. Treatment is with all-trans-retinoic acid (ATRA, a vitamin A derivative),
which binds the altered receptor and causes the blasts to mature (and
eventually die).
Acute monocytic leukemia
Acute myeloid leukemia
i. Proliferation of monoblasts; usually lack MPO
ii. Blasts characteristically infiltrate gums (Fig. 6.7).
Acute megakaryoblastic leukemia
Acute Myeloid leukemia
i. Proliferation of megakaryoblasts; lack MPO
ii. Associated with Down syndrome (usually arises before the age of 5)
Chronic Leukemia- basics
A. Neoplastic proliferation of mature circulating lymphocytes; characterized by a high
WBC count
B. Usually insidious in onset and seen in older adults
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
A. Neoplastic proliferation of naïve B cells that co-express CD5 and CD20; most common leukemia overall
B. Increased lymphocytes and smudge cells are seen on blood smear (Fig. 6.8).
C. Involvement of lymph nodes leads to generalized lymphadenopathy and is called small lymphocytic lymphoma.
D. Complications include
1. Hypogammaglobulinemia - Infection is the most common cause of death in CLL.
2. Autoimmune hemolytic anemia
3. Transformation to diffuse large B-cell lymphoma (Richter transformation) - marked clinically by an enlarging lymph node or spleen
HAIRY CELL LEUKEMIA
Neoplastic proliferation of mature B cells characterized by hairy cytoplasmic
processes (Fig. 6.9)
B. Cells are positive for tartrate-resistant acid phosphatase (TRAP).
C. Clinical features include splenomegaly (due to accumulation of hairy cells in red pulp) and “dry tap” on bone marrow aspiration (due to marrow fibrosis). Lymphadenopathy is usually absent.
D. Excellent response to 2-CDA (cladribine), an adenosine deaminase inhibitor;
adenosine accumulates to toxic levels in neoplastic B cells.
ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL)
A. Neoplastic proliferation of mature CD4 + T cells
B. Associated with HTLV-1; most commonly seen in Japan and the Caribbean
C. Clinical features include rash (skin infiltration), generalized lymphadenopathy
with hepatosplenomegaly, and lytic (punched-out) bone lesions with hypercalcemia.
MYCOSIS FUNGOIDES
Neoplastic proliferation of mature CD4+ T cells that infiltrate the skin, producing
localized skin rash, plaques, and nodules. Aggregates of neoplastic cells in the
epidermis are called Pautrier microabscesses. B. Cells can spread to involve the blood, producing Sezary syndrome.
1. Characteristic lymphocytes with cerebriform nuclei (Sezary cells) are seen on
blood smear (Fig. 6.10).
Myeloproliferative Disorders (MPD)- basics
A. Neoplastic proliferation of mature cells of myeloid lineage; disease of late adulthood
(average age is 50-60 years)
B. Results in high WBC count with hypercellular bone marrow
1. Cells of all myeloid lineages are increased; classified based on the dominant myeloid cell produced
C. Complications include
1. Increased risk for hyperuricemia and gout due to high turnover of cells 2. Progression to marrow fibrosis or transformation to acute leukemia
CHRONIC MYELOID LEUKEMIA (CML)
A. Neoplastic proliferation of mature myeloid cells, especially granulocytes and their
precursors; basophils are characteristically increased (Fig. 6.11).
B. Driven by t(9;22) (Philadelphia chromosome) which generates a BCR-ABL fusion
protein with increased tyrosine kinase activity.
1. First line treatment is imatinib, which blocks tyrosine kinase activity.
C. Splenomegaly is common. Enlarging spleen suggests progression to accelerated phase
of disease; transformation to acute leukemia usually follows shortly thereafter.
1. Can transform to AML (2/3 of cases) or ALL (1/3 of cases) since mutation is in a pluripotent stem cell.
D. CML is distinguished from a leukemoid reaction (reactive neutrophilic leukocytosis)
by 1. Negative leukocyte alkaline phosphatase (LAP) stain (granulocytes in a
leukemoid reaction are LAP positive) 2. Increased basophils (absent with leukemoid reaction) 3. t(9;22) (absent in leukemoid reaction)
POLYCYTHEMIA VERA (PV)
A. Neoplastic proliferation of mature myeloid cells, especially RBCs
1. Granulocytes and platelets are also increased.
B. Associated with JAK2 kinase mutation
C. Clinical symptoms are mostly due to hyperviscosity of blood.
1. 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)
D. Treatment is phlebotomy; second-line therapy is hydroxyurea.
1. Without treatment, death usually occurs within one year.
E. PV must be distinguished from reactive polycythemia.
1. In PV, erythropoietin (EPO) levels are decreased, and Sao2 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.
ESSENTIAL THROMBOCYTHEMIA (ET)
A. Neoplastic proliferation of mature myeloid cells, especially platelets (Fig. 6.12)
1. RBCs and granulocytes are also increased.
B. Associated with JAK2 kinase mutation
C. Symptoms are related to an increased risk of bleeding and/or thrombosis.
1. Rarely progresses to marrow fibrosis or acute leukemia
2. No significant risk for hyperuricemia or gout
MYELOFIBROSIS
Neoplastic proliferation of mature myeloid cells, especially megakaryocytes
1. Associated with JAK2 kinase mutation (50% of cases)
B. Megakaryocytes produce excess platelet-derived growth factor (PDGF) causing
marrow fibrosis (Fig. 6.13).
C. Clinical features include
1. Splenomegaly due to extramedullary hematopoiesis
2. Leukoerythroblastic smear (tear-drop RBCs, nucleated RBCs, and immature
granulocytes, Fig. 6.14) 3. Increased risk of infection, thrombosis, and bleeding
Lymphadenopathy- basics
A. LAD refers to enlarged lymph nodes.
1. Painful LAD is usually seen in lymph nodes that are draining a region of acute
infection (acute lymphadenitis). 2. Painless LAD can be seen with chronic inflammation (chronic lymphadenitis),
metastatic carcinoma, or lymphoma.
B. In inflammation, lymph node enlargement is due to hyperplasia of particular
regions of the lymph node (Fig. 6.15).
1. Follicular hyperplasia (B-cell region) is seen with rheumatoid arthritis and early
stages of HIV infection, for example.
2. Paracortex hyperplasia (T-cell region) is seen with viral infections (e.g.,
infectious mononucleosis). 3. Hyperplasia of sinus histiocytes is seen in lymph nodes that are draining a tissue
with cancer.
LYMPHOMA
basics
A. Neoplastic proliferation of lymphoid cells that forms a mass; may arise in a lymph
node or in extranodal tissue B. Divided into non-Hodgkin lymphoma (NHL, 60%) and Hodgkin lymphoma (HL,
40%) (Table 6.1) C. NHL is further classified based on cell type (e.g., B versus T), cell size, pattern of cell
growth, expression of surface markers, and cytogenetic translocations.
1. Small B cells - follicular lymphoma, mantle cell lymphoma, marginal zone
lymphoma, and small lymphocytic lymphoma (i.e., CLL cells that involve tissue) 2. Intermediate-sized B cells - Burkitt lymphoma 3. Large B cells - diffuse large B-cell lymphoma
Non Hodgkin vs Hodgkin Lymphoma
FOLLICULAR LYMPHOMA
A. Neoplastic proliferation of small B cells (CD20+) that form follicle-like nodules (Fig.
6.16A)
B. Presents in late adulthood with painless lymphadenopathy
C. Driven by t(14;18)
1. BCL2 on chromosome 18 translocates to the Ig heavy chain locus on
chromosome 14. 2. Results in overexpression of Bcl2, which inhibits apoptosis
D. Treatment is reserved for patients who are symptomatic and involves low-dose
chemotherapy or rituximab (anti-CD20 antibody).
E. Progression to diffuse large B-cell lymphoma is an important complication; presents
as an enlarging lymph node
F. Follicular lymphoma is distinguished from reactive follicular hyperplasia by
1. Disruption of normal lymph node architecture (maintained in follicular
hyperplasia) 2. Lack of tingible body macrophages in germinal centers (tingible body
macrophages are present in follicular hyperplasia, Fig. 6.16B,C) 3. Bcl2 expression in follicles (not expressed in follicular hyperplasia) 4. Monoclonality (follicular hyperplasia is polyclonal)
MANTLE CELL LYMPHOMA
A. Neoplastic proliferation of small B cells (CD20+) that expands the mantle zone
B. Presents in late adulthood with painless lymphadenopathy
C. Driven by t(11;14)
1. Cyclin D1 gene on chromosome 11 translocates to Ig heavy chain locus on
chromosome 14. 2. Overexpression of cyclin D1 promotes G1/S transition in the cell cycle,
facilitating neoplastic proliferation.
MARGINAL ZONE LYMPHOMA
A. Neoplastic proliferation of small B cells (CD20+) that expands the marginal zone
B. Associated with chronic inflammatory states such as Hashimoto thyroiditis, Sjögren
syndrome, and H pylori gastritis
1. The marginal zone is formed by post-germinal center B cells.
C. MALToma is marginal zone lymphoma in mucosal sites.
1. Gastric MAL Toma may regress with treatment of H Pylori.
BURKITT LYMPHOMA
A. Neoplastic proliferation of intermediate-sized B cells (CD20+); associated with EBY
B. Classically presents as an extranodal mass in a child or young adult
1. African form usually involves the jaw (Fig. 6.17A). 2. Sporadic form usually involves the abdomen.
C. Driven by translocations of c-myc (chromosome 8)
1. t(8;14) is most common, resulting in translocation o f c-myc to the Ig heavy chain
locus on chromosome 14. 2. Overexpression o f c-myc oncogene promotes cell growth.
D. Characterized by high mitotic index and ‘starry-sky’ appearance on microscopy (Fig.
6.17B)
DIFFUSE LARGE B-CELL LYMPHOMA
A. Neoplastic proliferation of large B cells (CD20 +) that grow diffusely in sheets
1. Most common form of NHL 2. Clinically aggressive (high-grade)
B. Arises sporadically or from transformation o f a low-grade lymphoma (e.g., follicular
lymphoma) 1. Presents in late adulthood as an enlarging lymph node or an extranodal mass
HODGKIN LYMPHOMA (HL)
- basics
A. Neoplastic proliferation of Reed-Sternberg (RS) cells, which are large B cells with multilobed nuclei and prominent nucleoli (‘owl-eyed nuclei’, Fig. 6.18); classically positive for CD15 and CD30
B. RS cells secrete cytokines.
1. Occasionally results in ‘B’ symptoms (fever, chills, weight loss, and night sweats) 2. Attract reactive lymphocytes, plasma cells, macrophages, and eosinophils 3. May lead to fibrosis
C. Reactive inflammatory cells make up a bulk of the tumor and form the basis for
classification of HL. Subtypes include 1. Nodular sclerosis 2. Lymphocyte-rich 3. Mixed cellularity 4. Lymphocyte-depleted
D. Nodular sclerosis is the most common subtype of HL (70% o f all cases).
1. Classic presentation is an enlarging cervical or mediastinal lymph node in a
young adult, usually female. 2. Lymph node is divided by bands of sclerosis (Fig. 6.19A); RS cells are present in
lake-like spaces (lacunar cells, Fig. 6.19B).
E. Important considerations regarding other subtypes o f HL 1. Lymphocyte-rich has the best prognosis of all types.
2. Mixed cellularity is often associated with abundant eosinophils (RS cells produce
IL-5). 3. Lymphocyte-depleted is the most aggressive of all types; usually seen in the
elderly and HIV-positive individuals
MULTIPLE MYELOMA
A. Malignant proliferation of plasma cells in the bone marrow
1. Most common primary malignancy of bone; metastatic cancer, however, is the
most common malignant lesion of bone overall. 2. High serum IL-6 may be present; stimulates plasma cell growth and
immunoglobulin production
B. Clinical features include
1. Bone pain with hypercalcemia - Neoplastic plasma cells activate the RANK
receptor on osteoclasts, leading to bone destruction. Lytic, ‘punched-out’ skeletal lesions are seen on x-ray (Fig. 6.20A), especially in the vertebrae and skull; increased risk for fracture
2. Elevated serum protein - Neoplastic plasma cells produce immunoglobulin; M
spike is present on serum protein electrophoresis (SPEP), most commonly due to monoclonal IgG or IgA.
3. Increased risk of infection - Monoclonal antibody lacks antigenic diversity;
infection is the most common cause of death in multiple myeloma. 4. Rouleaux formation of RBCs on blood smear - Increased serum protein
decreases charge between RBCs (Fig. 6.20B). 5. Primary AL amyloidosis - Free light chains circulate in serum and deposit in
tissues. 6. Proteinuria - Free light chain is excreted in the urine as Bence Jones protein;
deposition in kidney tubules leads to risk for renal failure (myeloma kidney).
MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)
A. Increased serum protein with M spike on SPEP; other features of multiple myeloma
are absent (e.g., no lytic bone lesions, hypercalcemia, AL amyloid, or Bence Jones proteinuria).
B. Common in elderly (seen in 5% of 70-year-old individuals); 1 % of patients with
MGUS develop multiple myeloma each year.
WALD ENSTRÖM MACROGLOBULINEMIA
A. B-cell lymphoma with monoclonal IgM production
B. Clinical features include
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 - Viscous serum results in defective platelet aggregation.
C. Acute complications are treated with plasmapheresis, which removes IgM from the
serum.
LANGERHANS CELL HISTIOCYTOSIS
basics
A. Langerhans cells are specialized dendritic cells found predominantly in the skin.
1. Derived from bone marrow monocytes 2. Present antigen to naïve T cells
B. Langerhans cell histiocytosis is a neoplastic proliferation of Langerhans cells.
1. Characteristic Birbeck (tennis racket) granules are seen on electron microscopy
(Fig. 6.21); cells are CD1a+ and S-100+ by immunohistochemistry.
LETTERER-SIWE DISEASE
A. Malignant proliferation of Langerhans cells
B. Classic presentation is skin rash and cystic skeletal defects in an infant ( < 2 years old).
C. Multiple organs may be involved; rapidly fatal
EOSINOPHILIC GRANULOMA
A. Benign proliferation of Langerhans cells in bone
B. Classic presentation is pathologic fracture in an adolescent; skin is not involved.
C. Biopsy shows Langerhans cells with mixed inflammatory cells, including numerous
eosinophils.
HAND-SCHÜLLER-CHRISTIAN DISEASE
A. Malignant proliferation of Langerhans cells
B. Classic presentation is scalp rash, lytic skull defects, diabetes insipidus, and
exophthalmos in a child.
