Pathoma - White Blood Cell Disorders Flashcards
Basic Principles of Leukopenia and Leukocytosis
- Hematopoiesis occurs via a stepwise maturation of CD34+ hematopoietic stem cells
- Cells mature and are released from the bone marrow into the blood
- A normal white blood cell (WBC) count is approximately 5-10K/uL
- LEUKOPENIA = a low WBC count
- LEUKOCYTOSIS = a high WBC count
Neutropenia
Decreased number of circulating neutrophils
Causes of neutropenia
- DRUG TOXICITY (eg chemotherapy with alkylating agents): damage to stem cells results in decreased production of WBCs, especially neutrophils
- SEVERE INFECTION (eg gram negative sepsis): increased movement of neutrophils into tissues results in decreased circulating neutrophils
- As a treatment GM-CSF or G-CSF may be used to boost granulocyte production, thereby decreasing risk of infection in neutropenic
Lymphopenia
Decreased number of circulating lymphocytes
Causes of lymphopenia
- IMMUNODEFICIENCY (eg DiGeorge syndrome or HIV)
- HIGH CORTISOL STATE (eg exogenous corticosteroids or Cushing syndrome): induces apoptosis of lymphocytes
- AUTOIMMUNE DESTRUCTION (eg systemic lupus erythematous)
- WHOLE BODY RADIATION: lymphocytes are highly sensitive to radiation; lymphopenia is the earliest change to emerge after whole body radiation
Neutrophilic leukocytosis
Increased circulating neutrophils
Causes of neutrophilic leukocytosis
- 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 Fc receptors (CD16)
- HIGH CORTISOL STATE: impairs leukocyte adhesion, leading to release of marginated pool of neutrophils
Monocytosis
Refers to increased circulating monocytes
Causes:
- Chronic inflammatory states (eg autoimmune and infectious)
- Malignancy
Eosinophilia
Increased circulating eosinophils. DRIVEN BY INCREASED EOSINOPHIL CHEMOTACTIC FACTOR.
Causes:
- Allergic reactions (type I hypersensitivity)
- Parasitic infections
- Hodgkin lymphoma
Basophilia
Increased circulating basophils
Causes:
- Chronic myeloid leukemia
Lymophocytic leukocytosis
Increased circulating lymphocytes
Causes of lymphocytic leukocytosis
- VIRAL INFECTIONS: T lymphocytes undergo hyperplasia in response to virally infected cells
- BORDATELLA PERTUSSIS INFECTION: bacteria produce lymphocytosis-promoting factor, which blocks circulating lymphocytes from leaving the blood to enter the lymph node
Infectious mononucleosis - Causes
- EBV infection that results in a lymphocytic leukocytosis comprised of reactive CD8+ T cells
- CMV is a less common cause
- EBV is transmitted by saliva (“kissing disease”); classically affects teenagers
Infectious mononucleosis - EBV infection
EBV primarily infects:
- OROPHARYNX, resulting in pharyngitis
- LIVER, resulting in hepatitis with hepatomegaly and elevated liver enzymes
- B CELLS
Infectious mononucleosis - CD8+ T Cell responses leads to
- Generalized lymphadenophathy (LAD) due to T cell hyperplasia in the lymph node PARACORTEX
- Splenomegaly due to T cell hyperplasia in the periarterial lymphatic sheath (PALS)
- High WBC count with atypical lymphocytes (reactive CD8+ T cells) in the blood
Infectious mononucleosis - Monospot test
- Used for screening
- Detects IgM antibodies that cross-react with horse or sheep RBC (HETEROPHILE ANTIBODIES)
- Usually positive within 1 week after infection
- A negative monospot test suggests CMV as a possible cause of infectious mononucleosis
- Definitive diagnosis is made by serologic testing for the EBV viral capsid antigen
Infectious mononucleosis - Complications
- Increased risk for splenic rupture (patients are generally advised to avoid contact sports for one month)
- Rash if exposed to penicillins/ampicillin
- Dormancy of virus in B cells leads to increased risk for both recurrence and B cell lymphoma, especially if immunodeficiency (eg HIV) develops
Acute Leukemia - Basic principles
- Neoplastic proliferation of blasts; defined as the accumulation of >20% blasts in the bone marrow
- Increased blasts “crowd-out” normal hematopoiesis, resulting in an “ACUTE” presentation with ANEMIA (fatigue), THROMBOCYTOPENIA (bleeding), or NEUTROPENIA (infection)
- Blasts usually enter the blood stream, resulting in a HIGH WBC count (blasts are large, immature cells, often with PUNCHED OUT NUCLEOLI)
- Acute leukemia is subdivided into ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) or ACUTE MYELOGENOUS LEUKEMIA (AML) based on the phenotype of the blasts
Acute lymphoblastic leukemia
Neoplastic accumulation of lymphoblasts (>20%) in the bone marrow
- Lymphoblasts are characterized by positive nuclear staining for TdT, a DNA polymerase
- TdT is ABSENT in myeloid blasts and mature lymphocytes
Acute lymphoblastic leukemia - Occurrence
- Most commonly arises in children
- Associated with Down syndrome (usually arises AFTER the age of 5)
Acute lymphoblastic leukemia - Subclassifications
B-ALL and T-ALL → based on SURFACE MARKERS
Acute lymphoblastic leukemia - B-ALL
- Most common type of ALL
- Usually characterized by lymphoblasts (TdT+) that express CD10, CD19 and CD20
- Excellent response to chemotherapy
- Requires prophylaxis to SCROTUM and CSF
- Prognosis is based on cytogenetic abnormalities
- t(12;21) has a GOOD prognosis; more commonly seen in CHILDREN
- t(9;22) has a POOR prognosis; more commonly seen in adults (Philadelphia+ ALL)
Acute lymphoblastic leukemia - T-ALL
- Characterized by lymphoblasts (TdT+) that express markers ranging from CD2 - CD8
- 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
Neoplastic accumulation of immature myeloid cells (>20%) in the bone marrow
Acute myeloid leukemia - Characterization
Usually characterized by positive staining for MYEOPEROXIDASE (MPO)
- Crystal aggregates of MPO may be seen as AUER RODS
Acute myeloid leukemia - Occurrence
Most commonly arises in older adults (average age 50-60 years)
Acute myeloid leukemia - Subtypes
- Acute promyelocytic leukemia (APL)
- Acute monocytic leukemia
- Acute megakaryoblastic leukemia
Acute myeloid leukemia - Acute promyelocytic 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
- Abnormal promyelocytes contain numerous primary granules that increase risk for DIC
- 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 myeloid leukemia - Acute monocytic leukemia
- Proliferation of monoblasts
- Usually lack MPO
- Blasts characteristically infiltrate GUMS
Acute myeloid leukemia - Acute megakaryoblastic leukemia
- Proliferation of megakaryoblasts
- Usually lack MPO
- Associated with DOWN SYNDROME (usually arises BEFORE the age of 5)
Acute myeloid leukemia arising from pre-existing dysplasia
- AML may arise from pre-existing dysplasia (MYELODYSPLASTIC SYNDROMES) especially with prior exposure to alkylating agents or radiotherapy
- Myelodysplastic syndromes usually present with CYTOPENIAS, HYPERCELLULAR BONE MARROW, ABNORMAL MATURATION OF CELLS, and INCREASED BLASTS (>20%)
- Most patients die from INFECTION or BLEEDING, though some progress to acute leukemia
Chronic Leukemia - Basic Principles
- Neoplastic proliferation of mature circulating lymphocytes
- Characterized by a HIGH WBC count
- Usually insidious in onset and seen in older adults
Includes:
- Chronic lymphocytic leukemia (CLL)
- Hairy cell leukemia
- Adult T cell leukemia/lymphoma (ATLL)
- Mycosis fungoides
Chronic lymphocytic leukemia
- Neoplastic proliferation of naïve B cells that co-express CD5 and CD20 → MOST COMMON LEUKEMIA
- Increased lymphocytes and SMUDGE CELLS are seen on blood smear
- Involvement of lymph nodes leads to generalized lymphadenopathy and is called SMALL LYMPHOCYTIC LYMPHOMA
Complications:
- HYPOGAMMAGLOBULINEMIA - infection is the most common cause of death in CLL
- Autoimmune hemolytic anemia
- Transformation of 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
- Cells are positive for TARTRATE-RESISTANT ACID PHOSPHATASE (TRAP)
- 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
- Excellent response to 2-CDA (cladribine) an adenosine deaminase inhibitor (adenosine accumulates to toxic levels in neoplastic B cells)
Adult T cell leukemia/lymphoma
- Neoplastic proliferation of mature CD4+ T cells
- Associated with HTLV-1 (most commonly seen in Japan and Carribbean)
- 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
- Cells can spread to involve the blood, producing SEZARY SYNDROME (characteristic lymphocytes with cerebriform nuclei - Sezary cells - are seen on blood smear)
Myeloproliferative Disorders - Basic Principles
- Neoplastic proliferation of mature cells of myeloid lineage
- Disease of LATE adulthood (avg age is 50-60 years old)
- Results in HIGH WBC count with hypercellular bone marrow (cells of all myeloid lineages are increased, CLASSIFIED BASED ON THE DOMINANT MYELOID CELL PRODUCED)
- Complications include: increased risk for HYPERURICEMIA and GOUT due to high turnover of cells; progression to BONE MARROW FIBROSIS or transformation to ACUTE LEUKEMIA
Includes:
- Chronic myeloid leukemia (CML)
- Polycythemia vera (PV)
- Essential thrombocythemia (ET)
- Myelofibrosis
Chronic myeloid leukemia
- Neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors
- BASOPHILS are characteristically increased
Chronic myeloid leukemia - Cause
- Driven by t(9;22) (Philadelphia chromosome) which generates a BCR-ABL fusion protein with INCREASED TYROSINE KINASE activity
- First line treatment is IMANTIB, which blocks tyrosine kinase acitivity
Chronic myeloid leukemia - Symptoms
- SPLENOMEGALY is common
- Enlargening spleen suggests progression to accelerated phase of disease → transformation to acute leukemia usually follows shortly thereafter
- Can transform to AML (2/3 of cases) or ALL (1/3 of cases) since MUTATION IS IN PLURIPOTENT STEM CELL
Chronic myeloid leukemia vs Leukomoid reaction (reactive neutrophilic leukocytosis)
- Negative leukocyte alkaline phosphatase (LAP) stain (granulocytes in a leukomoid reaction are LAP positive)
- Increased basophils (absent with leukemoid reaction)
- t(9;22) (absent in leukomoid reaction)
Polycythemia vera
- Neoplastic proliferation of mature myeloid cells, ESPECIALLY RBCs
- Granulocytes and platelets are also increased
Polycythemia vera - Cause
Associated with a JAK2 kinase mutation
Polycythemia vera - Symptoms
- Mostly due to the HYPERVISCOSITY of blood
- Blurry vision and headache
- Increased venous thrombosis (eg hepatic vein, portal vein, and dural sinus)
- Flushed face due to congestion (plethora)
- Itching, especially after bathing (due to histamine release from increased mast cells)
Polycythemia vera - Treatment
- First line: phlebotomy
- Second line: hydroxyurea
- Without treatment, death usually occurs within one year
Polycythemia vera vs Reactive polycythemia
- In PV, erythropoietic (EPO) levels are decreased and saturation of O2 is normal
- In reactive polycythemia due to high altitude or lung disease, saturation of O2 is low and EPO is increased
- In reactive polycythemia due to ectopic EPO production from renal cell carcinoma, EPO is high and saturation of O2 is normal
Essential thrombocytopenia
- Neoplastic proliferation of mature myeloid cells, especially PLATELETS
- RBCs and granulocytes are also increased
Essential thrombocytopenia - Cause
Associated with JAK2 kinase mutation
Essential thrombocytopenia - Symptoms
- Associated with increased risk of bleeding and/or thrombosis
- Rarely progresses to marrow fibrosis or acute leukemia
- No significant risk for hyperuricemia or gout
Myelofibrosis
Neoplastic proliferation of mature myeloid cell, especially megakaryocytes
Myelofibrosis - Cause
- Associated with JAK2 kinase mutation in 50% of cases
- Megakaryocytes produce excess PLATELET DERIVED GROWTH FACTOR (PDGF) causing bone marrow fibrosis
Myelofibrosis - Symptoms
- SPLENOMEGALY due to extramedullary hematopoiesis
- LEUKOERYTHROBLASTIC SMEAR (tear drop RBCs, nucleated RBCs and immature granulocytes)
- Increased risk for infection, thrombosis, and bleeding
Lymphadenopathy - Basic Principles
- Refers to enlarged lymph nodes
- PAINFUL LAD is usually seen in lymph nodes that are draining a region of ACUTE infection (ACUTE LYMPHADENITIS)
- PAINLESS LAD is usually seen with CHRONIC inflammation (CHRONIC LYMPHADENITIS), METASTATIC CARCINOMA or LYMPHOMA
Lymphadenopathy - Inflammation
- FOLLICULAR HYPERPLASIA (B cell region) is seen with rheumatoid arthritis and early stages of HIV infection, for example
- PARACORTEX HYPERPLASIA (T cell region) is seen with viral infections (eg infectious mononucleosis)
- HYPERPLASIA OF SINUS HISTIOCYTES is seen in lymph nodes that are draining tissue with cancer
Lymphoma - Basic Principles
- Neoplastic proliferation of lymphoid cells that forms a mass
- May arise in a lymph node or in extranodal tissue
- Divided into non-Hodgkin lymphoma (NHL, 60%) and Hodgkin lymphoma (HL, 40%)
NHL is further classified based on cell type, cell size, pattern of cell growth, expression of surface markers, and cytogenetic translocations:
- Small B cells: follicular lymphoma, mantle cell lymphoma (eg CLL cells that involve tissue)
- Intermediate sized B cells: Burkitt lymphoma
- Large B cells: diffuse large B cell lymphoma
Follicular Lymphoma
- Neoplastic proliferation of small B cells (CD20+) that form follicle-like nodules
- Presents in late adulthood with painless lymphadenopathy
Follicular Lymphoma - Causes
- Driven by t(14;18)
- BCL2 on chromosome 18 translocates to the Ig heavy chain locus on chromosome 14
- Results in overexpression of Bcl2, which inhibits apoptosis
Follicular Lymphoma - Treatment
Treatment is reserved for patients who are symptomatic and involves low dose chemotherapy or RITUXIMAB (anti-CD20 antibody)
Follicular lymphoma - Complications
Progression to diffuse large B cell lymphoma is an important complication; presents as an enlarging lymph node
Follicular lymphoma vs Follicular hyperplasia
Follicular lymphoma is distinguished from reactive follicular hyperplasia by
- Disruption of normal lymph node architecture (maintained in follicular hyperplasia)
- Lack of tangible body macrophages in germinal centers (tangible body macrophages are present in follicular hyperplasia)
- Bcl2 expression in follicles (not expressed in follicular hyperplasia)
- Monoclonality (follicular hyperplasia is polyclonal)
Mantle cell lymphoma
- Neoplastic proliferation of small B cells (CD20+) that expands the marginal zone
- Associated with chronic inflammatory states such as Hashimoto’s thyroiditis, Sjogren syndrome and H pylori gastritis (the marginal zone is formed by post-germinal center B cells)
- MALToma is marginal zone lymphoma in mucosal sites (Gastric MALToma may regress with treatment of H pylori)
Burkitt lymphoma
- Neoplastic proliferation of intermediate sized B cells (CD20+)
- Associated with EBV
- Classically presents as an extranodal mass in a child or young adult
- African form usually involves the JAW
- Sporadic form usually involves the ABDOMEN
Burkitt lymphoma - Cause
- Driven by translocations of c-myc (chromosome 8)
- t(8;14) is most common, resulting in translocation of c-myc to the Ig heavy chain locus on chromosome 14
- Overexpression of c-myc oncogene promotes cell growth
Burkitt lymphoma - Characterization
Characterized by high mitotic index and ‘starry-sky’ appearance on microscopy
Diffuse large B cell lymphoma
- Neoplastic proliferation of large B cells (CD20+) that grow diffusely in sheets
- MOST COMMON FORM OF NHL
- Clinically aggressive (high grade)
- Arises sporadically or from transformation of a low grade lymphoma
- Present in late adulthood as an enlarging lymph node or an extranodal mass
Hodgkin Lymphoma - Basic principles
- Neoplastic proliferation of Reed-Sternberg (RS) cells which are large B cells with multilobed nuclei and prominent nucleoli (owl-eyed nuclei)
- Classically positive for CD15 and CD30
Hodgkin Lymphoma - Reed-Sternberg cells
RS cells secrete cytokines:
- Occasionally result in B symptoms (fever, chills, weight loss and night sweats)
- Attract reactive lymphocytes, plasma cells, macrophages, and eosinophils
- May lead to fibrosis
Hodgkin lymphoma - Subtypes
Reactive inflammatory cells make up a bulk of the tumor and form the basis for classification of HL. Subtypes include:
- Nodcular sclerosis
- Lymphocyte rich
- Mixed cellularity
- Lymphocyte depleted
Hodgkin lymphoma - Nodular sclerosis
- MOST COMMON SUBTYPE OF HL (70% of all cases)
- Classic presentation is an enlarging cervical or mediastinal lymph node in a young adult, usually female
- Lymph node is divided by bands of sclerosis
- RS cells are present in lake-like spaces (lacunar cells)
Hodgkin lymphoma - Other subtypes
- Lymphocyte rich has the best prognosis of all types
- Mixed cellularity is often associated with abundance eosinophils (RS cells produce IL-5)
- Lymphocyte-depleted is the most aggressive of all types; usually seen in the elderly and HIV positive individuals
Mutltiple myeloma
Malignant proliferation of plasma cells in the bone marrow
- Most common primary malignancy of bone (metastatic cancer, however, is the most common malignant lesion of the bone overall)
- High serum IL-6 may be present; stimulates plasma cell growth and immunoglobulin production
Multiple myeloma - Symptoms
- 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, especially in the vertebrae and skull
- Increased risk for fracture
- 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
- INCREASED RISK FOR INFECTION: monoclonal antibody lacks antigenic diversity; infection is the most common cause of death in multiple myeloma
- ROULEAUX FORMATION OF RBC ON BLOOD SMEAR: increased serum protein decreases charge between RBCs
- PRIMARY AL AMYLOIDOSIS: free light chains circulate in serum and deposit in tissues
- 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)
- Increased serum protein with M spike on SPEP
- Other features of multiple myeloma are absent (eg no lytic bone lesions, hypercalcemia, AL amyloid, or Bence Jones proteinuria)
- Commonly seen in elderly (seen in 5% of 70 year old individuals)
- 1% of patients with MGUS develop multiple myeloma each year
Waldenstrom Macroglobulinemia
- B cell lymphoma with monoclonal IgM production
- Acute complications are treated with plasmapharesis, which removes IgM from the serum
Clinical features include:
- Generalized lymphadenopathy; lytic bone lesions are absent
- Increased serum protein with M spike (compromised IgM)
- Visual and neurologic deficits (eg retinal hemorrhage or stroke) - IgM (large pentamer) causes serum hyperviscosity
- Bleeding: viscous serum results in defective platelet aggregation
Langerhans cell histiocytes - Basic principles
Langerhans cells are specialized dendritic cells found predominantly in the skin
- Derived from bone marrow monocytes
- Present antigen to naïve T cell
Langerhans cell histiocytosis is a neoplastic proliferation of Langerhans cells
- Characteristic Birbeck (tennis racket) granules are seen on electron microscopy
- Cells are CD1a+ and S100+ by immunohistochemistry
Letterer-SIWE disease
- Malignant proliferation of Langerhans cells
- Classic presentation is skin rash and cystic skeletal defects in an infant (
Eosinophilic granuloma
- Benign proliferation of Langerhans cells in bone
- Classic presentation is pathologic fracture in an adolescent; skin is not involved
- Biopsy shows Langerhans cells with mixed inflammatory cells, including numerous eosinophils
Hand-Schuller-Christian disease
- Malignant proliferation of Langerhans cells
- Classic presentation is scalp rash, lytic skull defects, diabetes insipidus, and exophthalmos in a child
EXOPHTHALMOS = abnormal protrusion of the eyeball(s)
