Pathoma 6- White Blood Cell Disorders

Acute Monocytic Leukemia

(Subclassification of Acute Myeloid Leukemia) Proliferation of monoblasts; usually lack Myeloperoxidase Blasts characteristically infiltrate gums

Chronic Myeloid Leukemia is distinguished from a leukemoid reaction by

(a leukemoid reaction is a reactive neutrophilic leukicytosis) 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)

Acute myeloid leukemia 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 blast (<20%) 2. Most patients die from infection or bleeding, though some progress to acute leukemia

Acute megakaryoblastic leukemia

(subclassification of acute myeloid leukemia) Proliferation of megakarylblasts; lack MPO Associated with Down syndrome (usually arises before the age of 5)

Infectious Mononucleosis Complications

1. Increased risk for splenic rupture; patients are generally advised to avoid contact sports for one month 2. Rash if exposed to ampicillin 3. Dormancy of virus in B cells lead to increased risk for both recurrence and B-cell lymphoma, especially if immunodeficiency (e.g. HIV) develops

Leukocyte count

A normal white blood cell (WBC) count is approximately 5-10 K/mcL 1. A low WBC count (< 5K) 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

Burkitt Lymphoma Forms

African form usually involves the jaw Sporadic form usually involves the abdomen

Waldenstrom Macroglobulinemia

B-cell lymphoma with monoclonal IgM production 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 Acute complications are treated with plasmapheresis, wich removes IgM from the serum

Eosinophilic Granuloma

Benign proliferation of Langerhans cells in bone Classic presentation is pathologic fractue in an adolescent; skin is not involved Biopsy shows Langerhans cells with mixed inflammatory cells, including numerous eosinophils

Clinical symptoms of Polycythemia Vera (PV) are mostly due to hyperviscosity of blood

Blurry vision and headache Increased risk of venous thrombosis (e.g., 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

Clinical Features of Multiple Myleoma

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 of infection- Monoclonal antibody lacks antigenic diversity; infection is the most common cause of death in multiple myeloma Rouleaux formation of RBCs on blood smear- Increased serum protein decreases charge between RBCs Primary AL amyloidosis- Free light chains circulate in seru and deposit in tissues Proteinuria- Free light chain is excreted in the urine as Bence Jones protein; deposition ni kidney tubules leads to risk for renal failure (myeloma kidney)

T-ALL (T-Cell Acute Lymphoblastic Lymphoma)

Characterized by lymphoblasts (TdT+) that express markers ranging form 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 lympnoma because the malignant cells form am mass)

Acute promyelocytic leukemia (APL)

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 the risks for DIC Treatment is with all-trans-retinoic acid (ATRA, a vitamin A derivative), which binds the altered receptor and casues that blasts to mature (and eventually die) (Subclassification of Acute Myeloid Leukemia)

Follicular lymphoma is distinguished from reactive follicular hyperplasia by

Disruption of normal lymph node architecture (maintained in follicular hyperplasia) (non-Hodgkin lymphoma) Lack of tingible body macrophages in germinal centers (tingible body macrophages are present in follicular hyperplasia) Bc12 expression in follicles (not expressed in follicular hyperplasia) Monoclonality (follicular hyperplasia is polyclonal)

Infectious Mononucleosis (IM)

EBV infection that results in a lymphocytic leukocytosis comprised of reactive CD8+ T cells; CMV is a less common cause EBV primarily infects 1. Oropharynx, resulting in pharyngitis 2. Liver, resulting in hepatits with hepatomegaly and elevated livier enzymes 3. B cells 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

Infectious Mononucleosis (mono)

EBV is transmitted by saliva ("kissing disease"); classically affects teenagers The monospot test is used for screening 1. Detects IgM antibodies that cross-react with horse or sheep red blood cells (heteophile antibodies) 2. Usually turns positive within 1 week after infection 3. A negative monospot test suggest CMV as a possivle cause of IM 4. Definitive diagnosis is made by serologic testing for the EBV viral capsid antigen

In inflammation, lymph node enlargement is due to hyperplasia of particular regions of the lymph node

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 (e.g., infectious mononucleuosis) Hyperplasia of sinus histiocytes is seen in lymph nodes that are draining a tissue with cancer

Polycythemia Vera (PV) must be distinguished from reactive polycythemia

In PV, erythropoietin (EPO) levels are decreased, and Sao2 is normal In reactive polycythemia due to high altitude or lung disease, Sao is low, and EPO is increased In reactive polycythemia due to ectopic EPO production from renal cell carcinoma, EPO is high, and Sao2 is normal

Monoclonal Gammopathy of Undetermined Significance (MGUS)

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) Common in elderly (seen in 5% of 70-year-old individuals); 1% of patients with MGUS develop multiple myeloma each year

Non-Hodgkin's Lymphoma

Is 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 lymphocytyic lymphoma (i.e., CLL cells that involve tissue) 2. Intermediate sized B cells- Burkitt lymphoma 3. Large B cells- diffuse large B-cell lymphoma

Lymphadenopathy (LAD)

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)

Langerhans Cell Histiocytosis

Langerhans cells are specialized dendritic cells found predominantly in the skin 1. Derived from bone marrow monocytes 2. Present antigen to naive T cells Langerhans cell histiocytosis is a neoplastic proliferation of Langerhans cells 1. Characteristic Birbeck (tennis racket) granules are seen on electron microscopy; cells are CD1a+ adn S-100+ by immunohistochemistry

Important considerations regarding other subtypes of HL

Lymphocyte-rich has the best prognosis of all types Mixed cellularity is often associated with abundant eosinohils (RS cells produce IL-5) Lymphocyte-depleted is the most aggressive of all types; usually seen in the elderly and HIV-positive individuals

Hand-Schuller-Christian disease

Malignant proliferation of Langerhans cells Classic presentation is scalp rash, lytic skull defects, diabetes insipidus, and exophthalmos in a child

Letterer-Siwe disease

Malignant proliferation of Langerhans cells Classic presentation is skin rash and cystic skeletal defects in an infant (<2 years old) Multiple organs may be involved; rapidly fatal

Multiple Myleoma

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 bone overall -High serum IL-6 may be present; stimulates plasma cell growth and immunoglobulin production

MALToma

Marginal zone lymphoma in mucosal sites Gastric MALToma may regress with treatment of H Pylori

B-ALL (B cell acute lymphoblastic leukemia)

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 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)

Acute Myeloid Leukemia (AML)

Neoplastic accumulation of immature myeloid cells (>20%) in the bone marrow Myeloblasts are usually characterized by positive cytoplasmic staining for myeloperoxidase (MPO) Crystal aggregates of MPO mah be seen as Auer rods Most commonly arises in older adults (average age is 50-60 years) Subclassification based on cytogenetic abnormalities, lineage of immature myeloid cells, and surface markers.

Acute Lymphoblastic Leukemia (ALL)

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 Most commonly arises in children; associated with Down syndrome (usually arises after the age of 5 years) Sub-classified into B-ALL and T-ALL based on surface markers

Hodgkin Lymphoma (HL)

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 RS cells secrete cytokines Reactive inflammatory cells make up a bulk of the tumor and form the vasis for classification of HL. Subtypes include 1. Nodular sclerosis 2. Lymphocyte-rich 3. Mixed cellularity 4. Lymphocyte-depleted

Acute Leukemia

Neoplastic proliferation of blast; 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 -Blast are large, immature cells, oftern with punched out nucleoli Acute leukemia is subdivided into acute lymphoblatic leukemia (ALL) or acute myelogenous leukemia (AML) based on the phenotype of the blasts.

Burkitt Lymphoma

Neoplastic proliferation of intermediate-sized B cells (CD20+); associated with EBV (non-Hodgkin lymphoma) Classically presents as an extranodal mass in achild or young adult Driven by translocations of c-myc (chromosome 8) 1. t(8;14) is most common, resulting in translocation of c-myc to the Ig heavy chain locus on chromosome 14 2. Overexpression of c-myc oncogene promotes cell growth 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 1. Most common form of NHL 2. Clinically aggressive (high-grade) Arises sporadically or from transformation of a low-grade lymphoma (e.g.,follicular lymphoma) Presents in late adulthood as an enlarging lymph node or an extranodal mass

Lymphoma

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%)

Hairy Cell Leukemia

Neoplastic proliferation of mature B cells characteized 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 2CDA (cladribine), and adenosine deaminase inhibitor; adenosine accumulates to toxic levels in neoplastic B cells

Adult T-cell Leukemia/Lymphoma (ATLL)

Neoplastic proliferation of mature CD4+ T cells Associated with HTLV-1; most commonly seen in Japan and the Caribbean 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 (MPD)

Neoplastic proliferation of mature cells of myeloid lineage; disease of late adulthood (average age is 50-60 years) 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 1. Increased risk for hyperuricemia and gout due to high turnover of cells 2. Progression to marrow fibrosis or transformation to acute leukemia

Chronic Leukemia

Neoplastic proliferation of mature circulating lymphocytes; characterized by a high WBC count Usually insidious in onset and seen in older adults Includes CLL, Hairy cell Leukemia, ATLL, and Mycosis Fungoides

Chronic Myeloid Leukemia (CML)

Neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors; basophils are characteristically increased Driven by t(9;22) (Philadelphia chromosome) which generates a BCR-ABL fusion protein with increased tyrosine kinase activity -First line treatment is imatininb, which blocks tyrosine kinase activity Splenomegaly is common. Enlarging 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 a pluripotent stem cell

Myelofibrosis

Neoplastic proliferation of mature myeloid cells, especially megakaryocytes Associated with JAK2 kinase mutation (50% of cases) Megakaryocytes produce excess platelet-derived growth factor (PDGF) causing marrow fibrosis Clinical features include 1. Splenomaegaly due to extramedullary hematopoiesis 2. Leukoerythroblastic smear (tear-drop RBCs, nucleated RBCs, and immature granulocytes) 3. Increased risk of infection, thrombosis, and bleeding

Essential Thrombocythemia (ET)

Neoplastic proliferation of mature myeloid cells, especially platelets RBCs and granulocytes are also increased Associated with JAK2 kinase mutation Symptoms are related to an increased risk of bleeding and/or thrombosis Rarely progresses to marrow fibrosis or acute leukemia No significant risk for hyperuricemia or gout

Polycythemia Vera (PV)

Neoplastic proliferation of mature myeloid ells, especially RBCs Granulocytes and platelets are also increased Associated with JAK2 kinase mutation Clinical symptoms are mostly due to hyperviscosity of blood Treatment is phlebotomy; second-line therapy is hydroxyurea Without treatment, death usually occurs within one year

Chronic Lymphocytic Leukemia (CLL)

Neoplastic proliferation of naive B cells that co-express CD5 and CD20; most common leukemia overall 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 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

Mantle Cell Lymphoma

Neoplastic proliferation of small B cells (CD20+) that expand mantle zone (non-Hodgkin lymphoma) Presents in late adulthood with painless lymphadenopathy 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

Neoplastic proliferation of small B cells (CD20+) that expands the marginal zone (non-Hodgkin lymphoma) Associated with chronic inflammatory states such as Hashimoto thyroiditis, Sjogren syndrome, and H pylori gastritis The marginal zone is formed by post-germinal center B cells

Follicular Lymphoma

Neoplastic proliferation of small B cells (CD20+) that form follicle-like nodules (non-Hodgkin lymphoma) Presents in late adulthood with painless lymphadenopathy 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 Bc12, which inhibits apoptosis Treatment is reserved for patients who are symptomatic and involves low-dose chemotherapy or rituximab (anti-CD20 antibody) Progression to diffuse large B-cell lymphoma is an important complication; presents as an enlarging lymph node

Reed-Sternberg cells secrete cytokines

Occasionally results in 'B' symptoms (fever, chills, weight loss, and night sweats) Attract reactive lymphocytes, plasma cells, macrophages, and eosinophils May lead to fibrosis

Hematopoiesis

Occurs via a stepwise maturation of CD34+ hematopoietic stem cells Cells mature and are released from the bone marrow into the blood

Dyscrasias

Plasma cell Disorders

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

Neutropenia

Refers to a decreased number of circulating neutorphils. Causes include 1. Drug toxicity (e.g., chemotherapy with alkylating agents)- Damage to stem cells results in decreased production of WBCs, especially neutorphils. 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

Eosinophilia

Refers to increased circulating eosinophils Causes include allergic reactions (type I hypersensitivity), parasitic infections, and Hodgkin lymphoma Eosinophilia is driven by increased circulating basophils; classically seen in chronic myeloid leukemia

Lymphocytic leukocytosis

Refers to increased circulating lymphocytes. Causes include 1. Viral infections- T lymphocytes undergo hyperplasia in response to virally infected cells 2. Bordetella pertussis infection- Bactria produce lymphocytosis- promoting factor, which blocks circulating lymphocytes from leaving the blood to enter the lymph node

Monocytosis

Refers to increased circulating monocytes. Causes include chronic inflammatory stats (e.g. autoimmune and infectious) and malignancy

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 Fc receptors (CD16) 2. High cortisol state- impairs leukocyte adhesion, leading to release of marginated pool of neutrophils

Nodular sclerosis

the most common subytpe 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)