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- Lymphoid stem cells
- → ALL, CL
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Leukopenia
WBC count <5,000
- Usually due to one cell type:
- 1. Neutropenia
- -Cuase:drug toxicity - chemotherapy; severe infection
- -Tx: GM-CSF or G-CSF (to boost granulocyte production)
- 2. Lymphopenia
- -Cause: immunodeficiency (DeGeorge, HIV); corticosteroids/cushing syndrome; autoimmune destruction (SLE); whole body radiation
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Leukocytosis
- WBC > 10,000
- Also usually due to one cell type:
- 1. Neutrophilic leukocytosis:
- -bacterial infection, tissue necrosis; high cortisol state
- 2. Monocytosis
- -chronic inflammatory states, malignancy
- 3. Eosinophilia:
- -allergic reactions (type I hypersensitivity), parasitic infections, Hodgkin lymphoma
- 4. Basophilia
- -chronic myeloid leukemia
- 5. Lymphocytic leukemia
- -viral infection; Bordetella pertussis infection
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Infectious mononucleosis
- Cause:
- -EBV infection → lymphocytic leukocytosis (reactive CD8+ T cells)
- -CMV is less common cause
- Effects of EBV:
- -Oropharynx → pharyngitis
- -liver → hepatitis, hepatomegaly, ↑ liver enzymes
- -B cells
- T cell response:
- -Generalized lymphadenopathy
- -Splenomegaly
- -↑ WBC count with atypical lymphocytes
- Complications:
- -splenic rupture
- -rash if exposed to ampicillin
- -Recurrence, possibly B-cell lymphoma (especially if immunodeficient)
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Infectious mono
testing/screening
- Monospot test:
- -Detects IgM antibodies
- -Usually turns positive after 1 week
- -Negative monospot → possible CMV
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Acute leukemia
principles
- Proliferation of blasts - > 20% blast in bone marrow defines acute leukemia
- Presentation:
- -anemia (fatigue)
- -thrombocytopenia (bleeding)
- -neutropenia (infection)
- Types:
- -Acute lymphoblastic leukemia (ALL)
- -Acute myelogenous leukemia (AML)
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Acute Lymphoblastic Leukemia (ALL)
- Lymphoblasts (>20%) in the bone marrow
- Positive nuclear staining for TdT (DNA polymerase)
- Childhood neoplasia (after age 5)
- Associated with Down syndrome
- Subclass: B-ALL and T-ALL
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B-ALL
- Most common type
- Lymphoblasts (TdT+) that express CD10, CD19,CD20
- Prognosis based on cytogenetics:
- -t(12:21) has good prognosis - more common in children
- -t(9:22) has poor prognosis - more common in adults ("Philadelphia+ ALL)
- Tx: Excellent response to chemotherapy
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T-ALL
- Lymphoblasts (TdT+) that express CD2-CD8 (no CD10)
- Presentation: Teenagers, mediastinal (thymic) mass
- aka acute lymphoblastic lymphoma bc cells form a mass
- *T-ALL, Teenagers, Thymic mass
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Acute Myeloid Leukemia
- Accumulation of myeloblasts (>20%)
- Positive cytoplasmic staining for myeloperoxidase (MPO) - seen as Auer rods
- Presentation: Adults (50-60yrs)
- Subclass: cytogenetic abnormalities, lineage of myeloblasts, surface markers
- -Acute Promyelocytic Leukemia (APL)
- -Acute Monocytic Leukemia
- -Acute Megakaryoblastic Leukemia
- Pre-existing dysplasia: myelodysplastic syndrome
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Myelodysplastic syndrome
Can progress to AML, especially with exposure to alkylating agents or radiotherapy
- Presentation:
- -cytopenias
- -hypercellular bone marrow
- -abnormal maturation of cells
- -increased blasts (<20%)
*Most die from infection or bleeding; some progress to acute leukemia
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Acute promyelocytic leukemia (APL)
- -t(15:17) - retinoic acid receptor (RAR) on chrom 17 → chrom 15
- -Increase risk for DIC
- Tx
: - -all-trans-retinoic acid (ATRA) - a vitamin A derivative (causes blasts to mature)
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Acute monocytic leukemia
- Proliferation of monoblasts
- usually lack MPO
- Blasts infiltrate gums
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Acute megakaryoblastic leukemia
- Proliferation of megakaryoblasts
- Lack MPO
- Associated with Down syndrome (arises before the age of 5)
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Chronic leukemia
principles
- Proliferation of mature circulating lymphocytes
- High WBC count
- Insideous in onset
- Older adults
- Types:
- -Chronic Lymphocytic Leukemia (ALL)
- -Hairy Cell Leukemia
- -Adult T-Cell Leukemia/Lymphoma (ATLL)
- -Mycosis Fungoides
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Chronic Lymphocytic Leukemia (CLL)
- Proliferation of naïve B cells that co-express CD5 and CD20
- Most common leukemia overall
- Blood smear: lymphoctes, smudge cells
Can involve lymph nodes → generalized lymphadenopathy ("small lymphocytic lymphoma")
- Complications:
- -Hypogammaglobulinemia
- -Autoimmune hemolytic anemia
- -Transform to diffuse large B-cell lymphoma (Richter transformation)
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Hairy Cell Leukemia
- Proliferation of mature B cells - hairy cytoplasmic processes
- Positive for tartrate-resistant acid phosphatase (TRAP)
- Features: splenomegaly; "dry tap" on bone marrow aspiration
- Tx: 2-CDA (cladribine) (an adenosine deaminase inhibitor)
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Adult T-Cell Leukemia/Lymphoma (ATLL)
- -Proliferation of mature CD4+ T cells
- -Associated with HTLV-1 (Japan, Caribbean)
- Features:
- -rash
- -generalized lymphadenopathy
- -hepatosplenomegaly
- -lytic (punched-out) bone lesions with hypercalcemia
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Mycosis Fungoides
- Proliferation of mature CD4+ T cells that infiltrate the skin → localized rash, plaques, nodules
- "Pautrier microabscesses"
- *Cells can spread to involve the blood → Sezary syndrome
- -Sezary cells: cerebriform nuclei on blood smear (lobes)
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Myeloproliferative disorders
- Mature cells of myeloid lineage
- Epidemiology: late adulthood (50-60yrs)
- Presentation: high WBC count; hypercellular bone marrow; ↑ granuclocytes
- Complications: hyperuricemia, gout; progression to marrow fibrosis or transform to acute leukemia
- Types:
- -Chronic myeloid leukemia
- -Polycythemia vera
- -Essential thrombocythemia
- -Myelofibrosis
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Chronic Myeloid Leukemia (CML)
- Proliferation of myeloid cells, especially granulocytes and their precursors
- Basophils are characteristically increased
- t(9:22) (Philadelphia chromosome) → BCR-ABL fusion protein (↑ tyrosine kinase activity)
- Splenomegaly is common → suggests accelerated phase of disease
- Tx: imatinib (blocks tyrosine kinase)
- Complications: transform to AML (2/3 of cases) or ALL (1/3 of cases)
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CML vs leukemoid reaction (reactive neutrophilic leukocytosis)
- CML:
- -Negative leukocyte alkaline phosphatease (LAP) stain
- -Increased basophils
- -t(9:22)
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Polycythemia vera (PV)
- Proliferation of mature myeloid cells, especially RBCs (↑ granulocytes, ↑ platelets)
- JAK2 kinase mutation
- Clinical presentation: hyperviscosity of blood...-Blurry vision and headache
- -Increased risk of venous thrombosis (hepatic vein, portal vein, dural sinus)
- -Flushed face due to congestion
- -Itching
Tx: phlebotomy; hydroxyurea
- Distinguish from reactive polycythemia:
- -PV → EPO levels are decreased, SaO2 is normal
- -Reactive polycythemia (high altitude, lung disease) → SaO2 is decreased, EPO is high
- -Reactive polycythemia (ectopic EPO production from RCC) → both EPO and SaO2 are high
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Essential Thrombocythemia (ET)
- Proliferation of mature myeloid cells, especially platelets (↑ RBCs, ↑ granulocytes)
- *JAK2 kinase mutation
- Sx: increased risk of bleeding and/or thrombosis
- -rarely progresses to marrow fibrosis or acute leukemia
- -No significant risk for hyperuricemia or gout
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Myelofibrosis
- Proliferation of mature myeloid cells, especially megakaryocytes
- *JAK2 kinase mutation (50% of cases)
- Megakaryocytes → excess platelet-derived growth factor (PDGF) causing marrow fibrosis
- Clinical feature
:-Splenomegaly (extramedullary hematopoiesis)- -Leukoerythroblastic smear
- -Increased risk of infection, thrombosis, bleeding
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Lymphadenopathy (LAD)
- Painful LAD: acute infection (acute lymphadenitis)
- Painless LAD: chronic inflammation, metastatic carcinoma, lymphoma
- → hyperplasia of particular regions:
- 1. Follicular hyperplasia (B-cell region) seen in RA, early HIV infections
- 2. Paracortex hyperplasia (T-cell region) seen in viral infections (mono)
- 3. Hyperplasia of sinus histiocytes seen in LN that are draining cancer
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Lymphoma
principles
- Proliferation of lymphoid cells that form a mass; within LN or extranodul tissue
- non-Hodgkin
(NHL, 60%) vs Hodgkin lymphoma (HL, 40%)
- NHL subclasses:
- -Small B cells: follicular, mantle, marginal, small lymphocytic lymphoma (CLL cells that involve tissue)
- -Intermediate-sized B cells: Burkitt lymphoma
- -Large B cells: diffuse large B-cell lymphoma
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Non-Hodgkin Lymphoma
- Malignant cells: Lymphoid cells
- Composition of mass: lymphoid cells
- Clinical presentation: Painless LAD, usually arises in late adulthood
- Spread: diffuse; often extranodal
- Staging: limited importance
- Leukemic phase: occurs
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Hodgkin lymphoma
- Malignant cells: Reed-Sternberg cells
- Composition of mass: Predominantly reactive cells (inflammatory cells and fibrosis)
- Clinical presentation: Painless LAD occasionally with 'B' symptoms; young adults
- Spread: Contiguous; rarely extranodal
- Staging: guides therapy; radiation is mainstay of tx
- Leukemic phase: Does NOT occur
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Follicular lymphoma
- Neoplastic proliferation of small B cells (CD20+)
- Presentation: late adulthood, painless LAD
- t(14:18) - BCL2 on chromosome 18 translocates to the Ig heavy chain on chromosome 14
- → overexpression of Bcl2, which inhibits apoptosis
- Treatment: only when symptomatic, low dose chemo or rituximab (anti-CD20 antibody)
- Complication
: preogression to diffuse large B-cell lymphoma
- Follicular lymphoma vs reactive follicular hyperplasia:
- -disruption of normal LN architecture
- -lack of tingible body macrophages in germinal centers
- -Bcl2 expression in follicles
- -Monoclonality
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Mantle cell lymphoma
Neoplasatic proliferation of small B cells (CD20+) that expands the mantle zone
Presentation: late adulthood, painless LAD
- t(11:14)
- -Cyclin D1 gene on chromosome 11 translocates to Ig heavy chain locus on chromosome 14
- -Overexpression of cyclin D1 promotes G1/S transition in cell cycle
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Marginal zone lymphoma
Neoplasatic proliferation of small B cells (CD20+) that expands the marginal zone
- Associated with chronic inflammatory states:
- -Hashimoto thyroiditis
- -Sjögren syndrome
- -H pylori gastritis
MALToma is marginal zone lymphoma in mucosal sites
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Burkitt lymphoma
- Neoplastic proliferation of intermediate-size B cells (CD20+)
- Associated with EBV
- Presentation: extranodal mass in child or young adult (African → jaw; sporadic → abdomen)
- t(8:14) → c-myc on chromosome 8 to the Ig heavy chain locus on chromosome 14
- →overexpression of c-myc oncogene promotes cell growth
- "Starry-sky" appearance
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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)
- Sporadically or from transformation of a low-grade lymphoma (follicular lymphoma)
- Presentation: late adulthood as an enlarging lymph node or extranodal mass
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Hodgkin lymphoma
- Neoplastic proliferation of Reed-Sternberg (RS) cells; large B cells with multilobed nuclei
- Prominant nucleoli ('owl-eyed nuclei')
- CD15 and CD30 positive
- RS cells: secrete cytokines
- -"B" symptoms (fever, chills, night sweats)
- -Attract reactive lymphocytes, plasma cells, macrophages, eosinophils
- -May lead to fibrosis
- HL subtypes: based on reactive inflammatory cells (make up bulk of the tumor)
- -Nodular sclerosis (most common)
- -Lymphocyte-rich (best prognosis)
- -Mixed cellularity (abundant eosinophils)
- -Lymphocyte-depleted (most aggressive; seen in elderly and HIV-positive)
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Plasma cell disorders
- Myltiple myeloma
- Monoclonal gammopathy of undetermined significance (MGUS)
- Waldenström macroglobulinemia
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Multiple myeloma
- Malignant proliferation of plasma cells in the bone marrow
- -Most common primary malignancy of bone
- -High serum IL-6 is sometimes present (stimulates plasma cell growth and Ig production)
- Clinical features:
- -Bone pain with hypercalcemia (punched-out lesions, especially skull)
- -Elevated serum protein (M spike; IgG or IgA most commonly)
- -Increased risk of infection (antibodies lack antigenic diversity)
- -Rouleaux formation of RBCs on smear
- -Primary AL amyloidosis
- -Proteinuria
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Monoclonal gammopathy of undetermined significance (MGUS)
- Increased serum protein with M spike
- other features of multiple myeloma are absent
- Common in elderly (5% of 70 year olds)
- 1% of pts with MGUS develop multiple myeloma each year
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Waldenström macroglobulinemia
B-cell lymphoma with monoclonal IgM production
- Clinical features:
- -Generalized LAD (lytic bone lesions are absent)
- -Increased serum protein with M spike
- -Visual and neurologic deficits - IgM causes serum hyperviscosity
- -Bleeding
Tx: acute complications are treated with plasmapheresis, which removes IgM from the serum
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Langerhans cell histiocytosis
- Langerhans cells are specialized dendritic cells, found predominantly in the skin
- -from bone marrow monocytes
- -Present antigen to naive T cells
- Neoplastic proliferation of langerhans cells:
- -Birbeck (tennis racket) granules are seen on em
- -CD1a+ and S100+ by immunohistochemistry
- Types:
- -Letterer-Siwe disease
- -Eosinophilic granuloma
- -Hand-Schuller-Christian disease
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Letterer-Siwe disease
- Malignant proliferation of Langerhans cells
- Presentation: skin rash, cystic skeletal defects in an infant (<2 years old)
- Multiple organs may be involved
- rapidly fatal
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Eosinophilic granuloma
- Benign proliferation of Langerhans cells in bones
- Presentation: pathologic fracture in an adolescent
- Skin is not involved
- Bx: Langerhans cells with mixed inflammatory cells, eosinophils
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Hand-Schüller-Christian disease
- Malignant proliferation of Langerhans cells
- Presentation: scalp rash, lytic skull defects, diabetes insipidus, exopthalmos
- Children (>3 years old)
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