Week 1 Flashcards
Differential blood count normals
Neutrophils: 34-71 Lymphocytes: 19-53 Monocytes: 5-12 Eosinophils: 0-7 Basophils: 0-1
Granulocytes
Neutrophils: PMNs, kill bacteria via NADPH oxidase
Eosinophils: bi-lobed nucleus, red granules contain major basic protein (MBP), kill parasites, secrete leukotrienes
Basophils: contain histamine and heparin, similar to mast cells, invilved in allergy (IgE)
Agranulocytes
Monocytes: largest, horseshoe-nucleus, turn into macrophages, APCs
Lymphocytes: B and T, immune cells, viruses
Hematopoieses flow chart
Multipotent stem cell-> MSCs and hemangioblasts
Hemangioblasts-> endothelial progenitors and HSCs
HSCs(CD34,cKit)->myeloid and lymphoid progenitors
Lymphoid->B and T cells
Myeloid-> erythroblasts, myeloblasts, megakaryoblasts (all CD45)
Erythrocyte differentiation
Proerythroblast: large, blue cytoplasm, multiple nucleoli
Basophylic erythroblast: only one nucleoli, less cytoplasm, more blue
Polychromatic erythroblast: mottled nucleus/chromatin, more grey cytoplasm, smaller
Orthochromatic erythroblast/normoblast: grey cytoplasm, nucleus near edge of cell
Reticulocyte: nucleus extruded but still immature
Erythrocyte: no nucleus, red pale color
Myeloblast (Neutrophil) differentiation
Myeloblast: large, pale blue cytoplasm, multiple nucleoli
Promyelocyte: many blue granules, peripheral nucleus, large
Myelocyte: fewer blue granules, more pale cytoplasm
Metamyelocyte: slightly indented nucleus, no visible granules
Band: C or S shaped nucleus
Neutrophil: multi-lobulated nucleus
Leukomoid Reaction
High white count (leukocyte >50,000/uL)
reactive to infection, usually bacterial
NOT neoplastic
Leukoerythroblastic reaction
immature bone marrow cells in the peripheral blood
secondary to bone marrow fibrosis, metastatic cancer, or severe bone marrow stress
Neutrophilia
absolute neutrophils >7000/ul
due to infxn or drugs
in infxn, also undergo “toxic change” in which neutrophils have prominent blue primary granules
Neutropenia
absolute neutrophils <1500/ul
due to aplastic anemia, immune destruction, sepsis, chemotherapy, etc
Eosinophilia
eosinophils >700/ul
due to thype I hypersensitivity, parasites, addison’s, or neoplasms
Basophilia
basophils >200/ul
usually due to chronic myelogenous leukenia
Myeloproliferative Neoplasms (MPN)
chronic myelogenous leukemia (CML) Polycythemia vera (PV) Primary myelofibrosis (PMF) Essential thrombocytopenia (ET) more common in adults, rare CLONAL Hypercellular bone marrow with EFFECTIVE hematopoisis-> increased peripheral counts organomegaly, can progress to acute leukemia or fibrosis often increased tyrosine kinase activity
Myelodysplastic Syndromes (MDS)
CLONAL Hypercellular bone marrow with DECREASED peripheral counts
increased risk of AML
myeloblasts may increase, but <20%
chromosomal abnormalities common
more common in elderly
Tx: hypomethylating agents, growth factors, blood, allogenic stem cell transplant
Chronic Myelogenous Leukemia (CML)
MPN (mature cells)
BCR-ABL fusion gene (t(9,22), philidelphia chromosime-> tyrosine kinase activity
high leukocytosis (>100,000/ul), with neutrophilia and immature myeloid cells
often basophilia and thrombocytosis
progressive if not treated to accelerated and then blast phase (acute leukemia)
Tx: tyrosine kinase inhibitors (Imatinib)
Polycythemia vera (PV)
MPN
increased red cell mass, hypercellular bone marrow
JAK2 gene mutation
decreased serum EPO, normal O2sat
Primary myelofibrosis (PMF)
MPN
rapid bone marrow fibrosis and extramedullary hematopoiesis
splenomegaly-> portal HTN
anemia, teardrop cells, leukoerythroblastic reaction
JAK2 mutation in 50%
May develop AML
Essential Thrombocythemia (ET)
MPN proliferation of megakaryocytes elevated platelet count, atypical morphology hypercellular bone marrow JAK2 mutation in 50%
Acute Myeloid Leukemia (AML)
Primarily adults, poor outcome
proliferation of immature myeloblasts (large and uniform)
Auer rods,, myeloperoxidase (MPO)+, non-specific esterase+
CD34+, CD117+
cytopenias,, >20% myeloid blasts,, hypercellular bone marrow
leukopenia or leukocytosis
AML with chromosomal abnormalities= favorable
AML with myelodysplastic changes= bad
mutations: FLT3=bad,,NPM1=good
Tx: “7+3”,, induction then consolidation
AML with recurrent cytogenetic abnormalities
t(15,17) = favorable
t(9,11)(MLL) = intermediate
11q23(MLL) = unfavorable
MLL types: infantile AML, monocytic
t(15,17) = acute promyelocytic leukemia (APL)– hypergranular– PML-RARa– assoc with disseminated intravascular coagulation (DIC)-> respondes to ATRA
AML with myelodysplasia-related changes
monosomy 7 / del(7q)
monosomy 5 / del(5q)
older folks, unfavorable
Therapy-related AML or MDS
from chemotherapy or radiation
alkylating agents or topoisomerase II inhibitors
poor prognosis
Myeloid Sarcoma
extramedullary tumor of immature myeloid cells
can be assoc with AML
usually treated like AML
Histiocytic neoplasms
Proliferations of macrophages, wide spectrum
Langerhans cell
Langerhans Cell Histiocytosis
immature dendritic cells in epidermis
express CD1a and langerin,, Birbeck granules,, “tennis racket” appearance
Multisystem (etterer-Siwe): young children, fatal if untreated
Unisystem (eosinophilic granuloma): can spontaneous resolve,, Hand-Schuller-Christian triad= calvarial bone defects, diabetes insipidus, exophthalmos
BRAF mutations
Hemophagocytic lymphohistiocytosis / hemophagocytic syndrome
potentially fatal hyperinflammatory condition
Primary: genetic,, perforins and granzymes induce apoptosis
Secondary: infxns, rheumatoligic, malignant, metabolic
EBV infxn is assoc
very high ferritin
Hematopoietic growth factors
Erythropoietin (EPO): stimulates erythroid precursors to mature, produced in kidney response to hypoxia,, supplemented in kidney disease, chemotherapy, MDS, HIV, premature infants
Thrombopoietin (TPO): enhances megakaryocyte prolif and matureation, made in liver, Mpl receptor,, supplemented in immune thrombocytopenia
Granulocyte colony stimulating factor (GCSF/filgrastim): myeloid growth factor produced by monocytes, macrophages, endothelial cells,, increase with inflammation,, increase neutrophil production,, uses: neutropenia, prior to bone marrow txplant,, bone pain
Flow cytometry
Forward scatter: more for bigger cells
Side scatter: more with morecomplex cytoplasm (granules)
CD markers
3: T-cells
4: helper t-cells
8: cytotoxic t-cells
13: granulocytes, monocytes
14: monocytes
15: granulocytes, monocytes
19: B-cells
20: B-cells
34: blasts, stem cells
45: leukocytes
Lymphocytosis
lymphocytes >4k/ul
can be reactive (benign) or neoplastic
reactive: transient, <10k/ul, heterogenous, from infxn, stress, EBV, mononucleosis, etc
neoplastic: chronic, monotonous
Infectious Mononucleosis
lymphocytosis, atypical morphology
heterogenous, large, lightly basophilic cytoplasm, encroaches on neighboring RBCs
T-cells responding to EBV-infected B-cells
criteria: 1 >50% mononuclear cells (monocytes and lymphocytes) 2 marked lymphocyte heterogeneity 3 >10% reactive lymphocytes
Neoplastic Lymphocytoses
Chronic lymphocytic leukemia (CLL) hairy cell leukemia splenic marginal zone lymphoma large granular lymphocytic leukemia adult T-cell lymphoma (ATLL) Sezary syndrome
HTLV-1 and HTLV-2
HTLV-1: infective dermatitis in kids, adult T-cell lymphoma, tropical spastic paraparesis (TSP), risk for protozoal infxns
HTLV-2: rare cases of CD8 leukemia, disease resembling TSP, risk for bacterial infxns
Viral gene= Tax = lifelong-> activate host transcription factors, mod signal transduction, inhibit apoptosis
CDs in Lymphocytoses
T-cell: 3,4,5,8 B-cell: 10,19,20,21 Monocyte/macrophage: 11c(hairy cell),15(Reed-Sternberg) Progenitor cell: 34 Activation: 30(Reed-Sternberg) All leukocytes: 45
B-cell lymphoblastic leukemia / lymphoma
cell origin: bone marrow precursor B-cell
diverse chromosomal translocations: t(12,21)
mostly kids, pancytopenia, aggressive
T-cell acute lymphoblastic leukemia / lymphoma
cell origin: precursor T-cell (usually thymus)
diverse chromosomal translocations: NOTCH1 mutations
adolescent males, thymic masses, aggressive
Hairy cell leukemia
cell origin: memory B-cell no specific chromosomal abnormalities pancytopenia, splenomegaly, indolent middle age white males hairlike projections on leukemic cells,, "dry tap" complication on biopsy Coexpression of CD11c and CD22 overall good prognosis
Small lymphocytic lymphoma / Chronic lymphocytic leukemia
cell origin: naive B-cell or memory B-cell
trisomy 12, del(11q,13q,17p)
bone, lymph node, spleen, liver disease
autoimmune hemolysis, thrombocytopenia sometimes, indolent
CLL is most common leukemia of adults
lymphocyte count >5,000/ul
proliferation centers,, smudge cells
CD5, CD23, CD19, CD20 +
worse outcome: unmutated Ig segments, 11q and 17p deletions, lack of hypermutation, ZAP-70+
Staged on Rai staging (0-IV)
Adult T-cell leukemia/lymphoma
cell origin: helper t-cell
HTLV-1 provirus in tumor cells
adults, cutaneous lesions, hypercalcemia, aggressive
less aggressive if only in skin
Mycosis fungoides / Sezary syndrome
cell origin: helper T-cell
no specific chromosome abnormal
adult, cutaneous patches, erythema, indolent
lymphocytes have “cerebriform” nuclei with multiple delicate folds, brain-like nucleus
Large granular lymphocytic leukemia
cell origin: cytotoxic T-cell or NK cell
no specific chromosomal abnormal
adults, splenomegaly, neutropenia, anemia, autoimmune disease sometimes (rheumatologic)
Acute lymphoblastic leukemia/lymphoma (ALL)
85% are B-cell ALLs, childhood, CD10, CD19
less common are T-ALLs, adolescent males, thymic lymphoma, CD3
similar signs and symptoms to AML
Worse prognosis: age less than 2 or more than 10, white count more than 100,000, t(9,22), CSF involved
Good prognosis: age 2-10, low white count, hyperploidy
Plasma cell Dyscrasias
plasma cells: clock-face chromatin
Benign (reactive): chronic infxns (H pylori), autoimmune (lupus)
Neoplastic (clonal, M-protein): Multiple myeloma, MGUS, plasmacytoma, amyloidosis
Bence Jones Protein: free light chains (in urine)
Multiple Myeloma
most common plasma cell neoplasm, malignant
criteria: clonal plasma cells, M-protein, end organ damage (hypercalcemia, renal prob, anemia, bone prob)
Osteolytic,, immunosuppression
Always get BOTH serum and urine M-protein analysis
can progress to plasma cell leukemia if spills into blood
Monoclonal Gammopathy of Undetermined Significance (MGUS)
most common monoclonal gammopathy
criteria: <10% clonal plasma cells in bone marrow, no myeloma related organ damage
benign, but can transform into malignant
Plasmacytomas
localized growth of monoclonal plasma cells
can be seen in conjunction with multiple myeloma
when distinct: no clonal cells in bone marrow
Tx: radiation
usually extramedullary (upper resp tract),, can also be solitary
Amyloidosis
protein misfolding, deposition
inherited and acquired
Congo red +
primary: multiple myeloma, other plasma cell dyscrasias
secondary: chronic inflammation, renal failure
usually light chains
T and B cell Devo of receptors
variable region of heavy chain recombines D with J, then V with DJ then VDJ with constant to make heavy chain VDJC
light chain recombines V and J, then with C, to make VJC, then joins up with heavy chain
Only one chromosoma is expressed via allelic exclusion to ensure clonality
Then selection: if fail to express receptors-> death, if weak self-interaction then positive selection, if strong or none, then death
T-cells are first double positive, then mature to either CD4 or 8 depending on weak recognition of MHC
Lymph node histology
Hilum: artery, vein, efferent lymphatic
Capsule, subcapsular sinus, cortex, medulla,
Follicles: B-cells,, Germinal center (prolif, has light (centrocytes, antigen exposure) and dark(centroblasts, prolif) zones), Mantle zone (naive), Marginal zone (spleen only)
Paracortex: T-cells, high endothelial venules (traffic lymphocytes to/from blood), dendritic cells
Spleen Histology
white pulp= immune,, T-cell=PALS(arterioles), B-cell=follicles
Red pulp=filter RBCs
Follicular Hyperplasia
benign prolif of B-cells in follicles
causes: RA, infxn, HIV
Similar in morphology to Follicular Lymphoma
Architecture is preserved
Neoplasms of mature B-cells (Lymphomas)
Burkitt Diffuse large B-cell Extranodal marginal zone Follicular Mantle cell
Neoplasms of mature T/NK-cells (Lymphomas)
Peripheral T-cell / unspecified
Anaplastic large cell
Extranodal NK/T-cell
Burkitt Lymphoma
NHL
germinal center B-cell
t(8,14) - cMyc
sometimes assoc EBV
young adults, extranodal masses,, uncommonly leukemia
1 African/endemic(all EBV) 2 Sporatic 3 HIV-assoc
diffuse growth, high mitotic/apoptotic index
“starry sky” pattern
predeliction for abdominal/visceral involvement
CD19,20,10,BCL6+,, BCL2-
aggressive
Diffuse large B-cell lymphoma
NHL (most common) Germinal center B-cell Diverse chromosomal rearrangements BCL6, BCL2, c-Myc all ages, usually adults, rapidly growing mass diffuse pattern of growth CD19,20+ aggressive,, curable
Extranodal marginal zone lymphoma
NHL
Memory B-cell
t(11,18), t(1,14), t(14,18) - MALT1 or BCL10
adults with chronic inflammatory diseases, may be localized,, may regress if inciting agent is cleared (eg H. pylori)
indolent
Follicular Lymphoma
NHL (most common in US)
germinal center B-cell
t(14,18) - BCL2-IgH
older adults with generalized lymphadenopathy, marrow involvement (paratrabecular lymphoid aggregates)
CD19,20,10+ ,, CD5-
indolent,, often watch first, then treat w/ rituximab
Can transform into diffuse large cell, or Burkitt (cMyc)
Mantle Cell lymphoma
NHL Naive B-cell t(11,14) - CyclinD1-IgH older males, disseminated disease CD19,20,5+ ,, CD23- (unlike CLL) moderately aggressive
Peripheral T-cell lymphoma, unspecified
NHL helper or cytotoxic T-cell no specific chromosomal ab older adults, lymphadenopathy,, pleomorphic aggressive
Anaplastic large-cell lymphoma
NHL cytotoxic T-cell ALK rearrangements -->JAK/STAT kids and young adults, lymph node and soft tissue disease large anaplastic cells, hallmark cells aggressive, but good prognosis
Extranodal NK/T-cell lymphoma
NHL NK-cell more common EBV assoc adults, destructive extranodal masses, sinonasal, nasopharyngeal aggressive
Hodgkin Lymphoma
Tumor giant cell= Reed-Sternberg (“owl-eye”)
localized, spread contiguously
B-cell origin
Classical:Nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depletion
Non-classical: lymphocyte predominance
CD15,30+ ,, CD45-
Hodgkin Lymphoma: Nodular Sclerosis
Most common form
propensity for cervical, mediastinal nodes
adolescents or young adults
good prognosis
Lacunar cell: large cell, single multilobule nucleus, pale cytoplasm
CD15,30+ ,, CD20,45-
Collagen bands
Hodgkin Lymphoma: Luekocyte Predominance
Non-classical, more rare
lymphohistiocytic variant RS cells,, popcorn cells
cervical, axillary
CD15,30- ,, CD20,45+
Reactive Lymphadenopathy
Generally smaller, tender, low fevers, NO night sweats
Infectious or autoimmune
infectious mononucleosis - paracortical hyperplasia
Rituximab
CD20 antibody
causes induced cell death of B-cells
used for many lymphomas
Architecture of B-NHLs
Nodular/Follicular: Follicular, Mantle, Marginal zone, CLL/SLL
Diffuse: diffuse large, Burkitt
Tumor size of B-NHLs
Small: Follicular, Marginal zone, CLL/SLL
Large: Diffuse large B-cell, Burkitt
Any: Mantle
CD5, CD23, CD10 status of small B-NHLs
CD5+: CD23-: Mantle cell CD23+: CLL/SLL CD5-: CD10-: Marginal zone CD10+: Follicular
Lymphoma translocations
Follicular: t(14,18) - BCL2
Mantle: t(11,14) - CyclinD1
Burkitt: t(8,14) - cMyc
Marginal zone: t(11,18)
Chromosome 2=kappa, 22-lambda, 8=cMyc
