White Blood Cells Flashcards
Neutropenia/Agranulocytosis
Pathogenesis (6) Clinical Feature
Agranulocytosis is clinically significant neutropenia*
Inadequate Granulopoiesis:
Suppression of stem cells
Drug suppression of precursors (most common)
Ineffective hematopoiesis
Accelerated Destruction:
Immune mediated injury
Splenomegaly (sequestration)
Increased peripheral utilization
Infections causing mucosal ulcerations
Leukocytosis
Etiologies (4) Types with Causes (5)
Increased production in marrow (chronic disorders)
Increased release from marrow stores (infection)
Decreased margination (exercise)
Decreased extravasation into tissues (glucocorticoids)
Neutrophilic: Acute bacterial infection, inflammation
Eosinophilic: Allergies, Autoimmune Disorders
Basophilic: myeloproliferative disorders
Monocytosis: Chronic infections
Lymphocytosis: Chronic infections, Viral infections
Lymphadenitis Acute Etiologies (4) Chronic Morphology (4)
Cervical: Infections of teeth or tonsils
Axillary/Inguinal: Extremity infections
Mesenteric: Acute appendicitis
Generalized: Systemic viral infections and bacteremia
Follicular Hyperplasia (humoral germinal centers) Tingible Body Macrophages seen between GC's Paracortical Hyperplasia (T cell response) Sinus Histiocytosis (sinuses draining cancer)
Hemophagocytic Lymphohistiocytosis
Pathogenesis (4) Labs (4) Clinical Features (3) Treatment (2)
Activation of macrophages and CD8+ CTLs
Macrophages phagocytose bone marrow RBC progenitors
Familial forms caused by decreased degranulation from CTLs and NK cells
Triggered by EBV infection
Elevated Ferritin and IL-2r
Anemia, Thrombocytopenia
Acute febrile illness
Hepatosplenomegaly (hepatitis)
Disseminated Intravascular Coagulation
Treat with immunosuppression and mild chemotherapy
White Cell Neoplasias
Etiologic Factors
Mutations (4) Viruses (3) Others (4)
Chromosomal translocations:
Help malignant cells proliferate and survive
Create oncoproteins useful for protection and growth
Proto-oncogenes made during receptor rearrangements
Human T cell Leukemia Virus 1 (HTLV-1)
EBV
HHV-8
Smoking (acute myeloid leukemia)
Iatrogenic (radiation/chemo)
Chronic Inflammation (H. pylori)
Inherited Genes
Leukemia vs Lymphoma Definitions
Leukemia
Neoplasms with widespread involvement of bone marrow and peripheral blood
Lymphoma
Start as discrete tissue masses
Principles of Lymphoid Neoplasms (6)
All daughter cells of malignant progenitor share same antigen receptor genes (immunophenotype)
Most cells will appear to be at some point of B/T cell differentiation
Often associated with immune abnormalities
Neoplastic B and T cells will act similar to non-neoplastic
Hodgkin Lymphoma spread orderly
Non-Hodgkin Lymphoma spreads widely and unpredictably
Acute Lymphoblastic Leukemia/Lymphoma
B Cell ALL: Population, Mutations (3), Origin Site
T Cell ALL: Population, Mutation, Origin Site
Prognosis (2) Immunophenotype (3) Lymphoblast Morphology (3)
B Cell Acute Leukemia:
Most common cancer of Children**
t(12;21) translocations, RUNX1, ETV6 mutations
Hypercellular Bone marrow: causes pancytopenia
T Cell Acute Lymphoma
Adolescent males
NOTCH1 mutations
Thymus
Aggressive in both cases
Excellent prognosis with aggressive chemotherapy
TdT (+)
CD10/CD19/CD20 (+) (B Cell ALL)
CD1-CD8 (+) (T Cell ALL)
Small amount of cytoplasm
No granules
Condensed Chromatin
Acute Lymphoblastic Leukemia
Clinical Features (6)
Favorable (5) and Unfavorable (3) Prognostics
Abrupt onset of symptoms within weeks:
Anemia, Bleeding
CNS symptoms
Mass Effects: bone pain, General Lymphadenopathy, Hepatosplenomegaly, Testicle Enlargement
Favorable: Age > 2, Low WBC, Hyperdiploidy, Trisomies, t(12;21)
Unfavorable: Age < 2 or adolescent/adult, Peripheral Blasts > 100,000, t(9;22) Philadelphia gene (BCR-ABL)
Chronic Lymphocytic Leukemia and Small LL
Population (2) Genetics (4) Origin, Immunophenotype (4) Clinical Features (5) Morphology (2)
- CLL and SLL differ only in degree of lymphocytosis
- CLL is >5000
Most common leukemia in Adults Older Males (60s)
Deletions: 13q14.3, 11q, 17q
Trisomy 12q
Starts in Lymph Nodes
CD19
CD20
CD23
CD5
Asymptomatic at diagnosis Small Ig spike present in some patients Hypogammaglobulinemia Hemolytic anemia/Thrombocytopenia Progression to Diffuse Large B cell Lymphoma (poor prognosis)
Proliferation Centers** (T cell aggregates)
Smudge cells
Follicular Lymphoma
Prognosis (2) Origin, Genetics (2) Morphology (3) Immunophenotype (6) Clinical Features (3)
Most common indolent non-hodgkin lymphoma
Incurable, survival 7-9 years
Starts in Lymph Nodes
t(14;18) IGH-BCL2 translocation**
MLL2 mutations
Centrocytes (small cleaved cells)
Centroblasts
Peritrabecular lymphoid aggregates in bone marrow
CD10, CD19, CD20
surface Ig
BCL6
BCL2*
Painless generalized lymphadenopathy
Waxing and waning course
Possible histologic transformation to Diffuse Large B cell lymphoma
Diffuse Large B Cell Lymphoma
Population, Pathogenesis (2) Morphology (2) Immunophenotype (3) Clinical Features (2) Prognosis (2)
Subtypes (2) with Descriptions (2/2)
Most common Non-Hodgkin Lymphoma*
Older males (median age 60)
BCL6 dysregulation
Or BCL2 rearrangements t(14;18)
Diffuse growth pattern
Large cells with round/oval nuclei, appear vesicular
CD19, CD20, surface Ig
Rapidly enlarging mass at nodal/extranodal sites
Waldeyer ring involvement
Aggressive, death if untreated
About half cured with aggressive chemo
Immunodeficiency-associated LBCL:
Associated with HIV
Caused by EBV infection
Primary Effusion Lymphoma:
Pleural/Ascitic effusion associated with HIV
Caused by KSHV/HHV-8
Burkitt Lymphoma
Populations (2) Origin, Genetics (2) Morphology (4) Immunophenotype (5) Prognosis (2)
Subtypes: Endemic (3), HIV-Associated, Sporadic (2)
Children
Young adults
Germinal centers
Translocation of c-MYC onto Chromosome 8
High mitotic index
Apoptotic cells
Phagocytes with clear cytoplasm (Starry sky pattern)
Blue cytoplasm with multiple nuclei (if in marrow)
CD10, CD19, CD20, IgM, BCL6
Aggressive, fastest growing tumor in humans
Curable with intense chemotherapy
Endemic: EBV associated, jaw mass, involves viscera
HIV-associated: aggressive
Sporadic: mass in illeocecum and peritoneum
Plasma Cell Neoplasms (Dyscrasias)
Most Common, Diagnostic Factors with Descriptions (2) Common Immunophenotype (2)
Multiple Myeloma
M Component in blood (monoclonal Ig)
Bence Jones Proteins (free light chains in urine)
CD138 (syndecan-1)
CD56
Multiple Myeloma
Pathogenesis (3) Morphology (5) Clinical Features (5) Diagnostic Features (3) Genetic Prognostics (4)
Rearrangements of the IgH locus - Cyclin D1 mutations
IL-6 keeps myeloma cells alive
MIP1a upregulates RANKL, causes bone resorption
Rouleaux Formation** (red cells stuck together)
Punched out bone lesions** 1-4 cm
Plasmablasts, Flame cells, Mott cells
Inclusions: Fibrils, Crystalline rods
Russell or Dutcher bodies (globular inclusions)
**Multiple Lytic bone lesions (Pathologic Fx)
Hypercalcemia (neuro Sx)
Renal failure (from Bence Jones)
Amyloidosis (from Bence Jones)
**Recurrent bacterial infections (main cause of death)
Bone marrow shows >30% atypical plasma cells
> 3g M proteins in blood (usually IgG or IgA)
> 6g Bence Jones proteins
Cyclin D1 translocations, good
13q, 17p t(4;14), bad
Solitary Myeloma (Plasmacytoma)
Description and Prognosis
Osseous and Extraosseous
Single bone lesion
Inevitably progresses to mutliple myeloma (10-20 years)
Extraosseous lesions often in upper respiratory tract
Cured via excision
Smoldering Myeloma Clinical Description (2) and Prognosis
Asymptomatic multiple myeloma-like syndrome
Serum M protein greater than 3g
Often progresses to MM over 15 years
Monoclonal Gammopathy of Uncertain Significance Clinical Description (2) and Prognosis
*Most common plasma cell disorder
Asymptomatic multiple myeloma-like syndrome
Serum M protein less than 3g
Per year ~1% of patients develop multiple myeloma
Lymphoplasmacytic Lymphoma
Population, Pathogenesis (3) Locations (4) Morphology (2) Immunophenotype (2) Clinical Features (4) Hyperviscosity Syndrome (4)
Presents in 60-70s
MYD88 gene mutations
Tumor cells undergo differentiation into plasma cells
Creates mostly monoclonal IgM
Starts in bone marrow
Moves to LNs, liver, spleen
PAS (+) Russell Bodies and Dutcher Bodies
CD20 Surface Ig (usually IgM)
Lymphadenopathy
Hepatosplenomegaly
Anemia
Autoimmune hemolysis by cold agglutinins
Waldenstrom Macroglobulinemia:
Visual impairment (from venous congestion)
Neurologic Problems
Bleeding
Raynaud’s Phenomenon (from cyroglobulinemia)
Mantle Cell Lymphoma
Population (2) Genetics (3) Morphology (3) Immunophenotype (4) Clinical Features (2) Prognosis (3)
Males in 50s and 60s
t(11;14) translocation of Cyclin D1-IgH locus
Causes Cyclin D1 overexpression
Nodal tumor cells surrounds germinal centers
Homogenous population of small lymphocytes with irregular, deeply clefted nuclear contours
Lymphomatoid Polyposis (GI mucosa involvement)
Cyclin D1
CD19
CD20
CD5
Painless lymphadenopathy
Hepatosplenomegaly
Poor prognosis with no cure
Worst Prognosis: Blastoid variant and Proliferative expression
Marginal Zone Lymphomas Pathologic Description (2), Common Features (3) Pathogenesis (3)
B cell lymphomas that arise in LN’s, spleen or extranodal tissues (MALTomas)
After spreading, can transform into diffuse large B cell lymphoma
Arise in areas of Chronic Inflammation
Remain localized for long periods
Regress if inciting inflammation eradicated (H. pylori)
Begins as polyclonal immune reaction
Acquired mutations allow cells to be Ag independent
Mutations upregulate BCL10 or MALT1
Hairy Cell Leukemia
Population, Mutation, Morphology, Immunophenotype (4) Clinical Features (4) Prognosis
Middle aged (55) white males
Activating BRAF mutations
Cells with fine hair-like projections
CD11c
CD25
CD103
Annexin A1
Splenomegaly
Pancytopenia
Atypical mycobacterial infections
Bone marrow aspiration yields “dry tap”
Mostly indolent, excellent prognosis
Peripheral T cell Lymphoma
Morphology (2) Immunophenotype (5) Clinical Features (5) Prognosis
Diffusely effaced lymph nodes
Pleomorphic mixture of malignant T cells
CD2, CD4, CD5, CD8
alpha-beta or gamma-delta T cell receptors
Generalized lymphadenopathy Eosinophilia Pruritis Fever Weight loss
Poor prognosis
Anaplastic Large Cell Lymphoma
Mutation (2) Morphology (4) Immunophenotype (2) Prognosis
ALK gene rearrangements on Chr 2p23
Hallmark Cells: Anaplastic cells with horseshoe shaped nuclei and voluminous cytoplasm
Cells cluster around venules
Cells infiltrate lymphoid sinuses
ALK (+) cells are diagnostic
CD30
Aggressive but good prognosis
Adult T cell Leukemia/Lymphoma
Pathogenesis (2) Morphology (2) Presentation (5) Prognosis (2)
Adults with Human T cell Leukemia Retrovirus-1 (HTLV1)
HTLV-1 encodes Tax protein that actives NFKB
Multilobated nuclei (cloverleaf/flower cells) CD4+ T cells
Skin lesions Generalized lymphadenopathy Hepatosplenomegaly Peripheral blood lymphocytosis Hypercalcemia
If only skin, indolent
If systemic, rapidly progressive, death within 1 year
Mycosis Fungoides and Sezary Syndrome
Common Immunophenotype (4)
Mycosis: Phases (3) Histology (2) Late Phase (1)
Sezary: Presentation, Disease Association (2)
CD4+ T cells
CLA adhesion molecule
CCR4
CCR10
Mycosis Fungoides:
Phases: 1) Premycotic 2) Plaque 3) Tumor
Neoplastic T cells in Epidermis and Upper Dermis
Cerebriform appearnce to epidermis/dermis
Late phase spread to lymph nodes and bone marrow
Sezary Syndrome:
Generalized exfoliative erythroderma
Leukemia with Sezary cells showing cerebriform nuclei
Large Granular Lymphocytic Leukemia
Mutation, Morphology (3) Immunophenotype (2) Clinical Features (2) Associated Syndrome (3)
STAT3 mutations
Either T cells or NK cells
Large lymphocytes with abundant blue cytoplasm
Coarse azurophilic granules
CD3 (T cells)
CD56 (NK cells)
Neutropenia
Anemia
Felty Syndrome: Rheumatoid arthritis, Splenomegaly, Neutropenia
Extranodal NK/T cell Lymphoma
Pathogenesis, Morphology (3) Presentation (2) Prognosis
Highly associated with EBV**
Cell infiltrate surrounds small vessels, ischemic necrosis
Large azurophilic granules
Mostly NK cells, less T cells
Destructive nasopharyngeal mass**
Or mass in testes/skin
Aggressive, responds well to radiation (no chemo)
Hodgkin Lymphomas
Populations (2) Origin/Spread (3) Pathogenesis (3) Prognosis
Most common cancer of teenagers
Usually presents in 30s
Arises in Lymph Nodes
Spreads to contiguous lymphoid tissues
Spreads to Spleen, then Liver, then Bone marrow
Activation of NFKB via:
EBV (cells express LMP-1)
IkB or A20 (TNFAIP3) mutations
Good prognosis with radiation therapy
Hodgkin Lymphomas Characteristic Morphology (2) with Common Variants (3) Immunophenotype (3) Clinical Features (3)
Reed Sternberg Cells: Multinucleated giant cells with inclusion-like nucleoli
Variants: Mononuclear, Lacunar cells, Lymphohistiocytic
PAX5
CD15
CD30
Painless Lymphadenopathy
Fever, night sweats, weight loss (disseminated disease)
Cutaneous immune anergy
Hodgkin Lymphoma Subtypes
Nodular Sclerosis Type
Pathogenenesis, Locations (2) and Morphology (3)
Most common
Not usually EBV associated
Starts in Lower Cervical and Supraclavicular LN’s
Lacunar cells
Few Reed Sternberg Cells
Deposition of collagen that divides up lymph nodes
Hodgkin Lymphoma Subtypes
Mixed Cell Type
Population, Morphology, Clinical Feature, Prognosis
Older Males
Plentiful Reed Sternberg cells
Presents with Advanced tumor
Very good prognosis
Hodgkin Lymphoma Subtypes Lymphocyte Rich Type Cells Involved (3) Clinical Features (2)
Reactive Lymphocytes
Mononuclear cells
Reed Sternberg cells
Often EBV associated
Good Prognosis
Hodgkin Lymphoma Subtypes
Lymphocyte Depletion Type
Populations (2) Cells Involved, Pathogenesis, Prognosis
Least common
Older adults
HIV (+) people
Reed Sternberg cells and their subtypes
EBV associated 90% of time
Least favorable prognosis
Hodgkin Lymphoma Subtypes
Lymphocyte Predominance Type
Population (2) Morphology (3) Immunophenotype (2) Clinical Features (3)
*Non-Classical HL
Males under 35
Lymphocytic and Histiocytic variant cells Multilobed nuclei (popcorn kernel cells) Expanded B cell follicles (nodular growth)
CD20
BCL6
Cerivcal and Axillary lymphadenopathy
Can transform into Diffuse Large B cell lymphoma
NOT EBV associated
Acute Myeloid Leukemia Major Subtypes (3) with Prognoses Genetic Aberrations (4) Pathogenesis (2) Causal Therapies (3)
AML with Genetic Aberrations: mostly good prognosis
AML with MDS-like Features: poor prognosis
Therapy-related AML: worst prognosis
t(8;21) RUNX1/ETO fusion*
inv(16) CBFB/MYH11 fusion*
t(15;17) RARA/PML fusion (best prognosis)
Karytotypic aberrations
Mutations of transcription factors of myeloid differentiation
Epigenetic alterations
After alkylator, radiation or anti-Topoisomerase II therapy
Acute Myeloid Leukemia
Diagnosis, Morphology (3) Immunophenotype (2) Clinical Features (6)
Requires bone marrow biopsy showing at least 20% myeloid blasts
Myeloblasts with peroxidase (+) azurophilic granules
Auer rod granules
Monoblasts that are esterase (+)
CD33 and CD34
Anemia: fatigue
Neutropenia: fever
Thrombocytopenia: Bleeding, bruising, Petechiae
Opportunistic infections
Tissue Infiltration: Leukemia cutis (monocytic differentiation)
Granulocytic sarcoma
Myelodysplastic syndromes
Etiologies (2) Mutations (4) Morphology (6) Clinical Features (3)
Primary - idiopathic
Secondary - genotoxic drugs or radiation
Similar epigenetic factors to AML
Mutations involving RNA splicing factors
Transcription factor mutations
TP53 mutations
Myeloblasts < 20%
Megaloblasts
Ring sideroblasts
Nuclear budding abnormalities: misshapen outlines
Pseudo Pelger Huet cells (bilobed neutrophils)
Pawn ball megakaryocytes
Mean age 70
Pancytopenia
Progression to AML
Myeloproliferative Disorders Common Pathogenesis (2) Common Clinical Description (4)
Mutated, constitutively activated Tyrosine Kinases
Cause growth factor independence
Increased bone marrow proliferation
Increased extramedullary hematopoiesis
Spent phase: marrow fibrosis, peripheral cytopenias
Transformation to acute leukemia
Chronic Myelogenous Leukemia
Population, Genetics (4) Origin, Morphology, Diagnosis (3) Clinical Features (4)
Adult males
Philadelphia Chromosome
(9;22)(q34;q11)
BCR-ABL fusion gene
Constitutively activated ABL tyrosin kinase
Originates from pluripotent HSC’s
Macrophages with wrinkled green-blue cytoplasm
Hypercellular marrow
Leukocytosis
Decreased Leukocyte Alkaline Phosphatase (LAP)
Insidious onset: mild anemia
Splenomegaly: abdominal fullness or pain
Hepatomegaly, lymphadenopathy
Blast crisis during late accelerated phase
Polycythemia Vera
Mutation (2) Morphology (2) Labs (5) Presentation (5) Treatment
Activating JAK2 point mutation
Causes upregulated RBC production
Increased red cell, granulocyte and megakaryocyte precursors
Spent phase: marrow fibrosis
Low EPO Elevated HCT Increased Red Cell Mass (hyperviscous blood) Leukocytosis Thrombocytosis
Major bleeding episodes* Venous thrombosis* Hyperuricemia Spent stage May progress to AML
Treat with phlebotomy
Essential Thrombocytosis
Mutations (2) Labs, Morphology, Diagnosis, Clinical Features (3) Treatment
Activating mutations in JAK2
Activating mutations in MPL
Isolated elevated platelet count (thrombocytosis)
Large platelets
Elevated megakaryocyte count on bone marrow biopsy
Erythromelalgia (burn/throb of hands/feet)
Bleeding
Thrombosis
Gentle chemo to stop thrombopoiesis
Primary Myelofibrosis
Mutations (2) Pathogenesis (2) Clinical Features (2) Blood Smear (2) Prognosis (2)
Activating mutations in JAK2
Activating mutations in MPL
Obliterative bone marrow fibrosis via non-neoplastic fibroblasts making collagen
Caused by PDGF and TGF-Beta from megakaryocytes
Normochomic normocytic Anemia
Prominent splenomegaly
Tear drop shaped RBC’s (dacrocytes)*
Leukoerythroblastosis*
Poor prognosis, hard to treat
Death via infections, bleeding abnormalities
Langerhans Cell Histiocytosis
Mutation, Common Morphology (2) Common Immunophenotype (2)
BRAF point mutation Val-Glu
Birbeck granules (pentalaminar tubules) Abundant cytoplasm, nuclei with linear grooves
CCR6
CCR7
Multifocal Langerhans Cell Histiocytosis (Letterer-Siwe) Clinical Features (7) Prognosis
Seborrheic eruption cutaneous lesions Chronic ottitis media Mastoiditis Hepatosplenomegaly Lymphadenopathy Lung lesions Bone lesions
Rapidly fatal if untreated (50% survive if treated)
Uni/Multifocal Unisystem Langerhans Cell Histiocytosis
(Eosinophilic Granuloma)
Morphology (2) Origin (3) Unifocal Clinical Description (2) Multifocal Clinical Description (5)
Langerhans cells mixed with eosinophils, lymphocytes, plasma cells, and neutrophils
Arises in medullary cavity of calvarium, ribs, femur
Unifocal painful bone lesions
Indolent, may resolve spontaneously or with excision
Multifocal erosive painful bone lesions
Presents in young children
Hand-Schuller-Christian Triad: Diabetes Insipidus, Exopthalmus, Calvarium defects
Pulmonary Langerhans Cell Histiocytosis
Etiologies (2)
Chronic smoking
BRAF mutations
