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262 Cards in this Set
- Front
- Back
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myeloid tissues
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bone marrow and cells derived from it (red cells, platelets, granulocytes, monocytes)
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lymphoid tissues
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thymus, lymph nodes, spleen
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when do blood cell progenitors first appear
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3rd week in yolk sac
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when do definitive hematopoietic stem cells arise
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few weeks later in mesoderm of intraembryonic aorta/gonad/mesonephros region
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what do HSC give rise to
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common lymphoid and common myeloid progenitors
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nurse cells
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macrophages that provide some of the iron needed for synthesis of hemoglobin for RBCs
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leukierythroblastosis
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abnormal release of immature precursors into peripheral blood
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normal ratio of fat to hematopoietic elements in normal adult
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~1:1
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when is inadequate or ineffetive granulopoiesis observed
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suppression of hematopoietic stem cells, suppression of committed granulocytic precursors via drug exposure, ineffective hematopoiesis, congenital conditions
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examples of suppression of hematopoietic stem cells
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aplastic anemia, infiltrative marrow disorders
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examples of ineffective hematopoiesis
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megaloblastic anemias and myelodysplastic syndromes-defective precursors die in marrow
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accelerated removal or destruction of neutrophils occurs with
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immuologically mediated injury, splenomegaly, increased peripheral utilization
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most common cause of agranulocytosis
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drug toxicity
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neutropenia caused by chlorpromazine and related phenothiazines results from
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toxic effect on granulocytic precursors in bone marrow
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agranulocytosis following administration of aminopyrine, thiouracil, and certain sulfonamides stems from
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antibody-mediated destruction of mature neutrophils through mechaisms similar to those in drug-induced immunohemolytic anemias
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hypercellular bone marrow
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compensatory due to high destruction in periphery; ineffective granulopoiesis
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what is a neutropenic patient at particularly high risk for
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deep fungal infections caused by Candida and Aspergillus
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when are serious infections most likely with low neutrophil values
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<500 per mm^3
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leukocytosis
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increase in number of WBC in blood
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what influences peripheral blood leukocyte count
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size of myeloid and lymphoid precursor and storage cell pools in bone marrow, thymus, circulation, and peripheral tissues; rate of release of cells from storage pools into circulation; proportion of cells adherent to blood vessels; rate of extravasation of cells from blood into tissues
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IL-5 stimulates
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eosinophil production
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G-CSF stimulates
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neutrophilia
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toxic granules
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coarser and darker than normal neutrophilic granules; represent abnormal azurophilic (primary) granules
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Dohle bodies
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patches of dilated endoplasmic reticulum that appear as sky blue cytoplasmic 'puddles'
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what cases may be difficult to distinguish reactive and neoplastic leukocytoses
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acute viral infections in children; severe infections
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neutrophilic leukocytosis causes
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acute bacterial infections; sterile inflammation (MI, burns)
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eosinophilic leukocytosis causes
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allergic disorders; skin diseases; parasitic infections; drug rxns; certain malignancies; collagen vascular disorders and some vasculitides; atheroembolic disease transiently
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Basophilic leukocytosis causes
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rare; myeloproliferative disease
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monocytosis leukocytosis causes
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chronic infections, bacterial endocarditis, riskettsiosis, malaria, collagen vascular disease, IBS
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lymphocytosis leukocytosis causes
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accompanies monocytosis in many disorders associated with chronic immunological stimulation; viral infections; bordetella pertussis infection
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morphology of lymphadenitis
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nodes swollen, gray-red, and engorged; prominence of reactive germinal centers with numerous mitotic centers
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follicular hyperplasia of nodes (chronic)
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due to stimuli that activate humoral immune responses; large oblong germinal centers surrounded by a collar of small restinf naïve B cells
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germinal centers in follicular hyperplasia
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1) dark zone containing proliferatinf blastlike B cells 2) light zone composed of B cells with irregular or cleaved nuclear contours
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tingible-body macrophages
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interspersed btwn germinal B centers and form an inconspicuous network of antigen-presenting follicular dendritic cells and macrophages; contain nuclear debris of B cells that underwent apoptosis
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causes of follicular hyperplasia
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RA, toxoplasmosis, early HIV infection
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Paracortical hyperplasia of nodes
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stimuli that trigger T cell-mediated immune responses like acute viral infections
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T-cells in paracortical hyperplasia
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activated T cells 3-4 times size of resting lymphocytes, several prominent nucleoli, and moderate amounts of pale cytoplasm
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sinus histiocytosis (aka reticular hyperplasia)
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increase in number and size of cells that line lymphatic sinusoids; may be prominent in nodes draining cancers like breast
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lymphotoxin
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cytokine required for formation of normal Peyer's patches; involved in establishment of extranodal inflammation-induced collections of lymphoid cells
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lymphoid neoplasms
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diverse group of tumors of B, T, and NK-cell origin
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Myeloid neoplasms
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arise from early hematopoietic progenitors
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3 categories of myeloid neoplasms
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acute myeloid leukemias, myelodysplastic syndromes, and chronic myeloproliferative disorders
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acute myeloid leukemias
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immature progenitor cells accumulate in bone marrow
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myelodysplastic syndromes
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associated with ineffective hematopoisis and resultant peripheral blood cytopenias
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chronic myeloproliferative disorders
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increased production of one or more terminally differentiated myeloid elements usually leading to elevated peripheral blood counts
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histiocytes
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uncommon proliferative lesions of macrophages and dendritic cells; ex Langerhan cells-immature dendritic
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MALToma genetic aberrations
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MALT1 or BCL10 gene=bind one another in protein complex that regulates NF-kB
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BCL6
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encodes transcription factor expressed in germinal center B cells-germinal B cells can't form without; must be turned off for germinal B cells to mature into memory or plasma cells
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what occurs once B cell has antigen stimulation
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enter germinal centers and upregulate activation-induced cytosine deaminase (AID)
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AID fxn
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specialized DNA-modifying enzyme essential for 2 types of Ig gene modifications: class switching and somatic hypermutation
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class switching
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intragenic recombination event in which IgM heavy chain constant gene segment is replaced with different constant segment allowing an isotype switch of antibody class
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somatic hypermutation
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creates point mutations within Ig genes that may by chance increase antibody affinity for antigen
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EBV cancer assocaition
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subset of Burkett lymphoma; 30-40% Hodgkin lymphoma, many B-cell lymphomas in setting of T-cell immunodeficiency, and rare NK-cell lymphomas
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HHV8 cancer associations
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Kaposi sarcoma, unusual B-cell lymphoma that presents as malignant effusion often in pleural cavity
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gluten-sensitive cancer assocaition
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T-cell lymphomas
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H pylori cancer association
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B-cell lymphomas
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leukemia
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neoplasms present with widespread involvement of bone marrow and peripheral blood (not always, but usually)
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lymphoma
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proliferations that arise as discrete tissue masses
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plasma cell neoplasms
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most often arise in bone marrow and only infrequently involve lymph nodes or peripheral blood
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most common plasma cell neoplasm and presentation
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multiple myeloma-causes bony destruction of skeleton and often presents as pain due to pathologic fractures
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5 broad categories of lymphoid neoplasms used by WHO
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1) precursor B-cell neoplasms 2) peripheral B-cell neoplasms 3) precursor T-cell neoplasms 4) peripheral T cell and NK-cell neoplasms 5) Hadgkin lymphoma
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Acute lymphoblastic Leukemia/lymphomas (ALLs)
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neoplasms of immature B or T cells; 85% are B-ALLs as childhood acute leukemias
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what occurs in 55-70% of all T-ALLs
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mediastinal thymic masses-also more likely to be associated with lymphadenopathy and splenomegaly
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B- and T-ALL morphology
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tumor cells have scant basophilic cytoplasm and nuclei somewhat larger than those of small lymphocytes; nuclear chromatin delicate and finely stippled-nucleoli absent/inconspicuous; high mitotic rate
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differentiating ALL from AML
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lymphoblasts have more condensed chromatin, less conspicuous nuclei, and smaller amounts of cytoplasm that usually lacks granules; diffinitive differentiation must be done with stains on antibodies specific for B and T cell antigens
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histochemical stains
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lymphblasts are myeloperoxidase-neg and often contain periodic acid-Schiff pos cytoplasmic material
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what is positive in more than 95% of B and T-ALLs
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immunostaining for terminal TdT (specialized DNA polymerase expressed only in B and T pre-lymphblasts)
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B-ALLs usually express
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pan B-cell marker B19 and transcription factor PAX5 and CD10 (CD10 neg in very immature B cells)
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more mature B-ALLs express ("late pre-B")
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CD10, CD19, CD20, and cytoplasmic IgM heavy chain
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most cases of T-ALLs express
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CD1, CD2, CD5, CD7
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late pre-T cell tumors express
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CD3, CD4, and CD8
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70% T-ALLs have what genetic gain-of fxn mutation
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NOTCH1
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loss of fxn mutations in B-ALLs
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PAX5, E2A, and EBF, or balanced (12;21) involving genes TEL and AML1
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clinical characteristics of ALLs
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abrupt stormy onset within days to few weeks of first symptoms; depression of marrow fxn; mass effects caused by neoplastic infiltration; CNS manifestations due to meningeal spread
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pediatric ALL prognosis
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95% obtain complete remission with aggressive chemo and 75-85% are cured; only 35-40% adults cured
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what indicates worse prognosis with ALLs
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age under 2 (translocations involving MLL gene); adolescence or adulthood; peripheral blood blasts >100,000; philadelphia chromosome (9;22)
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favorable indicators of ALL prognosis
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age 2-10; low white cell count; hyperploidy; trisomy of 4, 7, and 10; (12;21)
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t(9;22) aka philadelphia chromosome
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created fusion gene that encodes a constitutively acitve BCR-ABL tyrosine kinase
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Chronic lymphocytic leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
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differ only in degree of peripheral blood lymphocytosis; chronic is >4000 per mm^3
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CLL and SLL morphology
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lymph nodes diffusely effaced by infiltrate of predominately small lymphocytes 6-12 um with round to slightly irregular nuclei (condensed chromatin and scant cytoplasm)
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proliferation centers of CLL/SLL
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larger activated lymphocytes that often gather in loose aggregates = pathognomonic for CLL/SLL
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immunophenotype of CLL/SLL
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pan B-cell markers CD19 and 20 as well as CD23 and 5; low-level expression of surface Ig typical
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chromosomal translocations in CLL/SLL
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rare
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where is growth of CLL/SLL
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largely confined to proliferation centers-receive critical cues from microenvironment
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leukocyte count in CLL/SLL
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highly variable-leukopenia can be seen with SLL marrow displacement and counts in excess of 200,000 sometimes seen in CLL with heavy tumor burdens
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CLL/SLL and immune fxn
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disrupts normal fxn via uncertain mechanisms; hypogammaglobulinemia common
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what correlates with worse outcomes for CLL/SLL
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deletions of 11q and 17p; lack somatic hypermutation; expression of ZAP-70
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ZAP-70
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protein that augments signal produced by Ig receptor
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Richer syndrome
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CLL prolymphocytic transformation or transformation to diffuse large B-cell lymphoma (5-10% patients)
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prolymphocytes
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large cells with single prominent, centrally placed nucleolus
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Follicular lymphoma
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tumor arises from germinal center B cells and is strongly associated with chromosomal translocations involving BCL2
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2 principle cell types in follicular lymphoma
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1) small cells with irregular or cleaved nuclear contours and scant cytoplasm (centrocytes) 2) larger cells with open nuclear chromatin, several nucleoli, and modest amount of cytoplasm (centroblasts)
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other sites involved in follicular lymphom
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peripheral blood 10%, bone marrow 85%-paratrabecular lymphoid aggregates, splenic white pulp and hepatic portal triads
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neoplastic cells in follicular lymphoma express
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CD19, CD20, CD10, surface Ig, BCL6; CD5 NOT expressed; BCL2 in more than 90%
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translocation in follicular lymphoma
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(14;18) that juxtaposes IgH locus on chromosome 14 and BCL2 locus on chromosome 18
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presentation of follicular lymphoma clinically
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painless, generalized lymphadenopathy; incurable-waxing and waning course
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histologic transformation of follicular lymphomas
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30-50% occurance; usually to diffuse large B-cell lymphoma; survival less than 1 year
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Diffuse large B-cell lymphoma (DLBCL)
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most common NHL; relatively large cell size and diffuse pattern of growth
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what do DLBCL express
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CD19, CD20, variable expression of germinal center B-cell markers like CD10 and BCL6; most have surface Ig
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BCL6
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DNA-binding zinc finger transcriptional repressor that is required for the fomration of normal germinal centers; can suppress p53
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immunodeficiency-associated large B-cell lymphomas
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severe T-cell immunodeficiency; neoplastic B cells usually infected with EBV
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primary effusion lymphoma
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malignant pleural or ascitis effusion-mostly with HIV or elderly; anaplastic in appaearance and fail to express surface B or T-cell markers, clonal IgH rearrangements; HHV8 infected
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presentation of DLBCL
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rapidly enlarging mass at nodal or extranodal site, virtually anywhere in body; bone marrow involvement usually late in course
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outcome of DLBCL
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rapidly fatal without treatment; wth chemo 60-80% complete remission with 40-50% cured
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Burkitt lymphoma morphology
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diffuse infiltrate of intermediate-sized lymphoid cells with round/oval nuclei, coarse chromatin, several nucleoli, and moderate cytoplasm; high mitotic index with numerous apoptotic cells
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immunophenotype of Burkitt lymphoma
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mature B cells that express IgM, CD19, 20, 10, and BCL6; fails to express BCL2
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translocations in Burkitt lymphoma
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c-MYC gene on chromosome 8
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endemic burkitt lymphoma common presentation
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mass involving madible and shows unusual predilection for abdominal viscera, especially kidneys, ovaries, and adrenals
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sporadic burkitt lymphoma common presentation
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mass involving ileocecum and peritoneum; involvement of bone marrow and peripheral blood uncommon
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M component
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monoclonal Ig identified in blood-in reference to myeloma
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Bence-Jones proteins
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free light chains small enough to be excreted in urine
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what are associated with monoclonal gammopathies
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1) multiple myeloma 2) Waldenstrom macroglobulinemia 3) heavy-chain disease 4) primary or immunocyte-associated amyloidosis 5) monoclonal gammopathy of undetermined significance (MGUS)
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multiple myeloma
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presents as tumorous masses scattered throughout skeletal system
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Waldenstrom macroglobulinemia
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high IgM lead to symptoms related to hyperviscocity of blood; usually in older adults with lymphoplasmacytic lymphoma
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Heavy-chain disease
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rare; associated with lymphoplastic lymphoma and unusual small bowel marginal zone lymphoma in malnourished populations; synthesis and secretion of free heavy-chain segments
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Primary or immunocyte-associated amyloidosis
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monoclonal proliferation of plasma cells secreting light chains deposited as amyloid; some due to overt multiple myeloma
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multiple myeloma molecular specs
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Ig genes in myeloma cells show evidence of somatic hypermutation; post-germinal center B cell that homes to bone marrow and differentiates into plasma cell
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what cytokines is the proliferation and survival of myeloma cells dependent on
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IL-6
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MIP1alpha
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myeloma-derived; up-regulates expression of receptor activator NF-kB ligand (RANKL) by bone marrow stromal cells, thus activating osteoclasts
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common translocation in multiple myeloma
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FGFR (chromosome 4-cellular proliferation) and cell cycle regulatory genes cyclin D1 (chromosome 11) and cyclin D3 (chromosome 6); among others
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bones most commonly affected in multiple myeloma
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vertebral column, ribs, skull, pelvis, femur, clavicle, and scapula
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where do multiple myeloma lesions begin
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in medullary cavity, erode cancellous bone, and progressively destroy bone cortex
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appearance of bone lesions in multiple myeloma
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punched-out defects usually 1-4 cm and grossly consist of soft, gelatinous, red tumor masses
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cell variants in multiple myeloma
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flame cells, plasmablasts, Mott cells (multiple grapelike cytoplasmic droplets), other inclusions like fibrils, crystalline rods and globules
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Russell bodies (cytoplasmic) or Dutcher bodies (nuclear)
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globular inclusions
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rouleaux formation
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red cells in peripheral blood stick to one another in linear arrays on smears
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myeloma kidney
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bence jones proteins excreted and contribute to this in multiple myeloma-toxic to renal tubular epithelial cells
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hypercalcemia from multiple myeloma can cause
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neurologic manifestations-confusion, weakness, lethargy, constipation, polyuria; contributes to renal dysfunction
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most common Ig in multiple myeloma
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IgG 55%, IgA 25%; 1% nonsecretory
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marrow involvement in multiple myeloma causes
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normocytic and chromatic anemia, sometimes accompanied by moderate leukopenia and thrombocytopenia
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proteasome inhibitors as treatment in multiple mueloma
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induce cell death by exacerbating inherent tendency of misfolded proteins
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solitary myeloma (plasmacytoma)
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inevitably progresses to multiple myeloma-can take 10-20 yrs or longer; upper respiratory tract can be cured by recestion
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smoldering myeloma
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middle ground btwn multiple myeloma and monoclonal gammoathy of uncertain significance; plasma cells 10-30% marrow cellularity, serum M protein elevated, patients asymptomatic; 75% progress to multiple myeloma over 15 yrs
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monoclonal gammopathy of uncertain significance (MGUS)
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most common plasma cell dyscrasia; patients asymptomatic and serum M protein <3gm/dL; ~1% dvlp symptomatic plasma cell neoplasm per year
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lymphoplasmic lymphoma
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B-cell neoplasm of older adults; bears special resemblance to CLL/SLL-differs due to small fraction of tumor cells undergo terminal differentiation into plasma cells (usually monoclonal IgM)
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what does hyperviscosity due to IgM in lymphplasmic lymphoma cause
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Walden-Strom macroglobulinemia: visual impairment associated with venous congestion, neurologic problems, bleeding, cryglobulinemia
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immunophenotype of lymphoplasmacytic lymphoma
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B cell markers like CD20 and surface Ig; plasma cell component secretes same Ig that is expressed on surface of lymphoid cells; usually lack translocations
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clinical presentation of lymphoplasmacytic lymphoma
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nonspecific; half have lymphadenopathy, hepatomegaly, splenomegaly; anemia caused by marrow infiltration common; 10% autoimmune hemolysis caused by cold agglutinins
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cryglobulinemia
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results from precipitation of macroglobulins at low temps-produces symptoms like Raynaud phenomenon and cold uticaria
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lymphoplasmacytic lymphoma prognosis
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incurable progressive disease. Median survival 4 yrs
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Mantle cell lymphoma demographics
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uncommon; 5th to 6th decades; male predominance; tumor cells resemble normal matle zone B cells that surround germinal center
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what distinguishes mantle cell lymphoma from follicular and CLL/SLL
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large cells resembling centroblasts and proliferation centers are absent
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what form of lymphoma is most likely to have involvement of the small bowel or colon with polyp-like lesions (lymphomatoid polyposis)
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mantle cell lymphoma
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immunophenotype of mantle cell lymphoma
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high levels of cyclin D1; most also express CD19, 20 and moderately high levels of surface Ig; usually CD5+ and CD23- (helps distinguish from CLL/SLL)
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what causes cyclin D1 overexpression in mantle cell lymphoma
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(11;14) translocation involving IgH locus (14) and cyclin D1 locus (11); promotes G1 to S phase progression
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mantle cell lymphoma prognosis
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poor-median survival 3-4 yrs; not currently curable
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marginal zone lymphomas
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heterogeneous group of B-cell tumors that arise within lymph nodes, spleen, or extranodal tissues (eg MALTomas); most of memory B-cell origin
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Hairy cell leukemia
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rare, distinctive B-cell neoplasm; middle-age white males
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morphology of hairy cell leukemia
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leukemic cells have hairlike projections that are best recognized under phase-contrast microscope
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hairy cell leukemia and aspirations
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generally cannot be aspirated since enmeshed in ECM composed of reticulin fibers
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splenic red pulp in hairy cell leukemia
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heavily infiltrated leading to obliteration of white pulp and beefy red gross appearance; hepatic portal triads also involved frequently
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immunophenotype of hairy cell leukemia
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pan B-cell markers CD19 and 20, surface Ig (usually IgG), and certain relatively distinctive markers like CD11c, CD25, and CD103; somatic hypermutation (post-germinal center memory B-cell origin)
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clinical manifestation of hairy cell leukemia
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infiltation of bone marrow, liver, and spleen; massive splenomegaly; 1/3 present with infection
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prognosis of hairy cell leukemia
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excellent; sensitive to 'gentle' chemo drugs
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peripheral T-cell lymphoma, unspecified
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tumors efface lymph nodes diffusely; typically composed of pleomorphic mixture of variably sized malignant T cells; prominent infiltrate of reactive cells; brisk neoangiogenesis may also be seen
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immunotype of peripheral T-cell lymphoma, unspecified
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CD2, 3, 5, and either aB or gd T-cell receptors; some express CD4 or 8
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prognosis of peripheral T-cell lymphoma, unspecified
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cures have been reported, but prognosis significantly worse than comparable aggressive mature B-cell neoplasms
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Anaplastic Large-cell lymphoma (ALK positive)
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uncommon; rearrangements in ALK gene (chromosome 2)-fusion gene with constitutively active tyrosine kinases (trigger pathways like Jak/STAT); tend to occur in children or young adults; frequently involve soft tissues
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hallmark cells of Anaplastic Large-cell lymphoma
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horseshoe-shaped nuclei and columinous cytoplasm; often cluster around cenules and infiltrate lymphoid sinuses (mimicking metastatic carcinoma)
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what is a reliable indicator of ALK gene rearrangement
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detection of ALK protein in tumor cells, as it is not expressed in normal lymphocytes
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prognosis of Anaplastic Large-cell lymphoma
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good; cure rate 75% with chemo
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Adult T-cell leukemia/lymphoma
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neoplasm of CD4+ T cells; infection with HTLV-1; endemic in Hapan, west africa, caribbean basin
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common findings of Adult T-cell leukemia/lymphoma
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skin lesions, generalized lymphadenopathy, hepatosplenomegaly, peripheral blood lymphocytosis, and hypercalcemia
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appearance of tumore cells in Adult T-cell leukemia/lymphoma
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varies, but multilobed nuclei (cloverleaf or flower cells) frequently observed
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HTLV-1 and tumor pathogenesis
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encodes a protein Tax, that is a potent activator of NF-kB, which enhances lymphocyte growth and survival
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presentation/prognosis of Adult T-cell leukemia/lymphoma
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present with rapidly progressive disease fatal within months to 1 yr despite aggressive chemo; sometimes only invades skin
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Mycosis Fungoides/Sezary syndrome
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manifestations of CD4+ tumor cells that home to skin; 3 somewhat distinct stages (premycotic, plaque, and tumor phases); indolent course survival 8-9 yrs
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sezary syndrome
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skin involvement is manifested as generalized exfoliative erythroderma-skin lesions rarely progress to tumefaction
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what do tumor cells of Mycosis Fungoides express
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adhesion molecule CLA and chemokine receptors CCR4 and CCR10-contribute to homing to skin
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Large granular lymphcytic leukemia
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T and NK cell variants; mainly in adults; tumor cells large lymphocytes with abundant blue cytoplasm and few course azurophilic granules
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T cell and NK cell variants in Large granular lymphcytic leukemia
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T cell: Cd3+; NK cell: CD3- and CD56+
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prognosis of Large granular lymphcytic leukemia
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T cell origin indolent and NK variants more aggressive
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extranodal NK/T-cell lymphoma
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destructive nasopharyngeal mass is most common presentation; infiltrate surrounds and invades small vessels leading to extensive ishemic necrosis; associated with EBV
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prognosis of extranodal NK/T-cell lymphoma
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highly aggressive-respond well to radiation, resistant to chemo; poor prognosis with advanced disease
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Hodkin lymphoma (HL) progression
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arises in single node/chain of nodes and spreads first to anatomically contiguous lymphoid tissues
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Reed-Sternberg cells
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neoplastic giant cells; seen in HL; release factors that induce accumulation of reactive lymphocytes, macrophages, and granulocytes (make up >90% tumor cellularity); derived from germinal center or post-germinal center B cells
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5 subtypes of HL
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1) nodular sclerosis 2) mixed cellularity 3) lymphcyte-rich 4) lymphocyte depletion 5) lymphocyte predominance; first 4 reed-sternberg cells have similar immunophenotype=classical HL
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morphology of Reed-sternberg cells
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>45 um with multiple nuclei or single nucleus with multiple nuclear lobes-each with large inclusion-like nucleolus about size of small lymphocyte; abundant cytoplasm
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lacunar cells
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seen in noduar sclerosis subtype; more delicate, folded, or multilobate nuclei and abundant pale cytoplasm often disrupted during cutting of sections (leaves empty hole = lacuna)
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what conditions can have cells resembling Reed-sternburg cells in HL
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infectious mono, solid-tissue cancers, and large-cell NHLs
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diagnosis of HL
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identification of Reed-Sternberg cells in a typical prominent background of non-neoplastic inflammatory cells
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nodular sclerosis type of HL
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most common 65-70%; lacunar variant and deposition of collagen in bands that divide involved lymph nodes into circumscribed nodules' associated with EBV; excellent prognosis
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immunophenotype of Reed-sternberg cells in nodular sclerosis type of HL
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PAX5 (B-cell transcription factor), CD15, CD30, neg for other B cell markers, t-cell markers, and CD45
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Mixed cellularity type of HL
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20-25% cases; involved nodes diffusely effaced by heterogeneous cellular infiltrate; EBV 70%
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Lymphocyte-rich type of HL
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uncommon-reactive lymphocytes make up vast majority of cellular infiltrate; nodes usually diffusely effaced, but vague nodularity due to presence of residual B-cell follicles sometimes seen; EBV 40%
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lymphocyte depletion type of HL
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least common <5%; paucity of lymphocytes and relative abundance of Reed-sternberg cells or variants; EBV >90%; less favorable outcome
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why is immunotypeing in lymphocyte depletion type important
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most tumors suspected to be this type actually prove to be large cell NHLs
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lymphocyte predominance type of HL
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uncommon nonclassical variant ~5%; effaced by nodular infiltrate of small lymphocytes admixed with variable # macrophages; L&H variants instead of Reed-sternberg cells
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L&H (lymphocytic and histocytic) variants
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multilobed nucleus resembling popcorn kernal; express B-cell markers typical of germinal-center B cells (CD20, BCL 6, neg for CD15 and 30); no EBV association
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EBV and NF-kB
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express latent membrane protein 1 (LMP-1) that transmits signals that upregulate NF-kB
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example of cross talk of Reed-sternberg cells with surrounding reactive cells
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T cells express ligands that activate CD30 and CD40 receptors found on Reed-sternberg cells-produce signals that up-regulate NF-kB
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copy number gains of what are common in Reed-sternberg cells
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c-REL proto-oncogene on chromosome 2
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alkylating chemotherapeutics increase risk for
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AML and myelodysplasia
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myeloid neoplasms
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heterogeneous group with origin from hematopoietic progenitor cells; primarily involve marrow and lesser degree secondary hematopoietic organs
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3 broad categories of myeloid neoplasms
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Acute Myeloid leukemias, myelodysplastic syndromes, and myeloproliferative disorders
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Acute Myeloid leukemia
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accumulation of immature myeloid forms in bone marrow suppresses normal hematopoiesis
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myelodysplastic syndromes
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ineffective hematopoiesis leads to cytopenias
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myeloproliferative disorders
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usually increased production of one or more types of blood cells
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Acute Myeloid leukemia specs
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tumor of hematopoietic progenitors caused by aquired oncogenic mutations that impede differentiation, leading to accumulation of immature myeloid blasts in marrow; occurs at all ages-rises throughout life
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4 subdivisions of AML
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particular genetic abberations, arising after myelodysplastic disorder or with MDS-features, therapy -related AML, wastebasket category=lack other features
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diagnosis of AML
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presence of at least 20% myeloid blasts in bone marrow
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myeloblasts in AML morphology
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delicate nuclear chromatin, 2-4 nucleoli, and more voluminous cytoplasm than lymphoblasts; Auer rods in cytoplasm
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Auer rods
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distinctive needle-like azurophilic granules
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Monoblasts in AML
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folded/lobulated nuclei, lack auer rods, and are nonspecific esterase-positive
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number of leukemic cells in blood in AML
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highly variable; blasts may be >10000/mm^3 but are <10000 in half ppl; occasionally blasts absent from blood
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AMLs arising de novo in younger adults are associated with
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balanced chromosomal translocations (8;21), inv(6), and (15;17)
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AMLs following MDS or exposure to DNA damaging agents
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deletions or monosomies involving chromosomes 5 and 7 and usually lack translocations
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AML occuring after treatment with topisomerase II inhibitors
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translocations involving MLL gene on chromosome 11
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AML in elderly
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bad' aberrations like deletions of schomosomes 5 and 7
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what do (8;21) and inv(16) disrupt in AML
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CBF1-alpha and CBF1-Beta genes; encode polypeptides that bind one another to form a transcription factor required for normal hematopoiesis
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t(15;17) in acute promyelocytic leukemia
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creates fusion gene that encodes part of retinoic acid receptor-alpha (RARa) fused to protein called PML; results in inhibition of granulocytic maturation
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FLT3
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receptor tyrosine kinase that transmites signals that increase cellular proliferation and survival; commonly occurs with t(15;17), also with NPM (nucleophosmin) and c-KIT mutations
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ATRA (all-trans retinoic acid)
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bonds PML-RARa fusion protein and antagonizes inhibitory effect
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clinical presentation of AML
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fatigue, fever, spontaneous mucosal and cutaneous bleeding (similar to ALL)
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leukemia cutis
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tumors with monocytic differentiation infiltrate skin
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AML localized soft-tissue masses are known as
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myeloblastoma, granulocytic sarcoma, or chloroma
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good prognostic indicators in AML
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(8; 21) or inv(6); absence of c-KIT mutations
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Myelodysplastic syndromes (MDS) specs
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clonal stem cell disorders characterized by maturation defects associated with ineffective hematopoiesis and high risl of transformation into AML
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MDS chromosomal aberration associations
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monosomies 5 and 7, deletions of 5, 7, and 20, and trisomy 8
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marrow in MDS
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usually hypercellular at diagnosis, sometimes normocellular or less commonnly hypocellular; disordered differentiation affecting erythroid, granulocytic, monocytic, and megakaryocytic lineages
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erythroid series in MDS
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ringed sideroblasts (iron-laden mitochondria); megaloblastoid maturation-resembles B12 and folate deficiencies; nuclear budding abnormalities
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neutrophils in MDS
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decreased secondary granules, toxic granulations, and/or Dohle bodies; pseudo-pelger-huet cells
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pseudo-pelger-huet cells
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neutrophils with only 2 nuclear lobes
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pawn ball megakaryocytes
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single nuclear lobes or multiple separate nuclei
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myeloid blasts in MDS
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may be increased, but <20% marrow cellularity; <10% leukocytes in blood
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myeloproliferative disorders specs
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presence of mutated, constitutively activated tyrosine kinases; GF independent proliferation and survival of marrow progenitors; don not impair differentiaton=increase production of one or more mature blood elements
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Chronic Myeloid leukemia (CML)
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presence of chimeric BCR-ABL gene derived from portions of 22 (BCR) and 9 (ABL); 90% philadelphia chromosome
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morphology of CML
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marrow markedly hypercellular-increased #maturing granulocytic precursors; megakaryocytes increased with small, dysplastic forms; scattered macrophages with abundant wrinkled, green-blue cytoplasm; increased deposition of reticulin
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blood in CML
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leukocytosis often over 100,000 cells/mm^3: predominately neutrophils, band forms, metamyelocytes, myelocytes, eosinophils, and basophils; blasts <10% blood cells; platelets increased
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Ikaros
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transcription factor that regulates differentiation of hematopoietic progenitors; 85% CML associated with mutations in
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imatinib
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BCR-ABL inhibitor; diminishes BCR-ABL pos cells in marrow and elsewhere, but does not extinguish hematopoietic stem cell
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polycythemia vera (PCV)
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increased marrow production of RBCs, granulocytes, and platelets; RBC increase responsible for most symptoms; activating point mutations in tyrosine kinase JAK2
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JAK2
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participates in JAK/STAT pathway, which lies downstram of multiple hematopoietic GF receptors (including erythropoietin receptor)
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2 mutated copies of JAK2 in PCV leads to
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higher WBC counts, more significant splenomegaly, symptomatic pruritis, and greater rate of progression to the spent phase
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morphology of marrow in PCV
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hypercellular, but residual fat usually present; moderate to marked increase in reticulin fibers in 10%
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why does intense pruritis and peptic ulceration occur in PCV
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release of histamine from basophils
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what does high cell turnover cause in PCV
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hyperuricemia-gout in 5-10% cases
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huge consequences of PCV
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bleeding or thrombosis
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spent phase of PCV
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obliterative fibrosis in marrow and extensive extramedullary hematopoiesis, especially spleen
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essential thrombocytosis (ET)
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point mutations in JAK2 (50%) or MPL (5-10%); elevated platelets, absence of polycythemia and marrow fibrosis
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MPL
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receptor tyrosine kinase that is normally activated by thrombopoietin
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what must be excluded before diagnosis of ET when JAK2 or MPL intact
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reactive thrombocytosis (inflammatory disorders and iron deficiency)
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bone marrow in ET
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cellularity only mildly increased; megakaryocytes increased and include abnormally large forms
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peripheral smears in ET
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abnormally large platelets, often accompanied by mild leukocytosis
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erythromelalgia
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throbbing and burning of hands and feet caused by occlusion of small arterioles by platelet aggregates; seen in PCV and ET
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primary myelofibrosis
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dvlp obliterative marrow fibrosis; cytopenias and extensive neoplastic extramedullary hematopoiesis; histologically similar to spent phase of other myeloproliferative diseases
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molecular pathogenesis of primary myelofibrosis
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JAK 2 (50-60%), activating MPL (1-5%)
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cause of primary myeloofibrosis
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fibrogenic factors released from neoplastic megakaryocytes causing ectensive deposition of collagen by non-neoplastic fibroblasts
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what factors from megakaryocytes may be cause for fibrosis in primary myelofibrosis
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PDGF and TBF-B
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Primary mylofibrosis vs PCV and ET
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nor clear whether truly distinct or merely reflects unusually rapid progression to spent phase
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osteosclerosis
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fibrotic marrow space converted into bone
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histiocytosis
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umbrella' designation for variety of proliferative disorders of dendritic cells or macrophages
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Langerhans cell histiocytosis
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abundant, often vacuolated cytoplasm and vesicular nuclei containing linear grooves or folds; presence of Birbeck granules in cytoplasm
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birbeck granules
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pentalaminar tubules, often with dilated terminal end producing a tennis racket-like appearance, which contain protein langerin
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what do langerhan cell histiocytes express
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HLA-DR, S-100, and CD1a
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clinicopathological entities of langerhan cell histoicytes
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1) multifocal multisystem (letterer-siwe disease) 2) unifocal and multifocal unisystem (eosinophilic granuloma) 3) pulmonary
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multifocal multisystem (letterer-siwe disease)
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before 2 yrs age, occasionally adults; cutaneous lesions resembling seborrheic eruption; rapidly fatal, intensive chemo 50% survive 5 years
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unifocal and multifocal unisystem (eosinophilic granuloma)
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eosinophils usually prominent infiltrate; arises in medullary cavity of bones (calvarium, ribs, femur)
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unifocal lesions
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commonly affect skeletal system in older children/adults; may heal spontaneously or cured by excision/irradiation
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multifical unisystem disease
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young children; present with multiple erosive bony masses that sometimes expand into adjacent soft tissue; posterior pit involvement 50%
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HandSchuller-Christian triad
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calvarial bone defects, diabetes insipidus, and exophthalmos
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Pulmonary Langerhans cell histiocytosis
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adult smokers; may regress spontaneously on smoking cessation; polyclonal population of langerhan cells-reactive hyperplasia rather than true neoplasm
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