leukemia – pathology I

what are the functions of the bone marrow?
formation & release of blood cells (hematopoiesis), phagocytosis/degradation of circulating microorganisms and abnormal blood cells, antibody production, and reserve store of lipids
how does the production of hematopoietic cells progress over time?
they are produced in the embryo/fetus and number of cells produced increases until it reaches a steady state in adulthood. new cells are derived from hematopoietic stem cells (this process slows down as people age)
what does it mean to say that hematopoietic stem cells are pluripotent?
they can mature into several kinds of cells (myeloid/lymphoid)
what are the 2 lines that hematopoietic stem cells can go down?
myeloid (granulocytes and RBCs) and lymphocytes (B/T/NK cells)
what do bone marrow stromal cells do?
secrete growth factors/regulatory cytokines
what do IL-1 and 6 do in the bone marrow?
stimulate pluripotent stem cells
what do IL-3 and GM-CSF do in the bone marrow?
stimulate multipotent myeloid stem cells (makes sense, granulocytes/macrophages are from myeloid stem cells)
what does IL-5 do in the bone marrow?
stimulates eosinophils (E is the 5th letter of the alphabet)
what does thrombopoietin do in the bone marrow?
stimulates megakaryocytes to make platelets
what does erythropoietin do in the bone marrow?
stimulates RBCs
what are growth factors for B cells?
IL-2, IL-4, IL-5, IL-6, and IL-11
what are growth factors for T cells?
IL-2, IL-3, IL-4, and IL-10
where are most growth factors produced?
the bone marrow, except erythropoietin which is produced in the kidney (renal cell tumors often produce too much erythropoietin and will have a very high RBC mass)
how early on in development do hematopoietic stem cells appear?
19 days after fertilization in the yolk sac, and eventually form in erosions of bone and become the major site of hematopoiesis by the 6th month of gestation
where is a bone marrow bx performed?
on the PSIS or anterior illiac crest
what are the 2 main aspects of the bone marrow bx, and what is tested for each?
1) liquid aspirate is made in to smears (slides prepared bedside), some is heparinized in tube for ancillary studies, and some is allowed to clot, embedded with paraffin and H&E slides are made. 2) the core (bone marrow cylinder) is made into H & E slides
what do you not want to see in a bone marrow bx?
monotony of blue cells
how should myeloid stem cells appear in bone marrow bx?
mostly fine/granular nucleus, little cytoplasm, large cells
how should myeloblasts appear in bone marrow bx?
a little more cytoplasm, maybe a nucleolus – but still immature nucleus
what is the progression of neutrophils that should be visible in a bone marrow bx?
myeloid stem cell (very little cytoplasm) -> myeloblast (a little more cytoplasm) -> neutrophil promyelocyte (important in promyelocytic leukemia) -> neutrophil myelocyte -> neutrophil metamyelocyte (kidney bean shaped nucleus, with 1/3 indentation, a little less cytoplasm) -> neutrophil band (indented 1/2way)-> mature neutrophil (nucleus so bent it looks segmented)
how should eosinophils appear in a bone marrow bx?
bi-lobed nucleus (sunglasses) with bright orange-pink granules
how should basophils appear in a bone marrow bx?
solid, somewhat segmented nucleus. dark purple/blue granules
how do immature monocytes appear in a bone marrow bx? mature?
immature: wrinkled nucleus, mature: folded w/some convolution and scalloping around edges (often have vacuoles in cytoplasm)
how do megakaryocytes appear in a bone marrow bx?
many lobed nucleus, piled up. very large w/granulous cytoplasm.
what is the erythrocyte line?
pronormoblast, basophilic normoblast, polychromatic normoblast (more blue gray), orthochromatic normoblast (pink w/smaller nucleus), erythrocyte
can B and T cells be differentiated using a normal stain?
no
what is normal to see in a bone marrow bx?
heterogenous mix of various cells, megakaryocytes, erythroid precursors (very round/dark blue nuclei), myleoid precursors (more pale, more abundant in cytoplasm), and mature cells
what should make up a majority of of WBC?
segmented neutrophils
what make up the next majority in WBCs after segmented neutrophils?
lymphocytes @ 20-50%
what % are monocytes in the blood?
0-8%
what % are eosinophils and band cells in the blood?
both 5%
what % basophils should you see in the blood?
<1%
what is the CBC usually for leukemia?
almost always ABnormal which promotes further testing
where are abnormalites with leukemia?
at least 2 major lineages
what is the anemia associated with leukemia characterized by?
anemia associated with leukemia is usually normocytic and normochromic -> most pts are anemic because leukemic cells squeezing out normal RBC precursors (not a problem with RBC production, but with space for it to happen)
why is the leukocyte count in leukemia usually elevated (>50% of cases)?
because of circulating blasts
what is a problem with 20% of leukemia pts?
extremely high leukocyte count that can cause hyperviscosity (can cause leukostasis where neutrophils get stuck in microcirculation, lung, kidney where vasculature is smaller), leading the pt to need leukopheresis
what is leukapheresis? why is it done?
a procedure designed to selectively remove WBCs from the blood before chemotherapy, while returning RBCs and plasma
what kind of leukemia is leukapheresis particularly helpful with?
AML, where WBC counts over 100,000 can start causing aggregates in the lung, kidney and brain (leukostasis). kidney failure in particular is common with AML pts
what subtypes of AML have the highest risk of tissue aggregates elsewhere in the body?
acute myelomonocytic leukemia (AMML) which is abnormal myeloid cells of neutrophilic lineage and monocytes and acture monocytic leukemia (AMoL), which is almost entirely monoblasts or monocytes. these often form tissue masses, e.g. gingival masses
why is leukostasis less of a concern with ALL and CLL?
these cells tend to be smaller
where are immature myeloblasts found after centrifugation?
on the mononuclear cell layer just below the platelets
what are the main forms of leukocytes that we are concerned about in AML? how do they appear histologically?
myleoblasts and promyeloblasts. the myleoblasts appear with very large nuclei and little cytoplasm, and many have nucleoli and are all monotonous. the promyeloblasts have a little more cytoplasm with granules -> some of which form auer rods (indicative of leukemia)
what are the dx modalities used to assess leukemia?
routine histology, special stains & immunochemistry (biochemical stains/monoclonal antibodies specific for particular cells), flow cytometry, molecular studies – very important in leukemia (karyotyping, and florescence in situ hybridization (FISH) – maybe too many genes or abnormal genes))
what cells are positive for a myeloperoxidase stain (MPO)? what is a particular dx utility of this stain?
myeloid cells: neutrophils, monocytes, and eosinophils. this stain is useful if cells are so immature you’re not sure which lineage you are looking at (differentiate myeloid from lymphoid)
what is the sudan black stain B (SBB) stain used for? any dx utility?
this stain will be positive on neutrophils and monocytes and like with the MPO, it can help differentiate cells that are too immature to differentiated myeloid – lymphoid
what is the non-specific esterase stain for? does it have a diagnostic utility?
the NSE is sensitive for monocytes and and differentiate acute monocytic from monoblastic leukemia
what are the mainstay of diagnosing leukemias?
monoclonal antibodies which are designated by “CD” – cluster of designation
what antigen should all leukocytes have?
CD45
what are the major myeloid markers?
CD13,14,15,33,117
what are the major lymphoid markers?
*CD3 for T cells and *CD20 for B cells
what is a general blast marker?
CD34
what is a lymphoblast marker?
TdT – terminal deoxytransferase
what is flow cytometry?
a process by which a machine can read monoclonal antibodies fixed with fluorescent compounts and can tell what kind of cell it is, it can also determine cell size, and granularity (which scatters light more -> myeloid have more deflection of light).
how is flow cytometery read?
antibodies are usually used in tandem, so a scatter plot is used to show what cells have which antibodies or both
what is karyotyping?
comparison of corresponding bands on chromosomes – looking for parts of chromosomes that are missing, extra, translocated, deleted
what does “acute” leukemia refer to? chronic?
acute refers to a process involving immature cells (notably blasts). chronic refers to a process involving mature cells
what are the three categories of myeloid neoplasms?
acute myeloid leukemia, myelodysplastic disorders, and chronic myeloproliferative neoplasms. these have their origin in progenitor cells that give rise to differentiated cells of myeloid lineage
what makes up 70% if all acute leukemias?
AML, which is mostly seen in adults and usually has unknown etiology – some cases related to radiation, chemotherapy, chemical exposures or myelodysplasia
how does AML present clinically?
amemia (weakness & pallor), thrombocytopenia (bleeding/bruising), granulocytopenia (fever/infections), leukemic infiltrates (bone & joint pain), possible lymphadenopathy/hepatosplenomegaly, leukemic cells in CSF may lead to headache/confusion (less common with AML than ALL)
why are there -penias that present with AML?
this is due to the normal cells being squeezed out of BM by leukemic infiltrate
what is the baseline dx for AML?
>20% myeloid blasts in the bone marrow. this can usually be dx with routine histology if they have granules in the cytoplasm. if they don’t – special stains, flow cytometry – blasts usually CD34, CD117, and molecular studies can be used
what are auer rods specific for? what are the composed of? what are they most commonly seen in?
blasts of myeloid lineage. they are mainly composed of primary granules (only found in myeloid cells). ** they are most commonly seen in acute promyelocytic leukemia FAB, M3 (APL)
what are the chromosomal pairings that can result in AML?
t(8;21);CBFalpha/ETO fusion gene, inv(16);CBFalpha/MYH11 fusion gene, **t(15;17)RARalpha/PML fusion gene, and t(11q23;v);diverse MLL fusion genes. (CBF: core binding factor, MHY:myosin heavy chain, RAR:retinoic acid receptor, PML:promyelocitic gene, MLL:mixed leukemia)
how can FISH be used to analyze gene abnormalities leading to leukemia?
particular areas of the gene can be stained for and show atypical fusions
what are other classifications of AML?
AML with multilineage dysplasia (w/ or w/o prior myelodysplastic syndrom), AML that is therapy related (esp w/alkylating agents – seen w/breast CA pts w/o prior myelodysplastic syndrome, and AML that is not otherwise specified (categorized depending on degree of differentiation and maturation)
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