myeloproliferative disorders pathology

how is a suspected myelodysplastic syndrome/myeloproliferative neoplasm evaluated?
peripheral blood smear, bone marrow aspirate, bone marrow trephine bx, blasts, cytochemistry/special stains, immunophenotype, and genetic studies
what are the myeloproliferative disorders?
CML (not truly considered a leukemia), chronic neutrophilic leukemia (rare), polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic eosinphilic leukemia, mastocytosis, and MPN (unclassifiable)
what are characteristics of myeloproliferative disorders?
usually increased bone marrow cellularity, slightly increased blasts (<10%), normal morphology, effective hematopoiesis, CBC (increase in 1+ cell lines), organomegaly common, abnormalities in tyrosine kinases (proliferation)
what is the myeloperoxidase stain sensitive for?
cells of myelioid lineage via the golgi(early monoblasts may not respond)
what does sudan black B stain for?
it is like a less specific myeloperoxidase stain, (sometimes picks up lymphoblasts)
what do the non-specific esterases stain for?
mostly monoblasts/monocytes
what is the naphthol-ASD-chloroacetate esterase stain for?
neutrophil lineage/mast cells
what gene is mutated in CML?
abl1 to the bcr gene
what is the prototypical myeloproliferative and most common disorder? what age are people that get it typically?
CML, 50-60
will you see increased basophils with CML?
yes (one in almost every field)
will many fat globules be see in CML bone marrow?
no – “chock full of cells” – but normal maturation
what are the three phases of CML? what happens w/o tx?
chronic, accelerated and blast phase; this progression will happen w/o tx
when are most pts diagnosed with CML? what are symptoms?
chronic phase. it may be asymptomatic, (but incidental CBC shows abnormal WBC). signs and symptoms may include fatigue, weight loss, night sweats, splenomegaly and anemia
why is the philadelphia chr important?
it was the first real genetic signature of malignancy, an abnormal tyrosine kinase growth advantage to normal cells
what is the characteristic chromosome translocation associated with the phila chr? is it related to any other diseases?
t(9:22) BCR-ABL, (but if it breaks down farther on the gene it can result in ALL)
where is the BCR gene? ABL1? what does this result in?
BCR is on chr 22 and ABL1 is on chr 9; resulting in an activated tyrosine kinase which gives malignant cells a growth advantage (therapeutic target)
what is the LAP score?
leukocyte alkaline phosphatase is a marker of terminally differentiated neutrophils. if it is low, it indicates an abnormal neutrophil development -> associated with CML and PNH
what does a low LAP score mean?
CML
what is the chronic phase of CML characterized by?
leukocytosis (median WBC: 100×10^9 -> mainly neutrophils), blasts <2% of WBCs, platelet count normal/increases, *megakaryocytes small/hypolobated, mild anemia, and basophilia
what is the basophilic peripheral %?
equal or >20%, also possibly prominent eosinophils
what is the accelerated phase of CML characterized by?
myeloblasts accounting for 10-19% of peripheral WBC count and peripheral blood basophils equal or >20% and EITHER thrombocytopenia OR thrombocytosis. WBC increase/spleen size will not be responsive to rx. there is evidence of clonal evolution
what is the blast phase of CML characterized by?
blasts equal or >20% of peripheral WBC/BM. this is the transition into AML or ALL. there is extramedullary proliferation of blasts and aggregates of blasts in the BM
what are 2 visible signs of CML?
enlarged spleen and “pseudo-gaucher/sea-blue histiocytes” (which are due to high cell turnover in BM)
what is tx for CML?
gleevec: manages malignant clone, does not cure it. bone marrow transplant: only potential cure (wipe out/destroy malignant clone, replace with donor myeloid precursors -> risky)
what if the M/A of gleevec?
gleevec (imatinib mesylate) competitively inhibits the inactive enzyme leading to configuration of BCR-ABL, by *blocking the ATP site (preventing the active form). this inhibits cell proliferation and will decrease up to 98% of CML colony growth w/o decreasing normal growth
can gleevec cure CML? what is primary/secondary resistance?
no, it just keeps normal myeloid elements at a sustainable level and reduces cytogenic expression of the fusion gene. primary resistance is when gleevec fails to achieve an initial response, secondary is when pts develop resistance to subsequent tx (due to reactivation of BCR-ABL, or alternate pathways). resistance is most likely to occur in the blast phase
what is a good way of monitoring CML progression?
molecular studies; accelerated/blast phase pts may have additional Ph chr or other altered genes
what is chronic neutrophilic leukemia?
this may be associated with multiple myeloma and is essentially sustained neutrophilia w/o any other cause. it presents with hepatosplenomegaly/gout/pruritis. very rare: diagnosis of excusion – WBC >25 has to be sustained. genetics are normal in 90%
what is polycythemia vera?
a chronic myeloproliferative neoplasm with *increased RBC production – independent of normal erythropoiesis (erythropoiten is going to be low). **almost all** have JAK2 V617F mutation (or a variant thereof)
what are symptoms of pts with polycythemia vera?
increased red cell mass and panmyelosis (other myeloid cells). there are symptoms related to HTN/vascular abnormalities due to increased red cell mass such as venous/arterial thrombosis, MI or stroke and portal-splenic thrombosis (budd-chiari syndrome)
what are JAK-2 mutations specific to?
myeloid neoplasms. chr 9p. janus kinase family – normally involved in signaling by cytokine receptors of hematopoietic cells (conquers proliferation damage)
what are *major diagnostic criteria for polycythemia vera?
hgb >18.5 men and >16.5 women (can be juked with dehydration). presence of JAK2 mutation (no BCR-ABL1) and no cause of secondary erythropoiesis (elevation of EPO due to hypoxia, high O2 affiniy Hb, or EPO production by a tumor), and splenomegaly
what are *minor diagnostic criteria for polycythemia vera?
bone marrow hypercellularity (trilineage growth), serum erythropoietin below reference range, and endogenous colony formation in vitro.
what are the phases of polycythemia vera?
prodomal/prepolychythmic: only mild erythrocytosis. overt polycythemic: significantly increased RBC mass. and spent phase: myelofibrosis, pancytopenia, and extensive marrow fibrosis.
what is the prognisis for pts with polycythemia vera?
survival: >10 yrs, most pts die of thrombosis. up to 20% develop MDS or leukemia, (if treated with cytoxic therapy, risk of progression is higher than if not)
what is budd-chiari syndrome?
most commonly caused by polycythemia vera, this is thrombotic/non-thrombotic obstruction to hepatic venous outflow. this can lead to hepatomegaly, ascites, and abdominal pain (high mortality)
what might pts with budd chiari syndrome present with?
icterus, ascities, hepatomegaly, splenomegaly, ankle edema, stasis ulcerations, and prominence of collateral veins
what do the acute and chronic forms of budd chiari syndrome cause?
acute: hepatic vein thrombosis (often fatal) chronic: cirrhosis/formation of collateral veins
what is primary myelofibrosis major?
proliferation of megakaryocytes (they aren’t squeezed out yet) with *reticulin and *collagen fibrosis that *does not meet criteria for CML, PV, or MDS. JAK2 is often involved.
what is primary myelofibrosis minor?
leukoerythroblastosis (immature neutrophil forms/RBCs in peripheral blood), increased serum LDH, anemia and palpable splenomegaly
how do RBCs in primary myelofibrosis appear?
pear shaped from squeezing out of fibrotic bone marrow
what is the correlation between primary myelofibrosis and JAK2 V617F mutations? can it progress to AML?
about 50% of pts have both. AML progression occurs in 5-30% of cases
what is essential thrombocythemia?
platelet count >450×10^9. it features megakaryocyte proliferation with large and mature morphology. it should not meet criteria for CML, PV, PMF, MDS, or other myeloid neoplasms. JAK 2 is a clonal marker in 40-50% of cases
how do pts with essential thrombocytothemia present?
spenic/hepatic vein thrombosis. they may have vascular occlusion hemorrhage, or bleeding from mucosal surfaces, GI tract, and upper airways
how are megakaryocytes in essential thrombocytothemia differentiated from those in CML?
essential thrombocytothemia: huge, hyperlobated. CML: micro-megakaryocytes
what are the criteria for post-essential thrombocytothemia myelofibrosis?
documentation of essential thrombocytothemia and a high bone marrow fibrosis grade
are platlets produced in essential thrombocytothemia functional?
many of them do not work very well
what is chronic eosinophilic leukemia (very rare)?
a persistent eosinophil count of >1.5×10^9. it cannot be releated to previous genetics or allergies, neoplasms w/secondary eosinophilia (T cell lymphomas, HD, ALL, mastocytosis), or a myeloproliferative dx. evidence of clonality should be available (ie X-linked polymorphism analysis of PGK or HUMARA genes)
how can chronic eosinophilic leukemia cause organ damage?
abnormal release of cytokines, IL-2,3,5, GM-CSF
how do cells appear histologically in chronic eosinophilic leukemia?
sparse granulation, cytoplasmic vacuolation, nuclear hyper/hypo-segmentation and enlarged size
what is hypereosinophilic syndrome?
a persistent eosinophil count (1.5×10^9) for 6 mos with no other explanation for eosinophilia and no evidence of clonality (polyclonal)
what is mast cell disease?
a clonal proliferation of mast cells in one or more organ systems – any age and 80% have skin involvement
what is cutaneous mastocytosis?
histological proof of abnormal mast cells in the dermis with NO evidence of systemic involvement. this may show uriticaria if the skin is stroked and there is intrapepidermal pigment accumulation (urticaria pigmentosa)
what happens in systemic mastocytosis?
fatigue, weight loss, skin manifestations, cytokine mediator events (GI distress/respiratory distress), musculoskeletal (myalgias, osteopenia), and organomegaly
what is diagnostic criteria for systemic mastocytosis?
dense infiltrates of mast cells in the marrow and serum tryptase exceeding 20 ng/mL (part of inflammatory mast cell secretion)
what is chronic myelomonocytic leukemia actually considered?
a myelodysplasia/myeloproliferative disease
what are characteristics of chronic myelomonocytic leukemia (CMML)?
persistent peripheral blood monocytosis >1×10^9, no phila chr, fewer than 20% blasts in the blood/bone marrow (not actually considered leukemia), it seen in older adults, and dysplasia is in 1+ myeloid lineages. rare.
how do pts with chronic monocyic myelomonocyic leukemia present?
fatigue, weight loss, fever, and night sweats. WBC count is increased at time of dx
what is the difference between CMML-1 and 2?
there are increased blasts in the blood in CMML-2 (BUT >20% in the bone marrow – AML)
what is juvenile myelomonocytic leukemia?
JMML is a disease in children where there is proliferation of granulocytic and monocytic lineages. 10% of cases are associated with neurofibromatosis type 1. (similar to CMML)
what are dx criteria for JMML?
peripheral blood monocytosis >1×10^9, blasts <20% of leukocytes, no phila chr, hemoglobin F increased for age and clonal chromosomal abnormality (monosomy 7 in the neoplasm)
what is neurofibromatosis type 1?
cafe au lait spots, lisch nodules, optic gliomas, intellectual handicap and 200-500x risk of developing a myeloid malignancy
what is myelodysplasia?
a group of hematopoietic stem/multipoten cell diseases w/dysplasia and ineffective hematopoiesis in 1+ myeloid line. there may be an increase in myeloblasts, and if it goes >20% = AML
what is seen with myelodysplasia?
usually increased bone marrow cellularity, normal/increased blasts <20%, maturation of cell lines, dysplasia of 1+ myeloid lineages, ineffective hematopoiesis, CBC w/cytopenias, but organomegaly is uncommon
how does peripheral blood appear in dysplasia?
RBCs are oval, discolored, dimorphic, nucleated. granulocytes are degranulated or have abnormally large granulesand pseudo pelger heut change (bilobed nuclei in neutrophils). platelets have giant forms and hypogranulation
how does bone marrow appear in dysplasia?
RBCs: megaloblastoid change, nuclear budding, and numerous howel-jolly bodies (fragments of the RBC nucleus that should have been removed by the spleen). granulocytes: degranulation, abnormally large granules, pseudo pelger heut change (bilobed nuclei in neutrophils), and increased blast count. megakaryocytes: micromegakaryocytes, hyper/hyplobation of nuclei, abnormal clustering and paratrabeular location
what are signs of dysplasia in RBC lineage?
vaculated cytoplasm, extensions, and ringed sideroblasts, multiple howell jolly bodies, lobated nucleus, nuclear-cytoplasmic dysynchrony, multinucleation and basophila stippling
are ringed sideroblasts always pathologic?
yes. the majority of iron entering RBCs is incorporated into heme, the rest should be stored as ferritin
how do sideroblasts form?
problems with ala-dehydrase which incorporates iron into the mitochondria for heme formation. this leads to a build up of iron around the nucleus (same ring formed by mitochondria)
what are some things that can lead to sideroblasts?
lead poisoning and beta thalassemia
how do myelodysplasia syndromes present clinically?
anemia refractory to iron therapy, symptoms of bone marrow if pancytopenia: infections secondary to neutropenia, mucosal bleeding due to thrombocytopenia
what is refractory anemia?
anemia with no or rare blasts (<5%) and <15% ringed sideroblasts due to erythroid dysplasia
what is refractory anemia with ringed sideroblasts (RARS)?
anemia with 15%+ ringed sideroblasts and erythroid dysplasia <5% blasts
what is refractory anemia? who does it happen to? what has to be ruled out? what is the risk of progression to acute leukemia?
refractory anemia is dysplasia in the erythroid line, it is uncommon but if seen, it is in older adults. other causes such as drugs that might be causing the dysplasia should be ruled out and it can take a protracted clinical course. progression to acute leukemia is low.
what is refractory anemia w/ringed sideroblasts? who does it happen to? what has to be ruled out? what is the risk of progression to acute leukemia?
refractory anemia w/ringed sideroblasts is a dysplasia only found in the erythroid line, it accounts for 10-12% of MDS cases, is seen in older adults and has an over all expected survival of ~ 6 yrs. progression to acute leukemia is low (1%)
what is refractory cytopenia with multilineage myeloid displasia (RCMD)?
dysplasia is seen in 10%+ of cells in 2+ myeloid lines and there are <15% ringed sideroblasts, no auer rods, and <5% blasts in the marrow. it accounts for 24% of MDS cases, is a disease of older adults, there are cytogenetic abornalities half the time and overall survival is ~33 mos. progression to acute leukemia is ~11%
what is refractory cytopenia with multilineage myeloid displasia and ringed sideroblasts? (RCMD-RS)?
dysplasia in 10%+ of the cells of 2+ myeloid cell lines and *>15% ringed sideroblasts. there are also no auer rods and <5% blasts in the marrow.
what are refractory anemia with excess blasts-1 and 2?
RAEB-1 is 5-9% blasts and no auer rods, RAEB-2 is 10-19% blasts and *auer rod +/-. progression to AML is 25-30% likely. overall survival is 10-18 mos
what is MDS with 5q?
unilineage dysplasia, <5% blasts and no auer rods. it is seen in middle-aged to elderly women, symptoms are related to severe anemia, survival should be long, and progression to leukemia is rare (except if additional chr abnormalities)
how is MDS treated?
consideration of co-morbities (esp in elderly), supportive care, RBC transfusions (iron overload can lead to secondary hemaochromatosis, caridac + liver complications), iron chelation, hematopoietic growth factors, and chemo (not if potential for leukemia)
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