| What is PF? | Proliferation of abnormal clone of hematopoietic stem cell in bone marrow and other sites results in fibrosis.
Myelofibrosis is a form of myeloid metaplasia, which refers to a change in cell type in the blood forming tissue of bone marrow, progressive scarring or fibrosis of bone marrow occurs, results in extramedullary hematopoiesis.
Anemia, with enlarged spleen the blood film with leukoeryt |
| How is hematopoiesis? | . |
| What is acute leukemia? | Disease of neoplastic leukocytes, predominance of immature forms especially blasts (myelo/lymphoblasts)- disease defined by >20% blasts in bone marrow.
Symptoms due to marrow failure secondary to leukemia infiltration causing pancytopenia (anemia, leukopenia, and thrombocytopenia) |
| What are etiologies of acute leukemia? | Chromosomal abnormalities (down syndrome)
ionizing radiation, chemical exposures, topoisomerase agents (chemotherapy), age. |
| What are subtypes of acute leukemia? | Acute myeloid leukemia (disease of immature granulocytes, seen in young to middle-age adults (15-60 yrs).
Acute lymphocytic leukemia (disease of immature lymphocyte [pre-B and pre-T ALLs], typically seen in children [0-15 yrs] number 1 leukemia of this age) |
| How is pathogenesis of acute leukemia? | Recurrent cytogenetic abnormalities (t(15;17) - acute promyelocytic leukemia [M3]
t(8;21) - acute myelobastic leukemia w/maturation [M2],
11q23 abnormalities
Genetic abnormalities lead to defects in stem cell maturation and clonal expansion of leukemic blasts |
| How is morphology of cells in acute leukemia? | Abnormal myeloid blasts (large nuclei and prominent nucleoli, APL (M3) [cytoplasmic granules w/occasional Auer rods, Azurophilic granules stain w/Ab against MPO] |
| How is the classification of AML? | M0 (undifferentiated)
M1 (AML w/out maturation)
M2 (w/maturation)
M3 (acute premyelocytic leukemia APL)
M4 (myelomonocytic)
M5 (moncytic/monoblastic - show gingival hypertrophy)
M6 (erythroleukemia)
M7 (megakaryoblastic leukemia) |
| What are symptoms of AML? | Weakness, pallor, fatigue [normocytic anemia], infection susceptibility [leukopenia], easy bleeding/bruising [thrombocytopenia], bone pain [marrow infiltration].
Clinical pathology of M3 (APL) associated with DIC can be effectively treated with all-trans retinoic acid (ATRA) |
| What is tx of acute myeloid leukemia? | Intensive chemo, induction chemo w/AraC and daunorubicin, consolidation therapy [2-3 courses of intensive chemo given each time blood count recovers].
Stem cell transplantation [high-risk disease pt, or if there is disease relapse] |
| How is pathogenesis of ALL? | defective maturation of lymphocyte precursors, pre-B or pre-T ALL, can be extramedullary (lymphoblastic lymphoma), metastasizes to CNS/testicles |
| How is morphology in ALL? | >20% lymphoblasts, smaller than myeloblasts w/large nuclei and scant, basophilic cytoplasm |
| What are differences between pre-B and pre-T ALL? | . |
| What are prognostic features of ALL? | . |
| What are chromosomal abnormalities in ALL? | . |
| How is tx of ALL? | Very complex involves blocks of chemotherapy given for 2-3 years, initial chemo kills off the great majority of tumor cells and achieves a normal blood count (remission induction)
Further courses of intensive chemo help remove the few remaining tumor cells (consolidation)
Finally, less intensive tx given for 1-2 years as maintenance tx. |
| What are chronic leukemias? | Chronic leukemias are derived from more mature leukocytes, these include: chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, and adult T cell leukemia/lymphoma. |
| What is chronic myelogenous leukemia (CML)? | presence of philadelphia chromosome t(9,22), results of fusion of BCR and ABL genes, ABL gene is tyrosine kinase that controls cell growth, BCR/ABL fusion protein results in increased, unregulated activity of ABL leading to uncontrolled growth of maturing myeloid cells |
| How is morphology in CML? | Peripheral blood shows leukocytosis w/increased immature granulocytes - myelocytes, metamyelocytes, bands...
Absolute basophilia |
| How is clinical pathology of CML? | over 40 yrs old, slow and insidious onset w/non-specific symptoms, symptoms can come from anemia (weakness, fatigue, pallor...) or splenomegaly (abdominal fullness, pain..)
Slowly progresses over years to accelerated phase (failure of treatment and increasing cytopenias) or blast crisis (identical to AML) |
| How is tx of CML? | Chronic phase treated w/gleevec (Imantinib - ABL tyrosine kinase inhibitor)
Gleevec-resistant disease treated w/bone marrow transplant |
| What is chronic lymphoid leukemia? | Neoplasm of maturing peripheral lymphocytes, may present as concurrent or isolated lymphoma (SLL), bone marrow always involved, spleen and liver can also be involved
Pathogenesis (disrupts normal immune function lead to hypogammaglobulinemia and increased infections, autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP).
Some transform to more aggressive forms like prolymphocytic transformation and Richter syndrome [transformation to diffuse large B cell lymphoma] |
| How is morphology in CLL? | Small monomorphic lymphocytes w/cracked chromatin, smudge cells |
| How is clinical manifestation of CLL? | Older pt (70 yrs), WBC varies from normal to very high (>100,000), insidious onset w/non-specific symptoms like fatigue, weight loss and anorexia, lymphadenopathy and hepatosplenomegaly are often present and progress slowly (4-6 yrs median survival, < 1 yr if disease transforms) |
| How is presentation of chronic lymphoid leukemia? | Develops from accumulation of clone of B cells in bone marrow, blood and lymph nodes.
Has a characteristic phenotype - CD5+CD23+, develops over many years and 90% of pt are diagnosed from routine CBC, tx only started when needed (anemia, swollen lymph nodes or splenomegaly) |
| How is tx of CLL? | Chemo and immunotherapy against B cells (CD20) (Rituximab)
6 courses given where possible and pt usually obtain remission for several years, tablets have recently been developed block B cell receptor signaling through inhibition of BTK or PI3Kg, may represent new std of care |
| Give table differentiate leukemias? | . |
| What is hairy cell leukemia? | Rare mature B cell leukemia, predominantly in older males, present w/splenomegaly and pancytopenia (monocytopenia), complications include opportunistic infections and vasculitis.
Good prognosis w/tx w/purine nucleoside analogs/splenectomy.
Typically seen in spleen, bone marrow and peripheral blood. |
| What is adult T cell leukemia (ATLL)? | Caused by retrovirus type 1, primarly found in HTLV1 endemic areas (japan, caribbean, central Africa), long latency, causing leukemia decades after infection.
Patients present with widespread lymph node and peripheral blood involvement, skin may be also involved.
Prognosis varies but generally poor w/death usually from opportunistic infections |
| What are myeloproliferative disorders? | A group of conditions arising from the marrow stem cells, clonal proliferation of one or more hematopoietic components in the bone marrow.
Four major disorders (polycythemia vera, essential thrombocythemia, primary myelofibrosis, and CML) |
| How are genetic in MPD? | Jak2 protein involved in signal transduction w/in hematopoietic cells, mediates response to growth factors and cytokines, mutated in 99% of PV and 60% of ET and PF.
Calreticulin mutations (CALR) are found in ET that do not have Jak2 mutation.
MPL gene mutation receptor of thrombopoietin is found in 5-10% of ET
All together are seen in 99% of PV, 90% of ET or MF. |
| What is ET? | increased platelet count resulting from MPD, main problem is thrombocytosis or bleeding, need for tx is based on risk of thrombosis.
Hydroxyuria, aspirin and interferon are all useful |
| What is PF? | Proliferation of abnormal clone of hematopoietic stem cell in bone marrow and other sites results in fibrosis.
Myelofibrosis is a form of myeloid metaplasia, which refers to a change in cell type in the blood forming tissue of bone marrow, progressive scarring or fibrosis of bone marrow occurs, results in extramedullary hematopoiesis.
Anemia, with enlarged spleen the blood film with leukoerythroblast and RBC w/tear drop. |
| What is polycythemia? | Excess RBC mass, primary neoplastic independent of erythropoietin in PV, secondary due to increased EPO (chronic hypoxemia [lung disease, congential heart disease, high altitude], paraneoplastic syndrome [RCC/HCC], Blood doping) |
| What is PV? | Myeloproliferative disorder, marked increased RBCs on peripheral smear, increased RBC and myeloid precursors in bone marrow.
Trilineage expansion [granulocytosis, thrombocytopenia, polycythemia], w/low EPO (normal is 11-48 mU/ml) |
| What is secondary polycythemia? | Expansion of RBCs only w/high EPO, increased mass is more viscous and puts pt at risk for thrombosis (stroke, bowel infarct, hepatic vein thrombosis) |
| How is difference between different polycythemias? | . |
| What are myelodysplasias? | Group of clonal disorders of hematopoietic stem cells, characterized by bone marrow failure in association w/dysplastic changes in one or more cell lineages.
Bone marrow is overactive (ineffective EPO) w/peripheral cytopenia
Pathogenesis (May precede AML, tends to occur in older individuals especially common in those treated w/prior chemotherapy
Presents w/ pancytopenia, shift to immaturity in granulocytes <20% blasts, dysplasia in one or more lineages |
| How is classification of myelodysplasia? | • Dysplasia may be in single lineage affecting red cells (refractory anemia, RA), WBC or Plt. Or can present in two or more myeloid lineages
• Erythroid dysplasia can be associated with ring sideroblasts (RARS)
• If the blast cell count is increased in the bone marrow, the diagnosis is refractory anemia with excess blasts (RAEB)
• 5q-Syndrome is more common in women and typically with presents macrocytic anemia and thrombocytosis |
| What are clinical features of myelodysplasia? | • Disorder of older patients
• Symptoms related to reduction in blood counts:
• ↓ HB → tiredness
• ↓ WBC → infection
• ↓ Plt → bleeding
• Diagnosis on basis of blood, bone marrow and cytogenetics |
