Hematological Manifestations of Trisomy 21 PDF

Hematological manifestations of trisomy 21 by:dalia mohammed bahjet 3rd stage supervised by: dr.rasha tareq Introduction : The most common human chromosome aneuploidy, trisomy 21 Down syndrome [DS] and Down s...

Hematological manifestations of trisomy 21 by:dalia mohammed bahjet 3rd stage supervised by: dr.rasha tareq Introduction : The most common human chromosome aneuploidy, trisomy 21 Down syndrome [DS] and Down syndrome mosaic),it is associated with a wide spectrum of hematologic abnormalities. Included in these abnormalities are peculiar hematologic findings in the neonate, transient leukemia (TL),high incidence of acute megakaryoblastic leukemia (AMKL) in infancy, increased incidence of leukemia throughout life, and abnormalities of the immunologic system. Laboratory finding in DS Peripheral blood: During the first week of life transient polycythemia is frequent. the HB ,MCHC,HCT , and RDW are high when compared to normal age-matched controls. MCV remains high or in the upper range of reference values throughout life in all patients with DS The white blood cell (WBC) count is quite stable after birth However, morphological and functional abnormalities of the granulocytes are observed include hyposegmented polyrnorphonuclei, and an increased number of nuclear projections in the nuclei that appear like small clubs, tags, and/or hooks. They are non-specific and can be observed in other disorders like trisomy 15 and 13, leukemias, inflammatory processes. chemotherapy. etc. Thrombocytopenia is frequent in neonates with DS, The platelet counts reach normal values within 2 to 3 weeks after birth.  PB showing multiple appendages in the nucleus of a PMN a common observation in children with DS and trisomy 13 and.18 Abnormal myelopoiesis in trisomy 21: Transient abnormal myelopoiesis (TAM) Myeloid leukemia of Down syndrome (ML-DS) Transient abnormal myelopoiesis (TAM) Definition: Transient disorder of newborns with Down syndrome or phenotypically normal neonates with trisomy 21 mosaicism Presents within 3 - 5 days of birth and resolves spontaneously within 3 months Proliferation of nonerythroid blasts (commonly megakaryoblasts) in the peripheral blood or organs. Essential features Leukocytosis with Increase in circulating blast more than 10% in PB Associated with acquired GATA1 mutation. Morphologically indistinguishable from other forms of AML. 20 - 30% may progress to AML (i.e. AMKL) within 1 - 3 years. Down syndrome neonates with GATA1 mutations have a peripheral blood blast percentage of 1–10 % and have no clinical features associated with TAM called silent TAM epidemiology Manifests in approximately 10% of neonates with Down syndrome 7 - 16% of TAM is seen in phenotypically normal neonates with trisomy 21 mosaicism Sites Peripheral blood :Common site of blasts, as fetal hematopoiesis occurs predominantly in the liver Bone marrow:Less common site of fetal hematopoiesis Other organs :Liver, spleen, skin, pancreas, kidneys, pleural fluid, pericardial fluid Pathophysiology 3 step process : Perturbation of fetal liver hematopoiesis by trisomy 21. Acquired or somatic mutation of GATA1 (chromosome X), hematopoietic transcription factor. 20 - 30% progress to AML with further acquisition of oncogenic mutations. Clinical features Most patients are asymptomatic but may present with myeloblast organ infiltration: Hepatosplenomegaly (common). Ascites, pericardial or pleural effusions, hepatic fibrosis, disseminated intravascular coagulopathy (less common). Severe organ dysfunction causing renal, hepatic or cardiopulmonary failure (rare). If in utero, may present as hydrops fetalis secondary to cardiopulmonary failure and anemia. LABROTARY FINDING : Presence of megakaryoblasts in peripheral blood Thrombocytopenia is most common Moderate leukocytosis with myeloid left shift Basophilia Coagulopathy, specifically disseminated intravascular coagulation (DIC) (10%) Elevated conjugated bilirubin (common)Secondary to liver involvement Bone marrow examination is not necessary but often done to rule out leukemia. Prognostic factors Majority resolve spontaneously over several weeks to 3 months Approximately 15 - 23% of patients may die as a result of secondary organ failure. Poor prognostic factors for early death include: High WBC count , Increased bilirubin ,Elevated liver function tests (LFTs)Failure to normalize blood counts.  Immunophenotyping study by using multiparameter flow cytometry in TAM and AML in DS patients suggests that the blast population of AML and TAM in DS share similar characteristics which include a positive reaction for CD45, CD33, CD41, CD61, CD34, and a negative reaction for CD14 and CD64 antigens indicating a megakaryocytic differentiation. Natural History of TAM and Progression to ML-DS: Most neonates with TAM (>80 %) undergo spontaneous resolution of both clinical and laboratory abnormalities within 3 months after birth with a 5-year overall survival of∼80 % and event-free survival of∼60 %. Estimates of the risk of progression of TAM to ML-DS are mainly based on retrospective studies and suggest that 20–30 % of neonates with TAM will subsequently present with ML-DS. Myeloid leukemia of DS AMKL represent approximately 10%of the pediatric AML although it exact incidence remain to be determined. AMKL is defined as a form of leukemia with >20% blasts, of which 50% or more are of the megakaryocyte lineage, and it is associated with extensive myelofibrosis. This leukaemia is unique to Down syndrome and has several distinct features: Firstly, ML-DS presents at a median age of 1–1.8 years and is rare after the age of 4 years.  Secondly, most cases of ML-DS have a preceding history of TAM in the neonatal period, and GATA1 mutations are found in neonates with ML-DS even in the absence of an antecedent history of TAM. Pt presented with progressive pancytopenia and BMexamination is necessary Bone Marrow Aspirate; IN AMKL because of the difficulties in obtaining a representative BMA sample In patients with fibrosis or in those cases in which the blast aggregates the blast count on BMA smears may be inaccurate. In those patients the diagnosis of M7 can be established by appropriate demonstration of megakaryoblasts in the peripheral blood and/or BMB.  Cellular samples show morphological blast variation in the BMA similar to that described for the peripheral blood. In addition to the cytological variations, megakaryoblasts often appear in clumps of two or more cells and/or syncytia, mimicking solid metastatic tumors. A useful clue for the differential diagnosis with a metastatic tumor is the presence of platelet shedding from the cytoplasmic borders or in the center of the clumps. Bone marrow biopsy often shows partial preservation of the hematopoietic tissue, and blasts tend to group infoci, giving a patchy pattern to the infiltration. Megakaryocytes with or without dysplastic changes may be increased and grouped in clusters. All stages of megakaryocytic differentiation and micromegakaryocytes with nuclear hypolobulation are frequently observed. Myelofibrosis may be prominent and quite extensive. It occurs in relation to the clusters of malignant cells but not in the areas where normal hematopoiesis is maintained. It resolves after successful therapy.  BMA showing a cluster of leukemia cells BMA showing blasts of variable size with encroached by fibrous tissue. multiple cytoplasmic projections. BMB from a child with a PB WBC of 44X10°/1 and 45% blast count in the WBCD, showing focal infiltrate. Cytochemistry and Immunocytochemistry: AMKL has a characteristic, but not diagnostic, cytochemical profile. PAS stain is positive in the blasts. Myeloperoxidase, Sudan black and a-naphthyl butyrate esterase are all negative. CD61, a very early cytoplasmic marker for megakaryoblastic differentiation, can be demonstrated by immunocytochemistry in BMsmears  Outcome The prognosis for patients with ML-DS is highly favorable with survival rates >85%, although patients with relapsed or refractory disease have poor out comes. Patients with T21 are also at higher risk for (DS-ALL) than the general pediatric population, although this is quite rare in young infants. Patients with DS-ALL experience worse outcomes than non-DS-ALL patients. Reference: https://www.pathologyoutlines.com/topic/leukemiaTAM.html https://link.springer.com/article/10.1007/s11899-016-0338-x https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10340042/