Diagnosis Of Acute Megakaryoblastic Leukemia Research Articles

Second Hematologic Malignancies Associated With Primary Mediastinal Germ Cell Tumors: A Population-based Study.

Studies addressing second hematologic malignancies (SHMs) in patients with primary mediastinal germ cell tumors (PMGCTs) are scarce. To better describe this phenomenon, we analyzed a large case series from a population-based registry. The Surveillance, Epidemiology, and End Results database was used to report the clinical characteristics and incidence of SHMs in patients with PMGCT. Among 1297 PMGCTs, 27 cases (2.08%) of SHM were found, with a median latency period of 12 months (95% CI: 5-41). All SHM occurred in males, 20 of whom (74.1%) had a previous nonseminomatous tumor. Acute myeloid leukemia was the most frequent SHM, accounting for 13 cases, 4 of which were acute megakaryoblastic leukemia that occurred within 5 months of diagnosis. The median survival after the diagnosis of SHM was 6 months (95% CI: 2-41). The risk of SHM was significantly higher than expected for the reference population, with a standardized incidence ratio of 6.21 (95% CI: 3.31-10.62) and an absolute excess risk of 19.19 per 10,000 person-years. Patients with PMGCT are at a higher risk of developing SHMs than the general population, particularly acute myeloid leukemia. This risk ranges from synchronous diagnosis of acute megakaryoblastic leukemia to the later onset of other hematological disorders that might be related to PMGCT therapies. Our findings may help create follow-up schedules for patients with PMGCT and raise the level of suspicion surrounding this association.

The Dilemma of Diagnosis of Acute Megakaryoblastic Leukemia in a Saudi Arabian Down Syndrome Patient with Mosaic Trisomy 21 Pattern-Case Report

The Dilemma of Diagnosis of Acute Megakaryoblastic Leukemia in a Saudi Arabian Down Syndrome Patient with Mosaic Trisomy 21 Pattern-Case Report

Acute monocytic leukemia with KMT2A::LASP1 developed 9months after diagnosis of acute megakaryoblastic leukemia in a 2-year-old boy.

Acute myeloid leukemia (AML) is known as one of the subsequent malignant neoplasms that can develop after cancer treatment, but it is difficult to distinguish from relapse when the preceding cancer is leukemia. We report a 2-year-old boy who developed acute megakaryoblastic leukemia (AMKL, French-American-British classification [FAB]: M7) at 18months of age and achieved complete remission with multi-agent chemotherapy without hematopoietic stem cell transplantation. Nine months after diagnosis and 4months after completing treatment for AMKL, he developed acute monocytic leukemia (AMoL) with the KMT2A::LASP1 chimeric gene (FAB: M5b). The second complete remission was achieved using multi-agent chemotherapy and he underwent cord blood transplantation 4months after AMoL was diagnosed. He is currently alive and disease free at 39 and 48months since his AMoL and AMKL diagnoses, respectively. Retrospective analysis revealed that the KMT2A::LASP1 chimeric gene was detected 4months after diagnosis of AMKL. Common somatic mutations were not detected in AMKL or AMoL and no germline pathogenic variants were detected. Since the patient's AMoL was different from his primary leukemia of AMKL in terms of morphological, genomic, and molecular analysis, we concluded that he developed a subsequent leukemia rather than a relapse of his primary leukemia.

A Rare Pediatric Case Report With Review of Literature for the Diagnosis of Acute Megakaryoblastic Leukemia (FAB M7)

Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) accounting for 3%–10% of primary AML in childhood. Clinical manifestations of AML patients can include low grade of fever, diarrhea, easy bruising, failure to growth, and life-threatening clinical manifestations. Laboratory tests are very crucial to make a definitive diagnosis and treatment. We report here an uncommon case of AMKL in a 12-month-old boy who presented with general paleness and fatigue. Based on blood film investigation, bone marrow examination report, and immunophenotyping, he was diagnosed as a case of AMKL without Down syndrome.

A common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia.

We report the findings from a patient who presented with a concurrent mediastinal germ cell tumor (GCT) and acute myeloid leukemia (AML). Bone marrow pathology was consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7), and biopsy of an anterior mediastinal mass was consistent with a nonseminomatous GCT. Prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous GCTs, and it was recently suggested that a common founding clone initiated both cancers. We performed enhanced exome sequencing on the GCT and the AML M7 from our patient to define the clonal relationship between the two cancers. We found that both samples contained somatic mutations in PTEN (C136R missense) and TP53 (R213 frameshift). The mutations in PTEN and TP53 were present at ∼100% variant allele frequency (VAF) in both tumors. In addition, we detected and validated five other shared somatic mutations. The copy-number analysis of the AML exome data revealed an amplification of Chromosome 12p. We also identified a heterozygous germline variant in FANCA (S858R), which is known to be associated with Fanconi anemia but is of uncertain significance here. In summary, our data not only support a common founding clone for these cancers but also suggest that a specific set of distinct genomic alterations (in PTEN and TP53) underlies the rare association between GCT and AML. This association is likely linked to the treatment resistance and extremely poor outcome of these patients. We cannot resolve the clonal evolution of these tumors given limitations of our data.

Abstract LB-109: Exome sequencing identifies common somatic mutations in an adult patient with a concurrent germ cell tumor (GCT) and acute myeloid leukemia (AML) suggesting a single clonal origin

Abstract The Genomics Tumor Board at Washington University was established to increase knowledge, competence, and performance in the application of genomic testing in cancer care. Here we report the findings from a Tumor Board case of concurrent germ cell tumor and acute myeloid leukemia. A 33-year old male presented with generalized weakness, weight loss, and dyspnea on exertion. Initial workup was notable for a platelet count of 5,000 platelets/μL, hemoglobin of 13.1g/dl, and a white count of 9,200 cells/μL with a normal differential. His AFP was 237 (ULN 8.1 ng/ml), LDH was 6760 U/L (ULN 250 U/L) and β-hCG <5 (normal <5 IU/L). Chest CT scan revealed an anterior mediastinal mass. A bone marrow biopsy and aspirate showed a cellularity of 70%, with the core biopsy showing a fibrotic marrow with a population of larger mononuclear cells. The hemodilute aspirate showed 15% large blasts, and a subset of the larger cells expressed CD61 and weak CD117. These findings were consistent with a diagnosis of acute megakaryoblastic leukemia (AML M7). The patient underwent incisional biopsy of the mediastinal mass with pathology showing necrotic fragments of tissue with scattered foci of moderately to poorly differentiated adenocarcinoma. Immunostaining was consistent with a nonseminomatous germ cell tumor. Multiple prior studies have described associations between hematological malignancies, including AML M7 and nonseminomatous germ cell tumors, and a recent study identified a patient with a concurrent AML and GCT that shared several mutations including PTEN, TP53, and chromosome 12 abnormalities, suggesting that a common founding clone initiated both cancers (Oshrine, B. R., et al. Cancer Genet 2014). To investigate the clonal relationship in our samples, we studied the GCT (whole genome amplification was performed on 2 ng of DNA isolated by laser capture microdissection of viable cells from the FFPE tumor specimen) and the M7 AML (cryopreserved cells from the diagnostic bone marrow biopsy were flow-sorted using the above markers) by whole exome sequencing. We found both samples contained somatic mutations in PTEN (C136R missense) and TP53 (R213 frameshift). Both the mutations in PTEN and TP53 were present at ∼100% variant allele frequency (VAF) in both tumors. A copy number comparison between the 2 samples revealed similar amplifications of chromosome 12p. In addition, we detected a heterozygous germline variant in FANCA (R858D), which is known to be associated with Fanconi anemia and is of uncertain significance here. In conclusion, the data not only support a common clonal ancestor for these cancers but also suggest that a specific set of distinct genomic alterations drives the rare association between GCT and AML, and likely underlies the poor outcome of these patients. Citation Format: Charles Lu, Peter Riedell, Peter Westervelt, Christopher Miller, Ian S. Hagemann, Eric J. Duncavage, Elaine R. Mardis, Richard K. Wilson, Bradley A. Ozenberger, Lukas D. Wartman. Exome sequencing identifies common somatic mutations in an adult patient with a concurrent germ cell tumor (GCT) and acute myeloid leukemia (AML) suggesting a single clonal origin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-109. doi:10.1158/1538-7445.AM2015-LB-109

Craig Issue Highlight 2015

Craig Issue Highlight 2015

Acute Megakaryoblastic Leukemia in Children: Diagnosis and Management Challenges in Resource-Poor Countries

Acute Megakaryoblastic Leukemia (AMKL) is a rare subtype of acute myeloid leukemia classified as AML M7 by the French-American-British (FAB) Leukemia Cooperative Study Group. We reviewed the records of children aged less than 18 years with AMKL during the period from January 2003 to December 2010. The diagnosis of AMKL was established on the basis of the FAB criteria and confirmed by immunophenotyping. Eight cases were assigned for this period. The incidence rate of AMKL was 5.5 % of AML. The median age at the time of diagnosis was 1 year. The karyotype presented translocation (1, 22) in two cases. One girl had Down syndrome (DS). Treatment included two inductions based on daunorubicin and cytosine arabinoside (7+3) followed by two consolidations with high dose of cytosine arabinoside (16 g/m 2 ). Complete remission (CR) was achieved in 3 patients (43%). One patient underwent allogeneic stem cell transplant (SCT) and is still enjoying continuous CR 5 years after treatment. Other patients died from failure or relapse. In this small series from a single institution, reported incidence of AMKL is underestimated probably due to the difficulties of diagnosis. The prognosis was poor, particularly because of unavailability of intensified chemotherapy treatment and allogeneic SCT.

Acute megakaryoblastic leukemia and severe pulmonary fibrosis in a child with down syndrome: Successful treatment with ultra low-dose cytarabine using GATA1 mutation to monitor minimal residual disease

Acute megakaryoblastic leukemia and severe pulmonary fibrosis in a child with down syndrome: Successful treatment with ultra low-dose cytarabine using GATA1 mutation to monitor minimal residual disease

Acute Megakaryoblastic Leukemia in Dogs: A Report of Three Cases and Review of the Literature

Three dogs of different breeds, ages, and genders were presented with pale mucous membranes, depression, anorexia, and splenomegaly. Observed were severe normocytic, nor-mochromic, nonregenerative anemia, thrombocytopenia, and leukopenia. Blood smears contained large, atypical cells with blue vacuolated cytoplasm, cytoplasmic blebs, round to oval central nuclei, and elevated numbers of cytoplasmic fragment resembling macroplatelets. Bi- and multinucleated atypical cells were found mainly in spleen, lymph nodes, and bone marrow. A final diagnosis of acute megakaryoblastic leukemia (AMegL) was made based on morphology and positivity to the megakaryocyte-derived cell-specific markers von Willebrand factor and CD61. In case nos. 1 and 2, no treatment was initiated, and the dogs died on days 4 and 3, respectively. Case no. 3 received supportive therapy with prednisone, and after a brief improvement the dog died spontaneously 35 days after initial presentation. Only 11 cases of AMegL have been reported in dogs, and the specific diagnostic criteria have not been well established. The presence of vacuolization, cytoplasmic blebs, central round nuclei, cytoplasmic fragments, and multinucleated cells in these three cases were considered useful to differentiate AMegL from other hematopoietic neoplasms.

Acute megakaryoblastic leukemia in a German Shepherd dog

An 11-year-old spayed-female German Shepherd dog was presented to the Veterinary Medical Teaching Hospital at Kansas State University with a history of weight loss, anorexia, depression, and lethargy for 2-3 weeks. Radiographic examination revealed a mass in the spleen and several round radiodense foci in the liver. CBC results included normocytic normochromic anemia, marked thrombocytopenia, and low numbers of neoplastic cells that frequently had cytoplasmic projections or blebs. A bone marrow aspirate contained about 80% neoplastic megakaryoblasts with the same microscopic features as those observed in peripheral blood. Using flow cytometry, cells of large size were identified in peripheral blood that expressed CD41/61, CD45, CD61, and CD62P (P-selectin) and were negative for markers of T cells, B cells, monocyte/macrophages, and dendritic cells. Because of the poor prognosis, euthanasia and subsequently necropsy were performed. On histopathologic examination, neoplastic megakaryoblasts were identified in spleen, liver, mesenteric lymph node, and the pulmonary vasculature. Using immunohistochemistry, the neoplastic megakaryoblasts weakly expressed von Willebrand factor. Based on microscopic and immunophenotypic findings, a diagnosis of acute megakaryoblastic leukemia (AMegL) was made. To our knowledge, this is the first report of AMegL in a domestic animal in which immunophenotyping by flow cytometry and a panel of antibodies against CD41/61, CD61, and CD62P were used to support the diagnosis.

CD34+, CD41+acute megakaryoblastic leukemia in a dog

A clinically normal, 5-year-old intact female German Shepherd dog was presented to the local veterinarian to be spayed. Results of a preoperative CBC included mild nonregenerative anemia, severe thrombocytopenia, and 17% unclassified cells. On cytologic examination of aspirates from the dog's enlarged spleen and peripheral lymph nodes, a population of primitive round cells that occasionally resembled megakaryocytes was observed. A bone marrow aspirate specimen was markedly hypercellular with approximately 65% of marrow cells comprising a homogeneous population of immature hematopoietic cells similar to those found in the spleen, lymph nodes, and peripheral blood. Using immunocytochemical stains with canine-specific antibodies, all neoplastic cells strongly expressed cytoplasmic CD41 and 20-70% of the neoplastic cells expressed CD34 weakly to moderately. Rare (<0.5%) neoplastic cells weakly expressed vWF. The cells were negative for all other markers. Based on these results and the morphology of the neoplastic cells, a diagnosis of acute megakaryoblastic leukemia (AMegL) was made. In spite of treatment, results of a CBC performed 1 week later indicated progressive anemia and thrombocytopenia, and the dog was euthanized. To our knowledge, this report documents the first case of canine AMegL diagnosed with both anti-canine CD34 and CD41 antibodies.

Clinical and Biological Features of 43 Acute Megakaryoblastic Leukemia (AMKL) in Children: A Comparison of Down Syndrome-AMKL and De Novo AMKL.

AMKL is a rare subtype of acute myelogenous leukemia. In children, AMKL frequently develops in patients with Down syndrome (DS-AMKL). Until now, few large series of childhood AMKL have been reported. We reviewed 43 children with AMKL diganosed between 1987 and 2005 at Nagoya University Hospital and Japanese Red Cross Nagoya First Hospital. The diagnosis of AMKL was established on the basis of cell morphology and was confirmed by the positivity of immunophenotyping against CD41 and CD36. The diagnosis for several patients was also confirmed by platelet peroxidase staining using an electron microscope. The morphology of blast cells was categorized into three groups according to the stage of cell maturation: type 1 = completely undifferentiated blasts; type 2 = intermediately differentiated blasts with characteristic blebs; and type 3 = blasts with dysmegakaryocytopoiesis, including the presence of micromegakaryocytes. Twenty-five patients (58%) had DS-AMKL and 18 (42%) had de novo AMKL. The median age was 20 months (range, 8–38 months) for DS-AMKL and 12 months (range, 2–185 months) for de novo AMKL. The ratio of boys to girls was 1: 0.8 for DS-AMKL and 0.5:1 for de novo AMKL. The initial white blood cell count and lactic dehydrogenase levels were much higher in patients with de novo AMKL than in those with DS-AMKL. The morphology of blast cells in DS-AMKL and de novo AMKL were distributed as follows: type 1 (67%, 57%), type 2 (24%, 43%), and type 3 (9%, 0%), respectively. The results of immunophenotyping in the DS-AMKL and de novo AMKL group, respectively, were as follows: CD41 (88%, 87%), CD7 (96%, 70%), CD33 (84%, 90%), Gly (67%, 0%), and CD34 (70%, 20%). Cytogenetic studies were performed for 23 patients with DS-AMKL and 18 patients with de novo AMKL. Normal karyotype including +21 in DS-AMKL was noted in 5 patients with DS-AMKL and in 1 patient with de novo AMKL. Numerical chromosomal anomalies were common in both groups. Patients with DS-AMKL had +8 (4 patients), additional +21 (1 patient), and −7/del(7q) (6 patients). Patients with de novo AMKL had +8 (5 patients), +21 (7 patients), and −7/del(7q) (2 patients). The specific AMKL-associated translocation such as t (1:22) was noted in 2 patients with de novo AMKL and 3q21q26 was noted in 1 patient with de novo AMKL. In patients with DS-AMKL, 24 of 25 (96%) achieved complete remission. Relapse occurred in 2 patients, and 2 different patients died of cardiac problems. Of the 25 patients with DS-AMKL, 21 (84%) are currently surviving. Of the 18 patients with de novo AMKL, 12 of 17 (71%) patients achieved complete remission. One patient did not receive induction therapy. Thirteen patients received stem cell transplantation (allogeneic, 6; autologous, 7), and 13 of 18 patients (72%) are currently surviving. The estimate of 5-year survival was 83.3% for patients with DS-AMKL and 71.8% for patients with de novo AMKL (p=0.38). Our study shows the diverse heterogeneity of childhood AMKL and the need for subclassification according to megakaryocytic maturation. The blast cells seem more immature in DS-AMKL than in de novo AMKL in terms of morphology and immunophenotyping. The prognosis of DS-AMKL is excellent. Although prognosis of de novo AMKL was very poor in previous studies, our results using stem cell transplantation are promising.

Eyelid Mass as the Presenting Finding in a Child With Down Syndrome and Acute Megakaryoblastic Leukemia

Children with Down syndrome are at increased risk of developing acute megakaryoblastic leukemia (AML). Therefore, physicians caring for children with Down syndrome should be familiar with the presenting features of AML. We describe a child with Down syndrome presenting with a left eyelid mass 1 month before a diagnosis of acute AML.

Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience

To describe the clinical and biologic features of pediatric acute megakaryoblastic leukemia (AMKL) and to identify prognostic factors, experience at St Jude Children's Research Hospital was reviewed. Of 281 patients with acute myeloid leukemia treated over a 14-year period, 41 (14.6%) had a diagnosis of AMKL. Six patients had Down syndrome and AMKL, 6 had secondary AMKL, and 29 had de novo AMKL. The median age of the 22 boys and 19 girls was 23.9 months (range, 6.7-208.9 months). The rate of remission induction was 60.5%, with a 48% rate of subsequent relapse. Patients with Down syndrome had a significantly higher 2-year event-free survival (EFS) estimate (83%) than did other patients with de novo AMKL (14%) or with secondary AMKL (20%; P < or =.038). Among patients who had de novo AMKL without Down syndrome, 2-year EFS was significantly higher after allogeneic bone marrow transplantation (26%) than after chemotherapy alone (0%; P =.019) and significantly higher when performed during remission (46%) than when performed during persistent disease (0%; P =.019). The 5-year survival estimates were significantly lower for de novo AMKL (10%) than for other forms of de novo AML (42%; P <.001). Treatment outcome is very poor for patients with AMKL in the absence of Down syndrome. Remission induction is the most important prognostic factor. Allogeneic transplantation during remission offers the best chance of cure; in the absence of remission, transplantation offers no advantage over chemotherapy alone. (Blood. 2001;97:3727-3732)

Acute megakaryoblastic leukemia in Down syndrome: orbital infiltration

%PURPOSE: To describe an uncommon ocular presentation of acute megakaryoblastic leukemia in a child with Down syndrome. METHOD: Case report. Initial manifestation of disease was bilateral proptosis with secondary exposure keratitis caused by leukemic infiltration of the orbits. RESULTS: Bone marrow biopsy and immunophenotyping established the diagnosis of acute megakaryoblastic leukemia (FAB-M7). The leukemia was treated successfully with chemotherapy, with resolution of proptosis. The patient remained in remission more than 1 year after cessation of treatment. CONCLUSIONS: Bilateral proptosis can be a presenting sign of acute megakaryoblastic leukemia, a malignancy associated with Down syndrome.

The Value of Intracellular CD41 Antigen Detection to the Diagnosis of Acute Megakaryoblastic Leukemia

The Value of Intracellular CD41 Antigen Detection to the Diagnosis of Acute Megakaryoblastic Leukemia

Severe Hypercalcemia in a Child with Relapsed Megakaryoblastic Leukemia: Report of a Case and Review of the Literature

Severe Hypercalcemia in a Child with Relapsed Megakaryoblastic Leukemia: Report of a Case and Review of the Literature

False-positive flow cytometric platelet glycoprotein IIb/IIIa expression in myeloid leukemias secondary to platelet adherence to blasts

Because neither morphologic nor routine cytochemical features are pathognomonic, the diagnosis of acute megakaryoblastic leukemia (AML- M7) is difficult, requiring either specialized ultrastructural or immunologic techniques. Because the ultrastructural techniques are cumbersome, immunologic assays for expression of several platelet- specific antigens, such as CD41a (platelet glycoprotein IIb/IIIa), have become the primary method used to detect megakaryoblastic differentiation. In our flow cytometric analysis of the immunophenotypes of over 1,000 cases of AML from patients registered to Southwest Oncology Group (SWOG) Treatment Protocols, we found that 38% of cases demonstrated CD41a reactivity. Because this frequency of CD41a expression by flow cytometry greatly exceeded the number of morphologically defined cases of AML-M7, we postulated that the reaction may be caused by platelets adherent to leukemic blasts. To investigate this hypothesis, we performed a side-by-side comparison of flow cytometric and cytospin immunofluorescence studies on 37 cases of adult de novo AML that demonstrated a wide range of CD41a expression by flow cytometric analyses. We found that the expression of CD41a detected by flow cytometric techniques was secondary to adherent platelets or platelet fragments in 85% of cases. Many of these cases also expressed the lineage-specific carbohydrate, LNF III (CD15), which may mediate platelet adhesion to mature monocytes and neutrophils. Only 15% of the CD41a flow cytometrically positive cases demonstrated true diffuse membrane and cytoplasmic positivity on cytospin slides indicative of megakaryoblastic differentiation. Cytospin immunofluorescence for CD41a should be performed on all cases of suspected AML-M7. If only flow cytometric techniques are used, adherent platelets may result in the erroneous diagnosis of this AML subtype.

False-Positive Flow Cytometric Platelet Glycoprotein IIb/IIIa Expression in Myeloid Leukemias Secondary to Platelet Adherence to Blasts

Because neither morphologic nor routine cytochemical features are pathognomonic, the diagnosis of acute megakaryoblastic leukemia (AML-M7) is difficult, requiring either specialized ultrastructural or immunologic techniques. Because the ultrastructural techniques are cumbersome, immunologic assays for expression of several platelet-specific antigens, such as CD41a (platelet glycoprotein IIb/IIIa), have become the primary method used to detect megakaryoblastic differentiation. In our flow cytometric analysis of the immunophenotypes of over 1,000 cases of AML from patients registered to Southwest Oncology Group (SWOG) Treatment Protocols, we found that 38% of cases demonstrated CD41a reactivity. Because this frequency of CD41a expression by flow cytometry greatly exceeded the number of morphologically defined cases of AML-M7, we postulated that the reaction may be caused by platelets adherent to leukemic blasts. To investigate this hypothesis, we performed a side-by-side comparison of flow cytometric and cytospin immunofluorescence studies on 37 cases of adult de novo AML that demonstrated a wide range of CD41a expression by flow cytometric analyses. We found that the expression of CD41a detected by flow cytometric techniques was secondary to adherent platelets or platelet fragments in 85% of cases. Many of these cases also expressed the lineage-specific carbohydrate, LNF III (CD15), which may mediate platelet adhesion to mature monocytes and neutrophils. Only 15% of the CD41a flow cytometrically positive cases demonstrated true diffuse membrane and cytoplasmic positivity on cytospin slides indicative of megakaryoblastic differentiation. Cytospin immunofluorescence for CD41a should be performed on all cases of suspected AML-M7. If only flow cytometric techniques are used, adherent platelets may result in the erroneous diagnosis of this AML subtype.