Cytogenetic studies of Brazilian pediatric myelodysplastic syndrome cases: challenges and difficulties in a large and emerging country

Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED). We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome). Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis.Univ São Paulo, Fac Med, Dept Hematol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Hematol, São Paulo, BrazilUniv São Paulo, Fac Med, Dept Hematol, Lab Citogenet, São Paulo, BrazilUniversidade Federal de São Paulo, Inst Oncol Pediat, São Paulo, BrazilUniv Estadual Paulista, Fac Med Botucatu, Dept Clin Med, Botucatu, SP, BrazilHosp Canc Barretos, Barretos, SP, BrazilCtr Tratamento Fabiana Macedo de Morais, Grp Assistencia Crianca Canc, Grp Cooperat Brasileiro Sindrome Mielodisplas Ped, Sao Jose Dos Campos, SP, BrazilUniversidade Federal de São Paulo, Dept Hematol, São Paulo, BrazilUniversidade Federal de São Paulo, Inst Oncol Pediat, São Paulo, BrazilWeb of Scienc

Morphological and cytogenetic bone marrow studies in patients with secondary myelodysplastic syndrome diagnosed at Department of Hematology of Clinical Hospital of São Paulo Medical School

As Síndromes mielodisplásicas (SMD) são doenças clonais da célula progenitora hematopoética, cursando com citopenias, medula óssea displástica e tendência à evolução para leucemia. As SMD secundárias estão associadas a fatores de risco como doenças congênitas (Anemia de Fanconi), doenças hematológicas adquiridas (aplasia medular, HPN), exposição à quimioterápicos (alquilantes, inibidores de topoisomerase II) e radioterapia e substâncias químicas (benzeno, petróleo). Agentes imunossupressores associados ou não a fatores hemopoéticos particularmente utilizados para tratamento da Aplasia medular também se associam à SMD secundária. A OMS recentemente adotou o termo síndrome mielodisplásica/neoplasia mielóde (SMD/NM) relacionada à terapêutica para englobar casos de neoplasias mielóides que preencham critérios morfológicos não somente de SMD, mas também de leucemia mielóide aguda (LMA) ou neoplasias mieloproliferativas. O objetivo do trabalho foi analisar dados clínicos, morfológicos e citogenéticos de 42 portadores de SMD/NM secundária em uma coorte de pacientes diagnosticados no SH-HCFMUSP no período de 1987 a 2008. Vinte e três pacientes (54,8%) eram homens, com mediana de idade de 53,5 (4-88) anos. 45,2% eram portadores de doenças onco-hematológicas, 26,2% de anemia aplástica, 14,3% de tumores sólidos e 14,3% de outras doenças (auto-imunes e transplante de órgãos sólidos). 33% dos pacientes utilizaram exclusivamente QT, 26% combinação QT e RT, 2% RT isolada e 28% agentes imunossupressores. Cinco (11,9%) pacientes haviam sido submetidos a TCTH autólogo para tratamento de doença oncohematológica prévia. A mediana da latência entre a doença primária e a SMD secundária foi de 85 meses (23- 221 meses). Oito pacientes foram submetidos ao TCTH alogênico aparentado para tratamento da SMD secundária. Anemia, neutropenia, plaquetopenia e blastos circulantes foram observados em 64,3%, 54,8%, 78,6% e 26,2% dos casos respectivamente. Cerca de 1/3 dos aspirados medulares apresentavam hemodiluição, 29,7% apresentavam hipocelularidade global, 62,2% apresentavam contagem de blastos superior a 5% e 14,3% sideroblastos em anel acima de 15%. Displasia da série eritróide, granulocítica e megacariocítica foi observada em 79,4%, 77,1% e 68,2% dos casos respectivamente. A histologia medular realizada em 22 casos revelou hipocelularidade global, ALIPs e nódulos linfóides em 9,1%, 23,8% e 40,9% dos casos. A detecção por imunoistoquímica de células CD34>1%, CD117>1%, agrupamento de células CD34+ e de CD117+ e da proteína p53+ foi observada respectivamente em 77,2%, 82,3%, 59%, 29,4% e 33,3% dos casos. Anormalidades clonais foram observadas em 84,3% dos casos, com grande predomínio das não balanceadas (96%), sendo 37% com monossomia 7, 44,4% cariótipos complexos e 18% com outras anormalidades . A mediana de sobrevida de sobrevida global foi de 5,7 meses, pacientes submetidos ao TCTH alogênico para tratamento da SMD/NM secundária tiveram mediana de 40 meses (p=0,007). Fatores associados à pior sobrevida incluíram: doença oncohematológica prévia, baixa contagem plaquetária, elevação de DHL e ferritina, presença de células CD117+ agrupadas, imunoexpressão positiva da p53, citogenética anormal, IPSS intermediário II ou alto risco. Nenhum parâmetro estudado do aspirado medular se associou à sobrevida. Houve tendência à associação da imunoexpressão positiva de p53 a cariótipo anormal e IPSS de maior risco. Não se observou associação entre a presença de ALIP, porcentagem de blastos na morfologia medular e células CD34+ e CD117+. Estes dados reforçam a importância da análise citogenética e da imunoistoquímica da biópsia de medula óssea para diagnóstico e prognóstico das SMD secundárias e do TCTH alogênico no seu tratamento. Mais estudos com maior número de casos devem ser realizados para confirmar a importância do escore IPSS na SMD secundárias, provavelmente substituindo a porcentagem de blastos ao aspirado medular, pela presença de células precursoras detectadas por imunoistoquímicaMyelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders, characterized by cytopenias, dysplastic bone marrow (BM) and propensity to progress to acute myeloid leukemia. Secondary MDS are associated with risk factors such as congenital disorders (Fanconis anemia), acquired bone marrow failures, exposure to chemotherapy (alkylating agents, topoisomerase II inhibitors) agents and radiation and chemicals (benzene, petroleum). Immunosuppressive agents associated with hematopoietic growth factors are also associated with secondary MDS. The WHO classification has recently adopted the term therapy-related myeloid neoplasms for cases of myeloid malignancies that fulfill morphological criteria not only for MDS but also for AML or myeloproliferative neoplasms.The aim of the study was to analyze clinical, morphological and cytogenetic features of 42 patients with secondary MDS/MN in a cohort of patients diagnosed at our institution from 1987 to 2008. 23 patients (54.8%) were male, median age 53.5 (4-88) years. 45.2% had primary hematologic malignancies, 26.2% aplastic anemia, 14.3% solid tumors and 14.3% other diseases (autoimmune diseases and solid organ transplantation). 33% had undergone chemotherapy alone, 2% RT alone, 26% both modalities and 28% immunosuppressive agents. Five (11.9%) patients had undergone autologous HSCT for treatment of previous malignancies. The median latency between the primary disease and secondary MDS/MN was 85 (23-221) months. Eight patients underwent allogeneic HSCT (allo- HSCT) for treatment of related secondary MDS. Anemia, neutropenia, thrombocytopenia and peripheral blasts were observed in 64.3%, 54.8%, 78.6% and 26.2%, respectively. BM aspirates was poorly representative in 1/3 of cases, 29.7% global hypocellularity, 62.2% more than 5% of blast counts and 14.3% more than 15% of ring sideroblasts. Dysplasia in erythroid, granulocytic and megakaryocytic series was observed in 79.4%, 77.1% and 68.2%, respectively. Twenty two BM biopsies were performed. Global hypocellularity, ALIP and lymphoid nodules were shown in 9.1%, 23.8% and 40.9%. The immunohistochemistry showed more than 1% of CD34+ and CD117+ cells, clusters of CD34+ and CD117+ and immunoexpression of p53 protein in 77.2%, 82.3%, 59%, 29.4% and 33.3%, respectively. Clonal abnormalities were observed in 84.3% of cases with high prevalence of unbalanced (96%) rearrangements. 37% showed monosomy 7 and 44.4% complex karyotypes. The median overall survival was 5.7 for all patients and 40 months for patients treated with allo-HSCT (P=0.007). Hematologic malignancies, low platelet count, serum high LDH and ferritin, detection of CD117+ clusters, positive immunoexpression of p53, abnormal cytogenetics, intermediate-II or high-risk IPSS groups were associated with poor survival. No parameter studied from bone marrow aspirate had impact in survival. p53 expression was associated to abnormal karyotype (P=0.092) and IPSS risk (P=0.054). There was no association between the presence of ALIP, BM blast counts and immunoexpression of CD34+ and CD117+. Our study shows that cytogenetic analysis and BM immunohistochemistry are very important in diagnosis and prognosis, and that allo-HSCT could improve the survival of secondary MDS/MN. More studies with larger numbers of cases should be conducted to confirm the importance of the IPSS for secondary MDS, probably replacing the bone marrow aspirate blast counts by the immunohistochemistry detection of precursor cell

Secondary myeloid neoplasms: bone marrow cytogenetic and histological features may be relevant to prognosis

Abstract Background: Secondary myeloid neoplasms comprise a group of diseases arising after chemotherapy, radiation, immunosuppressive therapy or from aplastic anemia. Few studies have addressed prognostic factors in these neoplasms. Method: Forty-two patients diagnosed from 1987 to 2008 with secondary myeloid neoplasms were retrospectively evaluated concerning clinical, biochemical, peripheral blood, bone marrow aspirate, biopsy, and immunohistochemistry and cytogenetic features at diagnosis as prognostic factors. The International Prognostic Scoring System was applied. Statistical analysis employed the Kaplan–Meier method, log-rank and Fisher's exact test. Results: Twenty-three patients (54.8%) were male and the median age was 53.5 years (range: 4–88 years) at diagnosis of secondary myeloid neoplasms. Previous diseases included hematologic malignancies, solid tumors, aplastic anemia, autoimmune diseases and conditions requiring solid organ transplantations. One third of patients (33%) were submitted to chemotherapy alone, 2% to radiotherapy, 26% to both modalities and 28% to immunosuppressive agents. Five patients (11.9%) had undergone autologous hematopoietic stem cell transplantation. The median latency between the primary disease and secondary myeloid neoplasms was 85 months (range: 23–221 months). Eight patients were submitted to allogeneic hematopoietic stem cell transplantation to treat secondary myeloid neoplasms. Important changes in bone marrow were detected mainly by biopsy, immunohistochemistry and cytogenetics. The presence of clusters of CD117+ cells and p53+ cells were associated with low survival. p53 was associated to a higher risk according to the International Prognostic Scoring System. High prevalence of clonal abnormalities (84.3%) and thrombocytopenia (78.6%) were independent factors for poor survival. Conclusion: This study demonstrated that cytogenetics, bone marrow biopsy and immunohistochemistry are very important prognostic tools in secondary myeloid neoplasms

Myelodysplastic syndromes in South America: A multinational study of 1080 patients

There are previously reported data describing differences between Asian and European patients with Myelodysplastic Syndromes (MDS), few direct comparisons based on cancer registration characteristics or using cohorts to validate scoring systems. This is the first study from South-America, which attempts to describe demographic, clinical features, and outcome of MDS patients. We retrospectively analyzed 1,080 patients with de novo MDS from Argentina (635), Brazil (345), and Chile (100). Chilean patients were younger (P=0.001) with female preponderance (P=0.071). Brazilian series showed a higher predominance of RARS subtype regarding FAB and WHO classifications (P0.05). Chilean series depicted a lower overall survival (OS; 35 months vs. 56 months-Argentine; 55 months-Brazil, P=0.030), which was consistent with a higher predominance of the high-risk group according both to the IPSS and IPSS-R (P=0.046 and P<0.001). The IPSS-R system and its variables showed a good reproducibility to predict clinical outcome for the whole South-American population. Epidemiological and clinical characteristics, distribution among prognostic subgroups, the OS, and the access to disease modifying therapies were more similar between Argentinean and Brazilian compared with Chilean MDS series. This will need further analysis in a larger group of patients. Descriptive and comparative studies are necessary to establish epidemiological features useful for public health attitudes to generate suitable therapeutic schemes.Fil: Belli, Carolina Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Pinheiro, Ronald Feitosa. Universidade Estadual do Ceará; BrasilFil: Bestach, Yesica Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: da Silva Tanizawa, Roberta Sandra. Universidade de Sao Paulo; BrasilFil: Alfonso, Graciela. Hospital General de Agudos “A. J. Posadas”; ArgentinaFil: Gonzalez, Jacqueline. Hospital General de Agudos “C Durand"; ArgentinaFil: Rosenhain, Mariana. Hospital General de Agudos “Tornu"; ArgentinaFil: Watman, Nora. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Cavalcante de Andrade Silva, Marcela. Universidade de Sao Paulo; BrasilFil: Negri Aranguren, Pedro. Instituto Privado de Hematologia y Hemoterapia; ArgentinaFil: Garcia Rivello, Hernan Jorge. Hospital Italiano; ArgentinaFil: Magalhaes, Silvia M. M.. Federal University of Ceara; BrasilFil: Valladares, Ximena. Hospital Del Salvador; ChileFil: Undurraga, María S.. Hospital Del Salvador; ChileFil: Velloso, Elvira R. P.. Universidade de Sao Paulo; Brasi