Oncologia Pediátrica LLA e Neuroblastoma

Apresentação em tema: "Oncologia Pediátrica LLA e Neuroblastoma"— Transcrição da apresentação:

1 Oncologia Pediátrica LLA e Neuroblastoma
Internato em Pediatria Apresentação: Matheus Roos Vale Coordenação Dra Carmen Lívia Brasília, 5 de novembro de 2015

2 Leucemia Linfóide Aguda (LLA)
LLA é a doença maligna mais comum em crianças; ¼ dos cânceres pediátricos. Although a few cases are associated with inherited genetic syndromes (eg, Down syndrome) or congenital immunodeficiencies (eg, Wiskott-Aldrich syndrome, ataxia-telangiectasia), the cause remains largely unknown Kanwar VS, Satake N, Yoon JM. Pediatric Acute Lymphoblastic Leukemia. Medscape. 2014

3 Leucemia Linfoide Aguda (LLA)
Epidemiologia EUA: 3,7-4,9 casos/ (0-14 anos), estimada para o mundo; Homens mais afetados – célula T; Branco > Negro; Pico 2-5 anos; Relacionado com Sd de Down ou imunodeficiências congênitas; Não é relacionado a exposição a radiação ou infecção viral.

4 Fisiopatologia Progenitor linfoide é desregulado e inicia expansão clonal; Sucessivos ciclos de mutação espontâneas e proliferação, podendo gerar um clone completo e posterior “seleção natural” clone dominante; Mutações hematopoiese fetal x pós natal; Organismo incapaz de controlar a célula alterada (Blasto); Lesão no ácido desoxirribonucleico da uma célula da medula óssea. Emerenciano M. As características moleculares das leucemias agudas de lactentes em coorte brasileira. UFRJ, 2006

5 Leucemia Linfoide Aguda (LLA)
Os principais tipos são diferenciados por imunofenotipagem; 2 grandes grupos: Células B (80%) Linfócitos T (20%) Pico de incidência 2-5 anos: Infecções virais (teoria) Resposta a infecções (teoria) Mutação intrauterina + pós natal SANDLER DP, ROSS JA. EPIDEMIOLOGY OF ACUTE LEUKEMIA IN CHILDREN AND ADULTS. SEMIN ONCOL, 1997

6 Leucemia Linfoide Aguda (LLA)
Quadro clínico geral: Anemia Trombocitopenia Neutropenia 20% apresenta apenas pancitopenia Fadiga, palidez, e sangramento Hepatoesplenomegalia e linfadenopatia Cloromas (tumor sólido de células da leucemia) Although the CNS, liver, spleen, and lymph nodes are common sites of extramedullary spread of leukemia, rare involvement of organs other than these and the testes can also occur (eg, skin, eyes, pleural space, ovaries).[1] Infants younger than 1 year are more likely than older children to have unusual presentations of leukemia, and they also have a poorer prognosis. Chloromas (granulocytic sarcomas) are solid tumors composed of leukemia cells that can be found virtually anywhere in the body, but the most common sites are the brain or spine (shown). Affected patients may present with cranial nerve palsies or focal neurologic deficits due to compression of the involved nerves by leukemic deposits. Leukemia cutis is infiltration of the dermis by leukemia cells

7 Quadro Clínico Precursor B Precursor T
Dor óssea, artrite, dificuldade de marcha ( apenas esses em 5% dos casos) Massa extra medular: Abdome, Cabeça e Pescoço e SNC SNC: cefaleia, vômito, letargia e rigidez de nuca Precursor T Massa extra medular: Mediastino pode causar sintomas respiratórios e estridor

8 Leucemia Linfoide Aguda (LLA)
Avaliação Inicial: Hemograma Completo Avaliação por hematologista (presença de linfoblastos no sangue periférico) Alterações metabólicas Raio X de Tórax – Avaliar massa mediastinal Imunofenotipagem – CD 10, 19, 20 Testes citogenéticos Aspirado e biópsia de medula óssea Punção Lombar – Comprometimento do SNC

9 Alterações Cromossomiais
Bhatt MD, Athale UH. Childhood Acute Lymphoblastic Leukemia: Diagnosis, Management, and Complications. 2014

10 Aspirado e Biópsia de Medula Óssea
ALL is a biologically heterogeneous disease[9] that may develop at any stage of lymphoid differentiation. The current standard for diagnosis is based on immunophenotype and cytogenetic or molecular analysis. The World Health Organization (WHO) classifies ALL as B or T lymphoblastic leukemia.[11,12] Some acute leukemias can have both lymphocytic and myeloid features. Previously, ALL lymphoblasts were classified using the French-American-British (FAB) criteria [6,11] on the basis of cell size, quantity of cytoplasm and granules, nucleoli prominence, and immunochemistry (shown), as follows: L1 (85% of childhood ALL): small blasts, scant cytoplasm, indistinct nucleoli L2 (14% of childhood ALL): large blasts, abundant cytoplasm, prominent nucleoli L3 (1% of childhood ALL): large blasts, abundant basophilic cytoplasm, prominent vacuoles (arrows), prominent nucleoli L3 Kanwar VS, Satake N, Yoon JM. Pediatric Acute Lymphoblastic Leukemia. Medscape. 2014

11 Estratificação de Risco
Patients are stratified into prognostic risk groups on the basis of information derived from diagnostic tests combined with demographic data.[2,6,16] ALL treatment protocols employ risk-based therapy to reduce toxicity in patients with low-risk ALL (low risk of treatment failure) and to indicate aggressive therapy for those with a high-risk of relapse. Features commonly included in risk stratification are the WBC count at diagnosis, age at diagnosis, immunologic subtype, CNS status, cytogenetic results, and treatment response (shown).[2,6] Different cooperative clinical trial groups use different combinations of these features for risk stratification and therapeutic planning. Risk-adapted therapy on the basis of these features has been well correlated with prognosis. iAMP21 = intrachromosomal amplification of chromosome 21; NCI = National Cancer Institute Bhatt MD, Athale UH. Childhood Acute Lymphoblastic Leukemia: Diagnosis, Management, and Complications. 2014

12 Tratamento Quimioterapia: Transplante: Fases:
Indução de Remissão Consolidação Profilaxia SNC Intensificação Eliminar doença residual Transplante: Refratárias e doenças de alto risco Drugs commonly used during remission induction therapy include dexamethasone or prednisone, vincristine, asparaginase, and daunorubicin. Consolidation therapy often includes methotrexate (MTX) and 6-mercaptopurine (6-MP) or cyclophosphamide and cytarabine. Drugs used for intensification include cytarabine, cyclophosphamide, etoposide, dexamethasone, asparaginase, doxorubicin, MTX, 6-MP, and vincristine. Continuation therapy is based on oral 6-MP and MTX with pulses of vincristine and glucocorticoid (prednisone or dexamethasone). Intrathecal chemotherapy includes primarily MTX, which may also be combined with hydrocortisone and cytarabine (“triple-intrathecal therapy”). Imatinib is also approved for children newly diagnosed with Ph+ ALL

13 Tratamento - QT The primary mode of treatment in newly diagnosed children with ALL is chemotherapy via systemic and intrathecal administration and supportive care.[2,6] Radiotherapy is limited for emergencies and patients with CNS or high-risk disease. Multidrug chemotherapy regimens are divided into different phases (shown); different cooperative therapy groups use different combinations of agents in various phases depending on the risk stratification of the patient. Induction therapy is the initial 4-6 weeks of treatment that achieves remission in over 95% of children with ALL.[2,6,9] During this period, patients are managed in the hospital or monitored closely because they can develop life-threatening toxicities as a result of their therapy. The goal of postinduction chemotherapy (lasting 2-3 y) is to remove any residual leukemia cells.[9] Bhatt MD, Athale UH. Childhood Acute Lymphoblastic Leukemia: Diagnosis, Management, and Complications. 2014

14 Leucemia Linfoide Aguda (LLA)
Complicações agudas Sd da Lise Tumoral Neutropenia Febril Sepsis – S. aureus, Candida, Varicela Zoster, PCP Enterocolite neutropênica

15 Leucemia Linfoide Aguda (LLA)
Complicações tardias: Doença maligna secundária Cardiomiopatia Necrose óssea avascular Baixa estatura (se radiação craniocaudal) Deficiência de GH Dificuldade de aprendizado

16 Leucemia Linfoide Aguda (LLA)
Prognóstico Cura: 80-90% Prognóstico ruim: < 1ano < 90 dias – sobrevida 20% em 5 anos > 12 anos Cromossomo Filadélfia Resposta ruim a quimioterapia

17 Neuroblastoma Neuroblastoma é o tumor sólido extra cranial mais comum na infância; Doença maligna embrionária do sistema nervoso simpático pós ganglionar(Neuroblasto), essas células invaginam e migram pelo neuro-eixo (pescoço-sacro-adrenal). Lacayo NJ, Davis KL. Pediatric Neuroblastoma. 2015

18 Neuroblastoma Epidemiologia 8-10% tumores pediátricos
Pico de incidência: 2-5ª 90% casos < 5anos Doença metastática em 50% no diagnóstico EUA: 650 casos novos por ano Doença esporádica – componente hereditário Relacionado a Doença de Hirschsprung Hereditario: 2% historico +, tumor mais cedo

19 Neuroblastoma Localização: Adrenal 40% Paraespinhal 25%
Toracico 15% (comum em lactentes) Pélvico 5% Cervical 3%

20 Neuroblastoma Tipos: Depende da maturação e diferenciação
Ganglioneuroblastoma Ganglioneuroma Diagnóstico Diferencial: Tumor de Wilms

21 Quadro Clínico Depende da localização
Dor abdominal, náuseas, perda de peso, anorexia, fadiga e dor óssea, febre, irritação, equimose periorbital e fratura patológica; Hipertensão por compressão da artéria renal; Diarréia por secreção de peptídio vasoativo intestinal; Paralisia, parestesia ou disfunção urinária por compressão nervosa da medula;

22 Quadro Clínico Sinais respiratórios por massa mediastinal Sd de Horner
< 6 meses: tumor confinado a fígado, pele e medula óssea (Estágio 4S) Opsoclonia e mioclonia (2% dos casos) bom prognóstico oncológico, ruim neurológico

23 Neuroblastoma Conduta: Exames Laboratoriais: Catecolaminas urinárias
Função renal/hepática Eletrólitos DHL Ferritina TDH, T4 Níveis de IgG Any child with a presumed diagnosis of neuroblastoma or any other childhood cancer should be referred to a pediatric cancer center for proper care and evaluation. Laboratory studies should include the following: CBC count and differential (Anemia or other cytopenias suggest bone marrow involvement.) Urine collection for catecholamines (VMA/HVA) and UAA single sample or collected urine test for VMA/HVA is highly accurate in CLIA approved laboratories. Centers usually send samples to a specialty laboratory and/or perform a timed collection of urine. A urinary catecholamine level is considered to be elevated if it is 3 standard deviations higher than the age-related reference range levels. Serum creatinine Liver function testsAlanine aminotransferase (ALT) Aspartate aminotransferase (AST) Total bilirubin Alkaline phosphatase Total protein Albumin Prothrombin time (PT)/activated prothrombin time (aPTT) Electrolytes Calcium Magnesium Phosphorus Uric acid Serum lactate dehydrogenase (LDH) Ferritin Thyroid-stimulating hormone (TSH), T4 Immunoglobulin (Ig)G levels

24 Neuroblastoma Conduta: Imagem: Histopatológico
Radiografias – massa mediastinal e/ou calcificações TC – extensão tumoral RNM – massa paraespinhal Cintilografia Iodo-MIBG (I 123/131 -methyliodobenzylguanadine) PET-Scan Histopatológico

25 Exames de Imagem Lacayo NJ, Davis KL. Pediatric Neuroblastoma. 2015

26 Tratamento Doença Localizada: Metástase: Doença Residual:
Cirurgia Metástase: Biópsia + QT + cirurgia Doença Residual: RT Doença de Alto risco: Transplante de medula óssea All chemotherapy orders are written by pediatric oncologists and countersigned, usually by another physician. With recurrent disease, various salvage protocols may be used; with refractory disease, a limited number of phase I/II studies are available through the Children's Oncology Group (COG) and New Approaches to Neuroblastoma Therapy (NANT) consortia. Resources presented in this section should serve as a guide to indication, usual dosages, and adverse effects of specific agents. Antineoplastic drugs have a narrow therapeutic index and effective doses usually cause severe toxicities, some of which can be life threatening. Individual chemotherapy drugs are discussed below. These agents are almost invariably given in combination. Commonly used combinations include the following: Vincristine, cyclophosphamide, and doxorubicin Carboplatin and etoposide Cisplatin and etoposide Ifosfamide and etoposide Cyclophosphamide and topotecan Consolidation regimens used in neuroblastoma include the following: Carboplatin and etoposide with melphalan or cyclophosphamide Thiotepa and cyclophosphamide Melphalan and total body irradiation In Europe, several studies have used busulfan with melphalan or cyclophosphamide. One commonly used salvage or relapse therapy regimen is the combination of topotecan and cyclophosphamide. The use or retinoids have been incorporated in maintenance regimens in the posttransplant setting. Irinotecan is also under investigation.

27 Prognóstico Sobrevida em 5 anos Prognóstico ruim: < 1 ano: 83%
Metástase, oncogene MYCN, níveis elevados de DHL, ferritina.

28 Turma 19