Fatores genéticos e ambientais na patogênese, constituição do microambiente tumoral e prognóstico clínico do linfoma de hodgkin pediátrico

O linfoma de Hodgkin classico (LHc) é caracterizado pelo pequeno número de células de Hodgkin e Reed-Sternberg (H-RS) em meio a um fundo de células não neoplásicas, principalmente T e B. Este microambiente tumoral tem sido considerado uma manifestação imune do hospedeiro contra as células H-RS. Uma vez que crianças e adultos apresentam diferenças quanto a constituição e funcionalidade do sistema imune, além de eventos patogênicos distintos, é de se esperar que o microambiente tumoral no LHc exiba diferenças entre crianças e adultos. Neste estudo, nós analisamos uma série de casos de LHc (100 casos) em relação as características clínico-histológicas, composição do microambiente tumoral através da imunomarcação para CD3, CD4, C-maf, T-bet, FoxP3, CD8, Tia-1, Granzima B (GrB) e CD20, além do impacto prognóstico destas características. O índice de proliferação celular (IPC) das células neoplásicas e benignas foi determinado a partir da imunoexpressão de Ki67. Os polimorfismos de base única (SNPs) da IL10 -1082A/G, -819C/T e -592C/A foram determinados através de PCR alelo-específica. Os SNPs de CTLA4 -1722 A/G, +49 A/G e CT60 A/G foram determinados por descriminação alélica. O vírus Epstein-Barr (EBV) foi determinado por hibridização in situ (EBER-ISH) e imunomarcação para LMP1. A idade ao diagnóstico variou de 3 a 18 anos (mediana 14 anos) com 27% dos casos 10 anos ao diagnóstico. A esclerose nodular (EN) foi o subtipo mais freqüente (69%), sendo comum nas crianças >10 anos, seguida da celularidade mista (CM, 23%), distribuída igualmente entre os grupos etários. 44,8% dos casos foram EBV+, sem associação com os grupos etários (10 anos). Os casos de CM estavam independentemente associados ao EBV (p= 0,045) e à relação CD4/CD20 4/mm2 (p= 0,045) estiveram independentemente associados a pior sobrevida livre de eventos (SLE). Um escore prognóstico foi construído e permitiu a separação dos casos em 3 grupos com diferenças na SLE (p= 0,005). Os genótipos da IL10 -1082GG e -592CC e o haplótipo GCC estiveram associados a características histológicas, baixo número de linfócitos Th2 e alto número de células T reguladoras (Tregs). O genótipo do CTLA4 CT60GG foi associado ao maior IPC das células H-RS. O SNP CT60A e o haplótipo +49A/CT60A estiveram relacionados ao maior número de linfócitos CD4+, enquanto o SNP CT60G e o genótipo cT60GG estiverem associados ao maior número de linfócitos CD8+ e Tregs. O haplótipo CTLA4 +49G/CT0G foi independentemente associado a pior SLE (p= 0,036). Em conclusão: 1) O LHc pediátrico no sudeste do Brasil deve ter um padrão epidemiológico intermediário entre o LHc pediátrico visto nas regiões menos e mais desenvolvidas. A histopatogênese da CM deve ser resultante de uma exposição precoce ao EBV num contexto de déficit imune, refletido pela razão CD4/CD20 <1 no microambiente tumoral; 2) Este é o 1º estudo a descrever a composição do microambiente tumoral no LHc pediátrico e a determinar que os SNPs da IL10 e CTLA4 são capazes de influenciar a composição do microambiente tumoral no LHc; e 3) O EBV tem uma influência significante na composição do microambiente tumoral e na modulação da resposta imune contra o tumor

Classical Hodgkin lymphoma (cHL) is characterized by a small number of neoplastic, Hodgkin and Reed-Sternberg (H-RS) cells in a background of non-neoplastic, mainly B and T cells. This tumor microenvironment has been considered to be a manifestation of host immune reactions to malignant cells. Since children and adults have difference in the constitution and functionality of the immune system, and pathogenic events differ in pediatric and adult cHL, it is likely that the tumor microenvironment in cHL may be distinct in the pediatric setting. In this study, we analyzed a series of pediatric cHL (100 cases) regarding the clinical and histological characteristics, as well as composition of the tumor microenvironment by CD3, CD4, C-maf, T-bet, FoxP3, CD8, Tia-1, Granzyme B (GrB) and CD20 immunostain and its prognostic impact. Proliferation index of neoplastic and benign infiltrating cells was determined by Ki67 immunostain. We determined also the IL10 -1082A/G, -819C/T and -592C/A genotype of single nucleotide polymorphisms (SNPs) and haplotypes by Allele-specific (AS) PCR and CTLA4 -1722 A/G, +49 A/G and CT60 A/G SNPs by allele discrimination with fluorogenic hydrolysis probes (Taqman® Applied Biosystems). Epstein-Barr virus (EBV) was determined by in situ hybridization (EBERs-ISH) and LMP1 immunostain. Age at diagnosis ranged from 3 to 18 years (median 14) with 27% of cases 10 years age group. Nodular sclerosis (NS) was the most frequent subtype (69%) and was more frequent in the >10 years age group, followed by mixed cellularity (MC, 23%) which was distributed equally between age groups. EBV was identified in 44.8% of cases, without preferential association with age groups (10 years). MC cases were independently associated with EBV (P= 0.045) and with a CD4/CD20 ratio 10) exhibiting a shift from more cytotoxic to more suppressive profile along with age. EBV influenced the lymphocyte composition with more CD8+, Tia-1+, GrB+, and T-bet+ (Th1) cells. Extranodal disease (P=0.016) and GrB+ lymphocytes >4 cells/mm2 (P= 0.045) were independently associated with worst event-free survival (EFS). A prognostic score was constructed and allowed to segregate the children in 3 groups with differences in EFS (P= 0.005). IL10 genotypes -1082GG and -592CC and haplotype GCC associated with histological characteristics, low number of Th2 and high number of regulatory T (Treg) cells. CTLA4 CT60GG genotype was associated with high H-RS proliferative index (Ki67>50%). The SNP CT60A and haplotype +49A/CT60A were related with high number of CD4+ T cells, while the SNP CT60G and the genotype CT60GG were associated with high number of CD8+ and Treg cells. The CTLA4 haplotype +49G/CT60G was independently associated with worst EFS (p= 0.036). In conclusion: 1) Pediatric cHL in Southeastern Brazil may have an intermediate epidemiological situation between childhood cHL in underdeveloped and developed regions. Histopathogenesis of MC subtype may result from early exposure to EBV in the context of an impaired immune system reflected by a CD4/CD20 ratio <1; 2) This the 1st study to describe the specific characteristics of tumor microenvironment composition in pediatric cHL and to determine that IL10 and CTLA4 SNPs are able to influence the tumor microenvironment composition in cHL; and 3) EBV-status has a significant influence in the tumor microenvironment composition and likely in the modulation of the imune response against the tumor

Enfermedad de Hodgkin en Chiriqui: aspectos epidemiologicos / Hodgkin's disease in Chiriqui: epidemiological aspects

Se estudia la relación observada entre la histopatología y la raza de los pacientes con enfermedad de Hodgkin diagnósticados en Chiriquí, R. de P., y los hallazgos observados en pacientes de países desarrollados, subdesarrollados y de raza de coloR. Además, notamos que la incidencia por edad fue mayor en pacientes de de 10 a 30 años, y en los que tenían más de 60 años

Malignant lymphomas in Korea

A retrospective histological study of 540 malignant lymphomas diagnosed at the Department of Pathology of the Seoul National University from 1976 through 1986 is presented. Malignant lymphoma is the 10th most common malignant tumor in Korea, comprising 3.07% of all malignancy during period of study. Among malignant lymphomas non-Hodgkin's lymphoma accounted for 82% and accordingly the Hodgkin's disease was for 18%. The most common type of non-Hodgkin's lymphoma was diffuse histiocytic lymphoma of Rappaport. Follicular lymphoma was very rare, comprising only 2.3%. T-cell lymphoma accounted for 9.6% of non-Hodgkin's lymphomas, the most frequent type being lymphoblastic lymphoma. Immunoblastic sarcoma and mycosis fungoides were occasionally seen but there was no case of pleomorphic adult T-cell lymphoma. Among Hodgkin's diseases, mixed cellularity type was the most common type, and nodular sclerosis type was relatively rare.