RESUMO
Hyaline vascular Castleman disease is traditionally regarded as a reactive hyperplastic process. Occasional cases, however, have been reported with cytogenetic anomalies bringing this concept into question. In this study, we used conventional and methylation-specific polymerase chain reaction methods to assess the human androgen receptor α (HUMARA) gene in 29 female patients with hyaline vascular Castleman disease and compared the results with three cases of plasma cell Castleman disease and 20 cases of age-matched lymphoid hyperplasia. We also assessed for immunoglobulin gene and T-cell receptor gene rearrangements, and conventional cytogenetic analysis was performed in three cases of hyaline vascular Castleman disease. In cases with informative results, conventional and methylation-specific human androgen receptor α gene analyses yielded a monoclonal pattern in 10 of 19 (53%) and 17 of 23 (74%) cases of hyaline vascular Castleman disease, respectively. A monoclonal pattern was also detected in three cases of plasma cell Castleman disease but not in cases of lymphoid hyperplasia. The frequency of monoclonality was higher for lesions >5 cm in size (100%) and for the stromal-rich variant (91%). Cytogenetic abnormalities in stromal cells were revealed in two cases of hyaline vascular Castleman disease and no cases showed monoclonal immunoglobulin or T-cell receptor gene rearrangements. Follow-up data showed persistent disease in 4 of 23 (17%) patients. We conclude that hyaline vascular Castleman disease is often a monoclonal proliferation, most likely of lymph node stromal cells.
Assuntos
Hiperplasia do Linfonodo Gigante/genética , Hiperplasia do Linfonodo Gigante/patologia , Receptores Androgênicos/genética , Cariótipo Anormal , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Aberrações Cromossômicas , Células Clonais , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Receptores de Antígenos de Linfócitos T/genética , Células Estromais/patologia , Adulto JovemRESUMO
Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). The pre-S(2) mutant large HBV surface antigen (LHBS) in type II ground glass hepatocytes (GGHs) has been recognized as an emerging viral oncoprotein; it directly interacts with the c-Jun activation domain-binding protein 1 (JAB1) and subsequently causes hyperphosphorylation of the tumor-suppressor retinoblastoma and, consequently, leads to disturbed cell cycle progression. The interaction of the pre-S(2) mutant LHBS with JAB1 could provide a potential target for chemoprevention. In this study, we found that the preneoplastic type II GGHs showed a significant decrease of the cyclin-dependent kinase inhibitor p27(Kip1), which serves as a marker for pre-S(2) mutant-JAB1 complex formation. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) elevated expression of the tumor-suppressor thioredoxin-binding protein 2 (TBP2), which subsequently enhanced the JAB1-TBP2 interaction and abolished the pre-S(2) mutant LHBS-induced degradation of p27(Kip1), which, in turn, recovered the normal cell cycle checkpoint. The pre-S(2) mutant LHBS-induced pro-oncogenic effects: increased cell proliferation, nuclear/cytoplasmic ratio and proliferating cell nuclear antigen expression, were all greatly ameliorated after SAHA treatments, which suggested SAHA as a promising chemopreventive agent for the pre-S(2) mutant oncoprotein-induced HCC. In conclusion, this study provides the mechanism of histone deacetylase (HDAC) inhibitor in preventing the pre-S(2) mutant-induced oncogenic phenotype. The HDAC inhibitor SAHA is therefore a potential chemopreventive agent for high-risk chronic HBV patients who may develop HCC.
Assuntos
Carcinoma Hepatocelular/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Antígenos de Superfície da Hepatite B/metabolismo , Hepatite B Crônica/prevenção & controle , Ácidos Hidroxâmicos/farmacologia , Neoplasias Hepáticas/prevenção & controle , Mutação/genética , Precursores de Proteínas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Complexo do Signalossomo COP9 , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Ciclo Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/genética , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Feminino , Imunofluorescência , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/complicações , Hepatite B Crônica/virologia , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Precursores de Proteínas/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Semelhantes à Proteína de Ligação a TATA-Box/genética , Proteínas Semelhantes à Proteína de Ligação a TATA-Box/metabolismo , Técnicas do Sistema de Duplo-Híbrido , VorinostatRESUMO
AIMS: To describe diffuse large B cell lymphoma (DLBCL) presenting initially in bone marrow, liver and spleen (BLS-type) without lymphadenopathy. METHODS AND RESULTS: The clinicopathological and cytogenetic features of 11 such cases (eight men, three women; mean age: 62.7 years are described). Usually presenting with fever and haemophagocytic syndrome suggesting infection and complicating timely diagnosis, bone marrow examination showed patchy and interstitial infiltration of large tumour cells without sinusoidal involvement. All cases had a high Ki-67 index (≥90%), commonly a non-germinal centre/activated B cell immunophenotype and were negative for Epstein-Barr virus and human herpesvirus 6 and 8. The more frequent cytogenetic changes involved chromosomal loci 14q32 and 9p24, as well as del(3)(q21), add(7)(p22), t(3;6), del(8)(p22), +18 and add(19)(p13). Clinical behaviour was very aggressive, with a 2-year survival rate of 18% (45% of patients died within 3 weeks). High-dose chemotherapy with haematopoietic stem cell transplantation prolonged survival in one patient. CONCLUSIONS: Although it shares with intravascular LBCL a subtle presentation and an aggressive clinical course, this primary BLS large cell lymphoma variant is distinguished by lacking an intravascular component and having different cytogenetic findings.