RESUMO
A total of 90% of follicular lymphomas (FLs) harbor the translocation t(14;18) leading to deregulated BCL2 expression. Conversely, 10% of FLs lack the t(14;18), and the majority of these FLs do not express BCL2. The molecular features of t(14;18)-negative FLs remain largely unknown. We performed microRNA expression analysis in 32 FL grades 1 to 3A, including 17 t(14;18)-positive FLs, 9 t(14;18)-negative FLs without BCL2 expression, and 6 t(14;18)-negative FLs with BCL2 expression. MicroRNA profiles were correlated with corresponding mRNA expression patterns, and potential targets were investigated by quantitative PCR and immunohistochemistry in an independent validation series of 83 FLs. Statistical analysis identified 17 microRNAs that were differentially expressed between t(14;18)-positive FLs and t(14;18)-negative FLs. The down-regulation of miR-16, miR-26a, miR-101, miR-29c, and miR138 in the t(14;18)-negative FL subset was associated with profound mRNA expression changes of potential target genes involving cell cycle control, apoptosis, and B-cell differentiation. miR-16 target CHEK1 showed increased expression in t(14;18)-negative FLs, whereas TCL1A expression was reduced, in line with a partial loss of the germinal center B-cell phenotype in this FL subset. In conclusion, t(14;18)-negative FL have distinct microRNA profiles that are associated with an increased proliferative capacity and a "late" germinal center B-cell phenotype.
Assuntos
Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , MicroRNAs/genética , Translocação Genética/genética , Quinase 1 do Ponto de Checagem , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 18 , Estudos de Coortes , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Centro Germinativo/patologia , Humanos , Fenótipo , Proteínas Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genéticaRESUMO
The genome of mantle cell lymphoma (MCL) is, in addition to the translocation t(11;14), characterized by a high number of secondary chromosomal gains and losses that probably account for the various survival times of MCL patients. We investigated 77 primary MCL tumors with available clinical information using high-resolution RNA expression and genomic profiling and applied our recently developed gene expression and dosage integrator algorithm to identify novel genes and pathways that may be of relevance for the pathobiology of MCL. We show that copy number neutral loss of heterozygosity is common in MCL and targets regions that are frequently affected by deletions. The molecular consequences of genomic copy number changes appear complex, even in genomic loci with identified tumor suppressors, such as the region 9p21 containing the CDKN2A locus. Moreover, the deregulation of novel genes, such as CUL4A, ING1, and MCPH1, may affect the 2 crucial pathogenetic mechanisms in MCL, the disturbance of the proliferation, and DNA damage response pathways. Deregulation of the Hippo pathway may have a pathogenetic role in MCL because decreased expression of its members MOBKL2A, MOBKL2B, and LATS2 was associated with inferior outcome, including an independent validation series of 32 MCLs.
Assuntos
Dosagem de Genes/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Feminino , Genes Supressores de Tumor , Homozigoto , Humanos , Estimativa de Kaplan-Meier , Perda de Heterozigosidade/genética , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Polimorfismo de Nucleotídeo Único , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/fisiologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Follicular lymphoma (FL) is genetically characterized by the presence of the t(14;18)(q32;q21) chromosomal translocation in approximately 90% of cases. In contrast to FL carrying the t(14;18), their t(14;18)-negative counterparts are less well studied about their immunohistochemical, genetic, molecular, and clinical features. Within a previously published series of 184 FLs grades 1 to 3A with available gene expression data, we identified 17 FLs lacking the t(14;18). Comparative genomic hybridization and high-resolution single nucleotide polymorphism (SNP) array profiling showed that gains/amplifications of the BCL2 gene locus in 18q were restricted to the t(14;18)-positive FL subgroup. A comparison of gene expression profiles showed an enrichment of germinal center B cell-associated signatures in t(14;18)-positive FL, whereas activated B cell-like, NFkappaB, proliferation, and bystander cell signatures were enriched in t(14;18)-negative FL. These findings were confirmed by immunohistochemistry in an independent validation series of 84 FLs, in which 32% of t(14;18)-negative FLs showed weak or absent CD10 expression and 91% an increased Ki67 proliferation rate. Although overall survival did not differ between FL with and without t(14;18), our findings suggest distinct molecular features of t(14;18)-negative FL.
Assuntos
Cromossomos Humanos Par 14 , Cromossomos Humanos Par 18 , Linfoma Folicular/genética , Translocação Genética , Estudos de Coortes , Hibridização Genômica Comparativa , Amplificação de Genes/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Variação Genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
Since 2007, a hospital in Tanzania has been supported with histopathological reports via telepathology (TP) by German pathologists. For this, the Internet-based platform iPath is used. The aim of this study was to analyse the rate of discrepancies in defined diagnostic groups. After shipment of paraffin-embedded tissue to Germany, specimens were processed according to recent diagnostic standards. All diagnoses were grouped into eight benign and 11 malignant main categories. The comparison comprised the following categories: 1, identical diagnosis; 2, mild discordance; 3, correct distinction between benign and malignant process, 4, false malignant; 5, false benign; and 6, no primary diagnosis possible. The cohort comprised 396 benign and 336 malignant diseases. Of the benign diseases, 62% were category 1, 23% category 2, 2% category 3, 6% category 4 and 7% category 6. Of the malignant diseases, 42% were category 1, 16% category 2, 12% category 3, 14% category 5 and 15% category 6. Exclusive support with static TP cannot meet all requirements of modern medical diagnostics. However, the project shows a approach for how pathologists in industrial countries can help low-income countries. In difficult cases, the opportunity for a final work-up using additional methods must be given for useful diagnostic purposes.
Assuntos
Telepatologia , Alemanha , Hospitais , Humanos , Patologistas , TanzâniaRESUMO
INTRODUCTION: Static telepathology (TP) was used to support a hospital in Tanzania that cannot employ a resident pathologist but has a basic laboratory. Histological slides were prepared by the local technical staff and digital images were uploaded into an Internet-based system; consultant pathologists in Germany could give their opinion. The aim of the study was to examine the diagnostic validity of this project without local pathologists. METHODS: The set-up period for special training of local technical assistants was 10 weeks. Diagnoses of the first 545 cases that were processed via TP were compared with the results of a second opinion on the basis of routine slides created from the corresponding paraffin blocks, which were sent to Germany. RESULTS: Of all cases, 384 (70%) TP diagnoses were completely confirmed by the second opinion. Minor deviations (e.g. divergent subtypes of tumours or other aetiology of non-specific reactive processes) were documented in 76 cases (14%), so that overall, 84% of diagnoses were useful in the setting of the available therapeutic possibilities. The results were better in some subgroups of diseases (90-100% useful diagnoses) and suboptimal (minimum 63%) in a few subgroups with rare diseases. Thirty (5%) malignant diseases were primarily misinterpreted as being benign and 12 (2%) benign diseases as malignant. Forty-three (8%) cases were insufficient for diagnosis using TP and could not be provided with a primary assessment. DISCUSSION: Static TP can help support medical services in low-income countries in the absence of local pathologists with a potentially high diagnostic validity, especially for selected groups of diseases. The procedure can significantly improve the diagnostic procedures before commencement of therapy - a substantial contribution within a globalised world.
Assuntos
Comunicação Interdisciplinar , Pobreza , Encaminhamento e Consulta/normas , Telepatologia/métodos , Países Desenvolvidos , Feminino , Humanos , Cooperação Internacional , Patologistas/normas , TanzâniaRESUMO
BACKGROUND/OBJECTIVE: In a project of telepathology (TP) between German pathologists and a hospital in Tanzania, trained technical assistants have uploaded digital histological images onto the internet-based platform ipath. The diagnoses from 486 paediatric specimens were analysed. METHODS: The investigation included diagnoses, either primarily done via TP or secondarily after a further workup of the paraffin-embedded tissue, which was sent to Germany for cases which could not be solved via TP. In the latter, the initial TP-diagnoses were compared with the results after re-evaluation. RESULTS: The median age was 11 years. The cohort comprised 390 benign diseases (80.2%) and 96 malignant diseases (19.8%). For benign diseases, the most frequent anatomic sites were lymph nodes, skin, and soft tissue, breast, and head&-neck. Frequent diagnoses were non-specific inflammations and benign tumors. In malignant diseases, the most sites were lymph nodes, skin, soft tissue, head&neck, and ovary and the most frequent diseases sarcomas and lymphomas. The paraffin embedded tissue of 179 cases (36.3%) was shipped to Germany. With the concordance analysis, we could discover the mandatory necessity for the possibility of second opinion in difficult cases. CONCLUSION: An exclusively TP-support cannot meet all requirements of modern medical diagnostics. The education of local pathologists is imperative.
Assuntos
Neoplasias/patologia , Telepatologia/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Hospitais , Humanos , TanzâniaRESUMO
OBJECTIVE: To study the clonal rearrangements and mutation status of IgVH genes in classic Richter's syndrome, the relationship between molecular findings of IgVH gene and clinical outcome, and to deciper the possible molecular mechanism of transformation. METHODS: The clonal rearrangements and mutation status of IgVH genes were analyzed in cases of classic Richter's syndrome by Genescan and sequencing. Immunohistochemical study for zeta-chain associated protein kinase 70 kDa (ZAP70), p53 and interferon regulation factor 4 (IRF-4) was also performed. RESULTS: Samples of 18 cases of B-chronic lymphocytic leukemia (B-CLL)/ diffuse large B-cell lymphoma (DLBCL,78. 3%) had identical tumor cell clones, whereas DLBCL developed as a clonally independent neoplasm in 5 patients (21.7%). Among the clonally related group, 12 cases carried unmutated VH genes in both B-CLL and DLBCL components and VH3-23, VH3-74 and VH1-2 were accounted for the B-CLL transformation to DLBCL. Immunohistochemical study showed that the transformed DLBCL expressed CD5 in 32.1% of cases, CD23 in 14.3%, ZAP70 in 23.8%, p53 in 80.6% and IRF-4 in 82.6% of the cases respectively. Follow-up data were available in 17 patients with classic Richter's syndrome. The median survival period was 7 months. No significant difference in survival rate was obtained between the clonally related or unrelated groups, between IgVH gene mutated or unmutated groups, and between the groups with or without expression of ZAP70, p53 and IRF-4. CONCLUSIONS: The ratio of clonally related transformed DLBCL from B-CLL to clonally unrelated DLBCL is 2:1. Clonal transformation to DLBCL predominantly occurs in B-CLL patients carrying unmutated IgVH genes. The biased IgVH gene usage suggests antigens are involved in classic Richter's syndrome. Molecular differences of IgVH genes and very poor clinical outcome of this group of transformed DLBCL indicate that there cases may be regarded as a distinct subset of DLBCL.
Assuntos
Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/genética , Linfoma de Células B/genética , Linfoma Difuso de Grandes Células B/genética , Proteína-Tirosina Quinase ZAP-70/genética , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/patologia , Genes p53/genética , Humanos , Masculino , Pessoa de Meia-Idade , Hipermutação Somática de Imunoglobulina/genéticaRESUMO
OBJECTIVE: To detect the clonal relationship, the rearrangement, and the mutational status of IgVH gene; the influence of these molecular characteristics on the clinical outcome in Hodgkin variant of Richter syndrome; and the possible molecular pathogenesis in this transformation. METHODS: The clonal rearrangements and mutational status of IgVH genes were analyzed in Hodgkin variant of Richter syndrome and B-CLL with Reed-Stemberg (R-S)-like cells by GeneScan analysis and sequencing. Semi-nest PCR based on laser capture microdissection was utilized to compare the clonal relationship between B-CLL and R-S/R-Slike cells. Immunohistochemical staining was used to detect the different expressions of ZAP70, p53, IRF-4 and LMP1 in the two components. RESULTS: (1) 5/6 B-CLL cases transformed to Hodgkin lymphoma (HL)/R-S-like cells carried the mutated IgVH genes; (2) 2 cases of R-S cells and 1 case of R-S-like cells were clonally distinct from B-CLL clone and express LMP1, whereas 1 case of R-S-like cells was relating to the surrounding B-CLL cells and did not express LMP1; (3) 2/6 B-CLL cases transformed to HL convey VH4-34 and VH3-48 respectively. CONCLUSIONS: (1) Richter transformation to HL/R-S-like cells evolves from the B-CLL which originates from the germinal center or post germinal center B cells, indicating that different lymphoma cells of different subtypes in Richter syndrome come from different B cell lineage and possibly involve a different pathogenesis and pathway; (2) HL and R-S-like cells evolve from either the B-CLL clone or may develop as a clonally unrelated lymphoma, the independent secondary malignancies are appear to be EBV-positive, possibly as a consequence of the underlying immunodeficiency; (3) The biased usage of IgVH genes suggested a role of antigens involved in the HL variant of Richter syndrome.
Assuntos
Doença de Hodgkin/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/genética , Células de Reed-Sternberg/patologia , Idoso , Idoso de 80 Anos ou mais , Células Clonais/patologia , Feminino , Herpesvirus Humano 4 , Doença de Hodgkin/classificação , Doença de Hodgkin/patologia , Doença de Hodgkin/virologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , SíndromeRESUMO
In the present study, 21 cases of adult/late-onset EBV-associated lymphoproliferative disease (AELPD) with an uncertain malignant potential were investigated with regard to their histomorphology, immunophenotype, clonal rearrangement of the heavy chain (IgH) and T-cell receptor (TCR) genes and clinical course. The cases were histomorphologically reevaluated and assigned to one of three morphological groups: mononucleosis-like, Hodgkin-like, or polymorphous. In addition, cases with or without detectable necrosis were investigated for differences in clinical outcome. Overall survival was highest in the group with Hodgkin-like morphology (4/4 patients), followed by patients with mononucleosis-like phenotype (4/5 patients surviving). Cases with polymorphous morphology showed the poorest survival rates with 7/12 patients dead of disease (58%). 4/6 patients with histologically detectable necrosis died (66%), but only 4/15 patients without necrosis (27%). 11/21 cases with AELPD showed clonal rearrangement for IgH (nâ¯=â¯4), TCR (nâ¯=â¯5) or IgHâ¯+â¯TCR (nâ¯=â¯2). 5/11 patients with clonal rearrangement died (45%), and this percentage was similar in all of the three subgroups. In conclusion, the present study shows that polymorphous morphology and detection of necrosis in AELPD are frequently linked to a fatal clinical course, whereas Hodgkin-like morphology seems to be associated with a more favourable prognosis. Clonal rearrangement of IgH or TCR is frequent in AELPD, but prognosis is unpredictable from this feature.
Assuntos
Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T/genética , Herpesvirus Humano 4/patogenicidade , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Genótipo , Humanos , Imunofenotipagem/métodos , Linfoma de Células B/virologia , Fenótipo , PrognósticoRESUMO
Session 7 of the Society for Hematopathology/European Association for Haematopathology Workshop was devoted to case presentations and discussion of enteropathy-type T-cell lymphoma (ETL) and other T-cell lymphomas involving the gastrointestinal tract. ETL is a rare type of T-cell lymphoma, often associated with a history of celiac disease, that usually arises in the jejunum but can involve other gastrointestinal tract sites (eg, stomach and colon). As the cases submitted illustrate, there are 2 histologic groups of ETL that correlate with clinical and immunophenotypic features. Pleomorphic-anaplastic ETL is usually associated with a history of celiac disease and histologic evidence of enteropathy and is most often CD56-. Monomorphic ETL often occurs without a history of celiac disease, has variable histologic evidence of enteropathy, and is usually CD56+. Comparative genomic hybridization has shown recurrent chromosomal gains and losses that are characteristic of ETL and uncommon in other T-cell lymphomas, providing useful ancillary data for the diagnosis of ETL.
Assuntos
Neoplasias Intestinais/patologia , Linfoma de Células T/patologia , Antígeno CD56/análise , Doença Celíaca/patologia , Aberrações Cromossômicas , Cromossomos Humanos Par 9 , Humanos , Hibridização in Situ Fluorescente , Neoplasias Intestinais/classificação , Neoplasias Intestinais/genética , Linfoma de Células T/classificação , Linfoma de Células T/genéticaAssuntos
Perfilação da Expressão Gênica , Linfoma de Células B/classificação , Linfoma de Células B/genética , Linfoma de Burkitt/classificação , Linfoma de Burkitt/genética , Linfoma de Burkitt/terapia , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/classificação , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma de Células B/terapia , Linfoma Folicular/classificação , Linfoma Folicular/genética , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/terapia , Linfoma de Célula do Manto/classificação , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/terapia , PrognósticoRESUMO
PURPOSE: Eight cycles of BEACOPP(escalated) (escalated dose of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by radiotherapy (RT) to initial bulk or residual tumor mass is the German Hodgkin Study Group standard of care for advanced-stage Hodgkin's lymphoma (HL). However, treatment-related toxicity is a concern, and the role of RT in this setting is unclear. The HD12 study thus aimed to reduce toxicity while maintaining efficacy. PATIENTS AND METHODS: In this prospectively randomized multicenter trial, eight cycles of BEACOPP(escalated) was compared with four cycles of BEACOPP(escalated) followed by four cycles of the baseline dose of BEACOPP (BEACOPP(baseline); 4 + 4), and RT with no RT in the case of initial bulk or residual disease. The study was designed to exclude a difference in 5-year freedom from treatment failure (FFTF) rate of 6%. RESULTS: Between January 1999 and January 2003, 1,670 patients age 16 to 65 years were enrolled onto the HD12 study. At 5 years, FFTF was 86.4% in the BEACOPP(escalated) arm and 84.8% in the 4 + 4 arm (difference, -1.6%; 95% CI, -5.2% to 1.9%), and overall survival was 92% versus 90.3% (difference, -1.7%; 95% CI, -4.6% to 1.1%). Deaths related to acute toxicity of chemotherapy were observed in 2.9% of patients (BEACOPP(escalated), n = 19; 4 + 4, n = 27). FFTF was inferior without RT (90.4% v 87%; difference, -3.4%; 95% CI, -6.6% to -0.1%), particularly in patients who had residual disease after chemotherapy (difference, -5.8%; 95% CI, -10.7% to -1.0%), but not in patients with bulk in complete response after chemotherapy (difference, -1.1%; 95% CI, -6.2% to 4%). CONCLUSION: The reduction of BEACOPP to the 4 + 4 regimen did not substantially reduce severe toxicity but might decrease efficacy. Our results do not support the omission of consolidation RT for patients with residual disease. Alternative strategies for improving the risk-to-benefit ratio for patients with advanced HL are needed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Quimiorradioterapia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Seguimentos , Doença de Hodgkin/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Procarbazina/administração & dosagem , Procarbazina/efeitos adversos , Procarbazina/uso terapêutico , Falha de Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêuticoRESUMO
Fifty-five consecutive cases of Hodgkin's lymphoma (HL), collected between 1996 and 1998 from Cairo, Egypt, were histologically subtyped, phenotyped, and then studied for the presence of Epstein-Barr virus (EBV). We used immunohistochemical stains for EBV latent membrane protein 1 (LMP-1) and in situ hybridization stains for EBV-encoded small RNA (EBER-1) transcripts. Forty-five cases (82%) had classic HL (cHL), and ten cases (18%) had nodular lymphocyte predominant HL (NLPHL), with each group expressing its typical phenotype. LMP-1 stains were positive in 63% and 0% of cHL and NLPHL cases, respectively. EBER-positive Reed-Sternberg cells and variants were also present in 62% and 0% of each group, respectively. The cHL cases showed variable EBER positivity: nodular sclerosis, 58%; mixed cellularity, 100%; lymphocyte depletion, 100%; and unclassifiable, 67%. Our findings are similar to those from other developing countries and point towards a pathogenic role of EBV in cHL.
RESUMO
BACKGROUND: In 1999, a World Health Organization (WHO) committee published histologic criteria for distinct thymoma entities (labeled as Type A, AB, B1, B2, B3 thymomas) and for the heterogeneous group of thymic carcinomas, collectively called Type C thymomas. Whether WHO-defined histologic thymoma subtypes are of independent prognostic relevance has yet to be proved. METHODS: Two hundred thymomas from the Shanghai Chest Hospital with a mean follow-up time of 15 years (range, 1-246 months) were studied for the relevance of WHO histologic subtype and other factors (stage, therapy, and myasthenia gravis [MG]) for survival. RESULTS: In order of frequency, 68 patients (34.0%) had Type AB, 39 (19.5%) had Type B2, 36 (18.0%) had Type C, 27 (13.5%) had Type B3, 17 (8.5%) had Type B1, and 8 (4.0%) had Type A thymoma. Five cases (2.5%) were rare thymomas not mentioned in the WHO classification. Survival data showed significant differences among the histologic subtypes (log rank test: P < 0.001). Among patients with Type A and AB thymomas, none died of tumor; of the Type B1 thymoma patients, only one (5.9%) died at 22 months. Type B2, B3, and C thymomas had a significantly worse prognosis with 5-year survival rates of 75.0%, 70.0%, and 48.0%, respectively. Ninety-six patients (48.0%) were in Masaoka Stage I, 26 (13.0%) were in Stage II, 65 (32.5%) were in Stage III, and 13 (6.5%) were in Stage IV. Stage was highly significant in predicting survival (log rank, test P < 0.001). The association between histologic subtype and invasive behavior (stage) was statistically significant (P < 0.001). However, histology was an independent predictive factor of survival in Stage I and II thymomas: Type B2, B3, and C thymomas had a worse prognosis than Type A, AB, and B1 thymomas (log rank test: P < 0.003). Thirty patients (15.0%) presented with MG. MG was significantly more frequent in Type B2 and B3 than in Type A, AB, and B1 thymomas (P < 0.01). On multivariate analysis, MG had no adverse effect on survival (P = 0.17). Radiation or chemotherapy improved patients' survival at 5 and 10 years in Type B2, B3, and C thymomas (log rank test: P < 0.003). CONCLUSIONS: Tumor stage is the most important determinant of survival in thymoma patients, but the WHO histologic subtype is an independent prognostic factor in Stage I and II thymomas, among which WHO Type A, AB, and B1 thymomas form a low-risk group. Patients with high-risk thymomas might profit from novel adjuvant radiochemotherapy regimens.