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Benzene (Bz) is widely regarded as a prototype environmental leukemogen and individuals chronically exposed are at risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It is widely assumed that initiation and pathogenesis of AML following Bz exposure (Bz-AML) is similar or identical to therapy-related AML (t-AML), in which clonal cytogenetic abnormalities, including aneuploidy, are initiating events. However, this assumption is not supported by studies reporting actual disease outcomes together with cytogenetic analyses. Here, using clinically relevant cytogenetic, hematologic, and epidemiological methods, we directly show for 722 consecutive AML cases that the pattern of clonal cytogenetic abnormalities encountered in Bz-exposed cases (n = 78) more closely resembles de novo-AML than t-AML. The prevalence of aneuploidy in Bz-exposed- and de novo-AML cases was identical (23%), and no significant increases in -5/5q- (RR = 0.79) (95% CI: 0.29-2.12) or -7/7q- (RR = 1.27) (95% CI: 0.55-2.92) abnormalities were observed between Bz- vs de novo-AML, respectively. Previous studies have suggested a role for autoimmunity in Bz related MDS including immune mediated inflammatory features and positive responses to immunosuppressive therapy which are indistinguishable from those reported in MDS with low risk of progression to AML. These observations are more consistent with an epigenetic model for initiation of Bz-AML in which altered homeostatic regulation in the bone marrow niche, not direct cytogenetic injury, predominates in the initial development of the leukemic stem cell phenotype, a mechanism biologically distinct from previous models of clonal cytogenetic injury. These findings are important for further understanding the biological basis of AML, particularly in environmental and occupational settings., (Copyright © 2013 Wiley Periodicals, Inc.)

We report results of a hospital-based case control study of 137 consecutive patients diagnosed with aplastic anemia (AA) in participating hospitals over a 4-year period. Diagnoses were made by a single laboratory, subjects were age- and gender-matched to two controls and interviewed concerning previous disease, work histories and exposures to potential etiologic agents. Analysis was conducted on two distinct subgroups: severe aplastic anemia (SAA) and moderate aplastic anemia (MAA). In univariate regression models, the strongest associations were observed for exposure to benzene and SAA (OR=3.12, 95% CI=1.12-8.65) and life on a farm and MAA (OR=3.08, 95% CI=1.44-6.56). Benzene exposure did not show a strong dose-response relationship with either subtype. When accounting for all of the potential confounders we considered in conditional regression models, the previous relationships persisted. Other explanatory variables included hair-dye use for MAA and farm exposures, such as livestock for SAA, although most of these additional variables fell just short of statistical significance. Adjusted R-squared values were only 10% for each subtype, leaving 90% of AA occurrence unexplained. Our results suggest that: (a) benzene exposure is more strongly related to SAA than MAA, (b) farm and livestock exposures are related to both forms of AA, confirming some previous results, and (c) a large percentage of AA remains unexplained, which may indicate that individual susceptibility has a major influence on AA occurrence., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

The clinical, cytogenetic and molecular features of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), a disease previously considered to be rare in Asia, were examined in consecutive series of 70 cases diagnosed by our laboratory over a 30-month period. Clonal abnormalities were observed in 80% of CLL/SLL cases using a combination of conventional cytogenetic and fluorescence in situ hybridization (FISH) analysis. Those involving 14q32/IGH were the most frequent (24 cases), followed by trisomy 12 and 11q abnormalities. IgV(H) gene usage was non-random with over-representation of V(H)4-34, V(H)3-23 and a previously unreported increase in V(H)3-48 gene use. Somatic hypermutation (SHM) of IgV(H) germline sequences was observed in 56.5% of cases with stereotyped patterns of SHM observed in V(H)4-34 heavy chain complimentary-determining (HCDR1) and framework region CFR2 sequences. These findings in a Chinese population suggest subtle geographical differences in IgV(H) gene usage while the remarkably specific pattern of SHM suggest that a relatively limited set of antigens may be involved in the development of this disease worldwide. IgV(H) gene mutation status was a significant predictor of initial survival in CLL/SLL. However, an influence of karyotype on prognosis was not observed.

We characterized the prevalence, clinical and cytogenetic characteristics and survival of 435 patients diagnosed with de novo MDS in a single laboratory according to WHO criteria, and compared the utility of different scoring systems to predict survival for individual subtypes of MDS. The mean follow-up period was 25.1 (5.5-53.2) months. Our results confirm major differences in the age-distribution and prevalence of individual subtypes of MDS between Asian and Western patients with a median age of 58 years and a predominance of RCMD (69.9%). Survival rates were similar to those reported in the West: the 3-year survival rate for MDS was 46.7% with a median survival time for RCMD of 38 months and RAEB, 10 months. We found that the IPSS and WPSS scoring systems, which are weighted heavily by blast cell count and karyotype, were not independent predictors for survival in RCMD patients. Multivariate analysis demonstrated that a scoring system based on age (> or =60 years), ANC (<1.0 x 10(9)/L), Hb (<90 g/L), number of cytopenias and complex karyotype is a more useful predictor of survival in RCMD.

Acute lymphoblastic leukemia (ALL) accounts for 20-30% of adult leukemia in the West. However, detailed studies of B-cell-specific ALL in adult Asian populations are lacking. We diagnosed and characterized 137 consecutive cases of precursor B lymphoblastic leukemia (precursor B-cell ALL) presented to our laboratory in Shanghai using the WHO 2001 classification system. Patient clinical, phenotypic and cytogenetic characteristics were correlated with outcome. In contrast to Western studies, females (71) outnumbered males (66) partly due to an increased prevalence of the CD10- pro B-cell phenotype. Females with a CD10- pro B-cell phenotype exhibited significantly better overall survival than males. The most common cytogenetic abnormality was the Philadelphia chromosome (PH/BCR/ABL) which was found in approximately 37% of the cases. Cases of precursor B cell ALL lacking the PH/BCR/ABL genotype exhibited a pronounced age-dependent, gender prevalence with a modal age in the sixth decade for females compared to the second decade for males. These findings suggest significant geographic heterogeneity in precursor B-cell ALL which may be of both etiological and therapeutic significance.

The frequency of subtypes of lymphoid neoplasms was determined in a prospective series of 831 patients presenting at 29 Shanghai hospitals over a 4-year period. Diagnosis and classification was established in a single laboratory according to the 2001 WHO classification system. The frequency of non-Hodgkin lymphoma was 87.6% (n = 728) and Hodgkin lymphoma was 12.4% (n = 103). The most prevalent NHL subtypes diagnosed using WHO criteria were diffuse large B cell lymphoma (DLBCL), precursor B lymphoblastic leukemia/lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Although a low incidence has been reported in some Asian populations, CLL/SLL was commonly encountered, indicating that chronic lymphoid neoplasms are not rare in Shanghai. Consistent with previous reports, our findings indicate a decrease in the frequency of follicular lymphoma and an increase in T cell neoplasms compared to the West. Precursor T lymphoblastic leukemia/lymphoma, anaplastic large T cell lymphoma, aggressive NK cell leukemia, angioimmunoblastic T cell lymphoma and peripheral T cell lymphoma were prominent subtypes of T cell NHL.

Aggressive natural killer cell leukemia (ANKL) is a rare Epstein-Barr virus (EBV)-associated fulminating disease that is widely disseminated at diagnosis. Because of its typically extranodal presentation, differing degrees of NK cell involvement, and varying bone marrow pathology, ANKL can be confused with a reactive process. These features, coupled with a rapidly fatal course, have hampered systematic study of the pathogenesis of ANKL. Nine cases of ANKL were diagnosed and characterized by a single laboratory over a 2-year period. Constant features at presentation included disseminated disease, high fever, bone marrow involvement, and a high lactate dehydrogenase index. All cases were positive for EBV early region protein and negative for latent membrane protein 1, and all had a germline T-cell receptor gene configuration. Peripheral blood counts were variable, with severe thrombocytopenia being the most frequently encountered abnormality (7 of 9 cases). Hematophagocytosis, dyserythropoiesis, and stromal degeneration were the most frequent findings in the bone marrow. Neoplastic cells in the bone marrow were consistently CD2+, CD56+, CD45+, CD34-, CD117-, CD4-, and surface CD3-. Most cases were HLA-DR+ (8/9) and CD8- (8/9). Complex clonal cytogenetic abnormalities were found in 8 of 9 cases. Because of its aggressive course, rapid and accurate diagnosis of ANKL is essential for a better understanding of the etiology, pathogenesis, and treatment of the disease.

The prevalence of subtypes of the myelodysplastic syndromes (MDS) was determined in a prospective series of 176 patients presenting at 28 Shanghai hospitals. Diagnosis was established in a single laboratory, analyzing morphologic, immunophenotypic, and cytogenetic data, using the World Health Organization (WHO) revised classification and directly compared to the French American British (FAB) criteria. The median age at diagnosis for all cases was 53 years. There was a striking increase in the prevalence of RCMD in younger patients relative to other subtypes (WHO). The overall frequency of clonal cytogenetic abnormalities was 26.5% (WHO) and 31% (FAB). The most frequently encountered lesions were trisomy 8, del(20)q, del(7q), and del(5q). These results are consistent with previously reported age-dependent differences in MDS and a decreased frequency of del(5q) abnormalities between China and the West. These results also indicate that multilineage dysplasia is a prominent feature in MDS developing in younger individuals in Shanghai and suggest distinguishing between RCMD and RA may be important in the design of studies to further understand regional differences in subtype prevalence and to elucidate the pathogenesis of this complex and multifactorial disease.