Comprehensive analysis of the differential cellular and EBV miRNA expression profiles in mature T and NK cell lymphomas.

Epstein-Barr virus (EBV) has been detected in several subtypes of Mature T and NK cell lymphomas. However, the impact of EBV status on the survival and the mechanism is still unknown. Numerous recent investigations have demonstrated that the EBV-encoded microRNAs (EBV-miRNAs) were associated with the development and prognosis of lymphoma. We used a miRNA microarray to identify the differentially expressed miRNAs in 175 Mature T and NK cell lymphomas including 5 subtypes. The result demonstrated that all the samples could be divided into three groups according to the relative expression of EBV-miRNAs, and the prognosis of the three groups was significantly different (P < 0.05). We also found that there were 72 differential cellular miRNAs with 11 up-regulated and 61 down-regulated miRNAs in the group with poorer prognosis compared with the group with better prognosis. GO and KEGG pathway analysis indicated that genes targeted by the upregulated miRNAs were significantly enriched in multiple tumor-related pathways including MAPK signaling pathway, Wnt signaling pathway, Focal adhesion and ErbB signaling pathway, while genes targeted by the downregulated miRNAs were significantly enriched in Axon guidance and VEGF signaling pathway. The current findings demonstrated that the higher expression of EBV-miRNA was related to shorter overall survival, and the signaling pathways enriched in the group with EBV infection could provide theoretical basis for the potential target therapy of the Mature T and NK cell lymphoma.

nm23, TOP2A and VEGF expression: Potential prognostic biologic factors in peripheral T-cell lymphoma, not otherwise specified.

Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is an aggressive lymphoma associated with a poor outcome. To date, the factor consistently associated with prognosis is the International Prognostic Index (IPI) score; however, it is considered that the IPI score cannot be beneficial for guiding potential targeted therapies. New scoring systems have recently been developed. The aim of the present study was to observe the expression of NME/NM23 nucleoside diphosphate kinase 1 (nm23), nuclear DNA topoisomerase 2-α (TOP2A), multiple myeloma oncogene-1 (MUM-1) and vascular endothelial growth factor (VEGF), and evaluate their prognostic value in PTCL-NOS. A retrospective analysis of 124 cases of PTCL-NOS showed that 70/122 (57.4%) cases were positive for nm23, 71/122 (58.2%) for TOP2A, 30/119 (25.2%) for MUM-1 and 64/122 (52.5%) for VEGF. Of note, 50/122 cases concurrently expressed nm23, TOP2A and VEGF. The univariate analysis results revealed that the nm23 (P=0.012), TOP2A (P=0.002) and VEGF (P=0.008) expression had a negative prognostic effect in patients with PTCL-NOS, while the MUM-1 expression did not have a significant prognostic value (P=0.918). In addition, the concurrent expression of nm23, TOP2A and VEGF was significantly associated with a worse prognosis (P=0.002). However, in multivariate Cox regression analysis, the concurrent expression of nm23, TOP2A and VEGF tended to predict a worse prognosis, however the P-value was borderline (hazard ratio, 1.495; 95% confidence interval, 0.993-2.250; P=0.054). It is speculated that there may be an association among the expression of nm23, TOP2A and VEGF, and that their expression may serve as a promising prognostic factor for PTCL-NOS.

The correlation of clinicopathological features and prognosis in extranodal natural killer/T cell lymphoma: a report of 42 cases in the early stage.

This study aimed to explore the clinicopathological features and prognostic correlation of extranodal natural killer (NK)/T cell lymphoma (ENKTCL) in the early stage, screen out the prognostic markers of ENKTCL, and to establish the molecular model of ENKTCL prognosis. A retrospective study was conducted in 88 patients from May 1999 to Dec 2013 in Chinese Academy of Medical Sciences Cancer Hospital, who were diagnosed with ENKTCL according to WHO lymphoid hematopoietic tumor classification (published in 2008). The clinical data and paraffin-embedded tissue blocks were collected. The expressions of CD56, MLH1, PDGFRA, VEGF, PD-L1, PD-1, CyclinD1, p53, and Ki-67 were detected by high-throughput tissue microarray and immunohistochemistry (IHC) staining. The relationship between nine protein expressions and the clinicopathological features and prognosis of patients with ENKTCL were analyzed. The survival time of the 42 patients with complete clinical and follow-up data was 0~153 months. The average survival time was 60.1 months. The survival rates of 1 year, 2 years, and 3 year were 85.7%, 78.6%, and 71.4%, respectively. Single factor survival analysis showed that the increase of serum lactate dehydrogenase (LDH ≥ 240UI/L) before treatment was associated with poor prognosis, and there was a significant difference in survival rate (P = 0.006). Different therapy methods were related with prognosis (P = 0.011); in specifically, radiotherapy alone had the best treatment effect, followed by concurrent chemoradiotherapy, and the worst was chemotherapy alone. But, multivariate statistics indicated that the LDH level and the treatment approach were not independent prognostic factors of ENKTCL. There was no statistical difference between epidemiological factors such as gender, age, and other clinicopathological factors including tumor location, B symptoms, ß2-microglobulin levels before treatment, and prognosis. Survival analysis of single factor showed that the positive expression of PDGFRA and PD-L1 was, respectively, related to the poor prognosis of patients with ENKTCL (P = 0.040, 0.007). The patients with Ki-67 overexpression (≥ 50%) had a worse prognosis than those with lower expression (< 50%), and the difference of survival rate between the two groups has statistical significance (P = 0.038). The expression of CD56, MLH1, VEGF, PD-1, CyclinD1, and p53 has no effect on survival rate (P > 0.05). Multivariate survival analysis showed that the expression levels of PDGFRA, PD-L1, and Ki-67 were independent factors in the prognosis of patients with ENKTCL. And the positive expressions of these three proteins were risk factors for prognosis of patients with ENKTCL (PDGFRA: P = 0.045, HR = 8.265, 95% CI: 1.050-65.054; PD-L1: P = 0.005, HR = 9.369, 95% CI: 1.950-45.003; Ki-67: P = 0.023, HR = 3.545, 95% CI: 1.187-10.585). The elevation of serum lactate dehydrogenase (LDH ≥ 240UI/L) before treatment and the treatment approach were associated with poor prognosis, which could be used as adjunct indexes to the prognosis. However, they were not independent factors for the prognosis of patients with ENKTCL. The expressions of PDGFRA, PD-L1, and Ki-67 were independent factors in the prognosis of patients with ENKTCL and these three proteins were risk factors of prognosis. The above markers combined with clinical factors may establish the prognosis model of ENKTCL.

Histological type distribution and expression of nm23, VEGF, TOP2A and MUM-1 in peripheral T-cell and NK-cell lymphomas in Chinese: analysis of 313 cases.

Peripheral T cell and natural killer cell lymphomas (PT/NKCLs) are rare malignant tumors of lymphoid tissue. The incidence varies by geographical region and race. We reclassified 313 cases of PT/NKCLs based on the 4th edition of the World Health Organization (WHO) classification to demonstrate the distribution of each histologic type of PT/NKCLs in Chinese populations. In our series, extranodal NK/T-cell lymphoma (ENKT) was the most common (37.1%) type, followed by peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) (31.3%) and angioimmunoblastic T-cell lymphoma (AITL) (12.8%). Also, we investigated the expression level of nm23, VEGF, TOP2A, and MUM-1 in all 313 cases. The positive rate of nm23, VEGF, TOP2A, and MUM-1 expression was more than 50% in most histologic types. Among the five common types, the expression rate of nm23 (34.5%) and TOP2A (27.6%) in ENKT were the lowest (P<0.05). VEGF expression was also lowest in ENKT (26.7%), but it was much higher in PTCL-NOS (54.1%), AITL (70.0%), and ALCL-ALK- (56.5%) and ALCL-ALK+ (42.9%). The difference of VEGF expression between ENKT and PTCL-NOS and AITL was significant (P<0.05). Fourteen of 23 (60.9%) cases of ALCL-ALK- and 9 of 14 (64.3%) cases of ALCL-ALK+ were positive for MUM-1, which was much higher than in ENKT (19.8%), PTCL-NOS (26.5%) and AITL (35.0%) (P<0.05). Although the significance of their expression in PT/NKCLs is not clear, we suggested that they may be novel tumor markers for developing targeted therapy in the future.

Correlation between the clinicopathological features and prognosis in patients with extranodal natural killer/T cell lymphoma.

OBJECTIVE: To investigate the correlation between the clinicopathological features and prognosis in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTCL). METHODS: One hundred and four patients diagnosed with ENKTCL at the Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China from November 1991 to September 2011 were included in the study. The clinicopathological features and their correlations with disease prognosis were evaluated in these patients. RESULTS: The number of effective follow-up cases was 56 (53.8%) by the end of last follow-up in October 2015. Univariate survival analysis showed that granzyme B, perforin, and Bcl-2 expression was significantly associated with a poor prognosis in ENKTCL (P = 0.033, 0.004, and 0.034, respectively), whereas platelet-derived growth factor receptor-alpha (PDGFRA) expression was significantly associated with a better prognosis (P = 0.034). Ki-67 overexpression (≥50%) was significantly associated with a poor prognosis (P = 0.017). Different treatment approaches were also associated with prognosis (P = 0.014); specifically, the efficacies of combination treatments including chemotherapy and radiotherapy, and autologous hematopoietic stem cell transplantation were significantly better than those involving radiotherapy and chemotherapy alone. Patient gender, age, tumor location, staging, the presence of B symptoms, pretreatment lactate dehydrogenase levels, and ß2-microglobulin levels were not associated with the prognosis of ENKTCL (P > 0.05). However, multivariate analyses showed that the treatment approach and all the immune markers were not independent prognostic factors for ENKTCL. CONCLUSION: Granzyme B, perforin, and Bcl-2 expression and Ki-67 overexpression (≥50%) might be adverse prognostic factors for ENKTCL, whereas PDGFRA-positivity suggested a better disease prognosis. In addition, different treatment approaches might be closely related to patient prognosis.

High frequency of clonal IG and T-cell receptor gene rearrangements in histiocytic and dendritic cell neoplasms.

The 2008 World Health Organization (WHO) diagnostic criteria of histiocytic and dendritic cell neoplasms from hematopoietic and lymphoid tissues no longer required the absence of clonal B-cell/T-cell receptor gene rearrangements. It is true that the clonal B-cell/T-cell receptor gene rearrangements have been identified in rare cases of histiocytic and dendritic cell neoplasms, such as those with or following lymphoma/leukemia or in some sporadic histiocytic/dendritic cell sarcomas, but the clonal features of such group of tumor are still not clear. Here we investigated the clonal status of 33 samples including Langerhans cell histiocytosis (LCH), Langerhans cell sarcoma (LCS), follicular dendritic cell sarcoma (FDCS), interdigitating dendritic cell sarcoma (IDCS) and histiocytic sarcoma (HS). Among them, twenty-eight cases were sporadic without current or past lymphoma/leukemia. Three cases were found with a past history of T-cell lymphoma, one case was followed by extraosseous plasmacytoma, and one case was found with diffuse large B-cell lymphoma (DLBCL). Our results showed that there was a high frequency of clonal IG and T-cell receptor gene rearrangements in these cases. Notably, 4 cases of LCH and 2 cases of FDCS showed both B and T cell receptor gene rearrangements concurrently. One case of FDCS synchronous with DLBCL showed identical clonal IGH in both tumor populations and clonal TCRß in FDCS alone. No matter if the presence of clonal receptor gene rearrangements was associated with the tumor origin or tumorigenesis, it might serve as a novel tumor marker for developing target therapy.