STAT3 Phosphorylation Is An Useful Marker To Faciliate The Diagnosis And Predict Clinical Outcome In Systemic Anaplastic Large Cell Lymphoma

Objective: Systemic anaplastic large cell lymphoma(S-ALCL)is an aggressive and a heterogeneous lymphoma with different outcomes and genetic alterations.Definite gene subtype is beneficial to the diagnosis and prognosis of this disease.We collected the clinicopathological data of 70 cases of S-ALCL and used immunohistochemistry and fluorescence in situ hybridization to investigate the expression of p STAT3 and the transformation of DUSP22 gene,respectively.The aim of this study is to explore the clinicopathological significance of p STAT3 expression and DUSP22 gene transformation in S-ALCL and reveal the clinicopathological features and genetic subtype of S-ALCL.Methods: Totally,70 cases of S-ALCL were collected from multiple centers between February 2010 to December 2018,We analysed the expression of T cell markers,cytotoxic molecules,CD30,ALK,EMA and p STAT3 were detected by using IHC.Whereas we also performed EBV small RNA in situ hybridization to reveal the relation between EBV and S-ALCL.The gene transformation of DUSP22 was detected by using FISH.SPSS17.0 was used for comparing differences and outcomes between ALK-negative ALCL and DUSP22-rearranged ALCL,and evaluating the correlation between p STAT3 expression and prognosis.Results: 1.Clinicopathological features: Among the 70 cases of S-ALCL,21 were ALK-positive ALCL,whereas the other 49 cases were ALK-negative ALCL.In ALK-positive ALCL,the ratio of male to female was 2:1 and the media age was 34 years.12 cases(57%)involved in the lymph nodes;9 cases showed an extranodal presentation.In ALK-negative ALCL,the male to female ratio was2.5:1 and the media age was 51 years.31 cases(63%)involved in the lymph nodes.18 cases showed an extranodal presentation.The ratio of male to female was 1:1.25 and the media age of 9 DUSP22-rearranged ALCL was 46 years.6 cases(67%)involved in the lymph nodes,3 cases showed an extranodal presentation.Statistical analysis demostrated that ALK-positive ALCL was younger than ALK-negative ALCL(P=0.002),no significant difference were found in other clinical features.2.Morphology: 62(89%)cases presented the common pattern(21 ALK-positive ALCL,41 ALK-negative ALCL);4 cases presented giant cell-rich varients;3 cases had a hypocellular varient;1 case with extensive ring-type tumor cell.8(89%)of 9 DUSP22-rearranged ALCL were common pattern;1(11%)case had ring-type tumor cell.3.Immunohistochemistry: The expression rates of T cell markers including CD3,CD2,CD5,CD7,CD4 and CD8 in ALK-positive ALCL were 29%,44%,47%,38%,75% and 0%,respectively;The expression rates of T cell markers including CD3,CD2,CD5,CD7,CD4 and CD8 in ALK-negative ALCL were 65%,81%,54%,29%,96% and 18%,respectively.Statistical analysis found that CD3(P=0.005)and CD2(P=0.006)was frequently absence expression in ALK-positive ALCL than that of ALK-negative ALCL.Cytotoxic molecule TIA-1 and Gran B were positive in 100% and 92% in ALK-positive ALCL,respectively;whereas were positive in 72% and 67% of ALK-negative ALCL,respectively.There was no significant difference between ALK-positive ALCL and ALK-negative ALCL.EMA was positive in 94% ALK-positive ALCL and 39% ALK-negative ALCL,respectively.Statistical analysis showed that EMA expressed higher in ALK-positive ALCL than ALK-negative ALCL(P<0.001).The expression rates of cytotoxic molecules were lower in DUSP22-rearranged ALCL comparing with other ALCL.4.DUSP22 gene rearrangement: Among the 41 ALK-negative ALCL,9(22%)exhibited DUSP22 rearrangements.5.The expression of p STAT3 in S-ALCL: Of the 55 S-ALCL,33(60%)were positive for p STAT3 in S-ALCL,including 14 ALK-positive ALCL,18 ALK-negative ALCL and 1 DUSP22-rearranged ALCL.Of the 9 DUSP22-rearranged ALCL,8(89%)were negative for p STAT3.6.Prognosis: The Kaplan-Meier analyses was performed by using SPSS17.0.We found that ALK-positive ALCL had a better outcome than ALK-negative ALCL(P=0.020),and the outcome of DUSP22-rearranged ALCL was similar to that of ALK-positive ALCL(P=0.593).Interestingly,we also found the p STAT3+ALCL had a better outcome with a tendency than p STAT3-ALCL(P=0.167)in DN-ALCL.Conclusions: 1.ALK-positive ALCL frequently occurs in young adults,and ALK-negative ALCL frequently occurs in old people.2.DUSP22 gene rearrangement was detected in 22% ALK-negative ALCL in Chinese.Importantly,DUSP22 gene rearrangement is a favorable prognostic factor in ALK-negative ALCL.The prognosis of DUSP22-rearranged ALCL was similar to that of ALK-positive ALCL.Therefore,we suggest perform DUSP22 gene rearrangement analysis is necessary to the daily pratice of ALK-negative ALCL.3.p STAT3 expression may predict the DUSP22 gene rearrangement in ALK-negative ALCL.4.In DN-ALCL,p STAT3 positive has a better outcome with a tendency than p STAT3 negative.