Prognostic Evalution Of Immunohistochemical Profiles In Diffuse Large B-cell Lymphoma

Background:Diffuse large B-cell lymphoma(DLBCL) is a heterogenetous malignant neoplasm,accounting for 30%～40%of the adult non-Hodgkin's lymphoma. Although approximate 40%～50%patients are potentially cured using anthracycline-based chemotherapy,more than half succumb to their disease with poor prognosis.Recently,the application of gene expression profiling(GEP) data identified three distinct molecular groups:germinal centre B cell-like type(GCB),activated B cell-like type(ABC),and type 3.GCB cases had the best prognosis of the three types; ABC and type 3 cases had a similar poor outcome,so they were generally combined and categorized into a "non-germinal centre(non-GCB)" group.These molecular groups reflect the biologic nature of DLBCL.Because gene array technology is expensive and not widely available,several groups have aimed to use immunohistochemical approaches to identify a prognostic biomarker and construct algorasims to subclassfy DLBCL with comparable differences in clinical behavior and outcome in clinical practice.The role of DNA repair genes in drug resistance to chemotherapy also has been proved.The aims of our study were therefore to,in a Chinese population,analyse the clinic,histologic and immunophenotypic characteristics of DLBCL patients,investigate their correlation to patient survival and define the applicability of identified immunohistochemical profiles.Includedly,the relationship between protein expression of DNA repair genes and drug resistance was also performed in immunohistochemistry.Methods:We studied DLBCLs diagnosed from 1999 to December 2006 in Huashan Hospital and collected their clinical data.The follow-up of their survival condition was also performed.The expression of CD 10,BCL-6,MUM1,CD138,CD5,MGMT, hMSH2,and hMLH1 was analysed by immunohistochemistry.Different algorithsms subclassing DLBCL were constructed.We then evaluated the correlations between these clinicobiologic factors and prognosis.Result:We collected 121 DLBCLs specimens,of which 91 cases had well-documented clinical and follow-up data.Age＜60,female sex,normal LDH, stageⅠ～Ⅱ,involvement of extranodal sites≤1,and without B symptoms, gastrointestinal site,and IPI≤2 were significantly favourable predictor of OS and PFS, in which IPI showed a stronger prognostic power.Among these clinical factors,LDH, gastrointestinal site,and IPI were independent predictor of prognosis in multivariate analysis.In histology,the centroblastic subtype was the most common(88%), followed by the immunoblastic subgroup(4%),anaplastic cases(3%),T-cell/histoyte rich type(1%),and other unclassifying cases(3%),among which no significant survival differences were found.The expression of CD10,BCL-6,MUM1,CD138, CD5,MGMT,hMSH2,and hMLH1 was detected in 21.5%,32.2%,32.2%,2.5%, 18%,60%,and 49%,respectively.Expression of CD10 and BCL-6 predicted favourable CR rate and OS(P=0.0231 and 0.0278 respectively) rate.In contrast, expression of MUM1 predicted unfavourable CR rate and OS rate(P=0.013) and was also independent of other biomarkers.The expression of MGMT,hMSH2,and hMLH1 showed no significant differences between the groups of response and resistance to chemotherapy,but correlated with survival rates relatively.Each of the algorithsms played a role in evaluation of the response and prognosis.In algorithsml, non-GCB group showed worse 5-year OS(27.6%) and PFS(24.69%) rates than GCB group(P=0.0040 and 0.0002,respectively).In algorithsm3,fewer non-GCB cases (28%) showed a much worse prognosis(OS,18.96%;PFS,15.08%) than GCB cases (P=0.0014 and 0.0012,respectively),which was independent of IPI and treatment in Cox analysis.The clinical characteristcs of non-GCB group were more aggressive than GCB group.Algorithsm3 still worked in intermediate risk group of IPI.Conclusion:The risk model of IPI was the most reliable and practical predictor of response and prognosis for DLBCL patients in clinical factors.The algorithsm based on CD10 and BCL-6 could identify different differentiated subgroup,GCB and non-GCB,with different prognosis and risk of progression or death,independent of IPI.For the cases in high risk of progression or death,the expression of MGMT, hMSH2,and hMLH1 did not show any correlation with the poor response to chemotherapy,which meant it could not evaluate the drug resistance in DLBCL using immunohistochemistry alone.