PKC-beta 2 Protein Expression Predicts for Poor Response to Chemotherapy and Survival in Patients with Low Risk Diffuse Large B-Cell Lymphoma.

The protein kinase C (PKC) superfamily includes conventional PKCs (alfa, beta 1, beta 2, and gamma) and PKC-mu. PKC plays an important role in the activation and survival of B cells. Recent studies using cDNA microarrays found that PKC-beta was overexpressed in refractary diffused large B-cell lymphoma (DLBCL). The purpose of this study is to analyze the clinical significance of PKC-beta 2 protein expression in a homogeneous series of patients with DLBCL. Seventy-six patients with primary DLBCL consecutively diagnosed between 1991 and 2002 were studied. The median age of patients was 58 years (range, 11–18 years), 30 women and 46 men. Advanced stage (III/IV) was observed in 36 cases (47%). Of 71 patients with available date, 36 (50%) presented with high serum lactic acid dehydrogenase (LDH) levels. The distribution according to the International Prognostic Index (IPI) (n = 71) was as follows: low risk, 32 cases (43%); low/intermediate risk, 17 cases (23%); high/intermediate risk, 8 cases (11%); and high risk, 14 cases (19%). All patients received an anthracycline-containing chemotherapy regimen. Formalin-fixed, paraffin-embedded tissue from 76 DLBCL tumors were immunostained with a monoclonal antibody against PKC-beta 2 protein. Tumors were considered positive for PKC-beta 2 if 5% o more of the tumor cells expressed the protein. The main clinical features (B symptoms, Ann Arbor stage, bulky disease, bone marrow disease, high LDH, IPI, and ECOG) of patients within the PKC-positive group were similar to those within the PKC-negative group. Twenty-six cases (34%) were positive for PKC-beta 2 protein. Within the patients whose tumors were PKC-positive, only 8 of 26 (31%) had a complete clinical remission, while that was achieved in the majority (31 of 50; 62%) of the PKC-negative patients (p = 0.015). Patients with PKC-positive tumors had a lower five-year disease free survival (DFS) (30% vs. 60%; p = 0.03) than the PKC-beta 2 negative group. Moreover, patients with low IPI whose tumors expressed PKC-beta 2 protein had an inferior five-year DFS (39% vs. 80%; p = 0.0046). Multivariate analysis confirmed the independent adverse prognostic value of PKC expression (OR = 3.7 [95%CI, 1.4–9.9]; p = 0.007) in patients with DLBCL and low IPI. These results indicate that PKC-beta 2 expression on DLBCL predicts for a low response rate to chemotherapy and unfavorable clinical outcome, specially in those patients with low IPI.