1Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
2Department of Laboratory Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea.
3Department of Laboratory Medicine and Genetics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea.
4Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) accounts for 5?10% of DLBCL cases and has poor patient outcomes. However, most studies on CD5+ DLBCL were performed in Japanese patients and only few data are available for Korean population. In this study, we investigated the clinical characteristics and prognostic impact of CD5 expression in Korean patients with bone marrow (BM) involvement of DLBCL.
Patients who were initially diagnosed with BM involvement of
Among a total of 57 patients, the number of patients with CD5+ and CD5? DLBCL were 13 and 44, respectively. Clinical and laboratory features of CD5+ DLBCL were not significantly different from those of CD5? DLBCL. The 3-year overall survival (OS) rates for CD5+ and CD5? DLBCL were 20.2% and 59.0%, respectively (
CD5+ DLBCL with BM involvement showed an inferior survival tendency compared to CD5? DLBCL, and thorough evaluation of CD5 expression might be helpful to predict the prognosis of patients with DLBCL.
Diffuse large B-cell lymphoma (DLBCL) is the most common subcategory of non-Hodgkin's lymphoma (NHL), accounting for 25–30% of NHL in Western countries  and approximately 43% in Korea . Patients with DLBCL have highly variable clinical outcomes, representing a heterogeneous group of tumors with different morphology, histology, clinical features, responses to treatment, and prognosis.
The International Prognostic Index (IPI) is the classical clinical tool for predicting outcomes in patients with aggressive NHL including DLBCL . Although the IPI is an important prognostic factor for DLBCL, the five components used for assessing the IPI provide limited information on biological features. The CD5-positive (CD5+) DLBCL, as a distinct subgroup that accounts for 5–10% of all DLBCL, has been reported to be associated with elderly onset, female gender, frequent involvement of extranodal sites, and inferior survival . Recently, several studies reported that CD5 expression is a prognostic factor for poor outcome in DLBCL, even with rituximab-containing therapy . However, most studies on CD5+ DLBCL were performed in Japan . In this study, we evaluated the clinicopathological characteristics and prognostic impact of CD5 expression in Korean patients with initial bone marrow (BM) involvement of DLBCL.
Patients who were initially diagnosed with BM involvement of
CD5 antigen expression was examined by flow cytometric analysis and/or immunohistochemistry. Flow cytometric analysis was performed with monoclonal antibodies for CD5, CD10, CD19, CD20, CD22, CD23, FMC7, nuclear TdT, and kappa (κ) and/or lambda (λ) immunoglobulin using the three-laser FACSCanto II flow cytometer (Becton-Dickinson, San Jose, CA, USA). Data were acquired and analyzed with the BD FACSDiva software (Becton-Dickinson). Immunohistochemical analysis was carried out using monoclonal antibodies against CD5, CD10, BCL2, BCL6, Ki-67, MUM1, and/or cyclin D1. To classify the samples into immunohistochemically defined germinal center B-cell like (GCB) or non-GCB phenotypes, we used an algorithm previously described by Hans et al. .
Conventional cytogenetic studies were performed on heparinized BM samples from study participants. Each sample was cultured for 24 and/or 72 hours of lipopolysaccharide stimulation using the protocol for routine clinical laboratory cancer cytogenetics. After harvest, cells were treated with a hypotonic solution, fixed in methanol/acetic acid (3:1 ratio), and G banded using standard methods. Twenty cells in metaphase were routinely analyzed for karyotyping. To rule out the translocation involving
Comparisons of clinical characteristics between the CD5+ and CD5 negative (CD5−) DLBCL were performed using a Chi-square test or Fisher's exact test for categorical variables. The overall survival (OS) was determined from the time of initial diagnosis to death from any cause or last follow-up. Progression-free survival (PFS) was determined from the time of initial diagnosis to disease progression, relapse, death, or last follow-up. The survival analyses were performed by Kaplan-Meier plots, and differences in survival were compared using the log-rank test. The 3-year OS and PFS of CD5+ and CD5− DLBCL were compared using the Z score. Univariate analysis was performed using Cox regression for variables including age, lactase dehydrogenase (LDH), B symptoms, IPI, ECOG performance status (PS), cell-of-origin, CD5 expression, and karyotype.
Among 768 patients with
The median OS was not reached and the median PFS was 14 months in patients with DLBCL (Fig. 1). The 2-year OS and PFS were 58.0% and 45.6%, respectively. Survival analysis was also performed in subgroups based on CD5 expression, cell-of-origin, and IPI score. The median OS was 10 months in CD5+ DLBCL, and not reached in CD5− DLBCL. The 3-year OS rate was 20.2% and 59.0% in CD5+ and CD5− DLBCL, respectively (
In univariate analysis, ECOG PS ≥2 (HR=4.344, 95% CI=1.847–10.218,
In this study, we compared the clinicopathologic characteristics and prognosis of patients with BM involvement of CD5+ and CD5− DLBCL. Previously, Yamaguchi et al. , demonstrated a higher age distribution, female predominance, higher frequency of ≥2 of performance status, high LDH level, stage III or IV disease at diagnosis, and presence of B symptoms, high incidence of central nervous system recurrence and non-GCB type, and inferior overall survival in CD5+ DLBCL, as compared to CD5− DLBCL. In this study, although statistically significant differences were not observed, CD5+ DLBCL showed more aggressive features correlated with age, LDH level, and karyotype than CD5− DLBCL; patients with CD5+ DLBCL tended to be older than 60 years (CD5+ vs. CD5−; 62% vs. 39%,
Regarding chromosomal abnormalities, Yoshioka et al. , reported that abnormalities of 8p21, 11q13, and 3q27 were common in CD5+ DLBCL; and Niitsu et al. , reported that translocations involving 19p13 were the most common. In this study, 11q13 abnormalities were absent, and 8p21 abnormalities were observed in two patients (4.5%) with CD5− and one patient (7.7%) with CD5+ DLBCL. Translocations of 19p13 were observed in each of the two patients with CD5− (4.5%) and CD5+ (15.4%) DLBCL. However, the number of patients with each chromosomal abnormality was insufficient to evaluate the association with CD5 expression.
BM involvement of DLBCL is reported in 10–20% of patients with DLBCL . In this study, the proportion of BM involvement of DLBCL at diagnosis was 9.9%, which was similar to the previously reported frequency of 9.2% in Korea . BM is the most frequently involved extranodal site in CD5+ DLBCL, with a higher frequency than CD5− DLBCL . Several studies have reported the poor prognostic impact of BM involvement or CD5 expression in DLBCL. Kajiura et al.  evaluated 37 patients with DLBCL initially manifesting in the BM; the mean survival was 14.9 months and approximately 70% of patients died within 2 years. Sehn et al.  demonstrated that 49–69% of 3-year OS, and Chung et al. , demonstrated 34.5% of 5-year OS in cases with BM involvement of DLBCL. For CD5+ DLBCL, Ennishi et al. , reported that 45% of 2-year OS and Alinari et al. , reported 65% and 40% of 3-year OS and PFS, respectively. Xu-Monette et al.  showed 35.5% and 29.6% of 5-year OS and PFS, respectively, in patients with CD5+ DLBCL treated with R-CHOP. In our study, the 3-year OS was significantly inferior in CD5+ DLBCL than CD5− DLBCL (20.2% vs. 59.0%,
By gene expression profiling, Miyazaki et al. , showed that most CD5+ DLBCL are activated B-cell like (ABC) type. However, in our study, the proportion of non-GCB type did not differ between patients with CD5+ and CD5− DLBCL (
For the IPI score, Chung et al.  showed that patients with BM involvement of DLBCL had higher IPI scores, as compared to the patients without BM involvement. In our study, approximately 83% of patients had an IPI score ≥3 and the proportion of patients with higher IPI score did not differ between CD5− and CD5+ DLBCL (
Our study had some limitations, including the small number of enrolled patients and the short follow-up duration. Since BM involvement of DLBCL was infrequent and not all patients with BM involvement were evaluated for CD5 expression, we could not include a sufficient number of patients. In addition, the patients with DLBCL without BM involvement were not included as a control group. However, we reviewed the previous studies evaluating CD5+ DLBCL regardless of BM involvement and compared the previously reported survival rates with those from our study.
We evaluated the prognostic significance of CD5 expression in patients with BM involvement of DLBCL. The results indicated that patients with CD5+ DLBCL showed an inferior survival tendency than patients with CD5− DLBCL. Thus, a thorough evaluation of CD5 expression might be helpful for prognosis prediction in patients with DLBCL. Further studies with a larger study population are needed to confirm the significance of CD5 expression in Korean patients with DLBCL.
Kaplan-Meier plots for the overall survival (OS) and progression-free survival (PFS) in
Kaplan-Meier plots for the (