MYC translocation and/or BCL 2 protein expression are associated with poor prognosis in diffuse large B‐cell lymphoma

Genomic alterations and protein expression levels have been established as prognostic factors for survival in patients with diffuse large B‐cell lymphoma (DLBCL). In particular, double‐hit DLBCL (DHL), which exhibits translocations in MYC and BCL2 and/or BCL6, is known to be associated with a poor prognosis. However, the clinical significance of gene alterations and protein expression levels for MYC, B‐cell lymphoma (BCL)2, and BCL6 are unclear. In this study, we analyzed 61 adult patients diagnosed with DLBCL without DHL, who were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, or similar regimens. There were no differences in the distribution of MYC expression rates among the different MYC gene statuses. In log–rank tests, MYC translocation was a prognostic factor for overall survival (OS; P = 0.011), whereas BCL2 and BCL6 translocation were not prognostic indicators (P = 0.999 and P = 0.925, respectively). Although the expression levels of MYC and BCL6 were not significantly associated with OS, the expression of BCL2 was a prognostic factor for OS (P = 0.027). Furthermore, copy number gains in the MYC, BCL2, and BCL6 genes did not affect OS. MYC translocation (hazard ratio, 4.769; range, 1.518–14.98; P = 0.007) and BCL2 protein expression (hazard ratio, 3.072; range, 1.002–9.413; P = 0.049) were independent prognostic factors for survival in multivariate analyses. In conclusion, MYC translocation and BCL2 expression may need to be investigated at the initial diagnosis to predict prognosis in patients with DLBCL.     

Combination of CD47 and signal‐regulatory protein‐α constituting the “don’t eat me signal” is a prognostic factor in diffuse large B‐cell lymphoma

The interaction between CD47 and signal‐regulatory protein‐α (SIRPα) inhibits phagocytosis, thus affecting the clinical outcomes of neoplastic diseases. Although CD47 upregulation is associated with poor prognosis in several malignancies, the effect of SIRPα expression and its coexpression with CD47 remains unclear. This study aimed to investigate the clinicopathologic effect of CD47 and SIRPα expression in diffuse large B‐cell lymphoma (DLBCL). Immunostaining of 120 biopsy samples showed that CD47 is primarily expressed in tumor cells, whereas SIRPα is expressed in nonneoplastic stromal cells, mostly macrophages. CD47^high cases showed higher MYC protein expression and lower MYC translocation. The SIRPα^high cases presented significantly shorter overall survival (OS) and progression‐free survival (PFS) than SIRPα^low cases in the activated B‐cell (ABC) subtype of DLBCL (P = .04 and P = .02, respectively). Both CD47^high and SIRPα^high presented significantly shorter OS and PFS than other cases among all DLBCL patients (P = .01 and P = .004, respectively), and the ABC type (P = .04 and P = .008, respectively) but not the germinal center B‐cell type. Both CD47^high and SIRPα^high yielded a constant independent prognostic value for OS and PFS in multivariate analysis (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.20‐7.43; P = .02; and HR, 2.87; 95% CI, 1.42‐5.85; P = .003, respectively). To the best of our knowledge, this is the first study to report that combinatorial CD47 and SIRPα expression is a potential independent prognostic factor for DLBCL. Evaluation of CD47 and SIRPα expression could be useful before CD47 blockade therapy.     

Hematopoietic stem cell transplantation for diffuse large B‐cell lymphoma having 8q24/MYC rearrangement in Japan

The prognosis of diffuse large B‐cell lymphoma (DLBCL) having MYC rearrangement (MYC‐R), including double hit lymphoma (DHL), is poor by standard immunochemotherapy. To evaluate the significance of hematopoietic stem cell transplantation (SCT) for DLBCL with MYC‐R, we retrospectively analyzed Japanese SCT registry data. In total, 54 patients with DLBCL with MYC‐R were identified from 4336 registered adult DLBCL patients. Detailed clinical and cytogenetic information was obtained for 48 patients. The median age at diagnosis of the 48 patients was 54.5 (range 21–67) years. Twenty‐six (54%) patients had MYC‐R only (single hit), and 22 (46%) had MYC‐R and BCL2, and/or BCL6 rearrangement (double/triple hit). In 12 patients who received auto‐SCT during the first complete response (CR), both the 2‐year overall survival (OS) and progression‐free survival (PFS) rates were 75.0% (95% confidence interval [CI], 40.8%–91.2%). In 20 patients who received auto‐SCT after relapsed or refractory state, the 2‐year OS and PFS rates were 68.2% (95% CI, 41.9%–84.5%) and 59.6% (95% CI, 35.1%–77.4%), respectively. In 17 patients who received allo‐SCT, only 4 patients underwent SCT in CR. The 2‐year OS and PFS rates were 29.4% (95% CI, 10.7%–51.1%) and 17.6% (95% CI, 4.3%–38.3%), respectively. The rate of non‐relapse mortality at 1 year was 41.2% (95% CI, 17.1%–64.0%) in this group. The outcomes of single hit and double or triple hit were not different. These findings suggest that auto‐SCT may be effective for MYC‐R DLBCL, including DHL patients of chemosensitive relapsed or refractory state. Since most patients received allo‐SCT not in CR, the outcome of allo‐SCT was unsatisfactory due to high non‐relapse mortality and early relapse. To clarify the role of allo‐SCT for MYC‐R DLBCL, further accumulation of patients is necessary.     

Prognostic Significance of BCL-2 and BCL-6 Expression in MYC-positive DLBCL

Background

Double-expression lymphoma (DEL) is a rare subgroup of diffuse large B-cell lymphoma (DLBCL), which has coexpression of MYC and BCL-2. Coexpression of MYC and BCL-2 is considered a prognostic marker portending poor outcomes. However, the prognostic effect of BCL-2 and BCL-6 expression in DLBCL remains controversial.

Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

BACKGROUND:

B‐cell lymphoma, Unclassifiable with features intermediate between diffuse large B‐cell lymphoma (DLBCL) and Burkitt lymphoma, for convenience referred to here as unclassifiable B‐cell lymphoma, is a category in the 2008 World Health Organization system used for a group of histologically aggressive neoplasms that are difficult to classify definitively. Currently, there is no established standard therapy for these neoplasms.

METHODS:

The authors assessed MYC status and correlated it with treatment response and outcome in a group of 52 patients with unclassifiable B‐cell lymphoma treated with either a standard DLBCL regimen (R‐CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone‐related therapy]) or more intensive regimens, such as R‐hyper‐CVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high‐dose methotrexate and cytarabine). The regimens were selected by the treating clinicians based on the overall clinical and pathological findings.

RESULTS:

Thirty (58%) unclassifiable B‐cell lymphomas had MYC abnormalities (MYC⁺) including 27 with rearrangement, 2 with amplification, and 1 with both. The MYC⁺ and MYC^? groups were similar in their age distribution and International Prognostic Index scores. Progression‐free survival of patients with MYC⁺ unclassifiable B‐cell lymphoma treated initially with R‐CHOP was significantly worse than patients treated with R‐hyper‐CVAD (P = .0358). In contrast, for the MYC^? unclassifiable B‐cell lymphoma group, some patients responded to R‐CHOP, and others were refractory to R‐hyper‐CVAD.

CONCLUSIONS:

MYC aberrations are common in unclassifiable B‐cell lymphoma. The presence of MYC aberrations identifies a patient subset that requires more aggressive therapy than R‐CHOP. In contrast, MYC^? unclassifiable B‐cell lymphoma patients responded variably to either R‐CHOP or aggressive therapy, and the latter showed no survival advantage. Cancer 2011;. © 2011 American Cancer Society.     

Radioimmunotherapy with (131)I-rituximab for patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (NHL)

Aim: To evaluate the efficacy and safety of radioimmunotherapy (RIT) with radioiodinated human/murine chimeric anti‐CD20 monoclonal antibody rituximab (¹³¹I‐rituximab) for treating Korean patients with relapsed or refractory B‐cell non‐Hodgkin's lymphomas (NHL). Methods: All patients received unlabeled rituximab 70 mg immediately prior to the administration of a therapeutic dose (median dose: 7.3 GBq) of ¹³¹I‐rituximab. The tumor response was evaluated 1 month later by contrast enhanced ¹⁸F‐fludeoxyglucose positron emission tomography‐computed tomography. Results: Between May 2004 and October 2006, 24 patients received single treatment with ¹³¹I‐rituximab. The overall response rate (ORR) was 29%; 46% (three complete responses, two partial responses (PR) for patients with low grade B‐cell NHL (LGL) and 9% (one PR) for patients with diffuse large B‐cell lymphoma (DLBCL). After a median follow‐up of 55 months, the median progression‐free survival (PFS) for all the patients was 2.2 months. The median overall survival (OS) was 11.3 months. There were statistically significant differences between the LGL and the DLBCL for the median PFS (4.5 months vs 1.3 months, respectively, P = 0.0007) and the median OS (30.3 months vs 6.5 months, respectively, P = 0.0295). Grades 3–4 thrombocytopenia and neutropenia occurred in 33% (8/24) and 21% (5/24) of the patients, respectively. Conclusion: RIT with ¹³¹I‐rituximab seems to be effective and tolerable for patients with refractory LGL, although this treatment had modest activity in patients with refractory DLBCL. Further studies are warranted to determine the efficacy of ¹³¹I‐rituximab for treating the patients with DLBCL.     

PD‐L1 expression is low in large B‐cell lymphoma with MYC or double‐hit translocation

In large B‐cell lymphoma (LBCL), MYC translocation and MYC/BCL2 or MYC/BCL6 double hit (DH) are associated with poor prognosis, and there is an unmet need for novel treatment targets in this patient group. Treatments targeting the PD‐L1/PD‐1 pathway are still poorly elucidated in LBCL. PD‐L1 expression might predict response to treatment targeting the PD‐L1/PD‐1 pathway. We therefore investigated the relationship between PD‐L1 protein and mRNA expression levels and MYC and DH translocation in LBCL. We detected MYC, BCL2, and BCL6 translocation by fluorescent in situ hybridization in tissue samples from 130 patients randomly selected from two cohorts of patients with LBCL: 49 patients with MYC translocation of whom 36 had DH and 81 without MYC translocation. PD‐L1 protein expression was detected by immunohistochemistry (IHC) in tissue samples from 77 patients and PD‐L1 mRNA expression by next‐generation RNA sequencing (NGS) in another 77 patients. Twenty‐four patients overlapped, ie, were analysed with both IHC and NGS. Nonparametric tests were performed to evaluate intergroup differences. PD‐L1 protein expression level was significantly lower in patients with MYC (n = 42, median = 3.3%, interquartile range [IQR] 0.0‐10.8) or DH translocations (n = 31, median = 3.3%, IQR 0.0‐10.0) compared with patients with no MYC (n = 35, median = 16.7%, IQR 3.3‐30.0) or no DH translocations (n = 46, 13.3%, IQR 2.5‐30.0), P = .004 and P ≤ .001, respectively. PD‐L1 mRNA expression was also significantly lower in patients with MYC or DH translocations, P = .001 and P = .006, respectively. Higher PD‐L1 protein and mRNA expression levels were associated with non–germinal centre (GC) type compared with germinal centre B‐cell (GCB)‐type diffuse LBCL (DLBCL), P = .004 and P = .002, respectively. In conclusion, we report an association between low PD‐L1 expression and MYC and DH translocation in patients with LBCL. Our findings may indicate that patients with MYC or DH translocation may benefit less from treatment with PD‐L1/PD‐1‐inhibitors compared with patients without these translocations. This should be evaluated in larger, prospective, consecutive trials.     

Multicentre phase II study of CyclOBEAP plus rituximab in patients with diffuse large B‐cell lymphoma

The R‐CHOP regimen has been found to improve the outcome of diffuse large B‐cell lymphoma (DLBCL). However, it does not provide a satisfactory treatment outcome in the high‐risk group. We previously administered the CyclOBEAP regimen to patients with DLBCL, and reported its safety and efficacy. The R‐CyclOBEAP regimen was administered over a total period of 12 weeks, and rituximab 375 mg/m² was given every 2 weeks. There were 101 eligible patients. CR was achieved in 96 patients (95%). The 5‐year overall survival (OS) rate was 85% and progression‐free survival (PFS) rate was 76%. When the patients were divided according to the IPI, the 5‐year OS and PFS rates did not significantly differ among the risk groups. The 5‐year PFS of the germinal centre B‐cell group was 80% and that of the non‐GCB group was 74% (NS). Univariate analysis showed that the presence of B symptoms, extranodal lesions ≧2, and sIL‐2R were significant poor prognostic factors. Grade 4 neutropenia was observed in 91 patients and thrombocytopenia in 9 patients. The addition of rituximab to CyclOBEAP therapy may enhance the effect of CyclOBEAP therapy for DLBCL. Copyright © 2010 John Wiley & Sons, Ltd.     

Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype

BACKGROUND:

There is a need to develop novel therapies for relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) and to identify biomarkers predictive for therapeutic response. Lenalidomide was previously shown to induce an overall response rate (ORR) of 28% in patients with relapsed/refractory DLBCL. It is currently unknown if response rates differ between patients with different DLBCL subtypes.

METHODS:

The authors retrospectively evaluated clinical outcomes of patients with germinal center B‐cell–like versus nongerminal center B‐cell–like DLBCL treated with salvage lenalidomide at 4 academic institutions.

RESULTS:

Forty patients with relapsed/refractory DLBCL were included (24 men; 16 women; median age, 66 years; median of 4 prior treatments, including rituximab chemotherapy). Patients were classified as germinal center B‐cell–like (n = 23) or nongerminal center B‐cell–like (n = 17) DLBCL according to the Hans algorithm. The subgroups were similar in terms of stage, international prognostic index score, prior number of treatments, and rituximab resistance. A significant difference in clinical response to lenalidomide was observed in nongerminal center B‐cell–like versus germinal center B‐cell–like patients. ORR was 52.9% versus 8.7% (P = .006); complete response rate was 23.5% versus 4.3%. Median progression‐free survival was 6.2 versus 1.7 months (P = .004), although no difference in OS was observed between nongerminal center B‐cell–like and germinal center B‐cell–like DLBCL patients.

CONCLUSIONS:

The data suggest that the 2 major subgroups of patients with DLBCL (germinal center B cell and nongerminal center B cell) have different antitumor responsiveness to lenalidomide in the relapsed/refractory setting. A large international trial (NCT01197560) has been opened to enrollment in an attempt to prospectively validate these retrospective observations. Cancer 2011;. © 2011 American Cancer Society.     

Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab

BACKGROUND:

Diffuse large B‐cell lymphomas (DLBCLs) are a biologically heterogeneous group in which various gene alterations have been reported. The aim of this study was to investigate the frequency and prognostic impact of BCL2, BCL6, and MYC rearrangements in cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R‐CHOP)‐treated DLBCL cases.

METHODS:

Tissue microarrays were constructed from 239 cases of DLBCL, and the expressions of CD10, BCL6, MUM1/IRF4, and BCL2 were evaluated by immunohistochemistry. MYC, BCL2, and BCL6 rearrangements were investigated by interphase fluorescence in situ hybridization on tissue microarrays. Survival analysis was constructed from 145 R‐CHOP–treated patients.

RESULTS:

MYC, BCL2, and BCL6 rearrangements were detected in 14 (6%), 36 (15%), and 69 (29%) of 239 DLBCL patients. Double or triple rearrangements were detected in 7 (3%) of 239 DLBCL cases. Of these, 4 had BCL2 and MYC, 2 had BCL6 and MYC, and 1 had BCL2, BCL6, and MYC rearrangements. The prognosis of these cases was extremely poor, with a median survival of 9 months. MYC rearrangement was associated with significantly worse overall survival (P = .01), especially for the cases with GC phenotype (P = .009). BCL6 rearrangement also predicted significantly shorter overall survival (P = .04), especially for the non‐GC phenotype (P = .03). BCL2 rearrangement had no prognostic impact on outcome. International Prognostic Index (P = .004) and MYC rearrangement (P = .009) were independent poor prognostic factors.

CONCLUSIONS:

Analysis of MYC gene rearrangement along with BCL2 and BCL6 is critical in identifying high‐risk patients with poor prognosis. Cancer 2012. © 2011 American Cancer Society.     

Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, Doxorubicin, vincristine, and prednisone

PURPOSE Approximately 5% of diffuse large B-cell lymphomas (DLBCLs) are double-hit lymphomas (DHLs) with translocations of both MYC and BCL2. DHLs are characterized by poor outcome. We tested whether DLBCLs with high expression of MYC protein and BCL2 protein share the clinical features and poor prognosis of DHLs. PATIENTS AND METHODS Paraffin-embedded lymphoma samples from 193 patients with de novo DLBCL who were uniformly treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were studied using immunohistochemistry for MYC, BCL2, CD10, BCL6, and MUM1/interferon regulatory factor 4, and fluorescent in situ hybridization (FISH) for MYC and BCL2. Results FISH analysis identified DHL in 6% of patients, who showed the expected poor overall survival (OS; P = .002). On the basis of immunohistochemical MYC and BCL2 expression, a double-hit score (DHS) was assigned to all patients with DLBCL. The DHS-2 group, defined by high expression of both MYC and BCL2 protein, comprised 29% of the patients. DHS 2 was significantly associated with lower complete response rate (P = .004), shorter OS (P < .001), and shorter progression-free survival (PFS; P < .001). The highly significant correlation with OS and PFS was maintained in multivariate models that controlled for the International Prognostic Index and the cell-of-origin subtype (OS, P < .001; PFS, P < .001). DHS was validated in an independent cohort of 116 patients who were treated with R-CHOP. CONCLUSION The immunohistochemical DHS defined a large subset of DLBCLs with double-hit biology and was strongly associated with poor outcome in patients treated with R-CHOP.     

Phenotype profiling of primary testicular diffuse large B‐cell lymphomas

Primary testicular diffuse large B‐cell lymphomas (tDLBCL) are rare neoplasms with few comprehensive studies conducted so far. We aimed to systematically characterize the phenotype of tDLBCL. Forty‐five patients from three Swiss hospitals diagnosed with tDLBCL between 1972 and 2009 were reviewed and included in this study. A tissue microarray was assembled, and the protein expression profiles were assessed by immunohistochemistry and fluorescence in situ hybridization for the C‐MYC locus. All tDLBCL expressed CD79a, followed by CD20 (98% of cases) and CD19 (93%). One case expressed the germ cell marker OCT4 and showed a rearrangement of C‐MYC. Eighty‐two per cent of cases showed active STAT signalling by expression of either pSTAT1 or pSTAT3 or both, but not pSTAT5. The p53 was overexpressed in 10% of cases, but p21 staining (?p21/p53) did not suggest the presence of TP53 mutations. tDLBCL had a median MIB1 labelling index of 40%, and only 6% of cases appeared to have C‐MYC rearrangements. Most cases were of the non‐germinal centre type (77%), and showed as expected for this cell of origin B‐cell lymphoma 2 (BCL2) rearrangements only in 4% and amplifications in 15% of cases, whereas BCL6 was rearranged in 48% of cases. CXCR4 was expressed in 52% of cases, and high CXCR4 expression was of prognostic significance for progression‐free survival (p = 0.003). Because 84% of cases expressed nuclear p50, the canonical NF‐κB signalling pathway seems to be active. Multimarker phenotyping is important for lineage determination of tDLBCL. Occasionally, tDLBCL can express germ cell markers like OCT4, and they have active STAT signalling mediated through pSTAT1 and pSTAT3 and active canonical NF‐κB signalling. tDLBCL are of non‐germinal centre/post‐germinal centre cell origin and not hyperproliferative. TP53 mutations are unlikely, and C‐MYC as well as BCL2 rearrangements are rare, whereas BCL6 is commonly rearranged. CXCR4 might prove to be the first protein‐based prognostic marker for tDLBCL, inciting studies in larger cohorts corroborating these findings. Copyright © 2013 John Wiley & Sons, Ltd.     

Gene expression profiling of primary vitreoretinal lymphoma

The characteristics of tumor cells of primary vitreoretinal lymphoma (PVRL) have not been defined, although researches have shown that most cases are of diffuse large B‐cell lymphoma (DLBCL). To determine the subtype and biological characteristics of tumor cells of PVRL, we performed a gene expression profiling analysis. RNA was extracted from the vitreous fluid of 7 PVRL patients and from nodal samples of 10 DLBCL patients: 6 of germinal center B‐cell (GCB) type and 4 of activated B‐cell (ABC) type determined by Hans’ criteria. Six PVRL samples showed gene expression profiles that were similar to each other. The patterns were different from those of the ABC‐type nodular DLBCL but relatively close to those of the GCB‐type nodular DLBCL. Interestingly, all of the 6 examined PVRL samples had either MYD88^L265P or mutation in the immunoreceptor tyrosine‐based activation motif (ITAM) region of CD79B. Five PVRL patients with similar gene expression profiles were treated with a standardized regimen: intravitreal administration of methotrexate (MTX) followed by six courses of systemic high doses of MTX. As a result, 2 patients had CD79B mutations and showed early central nervous system (CNS) progression. Patients without CNS progression did not have this mutation. In conclusion, PVRL had unique genetic features: an expression pattern different from ABC‐type and relatively close to GCB‐type DLBCL. CD79B mutations showed potential to serve as prognostic markers for CNS progression.     

Dysregulated CXCR4 expression promotes lymphoma cell survival and independently predicts disease progression in germinal center B-cell-like diffuse large B-cell lymphoma

Abnormal expression of the chemokine receptor CXCR4 plays an essential role in tumor cell dissemination and disease progression. However, the significance of CXCR4 overexpression in de novo diffuse large B cell lymphoma (DLBCL) is unknown. In 743 patients with de novo diffuse large B cell lymphoma (DLBCL) who received standard Rituximab-CHOP immunochemotherapy, we assessed the expression of CXCR4 and dissected its prognostic significance in various DLBCL subsets. Our results showed that CXCR4⁺ patients was associated with male, bulky tumor, high Ki-67 index, activated B-cell-like (ABC) subtype, and Myc, Bcl-2 or p53 overexpression. Moreover, CXCR4⁺ was an independent factor predicting poorer progression-free survival in germinal-center B-cell-like (GCB)-DLBCL, but not in ABC-DLBCL; and in patients with an IPI of ≤2, but not in those with an IPI>2. The lack of prognostic significance of CXCR4 in ABC-DLBCL was likely due to the activation of p53 tumor suppressor attenuating CXCR4 signaling. Furthermore, concurrent CXCR4⁺ and BCL2 translocation showed dismal outcomes resembling but independent of MYC/BCL2 double-hit DLBCL. Gene expression profiling suggested that alterations in the tumor microenvironment and immune responses, increased tumor proliferation and survival, and the dissemination of CXCR4⁺ tumor cells to distant organs or tissues were underlying molecular mechanisms responsible for the CXCR4⁺ associated poor prognosis.     

The t(14;18) is associated with germinal center-derived diffuse large B-cell lymphoma and is a strong predictor of outcome.

The t(14;18) is present in a significant proportion of diffuse large B-cell lymphomas (DLBCLs), however, the prognostic effect of the translocation and the relationship with transformed follicular lymphoma remains controversial. To clarify these uncertainties, interphase fluorescence in situ hybridization (FISH) was used to determine the incidence of the t(14;18) in nodal DLBCL, and this was correlated with BCL2 expression, germinal center (GC) immunophenotype, and patient outcome. FISH was performed on paraffin-extracted nuclei from 137 de novo nodal DLBCLs. Eighteen of 137 de novo DLBCLs were t(14;18) positive. The t(14;18) was most commonly associated with the subset of DLBCLs that expressed a GC phenotype, defined as CD10+, BCL6+ (GC-type DLBCL): positive in 14 of 47 (30%) cases, compared with 4 of 89 (5%) in the non-GC group (Pearson's chi(2) = 28.4; P < 0.0001). All cases with a translocation expressed BCL2 protein, however, 40 expressed BCL2 protein without a t(14;18). GC-type DLBCL patients with a t(14;18) had a significantly worse survival compared with GC-type DLBCL patients without the translocation (2-year survivals were 29 and 63%, respectively; P = 0.006). Of the cases without the translocation, BCL2 protein expression did not affect survival. In contrast, in the non-GC group of DLBCLs, BCL2 protein expression reduced the 2-year overall survival from 64% in the BCL2-negative group to 38%, with a median survival of 15.0 months (P = 0.02). In conclusion, the t(14;18) is common in DLBCLs, particularly in GC-type DLBCLs, where the presence of the translocation has a poor prognostic effect. BCL2 protein expression defines a group of non-GC DLBCL patients with a poor prognosis.     

MYC protein expression is associated with poor prognosis in diffuse large B cell lymphoma patients treated with RCHOP chemotherapy

This study aims to investigate the prognostic significance of the MYC protein expression in diffuse large B cell lymphoma (DLBCL) patients treated with RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). A total of 60 patients with DLBCL from 2008 to 2013 were included. Formalin-fixed, paraffin-embedded DLBCL samples were analyzed for MYC protein expression and divided into high or low MYC group. The MYC protein expression and the international prognostic variables were evaluated. The high MYC protein expression predicted a shorter 3-year estimated overall survival (OS) and progression-free survival (PFS) versus the low MYC protein expression (57 % vs. 96 %, P?<?0.001 and 50 % vs. 96 %, P?=?0.001, respectively). Multivariate analysis confirmed the prognostic significance of the MYC protein expression for both OS (HR, 11.862; 95 % CI, 1.462–96.218; P?=?0.021) and PFS (HR, 6.073; 95 % CI, 1.082–34.085; P?=?0.040). MYC protein expression with International Prognostic Index (IPI) score distinguished patients into three risk groups with different 3-year OS rates (χ ² 23.079; P?<?0.001) and distinct 3-year PFS rates (χ ² 15.862; P?<?0.001). This study suggests that the MYC protein expression is an important inferior prognostic factor for survival in patients with DLBCL treated with RCHOP. The combinative model with IPI score and MYC protein expression could stratify DLBCL patients into prognostically relevant subgroups more effectively than either the IPI or the MYC alone.     

Relapse in stage I(E) diffuse large B‐cell lymphoma

Despite a general favourable outcome in limited stage diffuse large B‐cell lymphoma (DLBCL), relapses occur in about 10 to 20% of patients. Prognostic models only partially identify patients at risk for relapse. Moreover, it is not known whether the outcome after such a relapse is similar to the outcome after relapse in advanced stages. From January 2004 through December 2012, all newly diagnosed patients with stage I(E) DLBCL were retrospectively analysed from 2 clinical databases to investigate the relapse pattern and outcome in relation to initial treatment and clinical characteristics. In 126 patients (median age 64 years), histologically confirmed stage I(E) DLBCL was diagnosed. With a median follow‐up of 53 months (range 5‐132 months), 1 progressive disease and 18 relapses occurred. The 5‐year time to tumour progression and disease‐specific survival were 85% (95% CI 79‐91%) and 92% (95% CI 87%‐97%), respectively. We observed no significant difference in relapse localization, time to tumour progression, and disease‐specific survival between patients treated with abbreviated R‐CHOP plus involved field radiotherapy or with 6 to 8 cycles of R‐CHOP. Analysis of relapses showed relapse >5 years after initial treatment (late relapse) in 5 of 19 patients (26%). Six of 19 patients (32%) had central nervous system relapse. Three of 11 relapsed cases available for analysis (28%) showed an MYC translocation, suggesting an overrepresentation in the relapse group. Outcome of patients with a relapse was poor with a median survival after relapse of 8 months. Only 1 patient (5%) underwent successful autologous stem cell transplantation. To improve outcome in these patients, early identification of new biological factors such as a MYC translocation or a high risk for CNS dissemination might be helpful. Moreover, treatment of any relapse after stage I disease should be taken seriously. Salvage treatment should be similar to relapses after advanced DLBCL.     

Predictive factors of the tumor immunological microenvironment for long‐term follow‐up in early stage breast cancer

The aim of this research was to investigate the correlation of immunologic factors in the tumor environment of breast cancer, using immunohistological staining to evaluate the expression of programmed death 1/programmed death ligand 1 (PD‐1/PD‐L1), phosphatase and tensin homolog (PTEN), tumor infiltrating lymphocytes (TILs), and macrophages, and to analyze the association between the immunologic factors and clinical outcome for patients with early stage breast cancer (EBC). A total of 97 EBC patients who underwent standard surgery were investigated. Expression of PD‐1/PD‐L1 and PTEN and the density of CD3⁺ TILs, CD8⁺ TILs, and CD163⁺ macrophages were evaluated by immunohistochemical analysis. The association between the immunologic factors and clinical outcome was statistically analyzed. The density of CD3⁺ TILs, CD8⁺ TILs, and CD163⁺ macrophages and non‐expression of PTEN was significantly higher in cases of triple negative breast cancer. CD8⁺ TIL density and CD8⁺/PD‐L1⁺ expression were predictive factors for disease‐free survival and overall survival (OS). Human epidermal growth factor 2 (HER2)‐positive patients with PTEN expression and luminal/HER2‐negative patients without PD‐L1 expression had significantly longer OS compared to patients without PTEN expression (P = 0.049) and with PD‐L1 expression (P = 0.036), respectively. Furthermore, patients with PD‐L1⁺/CD8⁺ expression had worse median progression‐free survival (P = 0.022) and median OS (P = 0.037) compared with patients without PD‐L1⁺/CD8⁺ expression. The CD3⁺ TILs, CD8⁺ TILs, and CD163⁺ macrophages were shown to infiltrate the tumor area of EBC. In particular, triple negative breast cancer had a higher rate of TIL infiltration within the tumor environment. Expression of PTEN and lack of PD‐L1 expression were associated with favorable survival in HER2‐positive and luminal/HER2‐negative EBC patients, respectively. The PD‐L1 expression combined with CD8⁺ density was significantly associated with an aggressive clinical outcome.