Shimin Hu

MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program

Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP.

CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study

CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD30 expression in DLBCL is unknown. Here we report that CD30 expression is a favorable prognostic factor in a cohort of 903 de novo DLBCL patients. CD30 was expressed in ∼14% of DLBCL patients. Patients with CD30(+) DLBCL had superior 5-year overall survival (CD30(+), 79% vs CD30(-), 59%; P = .001) and progression-free survival (P = .003). The favorable outcome of CD30 expression was maintained in both the germinal center B-cell and activated B-cell subtypes. Gene expression profiling revealed the upregulation of genes encoding negative regulators of nuclear factor κB activation and lymphocyte survival, and downregulation of genes encoding B-cell receptor signaling and proliferation, as well as prominent cytokine and stromal signatures in CD30(+) DLBCL patients, suggesting a distinct molecular basis for its favorable outcome. Given the superior prognostic value, unique gene expression signature, and significant value of CD30 as a therapeutic target for brentuximab vedotin in ongoing successful clinical trials, it seems appropriate to consider CD30(+) DLBCL as a distinct subgroup of DLBCL.

MYC cytogenetic status correlates with expression and has prognostic significance in patients with MYC/BCL2 protein double-positive diffuse large B-cell lymphoma.

MYC/BCL2 double-hit lymphoma (DHL), defined by conventional cytogenetic or fluorescence in situ hybridization (FISH) analysis, and MYC/BCL2 double-positive lymphoma (DPL), defined by immunohistochemistry, are associated with a poor prognosis. However, DHL and DPL are not concordant, and it is unclear whether MYC and BCL2 aberrations have prognostic impact in DPL patients. In a cohort of 135 patients diagnosed with large B-cell lymphoma between 2010 and 2014 in whom MYC/8q24 and BCL2/t(14;18)(q32;q21) statuses were assessed by FISH at diagnosis, we evaluated MYC and BCL2 expression by immunohistochemistry. A total of 54 (40%) cases were positive for MYC and BCL2 supporting DPL. Among them, 19 (35%) had MYC rearrangement including 11 DHLs, 12 (22%) had multiple copies of MYC, 19 had no MYC abnormalities, and in 4 cases FISH analysis failed. BCL2 abnormalities were present in 28/54 (52%) cases (20 rearranged and 8 multiple copies). MYC rearrangement correlated with a significantly worse overall survival in DPL (P<0.05), whereas BCL2 genetic status did not correlate with survival (P>0.05). MYC and BCL2 expression by immunohistochemistry correlates with gene status by FISH; however, immunohistochemistry is neither specific nor adequately sensitive to be used as a surrogate for MYC and BCL2 gene status using any cutoff level. In conclusion, MYC rearrangement identifies a subset of patients with DPL who have a significantly worse prognosis. Although immunohistochemical assessment for MYC and BCL2 may be a helpful initial screen to identify higher-risk patients, FISH analysis for MYC remains important for further risk stratification in patients with DPL.

Triple-hit B-cell Lymphoma with MYC, BCL2, and BCL6 translocations/rearrangements: Clinicopathologic Features of 11 Cases

Lymphomas with translocations/rearrangements of MYC, BCL2, and BCL6, so-called triple-hit B-cell lymphoma, are rare, and few studies on these tumors are available in the literature. We report 11 cases of triple-hit B-cell lymphoma and characterize their clinicopathologic findings. All patients were men, with a median age of 64 years (range, 45 to 80 y), and 4 patients had antecedent or concurrent follicular lymphoma. Using the 2008 World Health Organization classification, these cases were classified as: 5 B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma; 4 DLBCL; 1 DLBCL with concurrent follicular lymphoma; and 1 low-grade follicular lymphoma. All cases were positive for CD10, BCL2, and FOXP1. Ten of 11 cases were positive for CD20. MYC expression was high in 10/11 (91%), BCL6 was positive in 8/11 (73%), and MUM1/IRF4 was positive in 6/11 (55%) cases. T-cell antigens, TdT, and Epstein-Barr virus–encoded RNA were negative in all cases. Ten of 11 cases showed a high proliferation index—70% to 100%, and the follicular lymphoma had a 30% proliferation rate. Using most algorithms, all cases belonged to germinal center B-cell–like group. All patients received standard or more aggressive immunochemotherapy regimens. Three patients had no response to chemotherapy; 4 patients showed a partial response; 2 patients had complete remission after chemotherapy; and 2 patients had just begun chemotherapy. Three patients underwent a stem cell transplant. The median follow-up time was 5.3 months. Five patients died, and 6 patients were alive at last follow-up. Two patients who underwent stem cell transplant after complete response to chemotherapy were in remission with 16 to 19 months of clinical follow-up. In summary, triple-hit lymphomas are clinically aggressive tumors associated with a poor prognosis. Patients often respond poorly to chemotherapy, but a subset may completely respond to chemotherapy followed by stem cell transplant.

Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy

Clonal cytogenetic evolution with additional chromosomal abnormalities (ACAs) in chronic myelogenous leukemia (CML) is generally associated with decreased response to tyrosine kinase inhibitor (TKI) therapy and adverse survival. Although ACAs are considered as a sign of disease progression and have been used as one of the criteria for accelerated phase, the differential prognostic impact of individual ACAs in CML is unknown, and a classification system to reflect such prognostic impact is lacking. In this study, we aimed to address these questions using a large cohort of CML patients treated in the era of TKIs. We focused on cases with single chromosomal changes at the time of ACA emergence and stratified the 6 most common ACAs into 2 groups: group 1 with a relatively good prognosis including trisomy 8, -Y, and an extra copy of Philadelphia chromosome; and group 2 with a relatively poor prognosis including i(17)(q10), -7/del7q, and 3q26.2 rearrangements. Patients in group 1 showed much better treatment response and survival than patients in group 2. When compared with cases with no ACAs, ACAs in group 2 conferred a worse survival irrelevant to the emergence phase and time. In contrast, ACAs in group 1 had no adverse impact on survival when they emerged from chronic phase or at the time of CML diagnosis. The concurrent presence of 2 or more ACAs conferred an inferior survival and can be categorized into the poor prognostic group.

ALK-positive large b-cell lymphoma

Anaplastic lymphoma kinase–positive large B-cell lymphoma (ALK+ LBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma with characteristic ALK rearrangements. Diagnosis of ALK+ LBCL can be challenging because of its rarity, unique morphologic characteristics, and unusual immunophenotypic features, which significantly overlap with other hematologic and nonhematologic neoplasms. The purpose of this study is to further explore the clinicopathologic features of ALK+ LBCL to ensure the awareness and accurate diagnosis of this entity. We retrospectively reviewed the data from 26 cases in our institutions and additional 108 cases from the literature. ALK+ LBCL typically occurred in the lymph nodes of young and middle-aged, immunocompetent patients. The medium age was 35 years with a male to female ratio of 3.5:1. Vast majority of cases showed immunoblastic and/or plasmablastic morphology. All cases expressed ALK protein with a cytoplasmic granular pattern in most of them. Common B-cell markers (CD20, CD79a, and PAX5) were typically negative, but the tumor cells mostly expressed 2 B-cell transcriptional factors, BOB1 and OCT2. The 5-year overall survival (OS) was 34%, and the median survival was 1.83 years. In patients with stage III/IV disease, the 5-year OS was only 8%. Moreover, patients below 35 years of age had a significantly better OS than those aged 35 years or above.

Cytogenetic risk stratification of 417 patients with chronic myelomonocytic leukemia from a single institution

Approximately 30% of patients with chronic myelomonocytic leukemia (CMML) have karyotypic abnormalities and this low frequency has made using cytogenetic data for the prognostication of CMML patients challenging. Recently, a three‐tiered cytogenetic risk stratification system for CMML patients has been proposed by a Spanish study group. Here we assessed the prognostic impact of cytogenetic abnormalities on overall survival (OS) and leukemia‐free survival (LFS) in 417 CMML patients from our institution. Overall, the Spanish cytogenetic risk effectively stratified patients into different risk groups, with a median OS of 33 months in the low‐, 24 months in intermediate‐ and 14 months in the high‐risk groups. Within the proposed high risk group, however, marked differences in OS were observed. Patients with isolated trisomy 8 showed a median OS of 22 months, similar to the intermediate‐risk group (P = 0.132), but significantly better than other patients in the high‐risk group (P = 0.018). Furthermore, patients with more than three chromosomal abnormalities showed a significantly shorter OS compared with patients with three abnormalities (8 vs. 15 months, P = 0.004), suggesting possible a separate risk category. If we simply moved trisomy 8 to the intermediate risk category, the modified cytogenetic grouping would provide a better separation of OS and LFS; and its prognostic impact was independent of other risk parameters. Our study results strongly advocate for the incorporation of cytogenetic information in the risk model for CMML. Am. J. Hematol. 89:813–818, 2014.

Follicular T-cell lymphoma: A member of an emerging family of follicular helper T-cell derived T-cell lymphomas

Unlike B-cell lymphomas, where knowledge of normal B-cell origin and differentiation has greatly contributed to their classification, the current classification of peripheral T-cell lymphomas is limited by a lack of understanding of their cellular origin. In the current World Health Organization classification of lymphomas, follicular T-cell lymphoma was formally recognized as a morphologic variant of peripheral T-cell lymphoma, not otherwise specified. There is growing evidence, however, that follicular T-cell lymphoma may be a unique clinicopathologic entity based on its morphologic features and derivation from follicular helper T-cells. In addition, there are abundant recent data supporting the concept that follicular helper T-cells can give rise to other types of T-cell lymphoma, including angioimmunoblastic T-cell lymphoma, primary cutaneous CD4+ small/medium T-cell lymphoma, and a subset of neoplasms, in addition to follicular T-cell lymphoma, currently classified as peripheral T-cell lymphoma, not otherwise specified. In this review, we focus primarily on the clinicopathologic, immunophenotypic, and molecular features of follicular T-cell lymphoma and discuss its potential relationship with other types of T-cell lymphoma thought to be derived from follicular helper T-cells.

Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors.

Chromosome 3q26.2 abnormalities in acute myeloid leukemia, including inv(3)/t(3;3) and t(3;21), have been studied and are associated with a poor prognosis. Their prevalence, response to tyrosine kinase inhibitor (TKI) treatment, and prognostic significance in chronic myelogenous leukemia (CML) are largely unknown. In this study, we explored these aspects using a cohort of 2013 patients with CML diagnosed in the era of TKI therapy. Chromosome 3 abnormalities were observed in 116 (5.8%) of 2013 cases. These cases were divided into 5 distinct groups: A, inv(3)(q21q26.2)/t(3;3)(q21;q26.2), 26%; B, t(3;21)(q26.2;q22), 17%; C, other 3q26.2 rearrangements, 7%; D, rearrangements involving chromosome 3 other than 3q26.2 locus, 32%; and E, gain or loss of partial or whole chromosome 3, 18%. In all, 3q26.2 rearrangements were the most common chromosome 3 abnormalities (50%, groups A-C). 3q26.2 rearrangements emerged at different leukemic phases. For cases with 3q26.2 rearrangements that initially emerged in chronic or accelerated phase, they had a high rate of transformation to blast phase. Patients with 3q26.2 abnormalities showed a marginal response to TKI treatment, and no patients achieved a long-term sustainable response at a cytogenetic or molecular level. Compared with other chromosomal abnormalities in CML, patients with 3q26.2 rearrangements had poorer overall survival. The presence or absence of other concurrent chromosomal abnormalities did not affect survival in these patients, reflecting the predominant role of 3q26.2 rearrangements in determining prognosis. Interestingly, although heterogeneous, chromosome 3 abnormalities involving non-3q26.2 loci (groups D, E) also conferred a worse prognosis compared with changes involving other chromosomes in this cohort.

High-grade B-cell Lymphoma With MYC Rearrangement and Without BCL2 and BCL6 Rearrangements Is Associated With High P53 Expression and a Poor Prognosis.

Patients with MYC/BCL2 double-hit lymphoma (DHL) are known to have an aggressive clinical course and to respond poorly to various therapies including intensive chemotherapy and stem cell transplant. Less is known about high-grade B-cell lymphoma with MYC rearrangement without concomitant BCL2 and BCL6 rearrangement, designated here as single-hit lymphoma (SHL). In this study, we assessed 61 cases of SHL and compared them with 83 cases of DHL, all confirmed by MYC, BCL2, and BCL6 fluorescence in situ hybridization studies. Although many clinicopathologic features overlap between patients with SHL and those with DHL, distinct features were observed in SHL. Patients with SHL had tumors with a higher prevalence of p53 overexpression (P=0.047), less frequent expression of CD10, BCL2, and BCL6 (P<0.05), and less often had a history of low-grade B-cell lymphoma (P=0.01). In addition, MYC was more frequently partnered with IGH in SHL than in DHL (P=0.04). With a median follow-up of 25 months, the overall survival of 61 SHL patients was poor and similar to that of DHL patients (2-y overall survival rate of 41% in SHL vs. 48% in DHL; P=0.35) and significantly worse than patients with diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, without MYC and BCL2 rearrangements (P<0.0001). In conclusion, patients with SHL have distinct clinicopathologic features but a similar poor prognosis compared with patients with MYC/BCL2 DHL. The poor prognosis of patients with SHL may be partially related to the higher frequency and level of p53 expression in these tumors.