The expression of cyclin D1 in diffuse large B-cell lymphomas has been reported in the literature several times. However, cases with the t(11;14)(q13;q32) are very uncommon. Herein, we present two cases of diffuse large B-cell lymphoma with the t(11;14)(q13;q32) and cyclin D1 expression, BCL6 rearrangement and BCL2 amplification, but negative for SOX11 expression. Although presence of the t(11;14)(q13;q32) is a hallmark of mantle cell lymphoma, it can also be seen in diffuse large B-cell lymphoma, sometimes as a secondary aberration.

DNA methylation (DNAm) silences gene expression and may play a role in immune dysregulation that is characteristic of adolescent/young adult Hodgkin lymphoma (AYAHL). We used the Infinium HumanMethylation27 BeadChip to quantify DNAm in blood (N = 9 pairs, mean age 57.4 y) or saliva (N = 36 pairs, mean age 50.0 y) from long-term AYAHL survivors and their unaffected co-twins. Epigenetic aging (DNAm age) was calculated using previously described methods and compared between survivors and co-twins using paired t-tests and analyses were stratified by sample type, histology, sex, age at sample collection and time since diagnosis. Differences in blood DNAm age were observed between survivors and unaffected co-twins (64.1 vs. 61.3 years, respectively, p = .04), especially in females (p = .01); no differences in saliva DNAm age were observed. Survivors and co-twins had 74 (in blood DNA) and 6 (in saliva DNA) differentially methylated loci. Our results suggest persistent epigenetic aging in AYAHL survivors long after HL cure.

The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.

The World Health Organization classification of lymphoma recommends the subdivision of follicular lymphoma (FL) into 3 grades (FL1-3) based on the average number of centroblasts per high-power field in the neoplastic follicles, but does not recognize a form of FL characterized by a predominance of large cleaved cells (centrocytes) without enough centroblasts to meet the World Health Organization criteria for FL3. We have classified such cases as follicular large cleaved cell lymphoma (FLC) and, herein, describe the pathologic and clinical features of 72 cases of this entity. The features of FLC include a follicular growth pattern with pale follicles at low magnification and frequent follicular and/or interfollicular fibrosis. Cytologically, the cells are predominantly large cleaved cells with moderately coarse to fine chromatin, absent or inconspicuous nucleoli, and small to moderate amounts of pale cytoplasm. The mean nuclear diameter of the large cleaved cells was 10.1 μ, approximately twice that of small lymphocytes and similar to centroblasts. The t(14;18) was present in 83% of the cases, and a high proportion expressed BCL2 (84%), BCL6 (100%), and CD10 (88%) and had high Ki67 proliferation (81%). The clinical features of patients with FLC were similar to those with other types of FL, and survival was excellent with anthracycline-based chemotherapy plus rituximab. FLC is a variant of follicular lymphoma which should be recognized in future lymphoma classifications because the diagnosis of FLC may be important for the selection of therapy.

Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma are rare indolent lymphomas that are distinctive entities with excellent prognoses. We present the histopathology and the immunophenotypic, cytogenetic, and gene rearrangement findings of a unique, heretofore, unreported case of a 15-year old boy with a right-groin mass (5.5×4.5×3.5cm) with three discrete malignant components: 1) follicular lymphoma positive for CD20, CD10, and BCL6, but negative for BCL2; by flow cytometry, 9% of the cells were kappa monotypic B-cells that expressed CD10, CD19, CD20, and CD38; 2) typical marginal zone B-cell differentiation; marginal zone B-cells were positive for CD20, CD43, BCL2, and MUM-1, but CD10 and BCL6 negative. A small subset was weakly positive for intracytoplasmic IgM and kappa consistent with early plasmacytic differentiation; 3) Plasmacytoid forms, intracytoplasmic globules and crystals strongly expressed intracytoplasmic monotypic IgM and kappa.

Background: Hodgkin lymphoma is one of the most common malignancies among adolescents and young adults (AYA) in economically developed settings. Although the survival rate is very high (85%), severe late effects are common. Immune dysregulation is clinically and pathologically associated with HL at diagnosis and alterations in inflammatory cytokine levels are evident years after cure. Gut bacteria play a role in modulating immune responses and inflammation. In a pilot study of 13 AYA HL-discordant twin pairs, we saw significantly lower fecal microbial diversity in the HL survivor compared to their unaffected twin. We conducted a follow-up study in a larger set of twins to determine whether there are differences in the relative abundance of specific fecal microbiota in long-term AYAHL survivors compared to their unaffected twins. Twin pairs are an ideal study population because they are partially matched on genetic and early life factors, both of which influence the composition of the gut microbiome.

Introduction: The WHO classification recommends the subdivision of follicular lymphoma (FL) into three grades based on the average number of centroblasts per high-power field in the neoplastic follicles. However, we have encountered cases of FL in which the follicles are comprised predominately of large cells with cleaved nuclei (large centrocytes), but without enough centroblasts to meet the WHO criteria for grade 3 FL (FL3), and have classified such cases as follicular large cleaved cell lymphoma (FLC). The objective of this study was to describe the pathologic and clinical features of a large series of patients with FLC. Methods: The pathologic features of 72 cases of FLC were evaluated, including morphometry, immunostaining, and cytogenetic studies. Clinical features were tabulated and compared to a series of patients with the other subtypes of FL (332 FL1/2, 181 FL3), and survivals were compared for those treated with anthracycline-based chemotherapy plus rituximab. Results: FLC has a follicular growth pattern with pale follicles at low magnification and frequent follicular and/or interfollicular fibrosis. Cytologically, the cells are predominantly large cleaved cells (centrocytes) with moderately coarse to fine chromatin, absent or inconspicuous nucleoli, and small to moderate amounts of pale cytoplasm. The mean nuclear diameter of the large cleaved cells was 10.1 μ, similar to centroblasts and approximately twice that of small lymphocytes. The t(14;18) was present in 83% of the cases, and a high proportion expressed BCL2 (84%), BCL6 (100%), and CD10 (88%) and had high (≥30%) Ki67 proliferation (81%). However, almost one-half of the cases of FLC were misdiagnosed as low-grade FL. The clinical features of patients with FLC were similar to those with the other types of FL, and survival was excellent with anthracycline-based chemotherapy plus rituximab. The 5-year overall survival (OS) of these patients was 95% and the 5-year event-for survival (EFS) was 90%. No significant differences in OS were found between FLC, FL1/2, FL3A, or FL3B. However, FLC and FL3A had significantly better EFS than either FL1/2 (P = .05) or FL3B (P = .028). Conclusions: FLC is a distinctive variant of follicular lymphoma, which should be recognized in future lymphoma classifications. The correct diagnosis of FLC is critical for the selection of appropriate therapy. Keywords: B-cell lymphoma; follicular lymphoma (FL); R-CHOP

Cyclin D1 is an important regulator of the cell cycle and overexpression of this protein by immunohistochemistry is characteristically seen in mantle cell lymphoma and other B-cell neoplasms. However, little is known about the expression of this protein in T-cell lymphomas. Cyclin-dependent kinase pathway inhibitors are in development, therefore identifying cyclin D1-positive T-cell lymphomas may provide a therapeutic target in a disease where novel treatments are urgently needed. We collected 200 peripheral T-cell lymphomas from three institutions including the following types of cases: 34 anaplastic large cell lymphoma, ALK+, 44 anaplastic large cell lymphoma, ALK negative, 68 peripheral T-cell lymphomas, not otherwise specified, 24 angioimmunoblastic T-cell lymphomas, 7 extranodal NK/T-cell lymphomas, 4 enteropathy associated T-cell lymphomas, 3 hepatosplenic T-cell lymphomas, 12 cutaneous T-cell lymphomas, and 4 large granular lymphocytic leukemias. Immunohistochemical stains for cyclin D1 protein (SP4 clone) were performed on paraffin-embedded tissue. In a subset of cases, IGH/CCND1 fluorescence in situ hybridization analysis was also performed. Cyclin D1 staining was predominantly seen in anaplastic large cell lymphoma, including 8 of 34 cases with ALK+ anaplastic large cell lymphoma (24%), and 3 of 44 cases of ALK-negative (7%) anaplastic large cell lymphoma. Three cases of peripheral T-cell lymphoma, not otherwise specified, were also positive (3/68, 4%). All other T-cell lymphomas were negative for cyclin D1. In four of the cyclin D1-positive T-cell lymphomas by immunohistochemistry, fluorescence in situ hybridization analysis was negative for IGH/CCND1 translocation or extra copies of the CCND1 gene. Cyclin D1 overexpression by immunohistochemistry is not limited to B-cell lymphomas and is also observed in some peripheral T-cell lymphomas, particularly in anaplastic large cell lymphoma, ALK+. Cyclin D1 expression was not associated with extra copies or translocation of the CCND1 gene. Cyclin D1 overexpression may be the result of a post-translational phenomenon and may represent a potential therapeutic target using agents that target the cyclin-dependent kinase pathway.

Large and systematic studies of non-Hodgkin lymphoma (NHL) in the Far East (FE) with good comparative data are scarce in the literature. In this study, five expert hematopathologists classified 730 consecutive cases of newly-diagnosed NHL from four sites in the FE (excluding Japan) using the World Health Organization classification. The results were compared to 399 cases from North America (NA). We found a significantly higher male to female ratio in the FE compared to NA (1.7 versus 1.1; p < 0.05). The median ages of patients with low-grade (LG) and high-grade (HG) B-NHL in the FE (58 and 51 years, respectively) were significantly lower than in NA (64 and 68 years, respectively). The FE had a significantly lower relative frequency of B-NHL and a higher frequency of T-NHL (82 vs. 18 %) compared to NA (90.5 vs. 9.5 %). Among mature B cell lymphomas, the FE had a significantly higher relative frequency of HG B-NHL (54.8 %) and a lower frequency of LG B-NHL (27.2 %) than NA (34.3 and 56.1 %, respectively). Diffuse large B cell lymphoma was more common in the FE (49.4 %) compared to NA (29.3 %), whereas the relative frequency of follicular lymphoma was lower in the FE (9.4 %) compared to NA (33.6 %). Among T-NHL, nasal NK/T cell NHL was more frequent in the FE (5.2 %) compared to NA (0 %). Peripheral T cell lymphoma was also more common in the FE (9.1 %) than in NA (5.3 %). Further epidemiologic studies are needed to better understand the pathobiology of these differences.

We report a 13-year-old adolescent girl, the youngest thus far, with “an indolent T-lymphoblastic” proliferation (~10%) that uniquely presented within recurrent, large inguinal lymph node masses in a predominating (90%) background of Castleman disease. These nodal masses were resected thrice; the patient is well 5 years after diagnosis without further treatment. Histologically, the features of Castleman disease, hyaline vascular type, were present. Importantly, the interfollicular T-lymphoblastic component occurred as multiple clusters and islands of variable shapes and sizes composed of small “lymphoblasts” indistinguishable from normal cortical thymocytes but without thymic epithelial cells. Immunohistochemically, these lymphoblasts were consistent with the intermediate stage of T-cell differentiation (TdT+CD34−CD99+CD1a+CD2+CD3+CD4+CD8+CD5+CD7+CD10+ [subset]), with 80% Ki-67. Molecularly, the T cells were nonclonal. Our case provides evidence for the benign nature of this highly unusual and poorly understood entity; because the current terminology can be readily misinterpreted as an indolent lymphoblastic lymphoma, we suggest a new term accurately reflecting this entity.

The distribution of non-Hodgkin lymphoma subtypes varies around the world, but a large systematic comparative study has never been done. In this study, we evaluated the clinical features and relative frequencies of non-Hodgkin lymphoma subtypes in five developing regions of the world and compared the findings to the developed world. Five expert hematopathologists classified 4848 consecutive cases of lymphoma from 26 centers in 24 countries using the World Health Organization classification, and 4539 (93.6%) were confirmed to be non-Hodgkin lymphoma, with a significantly greater number of males than females in the developing regions compared to the developed world (P<0.05). The median age at diagnosis was significantly lower for both low- and high-grade B-cell lymphoma in the developing regions. The developing regions had a significantly lower frequency of B-cell lymphoma (86.6%) and a higher frequency of T- and natural killer-cell lymphoma (13.4%) compared to the developed world (90.7% and 9.3%, respectively). Also, the developing regions had significantly more cases of high-grade B-cell lymphoma (59.6%) and fewer cases of low-grade B-cell lymphoma (22.7%) compared to the developed world (39.2% and 32.7%, respectively). Among the B-cell lymphomas, diffuse large B-cell lymphoma was the most common subtype (42.5%) in the developing regions. Burkitt lymphoma (2.2%), precursor B- and T-lymphoblastic leukemia/lymphoma (1.1% and 2.9%, respectively) and extranodal natural killer/T-cell lymphoma (2.2%) were also significantly increased in the developing regions. These findings suggest that differences in etiologic and host risk factors are likely responsible, and more detailed epidemiological studies are needed to better understand these differences.

Epidemiologic studies of non-Hodgkin lymphoma (NHL) in Eastern Europe are scarce in the literature. We report the experience of the Ion Chiricuta Institute of Oncology in Cluj-Napoca (IOCN), Romania, in the diagnosis and outcome of patients with NHL. We studied 184 consecutive NHL patients diagnosed in the Pathology Department of IOCN during the years 2004-2006. We also obtained epidemiological data from the Northwestern (NW) Cancer Registry. In the IOCN series, the most common lymphoma subtype was diffuse large B-cell lymphoma (43.5%), followed by the chronic lymphocytic leukaemia/small lymphocytic lymphoma (21.2%). T-cell lymphomas represented a small proportion (8.2%). The median age of the patients was 57years, with a male-to-female ratio of 0.94. Patients with indolent B-cell lymphomas had the best overall survival, whereas those with mantle cell lymphoma had the worst survival. The NW Cancer Registry data showed that the occurrence of NHL in the NW region of Romania was higher in men [world age-standardized incidence rate/100000 (ASR)5.9; 95% CI 5.1-6.6] than in women (ASR4.1; 95% CI 3.5-4.7) with age-standardized male-to-female ratio of 1.44 (p=0.038). Chronic lymphocytic leukaemia/small lymphocytic lymphoma was the most common NHL in the NW region of Romania, accounting for 43% of all cases, followed by diffuse large B-cell lymphoma (36%). The 5-year, age-standardized cumulative relative survival for NHL in the County of Cluj in NW Romania, for the period of 2006-2010, was 51.4%, with 58.4% survival for men and 43.2% for women. Additional studies of NHL in Eastern Europe are needed. Copyright (c) 2015 John Wiley & Sons, Ltd.

Hodgkin lymphoma (HL) is derived from germinal center B-lymphocytes, has a peak incidence in adolescents and young adults (AYA) in developed countries and results in substantial treatment-related late effects. We previously identified a SNP (rs1860661G) in the TCF3 gene, inversely associated with HL risk, that is also mutated in tumor cells. The protein encoded by TCF3 is responsible for maintaining the B-cell program, which is downregulated in HRS cells; therefore higher expression levels may be protective.1 DNA methylation is associated with repression of gene expression and may thereby play a role in HL pathogenesis. We extracted DNA from blood samples obtained from HL survivors and their unaffected monozygotic MZ twins (4 female and 5 male twin pairs discordant for AYA HL). Average age at blood draw was 62 years, and average time since diagnosis of the case was 34 years. We also extracted DNA from blood samples from 25 unaffected MZ twin pairs as control pairs. DNAs were bisulfite converted and DNA methylation quantified using the Illumina Infinium HumanMethylation27 BeadChip array, which scores methylation levels as β values. We compared average DNA methylation β value differences at the TCF3 locus cg16524139 (near rs1860661) in HL survivors and their unaffected co-twins using a paired t-test. We also examined the TCF3 germline genotype by DNA methylation level rank in HL-discordant pairs. We also computed DNA methylation age, a global measure of physiological aging, using a validated algorithm2 and compared the result in the HL survivor to that of each corresponding unaffected co-twin using a paired t-test. We found a small but significantly higher DNA methylation level at the TCF3 locus in HL survivors compared to their unaffected co-twins (p=0.05), but no difference between the members of healthy MZ twin pairs (p=0.81). The protective allele (G) was more prevalent in the 6 pairs with higher DNA methylation level in HL survivors (33%), compared to the 3 pairs with higher levels in unaffected co-twins (17%). This pattern would be expected if methylation at the cg16524139 were to diminish TCF3 expression related to a protective rs1860661G variant. HL survivors had an average DNA methylation age of 64.1 years compared to 61.3 years in their unaffected MZ co-twins (p=0.04). Differential DNA methylation in HL survivors and their unaffected twins suggests a role for DNA methylation in HL, possibly as a result of treatment or disease. 1. Cozen W, Timofeeva MN, Li D, Diepstra A, Hazelett D, Delahaye-Sourdeix M, et al.: A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus. Nat Comm 25:3856. doi: 10.1038/ ncomms 4856, 2014 2. Horvath S: DNA methylation age of human tissues and cell types. Genome Biol, 14:R115 doi:10.1186/gb-2013-14-10-r115, 2013. Disclosures No relevant conflicts of interest to declare.

Comparative data on the distribution of non-Hodgkin lymphoma (NHL) subtypes in Southern Africa (SAF) is scarce. In this study, five expert haematopathologists classified 487 consecutive cases of NHL from SAF using the World Health Organization classification, and compared the results to North America (NA) and Western Europe (WEU). Southern Africa had a significantly lower proportion of low-grade (LG) B-NHL (34·3%) and a higher proportion of high-grade (HG) B-NHL (51·5%) compared to WEU (54·5% and 36·4%) and NA (56·1% and 34·3%). High-grade Burkitt-like lymphoma was significantly more common in SAF (8·2%) than in WEU (2·4%) and NA (2·5%), most likely due to human immunodeficiency virus infection. When SAF patients were divided by race, whites had a significantly higher frequency of LG B-NHL (60·4%) and a lower frequency of HG B-NHL (32·7%) compared to blacks (22·5% and 62·6%), whereas the other races were intermediate. Whites and other races had a significantly higher frequency of follicular lymphoma and a lower frequency of Burkitt-like lymphoma compared to blacks. The median ages of whites with LG B-NHL, HG B-NHL and T-NHL (64, 56 and 67 years) were significantly higher than those of blacks (55, 41 and 34 years). Epidemiological studies are needed to better understand these differences.

S100+ T-cell lymphomas are infrequent, and except 1 all have been CD4 negative. On the basis of an index case of CD4+ S100+ T-cell prolymphocytic leukemia (T-PLL), we studied S100 protein expression in 19 additional T-PLLs and 56 other T-cell lymphomas that are usually CD4+, including 15 angioimmunoblastic T-cell lymphomas, 24 anaplastic large cell lymphomas (16 ALK+ and 8 ALK−), 7 mycosis fungoides/Sézary syndrome, and 10 peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). Two additional S100+ CD4+ PTCL, NOS cases were also reviewed. Thirty percent (6/20) of T-PLLs were S100+ compared with 0/56 other T-cell lymphomas with previously unstudied S100 reactivity (40 CD4+, 2 CD8+, 11 CD4−/CD8−, 3 unknown) (P=0.0007). There were no significant differences between the S100+ and S100− T-PLLs with regard to the male:female ratio (2:1 vs. 1:1), age (71.6±7.7 vs. 65.4±9.3), peripheral blood lymphocyte count (67.2±116.6 vs. 101.1±159.7×109/L), or median survival (463 vs. 578 d, where known). The 2 S100+ PTCL, NOS cases occurred in a 7-year-old boy and a 45-year-old woman. Both had involvement of the bone marrow and peripheral blood but were morphologically unlike T-PLL and lacked TCL1 gene rearrangement. These results demonstrate that S100+ T-cell lymphomas include a subset that are CD4+ and most often, but not exclusively, are T-PLL. Although having diagnostic implications, there were no documented clinical differences between the S100+ and S100− T-PLLs.

We evaluated the association between common immune system-altering experiences and non-Hodgkin lymphoma (NHL) risk using a case-control study of 162 like-sex twin pairs discordant for NHL, identified from the International Twin Study. Information on medical history and evidence of childhood exposure to microbes was obtained by questionnaire from 1998 to 2002. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals. Intra-twin-pair agreement between twins on individual exposures was high (76%-97%). A negative association between NHL and seasonal hay fever (odds ratio (OR) = 0.28, 95% confidence interval (CI): 0.10, 0.75) and certain allergies (OR = 0.29, 95% CI: 0.13, 0.68) was observed. The number of atopic diseases was negatively associated with NHL (P for trend = 0.0003). A history of infectious mononucleosis was negatively associated with NHL risk (OR = 0.35, 95% CI: 0.14, 0.90). NHL risk was associated with more frequent childhood exposure to microbes during early life (P for trend = 0.04). No differences in association by NHL subtype were observed, although statistical power for these comparisons was low. These observations support the hypothesis that immune-related exposures, especially atopy, are associated with decreased NHL risk. Use of the within-twin-pair study design mitigates confounding by genome, family structure, and unmeasured characteristics of early childhood factors.