Young Adult Lymphoma Research Articles

Childhood determination of Hodgkin lymphoma among U.S. servicemen.

Hodgkin lymphoma in young adults is inexplicably linked to economic development. We conducted a nested case-control study of the 656 servicemen with Hodgkin lymphoma diagnosed between ages 17 to 32 while on active duty in the U.S. military during 1950-68. Controls, chosen randomly from the servicemen on duty at the time, were matched on service, birth year, and induction date. Information came from preinduction records and military records for the period ending at onset or the equivalent date. Risk was independently increased with small sib-ship size [OR, 2.3; confidence interval (CI), 1.6-3.5], low birth order (OR, 1.9; CI, 1.4-2.6), and an interval of at least 5 years between birth and that of a previous or subsequent sibling (OR, 2.1; CI, 1.5-3.1). Other factors independently and significantly associated with elevated risk of Hodgkin lymphoma were: tallness, high body mass index, more education (but not higher income) in the county of birth, BB or AB blood type, and past infectious mononucleosis (but a deficit of other childhood viral infections). Early fatherhood conveyed high risk (OR, 2.6; CI, 1.4-4.8), especially if with a high-risk sibling configuration. Factors unrelated to risk included personal education, preinduction or military occupation, induction test score, and rank. Findings were similar for nodular sclerosis and mixed cell histologic subtypes. Protection from the environment in childhood, but not in adulthood, increases the likelihood of young adult Hodgkin lymphoma, which may result from nonspecific isolation from early infections and/or exposure to late infection by a specific but unidentified ubiquitous childhood virus. Events in childhood protect against later Hodgkin lymphoma.

EBV-positive diffuse large B-cell lymphoma in young adults: is this a distinct disease entity?

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is defined only in adults older than 50 years. However, EBV-positive DLBCL can affect younger patients. We investigated the prevalence, clinical characteristics and survival outcomes of EBV-positive DLBCL in young adults. We analyzed patients with de novo DLBCL who were registered in the Samsung Medical Center (SMC) retrospective lymphoma cohort and prospective SMC Lymphoma Cohort Study I (ClinicalTrials.gov: NCT00822731). A total of 571 cases were included in the analysis. The prevalence of EBV positivity was 6.7% (13/195) and 9.3% (35/376) in the young group (≤50 years) and in the elderly group (>50 years), respectively. EBV status was closely associated with unique unfavorable clinical characteristics [older age, more advanced stage, two or more sites of extranodal involvement, higher International Prognostic Index (IPI), and age-adjusted IPI risk] only in the elderly group. Poor prognostic impact of EBV positivity on overall survival was observed only in the elderly group [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.83-4.47; P < 0.001], but not in the young group (HR 1.17; 95% CI 0.35-3.89; P = 0.801). A substantial proportion of EBV-positive DLBCL of the elderly can occur in young adults. EBV positivity of DLBCL in young adults was not associated with unfavorable clinical characteristics or worse outcomes. We suggest that EBV-positive DLBCL should not be confined only in the elderly and 'EBV-positive DLBCL in young adults' needs to be considered as a clinically distinct disease entity. ClinicalTrials.gov: NCT02060435.

Abstract 5096: Quiescence induced checkpoint activation in the absence of CIZ1

Abstract The CIZ1 protein is required for timely entry to S phase following exit from quiescence (1). We show here that CIZ1 is also required for accurate entry into quiescence. Analysis of quiescence entry following contact inhibition in a CIZ1-deletion model has revealed a role in dampening a previously unreported quiescence checkpoint, evidenced by ubiquitous post-replicative phosphorylation of histone H2AX and activation of checkpoint kinases ATM and CHK1. Subsequent emergence of proliferating colonies indicates escape from checkpoint-mediated arrest, and begins to implicate inappropriate response to contact induced signaling as a novel endogenous driver of oncogenesis. Unscheduled checkpoint activation was also observed in bone marrow cells from juvenile CIZ1 null mice, and high frequency B-cell lymphoma in young adults in the absence of any additional oncogenic stimulation, supporting the idea that CIZ1 plays a very early role in tumorigenesis. Analysis of cell cycle progression using immunofluorescence and flow cytometry of primary fibroblasts from post-natal CIZ1 null mice revealed cell cycle elongation, with extended expression of cyclins D2 and E1, increased cyclin A2, and altered p21, p27 and CDK2, but no checkpoint activation. Thus, CIZ1 null cells can tolerate altered expression, targeting and recruitment of multiple cell cycle regulators. Checkpoint activation occurs only after exit from the cell cycle, reflecting aberrant response to contact induced signaling and failure to accurately transition into a stable quiescent state. Inappropriate expression of CIZ1 splice variants has been previously linked with both adult and pediatric cancers (2-4), and shown to play a proliferation-promoting role in lung (4) and breast (5) tumor models. Furthermore, CIZ1 b-variant has biomarker capability for the early detection of lung cancer (4). Despite these advances, the precise role of CIZ1 in the cell is not yet understood. The CIZ1 knock out mouse model described here, and a related model (6), indicate a tumor suppressor function, which is apparently at odds with the DNA replication- and proliferation-promoting roles reported previously. The current work helps to reconcile these observations by showing that CIZ1s established activity in the promotion of cyclin A-mediated initiation of DNA replication (1) is as a coordinator. This in fact, influences multiple cyclins and CDKis, however, impairment of this capability during cell cycle progression may not underlie CIZ1s role in tumorigenesis. Our central finding is that altered cell cycle homeostasis in CIZ1 null cells does not lead to checkpoint activation, until they are driven to contact induced quiescence. 1 Copeland et al (2010) J Cell Sci 123, 1108-15 2 Warder &amp; Keherly (2003) J Biomed Sci.10, 406-17 3 Rahman et al (2007) Human Mutation 28, 993-1004 4 Higgins et al (2012) Proc Natl Acad Sci U S A 109, E3128-35 5 den Hollander et al (2006) Cancer Research 66, 11021-30 6 Nishibe et al (2013) FEBS Lett 587, 1529-35 Citation Format: Rosemary H.C Wilson, Jo-An Roulson, Sumia Bageghni, Ghadeer Albadrani, Justin F-X Ainscough, Dawn Coverley. Quiescence induced checkpoint activation in the absence of CIZ1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5096. doi:10.1158/1538-7445.AM2014-5096

Follicular Lymphoma In Young Adults: Clinical Characteristics and Early Treatment Outcomes

IntroductionAdolescents and young adults with hematologic malignancies have distinct tumor biology, treatment outcomes and psychosocial consequences from cancer diagnosis and its treatment. Follicular lymphoma (FL) is generally considered to be a disease of the elderly, with a median age at diagnosis of 67 years and 65% of patients 60 years or older. FL is rare among young adults (age<40, YA), and the clinical features, natural history and treatment outcomes have not been well defined in this vulnerable patient population, who have unique life challenges while facing what is often considered an incurable lymphoma. We describe the characteristics and outcomes of a large group of YA with newly diagnosed FL treated at our center and compare them to older patients MethodsThe Princess Margaret Cancer Centre lymphoma database was interrogated for patients registered with FL between 1995 and 2009. Database and retrospective chart review was undertaken to collect data on FLIPI score at diagnosis, time to first and subsequent second treatments, histologic transformation and overall survival (OS). Outcomes were compared between YA and older patients (age 40-65). The older age group was limited to< 65 years to ensure comparable therapies, and because patients in this age range may be potentially eligible for intensive therapy including stem cell transplantation. Results410 patients with newly diagnosed FL were identified. Stage at diagnosis: I:34.1%; II: 18.3%, III: 21%, IV: 26.7%; FLIPI score: 0 22.9%, 1: 25.8%, 2: 32.8%, 3: 15%, 4: 2.6%, 5: 1%. Fifty five patients (13.4%) were age< 40 at diagnosis. Median age in the YA cohort was 36 years, and 53 years in the older adults. Chi-square testing showed no difference in sex, stage or FLIPI score at diagnosis between YA and older adults. Initial treatment consisted of observation in 105 patients (25.7%); 11 of those managed expectantly were YA. With median follow-up in the observed group of 7.3 years (range 0.68-14.64), 52.3% required therapy (radiation, chemotherapy or combined modality), with median time to therapy from diagnosis of 22 months. Among all patients eventually treated, intial treatment included chemotherapy alone in 37.4%, radiotherapy in 33.8% and combined modality therapy in 25.6%. The most common chemotherapy regimens were CHOP and CVP, alone or with rituximab.Probability of requiring second treatment following initial radiation or chemotherapy was 54.5% at 2 years. FLIPI score strongly predicted time to second treatment (0=0.0047). Time to second treatment was similar for those initially observed compared to those receiving treatment at time of diagnosis, and for young compared to older adults.For the entire cohort, with median follow-up of 8.1 years (range 0.34-17.75), 5-year OS was 86.9%. On univariable analysis there was a significant difference in survival between YA and older patients: 10-year OS 89.3% v 74.2%, p=0.04. On analysis of lymphoma-specific death, there was lower probability of death in YA at 10 years: 4% compared to 15.3% for older adults, although this was not statistically significant (p=0.088).There was no significant difference in survival for patients initially observed compared to those receiving therapy at diagnosis (10-year OS 82.9% v 74%, respectively, p=0.18). Multivariable analysis demonstrated that FLIPI score at diagnosis and age<40 were significant independent variables predictive of OS. Furthermore, despite lack of significance on univariable analysis, in this model patients managed initially with observation had significantly improved OS compared to patients treated at diagnosis with radiation, chemotherapy or both (HR 2.05, p=0.0223). Histologic transformation occurred in 53 patients, 8 in YA (14.5% of all YA) and 45 in the older cohort (12.7% of all older patients). ConclusionsYA with follicular lymphoma present with similar clinical characteristics to older patients, and comparable proportions of patients requiring therapy at diagnosis for symptomatic disease. YA demonstrate improved OS independent of FLIPI score compared to older adults. Whether this reflects competing mortality risks or age-related differences in lymphoma biology warrants further investigation. Disclosures:Kuruvilla:Roche: Honoraria. Kukreti:Millennium Pharmaceuticals: Research Funding; Onyx: Research Funding. Tiedemann:Celgene: Honoraria; Janssen: Honoraria. Crump:Roche: Honoraria; Jansen-Ortho: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Seattle Genetics: Honoraria.

Follicular lymphoma in young adults: a clinicopathological and molecular study of 200 patients

Follicular lymphoma is clinically heterogenous, and therefore necessitates the identification of prognostic markers to stratify risk groups and optimize clinical management. It is relatively rare in patients younger than 40 years, and the clinicopathologic characteristics and biological behavior in this age group are poorly understood. In the current study, samples from a cohort of 200 patients between 19 and 40 years were evaluated retrospectively with respect to clinical, histologic, and genetic features. These were then correlated with clinical outcome. The median age at presentation was 35 years with a slight female prepoderance (56%). Most of the cases are presented with nodal disease (90%). Concomitant follicular lymphoma and diffuse large B-cell lymphoma were observed in 7 (4%) patients. Immunohistologic studies showed the expression of CD10 (91%), BCL6 (97%), BCL2 (95%), MUM1/IRF4 (12%), MDM2 (17%), and CD23 (25%). BCL2 rearrangement was present in 74%, and BCL6 in 20%. The estimated overall survival of patients was 13 years (mean). The presence of anemia, elevated lactose dehydrogenase, bone marrow involvement, and high-risk follicular lymphoma international prognostic index correlated with adverse overall survival. Our findings revealed that follicular lymphoma in young adults demonstrate similarities with that of older adults, including the frequency of presentation at various anatomic sites, grade, and adverse prognostic factors.

Health-Related Quality of Life After Treatment of Hodgkin Lymphoma in Young Adults

To describe changes in health-related quality of life (HRQOL) and to identify supportive care services used after treatment for Hodgkin lymphoma (HL) in young adults. A longitudinal, repeated-measures study design was used to test the feasibility of data collection at the conclusion of treatment for HL and at one, three, and six months post-treatment. Participants were identified from two large comprehensive cancer centers in New England. 40 young adults with newly diagnosed HL were enrolled in the study prior to the completion of chemotherapy or radiation. Data were collected by interviews, standardized questionnaires, and medical record reviews. HRQOL variables defined as symptom distress, functional status, emotional distress, and intimate relationships; use of specific supportive care services; and baseline demographic and disease-related information. Results indicate that symptom distress improved at one month post-treatment and remained low at three and six months. Similarly, functional status improved at one month post-treatment. Only 13% of the sample had significant emotional distress at baseline, and this decreased to 8% over time. Patients placed high value on their intimate relationships (i.e., family and friends or sexual partners). A variety of supportive care services were used after treatment, the most common of which were related to economic issues. However, by six months post-treatment, services shifted toward enhancing nutrition and fitness. The results from this study suggest that HRQOL in young adults with HL improved one-month post-treatment and that interest in using supportive care services was high. Facilitating the use of supportive care services at the end of cancer treatment appears to be an important part of helping young adults transition to survivorship. Supportive care services appear to be a vital component of the transition to survivorship and often change over time from an emphasis on economic issues to enhancing wellness through nutrition and fitness programs.

Flow Cytometry as a Diagnostic Tool in the Early Diagnosis of Aggressive Lymphomas Mimicking Life-Threatening Infection

Aggressive lymphomas can present with symptoms mimicking life-threatening infection. Flow cytometry (FC) is usually recommended for the classification and staging of lymphomas in patients with organomegaly and atypical cells in effusions and blood, after the exclusion of other possible diagnoses. FC may also have a place in the initial diagnostic investigation of aggressive lymphoma. Three cases are presented here of highly aggressive lymphomas in young adults, which presented with the clinical picture of fever of unknown origin (FUO) in patients severely ill. All followed a life-threatening clinical course, and two developed the hemophagocytic syndrome (HPS), but microbiological, immunological, and morphological evaluation and immunohistochemistry (IHC) failed to substantiate an early diagnosis. FC was the technique that provided conclusive diagnostic evidence of lymphoma, subsequently verified by IHC. Our experience with these three cases highlights the potential role of FC as an adjunct methodology in the initial assessment of possible highly aggressive lymphoma presenting with the signs and symptoms of life-threatening infection, although the definitive diagnosis should be established by biopsy. In such cases, FC can contribute to the diagnosis of lymphoma, independently of the presence of HPS.

Tonsillar Lesions of Infectious Mononucleosis Resembling MALT Type Lymphoma. A Report of Two Cases

Infectious mononucleosis (IM) is an acute lymphoproliferative disorder that typically occurs in young patients and is usually caused by Epstein-Barr virus. We report here, two cases of tonsillar lesion of IM resembling marginal zone B-cell lymphoma mucosa-associated lymphoid tissue (MALT) type. The patients consisted of an 18-year-old Japanese woman and a 36-year-old Japanese man. Both patients presented with tonsillar mass. Histologically, in one case, the tonsil showed diffuse proliferation of medium-sized lymphocytes. The medium-sized lymphocytes had round or slightly indented nuclei with a small solitary nucleoli and abundant clear cytoplasm and somewhat resembled monocytoid B-cells. In the remaining one case, the lymphoid follicles had hyperplastic germinal centers with ill-defined borders surrounded by a sheet-like proliferation of polymorphous infiltration showing a marginal zone distribution pattern. On high-power field, the interfollicular area was diffusely infiltrated by a polymorphous infiltrate of medium-sized lymphocytes with angulated nuclei somewhat resembling centrocyte-like cells, immunoblasts, plasma cells, plasmacytoid cells and histiocytes with or without epithelioid cell feature. However, there were no CD43+ B-cells in either lesion. Moreover, the polytypic nature of the B-cells was demonstrated by immunohistochemistry or polymerase chain reaction. Although MALT type lymphoma rarely affected young adults, notably, a number of cases have been reported in the tonsil. The present two cases indicated that acute IM should be added to the differential diagnosis for MALT type lymphoma in young adults.

Association of Killer Cell Immunoglobulin-Like Receptor Genes with Hodgkin's Lymphoma in a Familial Study

BackgroundEpstein-Barr virus (EBV) is the major environmental factor associated with Hodgkin's lymphoma (HL), a common lymphoma in young adults. Natural killer (NK) cells are key actors of the innate immune response against viruses. The regulation of NK cell function involves activating and inhibitory Killer cell Immunoglobulin-like receptors (KIRs), which are expressed in variable numbers on NK cells. Various viral and virus-related malignant disorders have been associated with the presence/absence of certain KIR genes in case/control studies. We investigated the role of the KIR cluster in HL in a family-based association study.MethodologyWe included 90 families with 90 HL index cases (age 16–35 years) and 255 first-degree relatives (parents and siblings). We developed a procedure for reconstructing full genotypic information (number of gene copies) at each KIR locus from the standard KIR gene content. Out of the 90 collected families, 84 were informative and suitable for further analysis. An association study was then carried out with specific family-based analysis methods on these 84 families.Principal FindingsFive KIR genes in strong linkage disequilibrium were found significantly associated with HL. Refined haplotype analysis showed that the association was supported by a dominant protective effect of KIR3DS1 and/or KIR2DS1, both of which are activating receptors. The odds ratios for developing HL in subjects with at least one copy of KIR3DS1 or KIR2DS1 with respect to subjects with neither of these genes were 0.44[95% confidence interval 0.23–0.85] and 0.42[0.21–0.85], respectively. No significant association was found in a tentative replication case/control study of 68 HL cases (age 18–71 years). In the familial study, the protective effect of KIR3DS1/KIR2DS1 tended to be stronger in HL patients with detectable EBV in blood or tumour cells.ConclusionsThis work defines a template for family-based association studies based on full genotypic information for the KIR cluster, and provides the first evidence that activating KIRs can have a protective role in HL.

Childhood Social Environment and Hodgkin's Lymphoma: New Findings from a Population-Based Case-Control Study

AbstractBackground: Risk of Hodgkin's lymphoma in young adults has previously been associated with higher childhood socioeconomic status (SES) and other markers of delayed infection with common childhood pathogens, especially the Epstein-Barr virus. This study examines the current role of childhood social environment in the development of Hodgkin's lymphoma. Methods: A population-based case-control study of 565 Hodgkin's lymphoma cases and 679 controls was conducted in the Boston, MA metropolitan area and the state of Connecticut to investigate the viral etiology of Hodgkin's lymphoma. Results: A novel association was detected between attendance of nursery school or day care and reduced risk of Hodgkin's lymphoma among individuals ages 15 to 54 years. The odds ratio (95% confidence interval) for having attended preschool for at least 1 year was 0.64 (0.45-0.92). Risk of young-adult Hodgkin's lymphoma was also associated with family history of hematopoietic cancer, Jewish ethnicity, and cigarette smoking. Other indicators of childhood SES were not associated with young-adult Hodgkin's lymphoma. Among older adults ages 55 to 79 years, Hodgkin's lymphoma was associated with lower childhood SES but not with preschool attendance. Conclusions: Early exposure to other children at nursery school and day care seems to decrease the risk of Hodgkin's lymphoma in young adults, most likely by facilitating childhood exposure to common infections and promoting maturation of cellular immunity. This finding supports the delayed infection model of Hodgkin's lymphoma etiology in young adults while introducing a new major determinant of age at infection. Hodgkin's lymphoma seems to have a separate pathogenesis among older adults.

Familial clustering of Hodgkin lymphoma and multiple sclerosis.

Epidemiologic similarities between Hodgkin lymphoma in young adults (i.e., between 15 and 44 years old) and multiple sclerosis have led to the suggestion that these diseases may have related etiologies. Previous investigations have not supported this hypothesis, but the negative results could have been caused by methodologic problems. We therefore assessed the risk of developing Hodgkin lymphoma for patients with multiple sclerosis and for their families and the risk of developing multiple sclerosis for patients with Hodgkin lymphoma and for their families. We identified 11,790 patients with multiple sclerosis and 19,599 of their first-degree relatives in Danish population-based registers and followed them for the occurrence of Hodgkin lymphoma. Analogously, we identified 4381 patients with Hodgkin lymphoma and 7388 of their first-degree relatives and followed them for the occurrence of multiple sclerosis. The relative risks (RRs) of Hodgkin lymphoma and multiple sclerosis were expressed as standardized incidence ratios (i.e., the ratio between observed and expected numbers of outcomes based on age, sex, and period-specific incidence rates). All statistical tests were two-sided. Overall, six cases of Hodgkin lymphoma were identified in patients with multiple sclerosis (RR for Hodgkin lymphoma = 1.40, 95% confidence interval [CI] = 0.63 to 3.12), two of which occurred in young adults (RR = 1.59, 95% CI = 0.40 to 6.37). The risk of young-adult-onset Hodgkin lymphoma was statistically significantly increased in the first-degree relatives of patients with multiple sclerosis (RR = 1.93, 95% CI = 1.01 to 3.71; n = 9 such lymphomas). Two cases of multiple sclerosis were identified among young adult patients with Hodgkin lymphoma (RR for multiple sclerosis = 0.82, 95% CI = 0.20 to 3.27), and the risk for multiple sclerosis was statistically significantly increased in their first-degree relatives (RR = 2.76, 95% CI = 1.44 to 5.31; n = 9 such multiple sclerosis cases). The observed familial clustering of multiple sclerosis and young-adult-onset Hodgkin lymphoma is consistent with the hypothesis that the two conditions share environmental and/or constitutional etiologies.

Characteristics of Hodgkin's Lymphoma after Infectious Mononucleosis

Infectious mononucleosis-related Epstein-Barr virus (EBV) infection has been associated with an increased risk of Hodgkin's lymphoma in young adults. Whether the association is causal remains unclear. We compared the incidence rates of Hodgkin's lymphoma in two population-based Danish cohorts of patients who were tested for infectious mononucleosis: 17,045 with serologic evidence of having had acute EBV infection, and 24,614 with no such evidence. We combined the cohort of patients who had serologically verified infectious mononucleosis with a cohort of 21,510 Swedish patients with infectious mononucleosis (combined total, 38,555). Biopsy specimens of Hodgkin's lymphomas occurring during follow-up in this combined cohort were tested serologically for the presence of EBV. Using this information, we modeled the relative risk of EBV-negative and EBV-positive Hodgkin's lymphoma in different periods after the diagnosis of infectious mononucleosis and estimated the median incubation time for mononucleosis-related EBV-positive Hodgkin's lymphoma. Only serologically confirmed infectious mononucleosis was associated with a persistently increased risk of Hodgkin's lymphoma. Sixteen of 29 tumors (55 percent), obtained from patients with infectious mononucleosis, had evidence of EBV. There was no evidence of an increased risk of EBV-negative Hodgkin's lymphoma after infectious mononucleosis. In contrast, the risk of EBV-positive Hodgkin's lymphoma was significantly increased (relative risk, 4.0; 95 percent confidence interval, 3.4 to 4.5). The estimated median incubation time from mononucleosis to EBV-positive Hodgkin's lymphoma was 4.1 years (95 percent confidence interval, 1.8 to 8.3). A causal association between infectious mononucleosis-related EBV infection and the EBV-positive subgroup of Hodgkin's lymphomas is likely in young adults.