Nodular Sclerosis Hodgkin Lymphoma Research Articles

Dual Time Point FDG-PET/CT Imaging Can Distinguish Between Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma

▪Introduction: 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) has become a standard of care imaging modality for multiple types of lymphoma, including Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL). However, many applications of PET/CT in lymphomas have not yet been explored. We investigated whether dual time point (DT) PET/CT would detect more sites of disease due to improved tumor to background ratio. It has also been reported that inflammatory lesions have decreased FDG accumulation over time, whereas malignant lesions accumulate FDG over time, becoming more FDG-avid. Histologically, HL lesions are predominantly composed of inflammatory cells and relatively few tumor cells. This tumor composition calls into question whether HL will behave as a malignancy or as an inflammatory lesion on DT PET/CT imaging compared to DLBCL and whether changes in FDG accumulation over time on DT PET/CT imaging will differ between HL and DLBCL.Methods: Patients (pts) with untreated, biopsy-confirmed, nodular sclerosing HL and DLBCL were prospectively enrolled on this clinical trial (clinicaltrials.gov NCT01004718). Pts with uncontrolled diabetes, active infection, and primary mediastinal large B-cell lymphoma were excluded. Following injection of FDG, pts underwent PET/CT at 60 minutes (DT60) and 180 minutes (DT180). Any lesion with a Deauville Score of 4-5 was considered positive (i.e. FDG uptake > liver at any site) (Meignan, Leuk Lymphoma 2012). SUVmax, SUVmean, and tumor to background ratio, defined as lesion SUVmax / liver SUVmean, were calculated for each lesion. Software using an automatic adaptive thresholding method (ROVER, ABX GmbH) was also used to measure the metabolically active volume (MAV) of lesions on PET images. Mean metabolic volumetric product (MVPmean) was calculated as MVPmean = SUVmean * MAV for each lesion, and total MVPmean for a given pt was calculated as the sum of MVPmean for all lesions.Results: 160 total lesions (78 lesions with DT60 and 82 lesions with DT180 images) were evaluated in this prospective study of 20 paired PET/CT scans in 10 pts. Five pts had HL and 5 had DLBCL. Median age was 51; 5 pts were men. Pts with DLBCL had higher SUVmax values at both 60 and 180 minutes than HL (DT60: DLBCL 22.4 v HL 10.8, p = 0.0007, t test; DT180: DLBCL 31.6 v HL 14.6, p = 0.0006, t test) as well as a higher average SUVmean than HL at both time points (DT60: DLBCL 9.2 v 4.5, p = 0.009 t test; DT180: DLBCL 12.7 v 5.8, p = 0.02 t test). We also observed that the average %change in tumor to background ratio for HL increased from DT60 to D180 by 75% whereas the %change in tumor to background ratio for DLBCL increased by 34% (p = 0.0001, t-test). DT180 detected 4 additional lesions that were not apparent on DT60; 3 lesions were in HL and 1 in DLBCL. The locations of these lesions were mesenteric, lung, external iliac, and subclavian regions. For each pt, %change in total MVPmean between DT60 and DT180 was higher in DLBCL (p=0.02, rank sum). Of interest, the %change in MAV between DT60 and DT180 decreased in HL compared to slight increase in DLBCL (HL 12% decrease v. DLBCL 2% increase in MAV). Thus, changes in MAV accounted for the difference detected in %change in total MVPmean between these histologies. There was no difference between HL and DLBCL in %change in SUVmean or %change in SUVmax.Conclusions: We report the first prospective study of dual time point PET/CT imaging of lymphomas, as well as the first study to specifically compare dual time point imaging of DLBCL and HL. Our results indicate that lesions of DLBCL are generally more FDG-avid than HL when measured as either SUVmax or SUVmean at 60 and 180 minutes. When measured as %change in total MVPmean, DLBCL accumulates significantly more FDG than HL, consistent with the differences in histologic composition of these tumors. Computerized algorithms for generation of MAV and SUVmean add additional information not reflected in measurement of SUVmax alone that may be useful for distinguishing between tumor histologies. Given variation between histologies, optimal timing of image acquisition for detection of lesions may be improved by choosing an imaging time point that optimizes tumor to background ratio. Tumor to background ratio is improved, especially for HL, with use of imaging that occurs at 180 minutes, and we demonstrate the ability to detect additional lesions not detected at 60 minutes. DisclosuresNo relevant conflicts of interest to declare.

Bulky Disease Does Not Adversely Affect Overall Survival in Early Stage Hodgkin Lymphoma: Role of Interim PET and Possible Omission of Radiotherapy in Select Patients

Background: Bulky disease is considered a major driver of unfavorable prognosis in early stage Hodgkin Lymphoma (HL). Treatment guidelines for bulky early stage HL call for more aggressive initial therapy compared to non-bulky disease. There are limited data on outcomes in bulky disease, particularly in patients treated with chemotherapy alone, or on the utility of interim PET scans. We retrospectively analyzed data on patients with early stage HL to assess the impact of disease bulk, interim PET and treatment modality on outcomes.Methods: We reviewed charts of 151 consecutive patients diagnosed with previously untreated early stage (I & II) HL at the Cleveland Clinic from 1995-2011. Bulky disease was defined as a mediastinal mass >1/3 intra-thoracic diameter on PA chest x-ray or any mass ≥ 10 cm on CT scan at diagnosis. Patients were grouped by intent to treat strategy as chemotherapy alone (C) or combined modality treatment (CMT) with chemo-radiation. Baseline characteristics were compared: categorical variables by the Chi-square or Fisher’s exact test; continuous variables by the Wilcoxon rank sum test. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method and compared by the log-rank test. Cox proportional hazards analysis was used to test univariable prognostic factors for OS and PFS.Results: 121 patients (mean age 40±16) with early stage HL had adequate clinical data for inclusion. At the time of review, 106 (87.6%) patients were alive with median follow-up of 47.4 (0-328) months. Characteristics at diagnosis were: 54% female; 80% Caucasian; 77% nodular sclerosis HL; 78% stage II; 31% with B-symptoms; 12% with extranodal disease; 30% (N =36) with bulky disease of whom 89% had bulky mediastinal disease. 96% patients received standard ABVD chemotherapy.The only significant differences in the baseline characteristics of patients with bulky vs. non-bulky disease were age (mean 35 vs. 42 years, P=0.03), hemoglobin (mean 12.4 vs. 13.4 g/dL, P=0.01) and absolute lymphocyte count (mean 1.29 vs. 1.71 k/µL, P=0.02). Although there was no statistically significant difference in the initial treatment strategy chosen, patients with bulky disease tended to receive CMT more often than patients with non-bulky disease (66% vs. 51%, P=0.16). More females were treated with C compared to CMT (70% vs. 43%, P=0.004). Patients with bulky disease received a greater number of chemotherapy cycles (mean 5.6 vs. 4.6, P=0.01).Five years after diagnosis, patients with non-bulky HL had Kaplan-Meier estimates of 83% OS and 69% PFS while patients with bulky HL had 88% OS and 81% PFS. There was no statistical difference in OS [Figure 1] or PFS based on disease bulk.Analysis of the available PET status (65 interim scans) revealed that both the bulky and non-bulky patients had comparable responses on interim PET (negative 82.6% vs. 95.2%, P=0.17). Interim PET scan was highly prognostic for all early stage HL patients for both OS (P < 0.01) and PFS (P < 0.001) as well as specifically for patients with bulky disease (negative vs. positive PET: 5 year OS 90% vs. 75%, P=0.012; 5 year PFS 95% vs. 25%, P<0.01 [Figure 2]).Among the 23 patients with bulky disease managed with initial CMT, 4 required 2nd line treatment including 3 who underwent autologous stem cell transplant (Auto-SCT). Among the 12 patients managed initially with C, 5 required 2nd line treatment and all 5 underwent Auto-SCT. In total, among those with bulky disease, the OS and PFS were similar irrespective of initial treatment strategy chosen.In univariate analysis, extra-nodal disease was the only baseline variable that impacted PFS (HR=2.7, CI 1.01-7.20, P=0.048) but did not affect OS (HR=2.46, CI 0.66-9.19, P=0.18).Conclusions: Patients with bulky early stage HL have comparable survival to patients with non-bulky disease. Among patients with bulky disease, treatment with initial C or CMT resulted in comparable OS and PFS, although a higher proportion of patients treated with C alone required 2nd line treatment. These data support the observation that radiation therapy is not essential to achieve cure in bulky HL. Specifically, omitting radiation in female patients who achieve a negative interim PET scan is a viable treatment strategy which may mitigate the long-term risks of radiation. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Meta-Analysis of Hodgkin Lymphoma and Asthma Genome-Wide Association Scans reveals common variants in GATA3

Both Hodgkin lymphoma (HL) and asthma are associated with relative isolation from early childhood infectious exposures (hygiene hypothesis) and a T-helper-2 (Th2)-skewed immune response. To test the hypothesis that there is some component of shared genetic etiology between HL and asthma, we examined the genetic overlap in data from genome-wide association study (GWAS) meta-analyses of the two diseases conducted in populations of European ancestry. The HL GWAS meta-analysis consisted of 1,816 HL cases and 7,877 controls, and the asthma GWAS meta-analysis consisted of 2,088 asthma cases and 2,743 controls. The combined HL-asthma GWAS data resulted in 904,634 common single nucleotide polymorphisms (SNPs) genotyped with both arrays. We observed a total of 9 common SNPs associated with both HL and asthma at p<0.0001, compared to 3 SNPs expected in both data sets at that significance level. Out of 66 genetic risk variants associated with HL at a genome-wide significance level of p<10-8, 5 variants replicated in the asthma GWAS dataset at p < 0.05. In a meta-analysis combining the HL and asthma GWAS data, we found genome-wide significant associations with two correlated SNPs (r2 =0.91) in the Th2 transcription factor gene GATA3 (rs422628, ORHL-asthma meta =1.25, p=3.36 x 10-9 and rs444929, ORHL-asthma meta = 1.26, p=2.09 x 10-8) that were not genome-wide significant in either disease alone (Table 1). The association with one SNP remained genome-wide significant in the meta-analysis combined with the nodular sclerosis subset (rs422628, ORHL-asthma meta =1.32, p=3.75 x 10-9), but not with other HL subtypes. An association with a SNP in IKZF3, a gene involved in B lymphocyte differentiation and proliferation, reached genome-wide significance only in the meta-analysis with the HL subset positive for Epstein-Barr virus (EBV) in the tumor (rs9909593, ORHL-asthma meta = 1.19, p=3.80 x 10-8). In a genetic diseasome analysis based on an ontological analysis of published GWAS data, HL, especially nodular sclerosis HL, was more closely related to asthma than to solid cancers. Recognition of overlap in genetic predisposition to HL and other immune diseases sheds light on the complex etiology of HL and may enable novel diagnostic and therapeutic approaches.Abstract 135. Table 1Genome-wide significant results of a meta-analysis combining Hodgkin lymphoma (HL) and asthma GWAS1data.HL GWAS1Asthma GWAS1Combined GWAS1SNP2Chr3BP4GeneOR5P-value6OR5P-value6OR5P-value6rs422628a108151415GATA31.241.13 x 10-51.316.39 x10-51.253.26 x 10-9rs444929b108150030GATA31.263.24x 10-61.288.90 x 10-41.262.09 x 10-8rs422628c108151415GATA31.337.77 x 10-61.316.39 x10-51.323.75 x 10-9rs9909593d1735223675IKZF31.112.60 x 10-11.255.06 x 10-81.193.80 x 10-81Genome-wide association scan2Single nucleotide polymorphism3Chromosome4Base pair position5Odds ratio6P-values are derived from a meta-analysis using a fixed effects model with weights proportional to the square root of the number of cases.aAll Hodgkin lymphoma casesbAll Hodgkin lymphoma cases, SNP association reported in Cozen et al., Nat Comm, 2014cNodular sclerosis cases onlydEBV-positive cases only DisclosuresNo relevant conflicts of interest to declare.

A prospective study of mediastinal gray-zone lymphoma

AbstractMediastinal B-cell lymphomas present in the mediastinum and are most frequent in young patients. Nodular sclerosis Hodgkin lymphoma (NSHL) and primary mediastinal B-cell lymphoma (PMBL) are the common types, whereas mediastinal gray-zone lymphoma (MGZL) is extremely rare and has pathological features intermediate between NSHL and PMBL. The indeterminate pathobiology of MGZL has led to uncertainty regarding therapeutic strategy, and its clinical characteristics and treatment have not been characterized. We conducted a prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim in untreated MGZL. We analyzed biomarkers of outcome and compared their clinical and biological characteristics to PMBL. Twenty-four MGZL patients had a median age of 33 years (range, 14 to 59 years), and 46% had mediastinal masses ≥10 cm. At 59 months median follow-up, the event-free survival and overall survival were 62% and 74%, respectively. The serum absolute lymphocyte count, the presence of tumor-infiltrating dendritic cells, CD15 expression on the malignant cells, and tumor morphology were biomarkers of outcome in MGZL. Compared with PMBL, MGZL patients were more likely to be male, express CD15, have lower expression of CD20, and have a worse outcome. DA-EPOCH-R alone is effective in MGZL. The trial was registered at ClinicalTrials.gov (NCT00001337).

Hodgkin lymphoma: 2014 update on diagnosis, risk‐stratification, and management

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 9,200 new patients annually and representing approximately 11.5% of all lymphomas in the United States. HL is composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte-predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL. An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography scan, are used to optimize therapy. Initial therapy for HL patients is based on the histology of the disease, the anatomical stage, and the presence of poor prognostic features. Patients with early stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by involved-field radiation therapy, while those with advanced stage disease receive a longer course of chemotherapy often without radiation therapy. Management of relapsed/refractory disease: High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, palliative chemotherapy, nonmyeloablative allogeneic transplant, or participation in a clinical trial should be considered.

Indoleamine 2,3-dioxygenase (IDO) is frequently expressed in stromal cells of Hodgkin lymphoma and is associated with adverse clinical features: a retrospective cohort study.

BackgroundRegulation of tumor microenvironment is closely involved in the prognosis of Hodgkin lymphoma (HL). Indoleamine 2,3-dioxygenase (IDO) is an enzyme acting as immune modulator through suppression of T-cell immunity. This study aims to investigate role of IDO in the microenvironment of HL.MethodsA total of 121 cases of HL were enrolled to do immunohistochemistry for IDO, CD163, CD68, CD4, CD8, and FoxP3. Positivity was evaluated from area fractions or numbers of positive cells using automated image analyzer. Correlations between IDO expression and various cellular infiltrates and clinicopathologic parameters were examined and survival analyses were performed.ResultsIDO was expressed in histiocytes, dendritic cells and some endothelial cells with variable degrees, but not in tumor cells. IDO positive cells were more frequently found in mixed cellularity type than other histologic types, and in cases with EBV+, high Ann Arbor stages, B symptoms, and high IPS (all p < 0.05). High IDO expression was associated with inferior survival (p < 0.001) and reflects an independent prognostic factor in nodular sclerosis HL.ConclusionsThis is the first study suggesting that IDO is the principle immunomodulator and is involved to adverse clinical outcomes of HL.

Hodgkin lymphoma incidence in California Hispanics: influence of nativity and tumor Epstein-Barr virus.

For classical Hodgkin lymphoma (HL), migrant studies could elucidate contributions of environmental factors (including Epstein-Barr virus (EBV)) to the lower rates in non-whites. Given the well-described etiologic complexity of HL, this research requires a large, immigrant population, such as California Hispanics. With 1988-2004 California Cancer Registry data (2,595 Hispanic, 8,637 white HL cases) and tumor cell EBV status on a subset (218 Hispanics, 656 whites), we calculated ethnicity- and nativity-specific HL incidence rates simultaneously by age, sex, and histologic subtype, and tumor cell EBV prevalence. Compared with white rates, Hispanic HL rates were lower overall (70 %) and for nodular sclerosis HL, particularly among young adults (60-65 % for females). However, they were higher among children (200 %) and older adults, and for mixed cellularity HL. Compared with rates in foreign-born Hispanics, rates in US-born Hispanics were higher among young adults (>threefold in females), lower for children and adults over age 70, and consistently intermediate compared with rates in whites. EBV tumor prevalence was 67, 32, and 23 % among foreign-born Hispanics, US-born Hispanics, and whites, respectively, although with variation by age, sex, and histology. Findings strongly implicate environmental influences, such as nativity-related sociodemographic differences, on HL occurrence. In addition, lower young adult rates and higher EBV prevalence in US-born Hispanics than in whites raise questions about the duration/extent of environmental change for affecting HL rates and also point to ethnic differences in genetic susceptibility. Lesser variation in mixed cellularity HL rates and greater variation in rates for females across groups suggest less modifiable factors interacting with environmental influences.

Primary refractory Hodgkin lymphoma: Limited options and poor survival—but not always

Primary refractory Hodgkin lymphoma: Limited options and poor survival—but not always

Guidelines for the first line management of classical Hodgkin lymphoma

The guideline group was selected to be representative of UK-based medical experts and patients’ representatives. MEDLINE and EMBASE were searched systematically for publications in English from January 1990 to June 2013 using the key words Hodgkin, Lymphoma, Treatment, Chemotherapy and Radiotherapy. References from relevant publications were also searched. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-Oncology Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of approximately 50 UK haematologists and the BCSH and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with classical Hodgkin Lymphoma (HL). The guidance may not be appropriate for all patients with HL and in all cases individual patient circumstances may dictate an alternative approach.

Lymphoid neoplasm incidence by WHO subtype in Australia 1982–2006

There are limited data characterizing the subtype-specific incidence of lymphoid neoplasms in the World Health Organization (WHO) Classification era. Data were obtained on all incident lymphoid neoplasms registered in Australia during 1982-2006. Subtypes were grouped using the InterLymph nested hierarchical classification, based on the 2008 WHO Classification. Temporal trends were examined using Joinpoint regression; average annual percentage change in incidence was computed. Multiple Poisson regression was used to compare incidence by sex and age. The incidence of all non-Hodgkin lymphoma (NHL) increased by 2.5%/year during 1982-1996 and was stable thereafter. During 1997-2006, several mature B- and natural killer (NK)-/T-cell NHL subtypes increased in incidence, including diffuse large B-cell (1.3%/year), follicular (2.5%/year), Burkitt (6.8%/year), marginal zone (13.2%/year), mantle cell (4.2%/year), peripheral T-cell lymphoma (4.7%/year) and plasmacytoma (7.1%/year). While chronic lymphocytic leukemia incidence was stable, small lymphocytic lymphoma incidence declined (8.1%/year). Hodgkin lymphoma (HL) incidence increased during 1997-2006 (2.2%/year), both classical (4.3%/year) and nodular lymphocyte predominant (12.1%/year) HL. Diagnostic artifact, evidenced by a sustained decline in the incidence of NHL not otherwise specified (NOS; 5.8%/year) and lymphoid neoplasms NOS (5.6%/year), limits the interpretation of temporal trends for some subtypes. A marked male predominance was observed for almost all subtypes. Incidence of mature B- and NK-/T-cell NHL subtypes increased sharply with age, except for Burkitt lymphoma/leukemia. For HL subtypes, a bimodal age distribution was only evident for nodular sclerosis HL. Variation in incidence patterns over time and by sex and age supports etiological differences between lymphoid neoplasm subtypes.

Grey-Zone lymphomas: the fear of all lymphoma pathologists

Grey-zone lymphomas (GZLs) are operationally defined as lymphomas that show morphologic, immunophenotypic and frequently genetic overlap between two well-defined and accepted lymphoid entities. In 2008, the WHO defined two provisional categories, including mediastinal grey-zone lymphomas (MGZL) [biopsies showing overlapping features between primary mediastinal large cell lymphoma (PMBCL) and nodular sclerosis Hodgkin lymphoma (NSHL)] and cases that lie between diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma (BL). A third grey-zone also exists between cases of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and so-called T cell/ histiocyte-rich large B cell lymphoma (TCHRBCL). MGZLs are typically of two major types: one that resembles NSHL but shows a B cell phenotype, and cases that are PMBCL-like but reveal overlapping phenotypic features with Hodgkin lymphoma. Both clinical features and survival distinguish these cases from both PMBCL and NSHL. The GZLs between DLBCL and BL are more frequent and pose a diagnostic challenge. They are less well defined, but show an enrichment of cases harbouring MYC translocations with BCL2 and/or BCL6 rearrangements. Distinguishing these cases from de novo DLBCL has clinical relevance. Lastly, the GZ between TCHRBCL and NLPHL will be discussed using illustrative cases.

Classical hodgkin lymphoma (nodular sclerosis type) associated with langerhans cell histiocytosis: a case report on fine-needle aspiration cytologic features

Langerhans cell histiocytosis (LCH) can be associated with a variety of malignant neoplasms, the most common being malignant lymphoma, especially Hodgkin lymphoma (HL). In the present report we describe the fine needle aspiration (FNA) cytologic features of a case with concurrent LCH and HL in a lymph node. A 20-year-old man presented with an enlarged left upper cervical lymph node. FNA smears from the swelling revealed numerous CD1a+ and S-100+ Langerhans histiocytes (LCs) along with many eosinophils, neutrophils, and lymphocytes; there were also large atypical cells with enlarged nuclei having prominent nucleoli. The cytodiagnosis was LCH and the possibility of association with or trans-differentiation into a lymphoma was suggested. The histopathological diagnosis of the excised lymph node was classical Hodgkin lymphoma-nodular sclerosis type (CHL-NS) with LCH. The lacunar type Reed-Sternberg (RS) cells were positive for CD30 and CD15 while the LCs were positive for CD1a and S-100 protein. PET/CT imaging of vertex to mid-thigh demonstrated hypermetabolic lymph nodes in the neck, abdomen, thorax and pelvis as well as pulmonary nodules and a splenic mass. The patient received courses of chemotherapy and two years later, the enhanced CT of neck, chest, abdomen and pelvis revealed regressive course of the disease.

Changes In The Use Of Radiation Therapy Among Adolescents and Young Adults With Early Stage Classical Hodgkin Lymphoma: Implications For Survival and Risk Of Secondary Malignancies

BackgroundEarly stage classical Hodgkin lymphoma (HL) is a highly curable disease with the combined use of chemotherapy and radiation therapy (RT). There has been a recent trend to abandon RT, driven mostly by concerns of development of secondary malignancies (SMN). However, it is unknown whether the omission of RT in adolescents and young adults (AYA) with early stage HL affects survival and the risk of developing SMN. MethodsWe used data from the National Cancer Institute's Surveillance Epidemiology and End Results program (SEER-13) to determine the overall survival (OS) and the risk of SMN among AYA with early stage HL treated or not with radiation therapy. Inclusion criterion was the diagnosis of stage I or II HL in the period of 1995-2010 as first malignant neoplasm among patients age 13 to 40 years. Patients with less than 6 months of follow up and patients with unknown use of RT were excluded. Follow up was updated to the end of 2012 (November 2012 submission). Cases were divided in two “eras”, 1995-2002 and 2003-2010, with the latter being expected to reflect changes in the use of RT. The impact of the era, RT, age, race, gender, and stage on survival were accessed utilizing multivariate analysis. Cumulative incidence of SMN among early stage HL survivors was calculated using a competing risk model, treating death from any cause in absence of SMN as the competing risk. ResultsA total of 5,336 early stage HL cases were included in the analysis with median follow up of 89 months (range 7-191). Median age of patients was 27 years, 2,459 (46%) were male, 1,327 (24.8%) had stage I, 512 (9.7%) had classical HL non otherwise specified, 4,231 (79.2%) had nodular sclerosing HL, 442 (8.3%), had mixed-cellularity HL, 130 (2.4%) had lymphocyte-rich HL, and 21 (0.4%) had lymphocyte depleted HL. Most patients were white (4,438; 83.2%), 513 (9.6%) black, 337 (6.4%) other ethnicity, and 44 (0.8%) unknown. There where 2,793 patients in the 1995-2002 era and 2,542 patients in the 2003-2010 era. Radiation was included in the initial treatment of 1,659 (59.4%) patients in the former and 1,351 (53%) patients in the latter era (P<0.001). Factors associated with use of RT were earlier era, white race and stage II HL. Within the 1995-2002 era, there was a trend towards better survival among patients treated with RT (5-year survival 95.0% vs. 93.6%, P=0.058). In the 2003-2010 cohort survival was superior among patients treated with RT (5-year survival 97.3% vs. 95.9%, P=0.008). In multivariate analysis, diagnosis of HL in the 1995-2002 era (HR=1.73, 95% C.I. 1.31-2.28, P < 0.001), black race (HR= 2.18, 95% C.I. 1.63-2.91, P <0.001), male sex (HR=1.55, 97% C.I. 1.24-1.93, P < 0.001), and omission of RT (HR=1.31, 95% C.I. 1.05-1.64, P=0.017) were associated with higher mortality. The cumulative incidence of SMN was not significantly different between patients treated or not with radiation, while the risk of death was higher among patients not treated with RT (Figure). [Display omitted] ConclusionThere has been a reduction in utilization of RT among AYA with early stage HL in the US. Omission of RT was associated with increased overall mortality but no reduction in incidence of SMN and should not be adopted outside clinical trials. Disclosures:No relevant conflicts of interest to declare.

Thrombotic Thrombocytopenic Purpura Associated With Hodgkin Lymphoma

Introduction Thrombotic thrombocytopenic purpura (TTP) is characterized by microangiopathic hemolytic anemia and thrombocytopenia with usually less than &lt;5% ADAMTS13 (a disintegrin and metalloprotease with thrombospondin repeats) activity level. Hodgkin lymphoma (HL) comprises 10% of newly diagnosed lymphoma cases. Case Report A 45 year old healthy African American male presented with diffuse abdominal pain with associated nausea and constipation. Labs showed decreased hemoglobin, platelets, and haptoglobin with elevated bilirubin, lactate dehydrogenase, and creatinine. ADAMTS13 level was &lt;1%. Peripheral smear revealed schistocytes. CT imaging demonstrated multiple lesions of liver, pleura, and bone, as well as diffuse adenopathy, all later confirmed to be hypermetabolic by PET scan. Pleura biopsy suggested HL. TTP was diagnosed, prompting start of high dose prednisone and plasma exchange (PE). Labs normalized after 5 exchanges, allowing for outpatient steroid and PE tapers. A pleura biopsy was suspicious but not definitive for HL. Three weeks later, he was admitted for opioid-induced constipation. He was still on PE. Despite labs without evidence of TTP, his ADAMTS13 persisted at &lt;1%. A definitive excisional cervical lymph node biopsy yielded classical nodular sclerosing HL. Patient started systemic chemotherapy with doxorubicin, bleomycin, vincblastine, and dacarbazine (ABVD). PE was discontinued 7 days later. At follow-up 3 weeks from cycle #1, ADAMTS13 was 55% without evidence of TTP. Conclusion A 2012 review notes 4 cases of microangiopathic hemolytic anemia associated with HL, proposing an underlying immune component to this uncommon entity. Though rare, management of TTP associated HL can be challenging due to underlying cytopenias delaying systemic chemotherapy and yet refractoriness of ADAMTS13 to correct, portending a high risk of TTP relapse, without chemotherapy. Supportive measures to stabilize TTP and prompt initiation of chemotherapy can be an effective approach. Disclosures: No relevant conflicts of interest to declare.

KIR Gene Repertoire and Hodgkin Lymphoma In Children and Adolescents: A Children's Oncology Group Study

An infectious origin for pediatric Hodgkin lymphoma (HL) has long been suspected and Epstein-Barr virus (EBV) has been detected in ∼50% of tumors. Because EBV infections are ubiquitous, yet only a minute fraction of those infected develops HL, it follows that individual differences in the innate immune system response, including the identification and elimination of virus-infected and tumor cells by natural killer (NK) cells, may contribute to HL susceptibility. NK cell effector responses are modulated by the surface expression of various killer cell immunoglobulin-like receptors (KIR) and their binding to human leukocyte antigen (HLA) class I ligands on target cells. Importantly, the specific KIRs expressed on a given NK cell surface are determined in part by the highly polymorphic KIR genes on chromosome 19q13.4. There is considerable interindividual variability in the type and number of these genes, however, two regions of strong linkage disequilibrium have been identified, defining the centromeric and telomeric haplotype segments, which are flanked on each end by highly conserved genes and joined by a recombination hotspot. Accordingly, the haplotypes for a striking majority (≥93%) of individuals examined to date can be formed combinatorially from 3 common centromeric and 2 telomeric motifs.KIR gene content has been associated with pregnancy outcomes, response to infection, susceptibility to autoimmune disease, and malignancy. Few epidemiologic studies examining KIR genotype and lymphoid neoplasms (LN) have been conducted in children and adults. Generally, these studies have reported inverse associations between presence of activating KIR genes and susceptibility to LN. Given the strong likelihood for a viral etiology and the known correlations with HLA type, we performed for the first time a case-control study of the association between KIR gene content and pediatric/adolescent HL using archived samples.Cases (n=171) diagnosed with HL in 1989-2003 at 3-17 years of age at North American Children's Oncology Group institutions and healthy adult controls (n=332) provided peripheral blood or buccal cell samples. Presence/absence of KIR genes (KIR2DS2, KIR2DL2/2DL3, KIR2DL5, KIR2DS3, KIR2DS5, KIR2DL1, KIR3DS1/3DL1, KIR2DS1, KIR2DS4) was determined using a Luminex DNA-based sequence-specific oligonucleotide (SSO) typing methodology. Each individual's repertoire of genes was then classified into centromeric and telomeric KIR haplotype groups. Case haplotypes were compared to those of controls via unconditional logistic regression, resulting in odds ratios (ORs) and 95% confidence intervals (CIs) for the presence of one or two copies of a B haplotype (A/B and B/B) versus no copies (A/A), where B haplotypes encompass greater numbers of activating KIR. Associations were examined for HL overall, for the nodular sclerosis histologic subtype, and for the 3-9 and 10-17 year age groups.The presence of two centromeric B haplotype motifs was associated with development of pediatric and adolescent HL (OR=1.92, 95% CI: 1.12-3.26), but there was no evidence for an association with telomeric haplotypes. Similar results were observed for nodular sclerosis HL (OR=2.13, 95% CI: 1.02-4.43) and for the younger and older age groups (OR=1.80, 95% CI: 0.69-4.66; OR=1.76, 95% CI: 0.91-3.38), respectively.Our results suggest that activating centromeric KIR may play a role in increasing susceptibility to pediatric and adolescent HL. Although these findings differ from those of prior studies of adult HL and other LN, activating KIR have been positively associated with other virally-driven malignancies, such as nasopharyngeal and cervical carcinomas; underlying mechanisms have yet to be discovered. Examination of compound KIR-cognate HLA ligand genotypes is in progress; additional results will be presented. Disclosures:No relevant conflicts of interest to declare.

Obstructive Jaundice in Hodgkinʼs Lymphoma: A Diagnostic Dilemma

Purpose: Hodgkin's lymphoma is a disease that arises from B cells in the germinal or post-germinal center. It accounts for 11% of all lymphomas, and 0.55% of all cancers in the developed world. Involvement of the liver is not rare, though having liver involvement as part of the initial manifestations is uncommon, and occurs in less than 4% of the patients. Obstructive jaundice is most commonly caused by a mass compression of the common bile duct, though other causes may include lymphoma infiltration and vanishing bile duct syndrome. Case Presentation: The patient is a 43-year-old male with past medical history of HIV/AIDS, hypertension completely treated latent syphilis, and a recently diagnosed Hodgkin's lymphoma nodular sclerosis type, who was referred from his HIV clinic for diarrhea and yellowish discoloration of the sclera. He reported starting anti-retroviral therapy a month prior to presentation, and he developed watery diarrhea 1-2 weeks after initiating therapy. Along with the diarrhea, the patient developed gradually worsening yellowish discoloration of the skin and eyes, associated with cola-colored urine. The initial work-up showed severe hyperbilirubinemia mainly conjugated, though imaging with ultrasound of the liver, followed by contrasted abdominal CT and MRCP, were all within normal limits. The patient had a liver biopsy, which showed lymphoma involvement of the liver. Discussion: In a previous case series, the prevalence of initial liver involvement with lymphoma was 7.4%, with 1.4% of the cases having liver disease as the presenting symptom. It was more associated with the more aggressive lymphocytic depletion and mixed cellularity histologic types. In this case, the patient was diagnosed with lymphoma involvement of the liver, and improved on treatment with chemotherapy. Vanishing bile duct syndrome is a rare disorder that can be a paraneoplastic disorder associated with Hodgkin's disease. The diagnosis can be delayed, as usually, patients have normal cholangiography, and the ductopenia might be subtle on the liver biopsy.

Reed–Sternberg cells detected in the bone marrow aspirate in a young patient with nodular sclerosis Hodgkin lymphoma

A 19-yr-old Caucasian male presented with left neck lymphadenopathy and flu-like symptoms. A computer tomography (CT) scan of the neck demonstrated extensive left-sided cervical lymphadenopathy suggestive of lymphoproliferative disorder (Fig. 1A). An excisional biopsy was performed, and nodular sclerosis classical Hodgkin lymphoma was diagnosed based on histology features and positive staining of CD30, CD15, Pax5 and EBV. Laboratory investigations showed a pancytopenia with hemoglobin concentration 96 g/L, thrombocytopenia with platelet 92 9 10/L and neutropenia with a neutrophil count of 1.4 9 10/L. Due to the pancytopenia, bone marrow involvement was suspected, and a bone marrow staging was performed. Microscopic evaluation of bone marrow aspirate revealed trilineage hematopoiesis without dysplasia. In one location adjacent to a bone marrow particle, a giant binucleated Reed– Sternberg cell resembling an ‘OWL’s Eye’ appearance with prominent eosinophilic inclusion-like nucleoli (Fig. 1B) was observed. The Reed–Sternberg cell had a 3.5-fold diameter longer than an adjacent band with a bluish cytoplasmic hue and vacuolations. In the touch preparation film, another binucleated atypical Reed–Sternberg cell was found, suggesting a bone marrow involvement of the Hodgkin lymphoma. Bone marrow biopsy demonstrated normal marrow without fibrosis; further immunostaining with CD30, CD15, Pax5 and EBER was equivocal due to the small suboptimal size of the biopsy samplings. A repeat bone marrow biopsy request was declined by the patient. Based on the pancytopenia and patient’s conditions, a clinical diagnosis of stage 4 Hodgkin lymphoma was established. Patient received the standard chemotherapy for Hodgkin lymphoma, but was refractory to the treatment. An autologous bone marrow transplant was performed, but patient died of relapsed Hodgkin lymphoma 6 months post diagnosis. Reed–Sternberg cells are pathognomonic for classical Hodgkin lymphoma. They can be found in the tissue sampling of the bone marrow. Observation of Reed–Sternberg cells in the bone marrow aspirate is rare, possibly due to the fibrotic nature of the disease. But in certain age population especially children and young adult, Reed–Sternberg cells can be detected in the aspirate possible due to the less fibrotic young marrow. Thus, careful examination of bone marrow aspirate in young patients with known Hodgkin lymphoma can be useful in making the clinical decision as shown in this case. Financial support

Progress in the initial management of Hodgkin’s Lymphoma

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy composed of two distinct disease entities; the more commonly diagnosed classical HL and the rare nodular lymphocyte predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups under the designation of classical HL. An accurate assessment of the stage of disease in patients with HL is critical for the selection of appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence are used to optimize therapy for patients with limited or advanced stage disease and predict their outcomes while reducing the toxicities. Initial therapy for HL patients is based on the histology, anatomical stage and the presence of poor prognostic features. Management of localized HL has shifted from radiation alone to combined modality strategies with brief courses of combination chemotherapy followed by involved-field radiation therapy. Patients with advanced stage disease receive a longer course of chemotherapy commonly without radiation therapy. Clinical trials are being conducted using the early interim response or response at the end of therapy as measured by PET scan to determine treatment.

Use of volumetric-modulated arc therapy for treatment of Hodgkin lymphoma

To evaluate volumetric-modulated arc therapy (VMAT) for treatment of Hodgkin lymphoma (HL) in patients where conventional radiotherapy was not deliverable. A planning computed tomography (CT) scan was acquired for a twelve-year-old boy with Stage IIIB nodular sclerosing HL postchemotherapy with positive positron emission tomography scan. VMAT was used for Phase 1 (19.8Gy in 11 fractions) and Phase 2 (10.8Gy in 6 fractions) treatment plans. Single anticlockwise arc plans were constructed using SmartArc (Philips Radiation Oncology Systems, Fitchburg, WI) with control points spaced at 4°. The inverse-planning objectives were to uniformly irradiate the planning target volume (PTV) with the prescription dose while keeping the volume of lung receiving greater than 20Gy (V20Gy) to less than 30% and minimize the dose to the other adjacent organs at risk (OAR). Pretreatment verification was conducted and the treatment delivery was on an MLCi Synergy linear accelerator (Elekta Ltd, Crawley, UK). The planning results were retrospectively confirmed in a further 4 patients using a single PTV with a prescribed dose of 19.8Gy in 11 fractions. Acceptable dose coverage and homogeneity were achieved for both Phase 1 and 2 plans while keeping the lung V20Gy at 22.5% for the composite plan. The beam-on times for Phase 1 and Phase 2 plans were 109 and 200 seconds, respectively, and the total monitor units were 337.2MU and 292.5MU, respectively. The percentage of measured dose points within 3% and 3mm for Phase 1 and Phase 2 were 92% and 98%, respectively. Both plans were delivered successfully. The retrospective planning study showed that VMAT improved PTV dose uniformity and reduced the irradiated volume of heart and lung, although the volume of lung irradiated to low doses increased. Two-phased VMAT offers an attractive option for large volume sites, such as HL, giving a high level of target coverage and significant OAR sparing together with efficient delivery.

Clinical Features and Prognostic Factors of Hodgkin's Lymphoma: A Single Center Experience.

Hodgkin's lymphoma (HL) is a B cell lymphoma characterized by the presence of Reed-Sternberg cells. HL comprises 1% of all cancer cases and 14% of all lymphoma cases. We designed a retrospective study to investigate the clinical features and prognostic factors of HL patients diagnosed at an experienced oncology centre. Retrospective study. Demographic characteristics, histopathological and clinical features, treatment modalities and response to treatment were obtained from hospital records. Dates of initial diagnosis, remission and relapse, last visit and death were recorded for survival analyses. We analysed data of 391 HL patients (61% male, 39% female; mean age 35.7±15.1 years). The most common classical HL histological subtype was nodular sclerosing HL (NSHL) (42.7%). The most common stage was II 50.4%. The most common chemotherapy regimen was doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) (70.6%). Five and 10-year survival rates were 90% and 84%, respectively. Early-stage patients with good prognostic factors had better overall and relapse-free survival rates. The presence of "B" symptoms, albumin level, Eastern Cooperative Oncology Group (ECOG) performance score, and LDH were prognostic factors that affect the survival in both univariate and multivariate analyses. This is the first study that demonstrates the demographic, clinical and prognostic features of HL patients in Turkey, and provides a general picture of the HL patients in our country.