Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1-4. Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq5, we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential.

Nodular lymphocyte predominant Hodgkin lymphoma: Experience of Polish Pediatric Leukemia/Lymphoma Study Group.

Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL) is a rare clinical entity. To investigate NLPHL clinical course and treatment a survey was performed within Polish Pediatric Leukaemia/Lymphoma Study Group (PPLLSG) participating centers. A questionnaire was sent to all participating centers and analysis of clinical data was performed. From 2010 to 2019, 19 pediatric patients with confirmed NLPHL were registered in Poland. Median age of patients was 12.2 (5.5 - 17.8) years. NLPHL occurred mainly in males (n = 17). Most of the patients (n = 16) had early stage disease - Stage I (n = 6) and stage II (n = 10). Four of the six patients with stage I disease (I A, n = 5; I B, n = 1) underwent complete primary resection. One of these relapsed and was treated with CVP (cyclophosphamide, vinblastine, prednisone) chemotherapy. Two other patients who were not resected completely received CVP chemotherapy and no relapses were observed. Thirteen patients presented with unresectable disease. Of these, eight received three CVP chemotherapy cycles, and five were treated with other chemotherapy regimens. Three relapses were observed and these patients were further treated with chemotherapy and rituximab. One patient underwent autologous stem cell transplantation (auto-SCT). All patients remain alive. Five-year progression-free survival and overall survival for the entire group of patients was 81.6% and 100%, respectively. NLPHL treatment results are consistent with results noted in other countries. Early stage patients have very good outcomes with surgery and observation or low intensity chemotherapy, but this approach may be insufficient in advanced disease.

Reclassifying patients with early-stage Hodgkin lymphoma based on functional radiographic markers at presentation.

The presence of bulky disease in Hodgkin lymphoma (HL), traditionally defined with a 1-dimensional measurement, can change a patient's risk grouping and thus the treatment approach. We hypothesized that 3-dimensional measurements of disease burden obtained from baseline 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scans, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), would more accurately risk-stratify patients. To test this hypothesis, we reviewed pretreatment PET-CT scans of patients with stage I-II HL treated at our institution between 2003 and 2013. Disease was delineated on prechemotherapy PET-CT scans by 2 methods: (1) manual contouring and (2) subthresholding of these contours to give the tumor volume with standardized uptake value ≥2.5. MTV and TLG were extracted from the threshold volumes (MTVt, TLGt) and from the manually contoured soft-tissue volumes. At a median follow-up of 4.96 years for the 267 patients evaluated, 27 patients were diagnosed with relapsed or refractory disease and 12 died. Both MTVt and TLGt were highly correlated with freedom from progression and were dichotomized with 80th percentile cutoff values of 268 and 1703, respectively. Consideration of MTV and TLG enabled restratification of early unfavorable HL patients as having low- and high-risk disease. We conclude that MTV and TLG provide a potential measure of tumor burden to aid in risk stratification of early unfavorable HL patients.

Are EBV-related and EBV-unrelated Hodgkin lymphomas different with regard to susceptibility to checkpoint blockade?

Epstein-Barr virus (EBV)-related and EBV-unrelated classical Hodgkin lymphomas (cHLs) are morphologically and phenotypically indistinguishable. However, the tumor microenvironment of EBV-related cHLs contains higher numbers of macrophages and higher expression levels of PD-L1 than that of EBV-unrelated cHLs. Moreover, viral oncoprotein LMP1 may sustain an immunosuppressive microenvironment by inducing/enhancing production of immunosuppressive cytokines and the expression of PD-1. The presence of enhanced immunosuppressive features in EBV-related cHL should make EBV-related cHL patients more susceptible to checkpoint blockade.

Definition of cortical bone involvement in the staging of newly diagnosed pediatric Hodgkin lymphoma: A report from the International Working Group on Staging Evaluation and Response Criteria Harmonization (SEARCH).

BACKGROUND: The International Working Group on Staging Evaluation and Response Criteria Harmonization (SEARCH) seeks to provide a universally acceptable definition of cortical bone involvement in the staging of newly diagnosed pediatric Hodgkin lymphoma. PROCEDURE: A comprehensive literature search was performed using PubMed and Google Scholar with the search terms "Hodgkin lymphoma," "osseous lesions," "bony involvement," and "pediatric." Publications reviewed included case reports, retrospective analyses, and literature reviews. Each was evaluated for study design, number of participants, median age and age range at diagnosis, percentage of pediatric patients, criteria of interest definition, diagnostic tools, study objectives, and level of evidence. The final definition was based on the available data and consensus of the SEARCH working group. RESULTS: Twenty-five papers specifically addressing cortical bone involvement in Hodgkin lymphoma met the inclusion criteria. Eighteen papers were case reports with literature reviews; the remainder were observational cohort studies. Of these, 14 included pediatric patients (aged 0-21 years). The criteria for cortical bone involvement were not clearly defined in any paper, often varied within a study, and were inconsistent between publications. CONCLUSIONS: The SEARCH group for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL) proposes the following criteria as defining cortical bone involvement: any cortical bone biopsy-proven lesion; a positive bony window lesion on computer tomography (CT), with an FDG-PET positive correlate in a patient with biopsy-proven Hodgkin lymphoma, if there is no other typical skeletal pathology; auspicious skeletal lesions on FDG-PET or magnetic resonance imaging should be confirmed by CT or Tc-99m scan to distinguish cortical lesions from bone marrow involvement. Nodal masses that extend into bone with bony destruction are considered extranodal extension or "E" lesions and do not represent metastatic or stage IV disease.

Quantitative Analysis of Carbonic Anhydrase IX Uncovers Hypoxia-Related Functional Differences in Classical Hodgkin Lymphoma Subtypes.

Upregulation of carbonic anhydrase IX (CAIX) was found to be associated with unfavorable prognosis and resistance to treatment in a broad spectrum of malignancies, recently also in classical Hodgkin's lymphoma (cHL). As demonstrated, variable CAIX expression in a significant number of cHL cases was associated with poor treatment response. The current study focused on the quantification CAIX immunopositivity and its relative expression compared to the total CD30+ neoplastic pool using digital image analysis. One hundred and one lymph node samples featuring cHL histology were analyzed for both CD30 and CAIX by immunohistochemistry. Whole histological slides were scanned and immunopositivity was determined as the histoscore (H-score) using the DensitoQuant software module (3DHistech Kft., Budapest, Hungary). CAIX positivity was observed in the HRS-cells of 56/101 cases (55.44%) and frequently observed in the proximity of necrotic foci. CAIX H-scores were highly variable (range: 2.16-90.36, mean 18.7 ± 18.8). Individual CAIX values were independent of the much higher CD30 values (range 3.46-151.3, mean 52.37 ± 30.74). The CAIX/CD30 index proved to be the highest in the aggressive lymphocyte-depleted (LD) subtype (CAIX/CD30: 0.876). The CAIX expression and the CAIX/CD30 relative index can be precisely determined by image analysis, and values reflect the extent of a tumor mass undergoing hypoxic-stress-related adaptation in the most aggressive forms of cHL.

The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis.

The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so-called Hodgkin and Reed-Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL-derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumor cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease. In 20-40% of cHL cases, HRS cells carry a monoclonal infection by Epstein Barr virus (EBV), which is considered a tumor-initiating factor. In these cases, EBV shows a latency type II infection pattern with the expression of latent membrane protein-1 (LMP-1), a viral oncoprotein that mimics CD40 activation. This scenario is particularly intriguing for the pathogenesis of cHL arising in HIV-infected patients, which, for still obscure reasons, is invariably EBV-associated with LMP-1 expression in HRS cells. Recent evidences are consistent with the occurrence of different pathogenic pathways variably triggered by virus infections (EBV and HIV), genetic alterations, and interactions with critical microenvironmental components. This review focuses on the different microenvironmental niches that characterize cHL of the general population as well as cases of HIV-infected patients. A more comprehensive understanding of the complex interplay existing between HRS and tumor microenvironment is pivotal for the development of more effective treatments, particularly for relapsed or refractory diseases.

[Update on nodular lymphocyte predominant Hodgkin's lymphoma and related lesions]. / Update zum nodulären lymphozytenprädominanten Hodgkin-Lymphom und verwandten Läsionen.

The present article gives an overview of novel developments in the diagnosis of nodular lymphocyte predominant Hodgkin's lymphoma with reference to the revised WHO classification from 2016. Differential diagnoses that are discussed are progressively transformed germinal centers, T cell/histiocyte-rich large B cell lymphoma as well as transformation into a diffuse large B cell lymphoma.

Relationship between ambient ultraviolet radiation and Hodgkin lymphoma subtypes in the United States.

BACKGROUND: There are few modifiable risk factors for Hodgkin lymphoma (HL), the most common cancer among young adults in Western populations. Some studies have found a reduced risk with exposure to ultraviolet radiation (UVR), but findings have been inconsistent and limited to HL as a group or the most common subtypes. METHODS: We evaluated UVR and incidence of HL subtypes using data from 15 population-based cancer registries in the United States from 2001 to 2010 (n=20 021). Ground-based ambient UVR estimates were linked to county of diagnosis. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for UVR quintiles using Poisson regression models adjusted for age, sex, race/ethnicity, diagnosis year, and registry. RESULTS: Hodgkin lymphoma incidence was lower in the highest UVR quintile for nodular sclerosis (IRR=0.84, 95% CI=0.75-0.96, P-trend<0.01), mixed cellularity/lymphocyte-depleted (IRR=0.66, 95% CI=0.51-0.86, P-trend=0.11), lymphocyte-rich (IRR=0.71, 95% CI=0.57-0.88, P-trend<0.01), and nodular lymphocyte predominant HL (IRR=0.74, 95% CI=0.56-0.97, P-trend<0.01), but 'not otherwise specified' HL (IRR=1.19, 95% CI=0.96-1.47, P-trend=0.11). CONCLUSIONS: This is the largest study of UVR and HL subtypes covering a wide range of UVR levels; however, we lack information on personal UVR and other individual risk factors. These findings support an inverse association between UVR and HL.

Subtype distribution of lymphomas in South of Iran, analysis of 1085 cases based on World Health Organization classification.

Lymphoma is one of the most common malignancies worldwide. Subtype distribution is different throughout the world. Some reports from the Middle East are in record. This article is trying to report the subtype distribution of lymphoma in Iran and compare it to that of Western, Far East Asian and Middle Eastern countries. A retrospective study was done on all lymphomas diagnosed in a large referral center in the South of Iran during a time period between 2009 and 2014. All diagnoses have been made according to 2008 WHO classification. A total number of 1085 cases with diagnoses of lymphoma retrieved. Twenty-nine cases (2.6 % of all) were precursor lymphoid neoplasm, 608 cases (56 % of all) were mature B cell neoplasm, 115 cases (10.5 % of all) were mature T and NK cell neoplasm, and 333 cases (30.6 % of all) were Hodgkin lymphoma. The six most frequent subtypes of mature B cell neoplasm were diffuse large B cell lymphoma, NOS (57 %), Burkitt lymphoma (7 %), small lymphocytic lymphoma (6.9 %), mantle cell lymphoma (5.7 %), extranodal marginal zone B cell lymphoma (5.2 %) and follicular lymphoma (3.6 %). Among mature T and NK cell neoplasm, mycosis fungoides was the most common type (43.4 %) followed by peripheral T cell lymphoma, NOS (20 %) and angioimmunoblastic T cell lymphoma (9.9 %). Of Hodgkin lymphoma cases, 90.6 % were classical type and 9.3 % were nodular lymphocyte predominant Hodgkin lymphoma. Extranodal involvement was seen in 42.2 % and GI tract was the most common site. Lymphoma frequencies were similar to that of Middle Eastern countries except for lower rate of follicular lymphoma and higher incidence of diffuse large B cell lymphoma, NOS and small lymphocytic lymphoma.

[Mediastinal lymphomas]. / Lymphome des Mediastinums.

Lymphomas infiltrating the mediastinum are a challenge for the treating physician as well as for the pathological diagnostics. The clinical scenario is often an emergency situation, while the pathologist is usually confronted only with small biopsy samples. Classical Hodgkin's lymphoma is by far the most frequently occurring lymphoma in the mediastinum and predominantly the nodular sclerosis subtype. In small and very sclerotic specimens it can be difficult to morphologically detect Hodgkin and Reed-Sternberg cells and to identify the characteristic phenotype by immunohistochemistry. Primary mediastinal large B­cell lymphomas should be distinguished from classical Hodgkin's lymphomas as the treatment is different. This is characterized by the detection of sheets of blast cells, which immunohistochemically show a strong B­cell phenotype (positivity for CD20 and CD79a), while CD30 can also often be expressed. The intimate biological relationship between classical Hodgkin's lymphomas and mediastinal large B­cell lymphomas is illustrated by the existence of B­cell lymphomas with intermediate features (so-called mediastinal grey zone lymphomas). It is important to recognize and diagnose these lymphomas as they are associated with a slightly inferior prognosis. Extranodal thymic marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT) type are a rare form of lymphoma encountered in the mediastinum, which can be associated with autoimmune diseases. T­lymphoblastic lymphomas and leukemia, which occur predominantly in children and young adults, represent a rapidly growing precursor cell neoplasia and must be distinguished from thymomas in the differential diagnostics as well as from normal and hyperplastic thymus glands.

[The understanding of Epstein-Barr virus associated lymphoproliferative disorder].

In recent years, there are increasing articles concerning Epstein-Barr virus associated lymphoproliferative disorder (EBV+ LPD), and the name of EBV+ LPD is used widely. However, the meaning of EBV+ LPD used is not the same, which triggered confusion of the understanding and obstacles of the communication. In order to solve this problem. Literature was reviewed with combination of our cases to clarify the concept of EBV+ LPD and to expound our understanding about it. In general, it is currently accepted that EBV+ LPD refers to a spectrum of lymphoid tissue diseases with EBV infection, including hyperplasia, borderline lesions, and neoplastic diseases. According to this concept, EBV+ LPD should not include infectious mononucleosis (IM) and severe acute EBV infection (EBV+ hemophagocytic lymphohistiocytosis, fatal IM, fulminant IM, fulminant T-cell LPD), and should not include the explicitly named EBV+ lymphomas (such as extranodal NK/T cell lymphoma, aggressive NK cell leukemia, Burkitt lymphoma, and Hodgkin lymphoma, etc.) either. EBV+ LPD should currently include: (1) EBV+ B cell-LPD: lymphomatoid granulomatosis, EBV + immunodeficiency related LPD, chronic active EBV infection-B cell type, senile EBV+ LPD, etc. (2) EBV+ T/NK cell-LPD: CAEBV-T/NK cell type, hydroa vacciniforme, hypersensitivity of mosquito bite, etc. In addition, EBV+ LPD is classified, based on the disease process, pathological and molecular data, as 3 grades: grade1, hyperplasia (polymorphic lesions with polyclonal cells); grade 2, borderline (polymorphic lesions with clonality); grade 3, neoplasm (monomorphic lesions with clonality). There are overlaps between EBV+ LPD and typical hyperplasia, as well as EBV+ LPD and typical lymphomas. However, the most important tasks are clinical vigilance, early identification of potential severe complications, and treating the patients in a timely manner to avoid serious complications, as well as the active treatment to save lives when the complications happened.

Exposure to UV radiation and risk of Hodgkin lymphoma: a pooled analysis.

Ultraviolet radiation (UVR) exposure has been inversely associated with Hodgkin lymphoma (HL) risk, but only inconsistently, only in a few studies, and without attention to HL heterogeneity. We conducted a pooled analysis of HL risk focusing on type and timing of UVR exposure and on disease subtypes by age, histology, and tumor-cell Epstein-Barr virus (EBV) status. Four case-control studies contributed 1320 HL cases and 6381 controls. We estimated lifetime, adulthood, and childhood UVR exposure and history of sunburn and sunlamp use. We used 2-stage estimation with mixed-effects models and weighted pooled effect estimates by inverse marginal variances. We observed statistically significant inverse associations with HL risk for UVR exposures during childhood and adulthood, sunburn history, and sunlamp use, but we found no significant dose-response relationships. Risks were significant only for EBV-positive HL (pooled odds ratio, 0.56; 95% confidence interval, 0.35 to 0.91 for the highest overall UVR exposure category), with a significant linear trend for overall exposure (P = .03). Pooled relative risk estimates were not heterogeneous across studies. Increased UVR exposure may protect against HL, particularly EBV-positive HL. Plausible mechanisms involving UVR induction of regulatory T cells or the cellular DNA damage response suggest opportunities for new prevention targets.

Nodular lymphocyte predominant Hodgkin lymphoma: a Lymphoma Study Association retrospective study.

Nodular lymphocyte predominant Hodgkin lymphoma represents a distinct entity from classical Hodgkin lymphoma. We conducted a retrospective study to investigate the management of patients with nodular lymphocyte predominant Hodgkin lymphoma. Clinical characteristics, treatment and outcome of adult patients with nodular lymphocyte predominant Hodgkin lymphoma were collected in Lymphoma Study Association centers. Progression-free survival (PFS) and overall survival (OS) were analyzed, and the competing risks formulation of a Cox regression model was used to control the effect of risk factors on relapse or death as competing events. Among 314 evaluable patients, 82.5% had early stage nodular lymphocyte predominant Hodgkin lymphoma. Initial management consisted in watchful waiting (36.3%), radiotherapy (20.1%), rituximab (8.9%), chemotherapy or immuno-chemotherapy (21.7%), combined modality treatment (12.7%), or radiotherapy plus rituximab (0.3%). With a median follow-up of 55.8 months, the 10-year PFS and OS estimates were 44.2% and 94.9%, respectively. The 4-year PFS estimates were 79.6% after radiotherapy, 77.0% after rituximab alone, 78.8% after chemotherapy or immuno-chemotherapy, and 93.9% after combined modality treatment. For the whole population, early treatment with chemotherapy or radiotherapy, but not rituximab alone (Hazard ratio 0.695 [0.320-1.512], P=0.3593) significantly reduced the risk of progression compared to watchful waiting (HR 0.388 [0.234-0.643], P=0.0002). Early treatment appears more beneficial compared to watchful waiting in terms of progression-free survival, but has no impact on overall survival. Radiotherapy in selected early stage nodular lymphocyte predominant Hodgkin lymphoma, and combined modality treatment, chemotherapy or immuno-chemotherapy for other patients, are the main options to treat adult patients with a curative intent.

Next-generation surveillance strategies for patients with lymphoma.

While remission and cure rates for Hodgkin and non-Hodgkin lymphoma continue to improve, surveillance approaches remain controversial, especially in light of recent reports suggesting limited benefit for routine radiologic assessment. Routine cross-sectional imaging results in considerable patient expense and anxiety, and this approach does not clearly improve patient outcomes. Next-generation approaches including minimal residual disease detection may provide an opportunity to identify relapse early and intervene prior to progression of clinical disease. This review discusses the role of surveillance imaging in Hodgkin and non-Hodgkin lymphoma and provides an introduction to serologic assessment of minimal residual disease. Future studies will need to focus on the clinical application of minimal residual disease surveillance and its ability to predict relapse, treatment response and survival.

A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma.

Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma share many features like strong CD30 expression and usually loss of B- and T-cell markers. However, their clinical course is dramatically different with curability rates of >90% for classical Hodgkin lymphoma and an unfavorable prognosis for anaplastic large cell lymphoma. Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma can usually be distinguished by PAX5 expression in the Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma and expression of cytotoxic molecules in tumor cells of anaplastic large cell lymphoma. However, in some cases the differential diagnosis is difficult owing to absence of established markers. To be able to better classify these cases, we reevaluated gene expression data of microdissected tumor cells of both lymphomas for differentially expressed genes. A classifier was established, comprising four genes strongly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (MDC/CCL22, CD83, STAT3, and TUBB2B). Applying this classifier to a test cohort, Hodgkin lymphoma was successfully distinguished from ALK(-) anaplastic large cell lymphoma with an accuracy of 97% (43/44). MDC/CCL22, CD83, and STAT3 have also been found to be expressed in antigen-presenting cells. Therefore, based on our established classifier, Hodgkin and Reed-Sternberg cells differ from tumor cells of anaplastic large cell lymphoma, which can successfully be applied for practical purposes in histopathologic diagnostics.

Treating limited-stage nodular lymphocyte predominant Hodgkin lymphoma similarly to classical Hodgkin lymphoma with ABVD may improve outcome.

The appropriate therapy for limited-stage nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is unclear. In contrast to classical Hodgkin lymphoma (CHL), chemotherapy is often omitted; however, it is unknown whether this impacts the risk of relapse. Herein, we compared the outcome of patients with limited-stage NLPHL treated in an era in which ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy was routinely incorporated into the primary therapy to an earlier era in which radiotherapy (RT) was used as a single modality. Using the British Columbia Cancer Agency Lymphoid Cancer Database, 88 patients with limited-stage NLPHL (stage 1A/1B or 2A, nonbulky disease < 10 cm) were identified. Treatment followed era-specific guidelines: before 1993, (n = 32) RT alone; and 1993 to present (n = 56), ABVD-like chemotherapy for 2 cycles followed by RT with the exception of 14 patients who received ABVD chemotherapy alone. Most patients were male (75%) with stage I disease (61%). In an era-to-era comparison, the 10-year time to progression (98% vs 76% P = .0074), progression-free survival (91% vs 65% P = .0024), and OS (93% vs 84%, P = .074) favored the ABVD treatment era compared with the RT alone era. Treating limited-stage NLPHL similarly to CHL may improve outcome compared with the use of radiation alone.

Multiple HLA class I and II associations in classical Hodgkin lymphoma and EBV status defined subgroups.

The pathogenesis of classical Hodgkin lymphoma (cHL) involves environmental and genetic factors. To explore the role of the human leukocyte antigen (HLA) genes, we performed a case-control genotyping study in 338 Dutch cHL patients and more than 5000 controls using a PCR-based sequence-specific oligonucleotide probe hybridization approach. HLA-A68 and HLA-DR11 (5) were significantly increased in the cHL patient population compared with the controls. Three class II associations were observed in the EBV(-) cHL population with an increase of HLA-DR15 (2) and a decrease of HLA-DR4 and HLA-DR7. Allele frequencies of HLA-A1, HLA-B37, and HLA-DR10 were significantly increased in the EBV(+) cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in whites. The allele frequency of HLA-A2 was significantly decreased in the EBV(+) cHL population. Sequence-specific oligonucleotide probe analysis revealed significant differences between EBV(+) and EBV(-) cHL patients for 19 probes that discriminate between HLA-A*01 and HLA-A*02. In conclusion, the HLA-A1 and HLA-A2 antigens and not specific single nucleotide variants shared by multiple alleles are responsible for the association with EBV(+) cHL. Furthermore, several new protective and predisposing HLA class I and II associations for the EBV(+), the EBV(-), and the entire cHL population were identified.