Parenthood in adult female survivors treated for Hodgkin's lymphoma during childhood and adolescence: a prospective, longitudinal study.

BACKGROUND: Little is known about parenthood in women who were treated for Hodgkin's lymphoma during childhood and adolescence. We aimed to assess the frequency of parenthood in female survivors of Hodgkin's lymphoma younger than 18 years at diagnosis, and to compare it with that in a female population control group. METHODS: In this prospective, longitudinal study, our cohort consisted of 590 female patients younger than 18 years at diagnosis who participated in one of five Hodgkin's lymphoma treatment studies between June 19, 1978, and July 12, 1995. Women who had been followed up for 5 years or longer, were in continuous complete remission, and had no second malignancy or Hodgkin's lymphoma relapse before parenthood were included in our parenthood analysis. Parenthood was defined as the delivery of a liveborn child. Frequency of parenthood was compared with that in the German female population aged 16-49 years, using data from the 2012 Mikrozensus population survey. We assessed parenthood by estimating cumulative incidences and hazard ratios (HRs) with associated variables. FINDINGS: 467 of 590 patients in our cohort had long-term follow-up (median 20·4 years [IQR 16·3-24·8]) and were in continuous complete remission. 228 (49%) of 467 patients had 406 children (median of 1·78 children per mother, range 1-7). Cumulative incidences of parenthood were 67% (95% CI 64-75) at 27·7 years of follow-up (the longest number of years that a patient was followed up before she had her first child) and 69% (61-74) at 39·8 years of age (the oldest age of a patient before she had her first child). The incidence of parenthood did not differ between our cohort and the female German population for any age group up to 49 years, except for the 66 women aged 40-44 years at the time of last information, who had a significantly lower frequency of parenthood compared with the general population (40 [61%] of 66 vs 2,208,000 [78%] of 2,847,000; p=0·001). Procarbazine in cumulative doses up to 11,400 mg/m(2), cyclophosphamide in cumulative doses up to 6000 mg/m(2), alkylating agent dose scores of 1-5, therapy group based on disease stage at diagnosis, abdominal and supradiaphragmatic radiation, and age at treatment had no significant or only minor effects on parenthood. Parenthood was significantly reduced in survivors receiving pelvic radiation compared with those who received abdominal and supradiaphragmatic radiation (HR 0·76, 95% CI 0·61-0·95; p=0·01). INTERPRETATION: The results of this study document an overall favourable prognosis for parenthood in female survivors of Hodgkin's lymphoma. They will assist counselling of female survivors about their positive potential for future parenthood. FUNDING: Deutsche Kinderkrebsstiftung, Jens-Brunken-Stiftung für Leukämie und Lymphomforschung, and Kinderkrebshilfe Münster.

Quality of life in long-term survivors following treatment for Hodgkin's disease during childhood and adolescence in the German multicentre studies between 1978 and 2002.

PURPOSE: The purpose of this study was to cross-sectionally assess quality of life (QoL) in survivors of childhood Hodgkin's disease (HD) in a cohort treated for HD in the successive German-Austrian therapy studies HD-78, HD-82, HD-85, HD-87, HD-90, HD-95, respectively, in accordance with the HD-Interval-Treatment recommendation between 1978 and 2002. PATIENTS AND METHODS: Data from QoL questionnaires were provided by 1,202 (66 %) of 1,819 invited survivors. These included the EORTC QLQ-C30 and socio-demographic variables. Data of a homogenous sub-sample (n = 725) defined by age (21-41 years) and event- free-survival (no progress, relapse or secondary malignancies) were compared to an age-adjusted German reference sample (n = 659). RESULTS: While the global and physical QoL scores were comparable to those of the general population, survivors' mean scores were more than 10 points lower on the EORTC QLQ-C30 scales "Emotional" and "Social Functioning". On the symptom scales, higher mean scores, exceeding 10 points, were obtained for the scales "Fatigue" and "Sleep". In general, there was a gender effect showing lower functioning and higher symptom levels in women, most prominently in the group of young women (21-25 years). The results within the group of HD survivors could not be associated with the time since treatment, the age of HD survivors at diagnosis or the extent of therapy burden. CONCLUSION: Clinicians engaged in follow-up care should be sensitive to aspects of fatigue and related (emotional) symptoms in HD childhood cancer survivors and encourage their patients to seek further support if needed.

Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for Hodgkin disease in children and adolescents: report from the longitudinal GPOH follow-up project of the German-Austrian DAL-HD studies.

BACKGROUND: To analyze the impact of mediastinal irradiation on the incidence of cardiac late effects in long-term survivors of pediatric Hodgkin disease (HD). METHODS: The study cohort comprised 1,132 survivors of HD who received treatment before 18 years of age in consecutive trials between 1978 and 1995. They had maintained remission without secondary malignancy for 3.1-29.4 years. The cumulative doxorubicin dose was uniformly 160 mg/m(2), the mediastinal radiation dose (MedRD) was 36, 30, 25, 20, or 0 Gy. Follow-up questionnaires complemented by additional contacts served to collect information on late effects from patients and physicians. A central expert panel reviewed all reported cardiac abnormalities. RESULTS: By October 2008, cardiac diseases (CD) had been diagnosed in 50 of 1,132 patients aged 15.0-41.7 (median 32.2) years. The interval since HD therapy was 3.0-28.2 (median 19.5) years. Valvular defects were diagnosed most frequently, followed by coronary artery diseases, cardiomyopathies, conduction disorders, and pericardial abnormalities. The cumulative incidence of CD after 25 years was highest in the MedRD-36 group (21%) decreasing to 10%, 6%, 5%, and 3% in the lower MedRD groups (P < 0.001). Multivariate Cox analysis of several putative risk factors showed MedRD to be the only significant variable predicting for CD-free survival (P = 0.0025). CONCLUSIONS: Our results indicate that lower MedRDs are less cardiotoxic. Consequently, reduction of cardiac late effects may be expected with the lower radiation doses used in current HD protocols. Longer follow-up is needed to confirm the present results.

Impact of latent Epstein-Barr virus infection on outcome in children and adolescents with Hodgkin's lymphoma.

PURPOSE: The prognostic significance of latent Epstein-Barr virus (EBV) infection in Hodgkin's lymphoma (HL) is debated controversially. Especially in the pediatric age group, no conclusive data are available. PATIENTS AND METHODS: Eight hundred forty-two children and adolescents (median age, 13.7 years) from pediatric multicenter treatment studies HD-90 and HD-95 were studied for latent EBV infection in Hodgkin's and Reed-Sternberg cells by immunostaining against latent membrane protein 1 (LMP-1). Results were compared with established risk factors. RESULTS: Two hundred sixty-three patients (31%) were LMP positive. EBV infection correlated with sex (39% male v 23% female; P < .001), histologic subtype (69% mixed cellularity v 22% nodular sclerosis v 6% lymphocyte predominance; P < .001) and young age. With a median follow-up of 4.9 years, 820 patients (97%) are alive. Probability of overall survival at 10 years (+/- standard deviation) for EBV-negative and -positive patients was 98.1% +/- 0.6% and 95.1% +/- 1.4%, respectively (P = .017 by log-rank test). A negative effect of EBV infection became evident for patients with nodular sclerosis subtype Bennett II (P = .02), and those treated for advanced stages (P = .003). In multivariate analysis, LMP positivity was an independent factor for adverse outcome (RR = 3.08). Probability of failure-free survival (FFS) in LMP positive and negative patients was 89.1% +/- 2.3% and 84.1% +/- 3.9%, respectively (P = .86). CONCLUSION: With effective combined treatment modalities in pediatric HL, latent EBV infection has no influence on FFS but is associated with an inferior overall survival in crucial subgroups.

Salvage therapy of progressive and recurrent Hodgkin's disease: results from a multicenter study of the pediatric DAL/GPOH-HD study group.

PURPOSE: To evaluate a salvage therapy (ST-HD-86) for patients with progressive and relapsed Hodgkin's disease after primary treatment in the pediatric DAL/GPOH studies. The essential chemotherapeutic regimens were ifosfamide, etoposide, and prednisone (IEP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: One hundred seventy-six patients with progression (n = 51) or first relapse (n = 125) were enrolled by 67 centers. The median time from initial diagnosis to progression/relapse was 1.1 year (range, 0.1 to 15.3 years), and the patients' median age was 14.7 years (range, 4.3 to 24.5 years). Salvage chemotherapy consisted of two to three cycles of IEP alternating with one to two cycles of ABVD supplemented in part by one to two cycles of cyclophosphamide, vincristine, procarbazine, and prednisone or lomustine (CCNU), etoposide, and prednimustine. Radiotherapy was given to involved areas using individualized doses. In the 1990s, additional high-dose chemotherapy with autologous stem-cell transplantation (SCT) was introduced for patients with unfavorable prognosis. RESULTS: Disease-free survival (DFS) and overall survival (OS) after 10 years are 62% and 75%, respectively (SE, 4% each). Of 176 patients, 73 suffered second events. The risk-factor analysis revealed the time to progression/relapse as the strongest prognostic factor (P = .0001). Patients with progression have an inferior outcome (DFS, 41%; OS, 51%), whereas patients with late relapse (> 12 months after end of therapy) do well (DFS, 86%; OS, 90%), although none of them received SCT in second remission. CONCLUSION: The result can be considered favorable. Whereas the salvage strategy for progressive disease has to be optimized further, it is possible to reduce intensity and avoid SCT in late relapses after Hodgkin's disease in childhood/adolescence.

Secondary Malignancies Following Treatment for Hodgkin's Lymphoma in Childhood and Adolescence.

BACKGROUND: About 155 persons under age 18 develop Hodgkin's lymphoma (HL) in Germany every year. More than 90% survive at least 20 years. They may, however, suffer from late sequelae of treatment, including secondary malignant neoplasia (SMN). METHODS: 2548 patients from the German, Austrian, and Swiss pediatric Hodgkin's lymphoma studies that were conducted over the period 1978-2002 were asked every 2-3 years about possible late sequelae of treatment, either directly or through their physicians. The documented cases of SMN were analyzed for cumulative incidence, standardized incidence rates (SIR), and absolute excess risk (AER). RESULTS: 147 cases of SMN were diagnosed in 138 of the 2548 patients, including 47 cases of thyroid cancer, 37 of breast cancer, and 15 of hematopoietic neoplasia. The cumulative incidence of SMN at 20, 25, and 30 years was 7% , 11.2% , and 18.7% , respectively. These percentages are rather low compared to other international studies. For all types of SMN, the SIR was 9.1 and the AER was 16.8. Among the 123 patients with secondary solid tumors, 105 (85% ) had a tumor in the irradiated region. CONCLUSION: Survivors of pediatric HL must be informed about the risk of late sequelae of treatment for HL, including SMN in the irradiated region, and that they will need regular follow-up examinations. In the future, radiotherapy for children and adolescents should be further reduced or entirely avoided.

Does bulky disease at diagnosis influence outcome in childhood Hodgkin's disease and require higher radiation doses? Results from the German-Austrian Pediatric Multicenter Trial DAL-HD-90.

PURPOSE: The identification of risk factors is required for risk-adapted treatment strategies in the treatment of Hodgkin's disease. To assess the influence of bulky disease at diagnosis as compared with other risk factors on event-free survival (EFS) in pediatric Hodgkin's disease such as stage, B-symptoms, number of involved lymph node regions, histology, and remission status after chemotherapy, we analyzed the outcome of 552 patients treated with a risk-adapted treatment strategy consisting of OPPA(OEPA)/COPP (vincristine, procarbazine, etoposide, prednisone, adriamycin, cyclophosphamide) and involved-field radiotherapy. METHODS AND MATERIALS: Between 1990 and 1995, 578 patients with primary Hodgkin's disease (HD) were enrolled in the German/Austrian Pediatric Hodgkin's Disease Study Group (DAL) Multicenter Study (HD-90). Patients were stratified into three treatment groups (TGs) for early, intermediate, and advanced stage. All patients received induction chemotherapy (CT) with two cycles of OEPA for boys and two cycles of OPPA for girls. Patients in TG2 and TG3 received another two or four cycles, respectively, of COPP. Chemotherapy was followed by involved-field radiotherapy. The radiation field, which was prescribed by the study center, was treated with a dose of 25 Gy/25 Gy/20 Gy (TG1/TG2/TG3), and in case of insufficient remission with a local boost of 5 Gy to 10 Gy. The following prognostic factors were analyzed with regard to their impact on EFS: bulky disease, mediastinal tumor, number of involved lymph node regions, histology, treatment group, B-symptoms, sex, age, and remission status after chemotherapy. RESULTS: Significant univariate predictive factors for the EES were: nodular sclerosis type 2 (NS2) histology (relative risk [RR] 3.43; p = 0.0002), presence of B-symptoms (RR 2.70; p = 0.0014), number of involved regions (1.55; p = 0.019), and treatment groups (RR 1.33; p = 0.017). There was a higher risk (RR 1.92; p = 0.040) for patients with bulky compared with nonbulky disease (5-year EFS 89.6%/94.6%). In the multiple regression model, only NS2 and B-symptoms remained strong predictive factors. The remission status after chemotherapy did not correlate with EFS (p = 0.66). CONCLUSION: Treatment strategies in Hodgkin's disease have an impact on different risk factors. In the risk-adapted treatment strategy of the HD-90 study, tumor burden indicated as bulky disease or as number of involved lymph nodes loses its importance, whereas NS2 histology and B-symptoms have a major impact on treatment outcome. Bulky disease at diagnosis might require higher radiation doses only in case of insufficient remission.

Up-front centralized data review and individualized treatment proposals in a multicenter pediatric Hodgkin's disease trial with 71 participating hospitals: the experience of the German-Austrian pediatric multicenter trial DAL-HD-90.

BACKGROUND AND PURPOSE: A systematic procedure for up-front centralized data review and the set-up of individualized treatment proposals was integrated prospectively into the German-Austrian multicenter trial DAL-HD-90 for pediatric Hodgkin's disease (HD) in order to introduce local radiotherapy according to the individual patient's spread of disease within a combined-modality treatment. This paper investigates the feasibility of such a procedure and its impact on the final definition of the extent and stage of disease as well as on the choice of treatment. PATIENTS AND METHODS: Between October 1990 and July 1995, 578 children and adolescents <18 years (259 girls, 319 boys, median age 12.9 years) with HD were enrolled into the HD-90 trial. After clinical and pathological staging (66.4/33.6%), patients were allocated to treatment groups (TG) 1 'early stage', TG2 'intermediate stage', or TG3 'advanced stage'. All groups underwent two cycles of OPPA (vincristine, prednisone, procarbazine, doxorubicin) (girls) or OEPA (E, etoposide) (boys) for induction chemotherapy. TG2 and TG3 continued on as two or four cycles, respectively, of COPP (C, cyclophosphamide). Low-dose local radiotherapy was given to the initially involved sites, with radiation doses of 25 Gy in TG1/TG2, and 20 Gy in TG3. All documentation forms, radiographs, and chest and abdominal computed tomography (CT) scans were centrally reviewed, addressing in particular the individual patient's extent and stage of disease. This review and the set-up of individualized treatment proposals were in the hands of the study coordinator, one additional pediatrician and two radiation oncologists and radiologists at the study center. During a time slot of at least 8 weeks (two cycles of standard chemotherapy in all three TGs) the individualized treatment proposals were to be sent to the participating hospital. RESULTS: Complete sets of documentation from 564/578 patients (97.6%) were submitted sufficiently early to the study center. A total of 285 out of 574 chest radiographs, 468 out of 553 chest CT scans and 421 out of 548 abdominal CT scans were available from 71 hospitals. A total of 564 individualized treatment proposals were worked out by the review group and sent to the hospitals before radiotherapy began. Re-analysis of images and documentation forms, including laboratory and clinical data, resulted in a revision of stage in 115/571 patients (20.1%) and of TG in 76/571 patients (13.3%). A total of 67/76 patients were shifted into a higher TG, 60 patients on account of additionally detected extralymphatic involvement, five patients because of additionally detected lymph node involvement and two patients due to clinical data which had to be classified as B-symptoms. A total of 9/76 patients were shifted into a lower TG; in three patients extranodal disease and in six patents local lymph node involvement could not be confirmed. CONCLUSIONS: The up-front centralized review of patient data and consecutive set-up and delivery of individualized treatment proposals for almost every patient are feasible within a large multicenter trial. Sufficient time and manpower at the study center are needed for the review process and the set-up of individualized treatment proposals. Such a procedure has a significant impact on the homogeneity of stage definition, allocation to TG, and individualized treatment proposals.

Breast cancer in young women after treatment for Hodgkin's disease during childhood or adolescence--an observational study with up to 33-year follow-up.

BACKGROUND: The treatment of Hodgkin's disease (HD; also called Hodgkin's lymphoma) in children and adolescents with radiotherapy and chemotherapy leads to high survival rates but has a number of late effects. The most serious one is the development of a secondary malignant tumor, usually in the field that was irradiated. In women, breast cancer can arise in this way. METHOD: Data on the occurrence of secondary breast cancer (sBC) were collected from 590 women who were treated in five consecutive pediatric HD treatment studies in the years 1978-1995 and then re-evaluated in a late follow-up study after a median interval of 17.8 years (maximum, 33.7 years). Information was obtained from 1999 onward by written inquiry to the participants and their treating physicians. The cumulative incidence of sBC was calculated by the Gooley method. RESULTS: By July 2012, sBC had been diagnosed in 26 of 590 female HD patients; the breast cancer was in the irradiated field in 25 of these 26 patients. Their age at the time of treatment for HD was 9.9 to 16.2 years (the pubertal phase), and sBC was discovered with a median latency of 20.7 years after HD treatment (shortest latency, 14.3 years) and at a median age of 35.3 years (youngest age, 26.8 years). The radiation dose to the supradiaphragmatic fields ranged from 20 to 45 Gy. The cumulative incidence for sBC 30 years after treatment for HD was 19% (95% confidence interval, 12% to 29%). For women aged 25 to 45 in this series, the frequency of breast cancer was 24 times as high as in the corresponding normal population. CONCLUSION: Women who were treated for HD in childhood or adolescence have an increased risk of developing breast cancer as young adults. The risk is associated with prior radiotherapy and with the age at which it was administered (the pubertal phase). Because of these findings, a structured breast cancer screening project for this high-risk group has been initiated in collaboration with the German Consortium for Hereditary Breast and Ovarian Cancer (Deutsches Konsortium für familiären Brust- und Eierstockkrebs).

The impact of central review and central therapy planning on the treatment of children and adolescents with Hodgkin lymphoma.

PURPOSE: The multicentre response-adapted paediatric Hodgkin lymphoma trial GPOH-HD95 (1995-2001, 925 patients) was followed by the 'HD-Interval' period (2001-2002, 203 patients). During this period, treatment was recommended according to GPOH-HD95 protocol with only minor changes. Central review and treatment planning as in HD95, however, had to be omitted in the absence of funding. Results of both periods were compared to evaluate the impact of central review on staging, stratification, treatment planning and outcome. METHODS: Pre- and post-chemotherapy computed tomography and magnetic resonance imaging of HD-Interval patients were evaluated with respect to reliability of staging, response assessment and subsequent treatment stratification. RESULTS: Despite more favourable patient characteristics and treatment group stratifications, the 10-year progression-free survival (PFS) was inferior in HD-Interval patients compared to GPOH-HD95 patients with nearly identical therapy (86% versus 91%, P=0.01). Of 142 patients without guidance by the reference centre, 56 (39%) received a treatment deviating from protocol recommendations: chemotherapy doses were either lower or higher than recommended in 17% of patients, and deviations concerning radiotherapy dose and treatment volume occurred in 25% and 20%, respectively. In both periods, the 10-year PFS was lower in patients with diminished therapy compared to those with adequate treatment according to the given recommendations (HD-Interval: 72% versus 89%, P=0.02; GPOH-HD95: 80% versus 92%, P=0.04). CONCLUSIONS: Deviations from protocol treatment may influence negatively the outcome in paediatric oncology. Protocol enrolment and compliance including timely and correct treatment are crucial. Central reference and consultation centres offer quality assurance, support protocol adherence, and hence influence PFS.

Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: final results of the multinational trial GPOH-HD95.

UNLABELLED: PURPOSE To minimize the risk of late effects in pediatric Hodgkin lymphoma (HL) by omitting radiotherapy (RT) in patients in complete remission (CR) after chemotherapy and reducing the standard radiation dose to 20 Gy in patients in incomplete remission. PATIENTS AND METHODS: Between 1995 and 2001, 925 patients with classical HL (cHL) were registered from seven European countries in German Society of Pediatric Oncology and Hematology Hodgkin Lymphoma Trial 95. Patients in treatment group 1 (TG1; early stages) received two cycles of vincristine, prednisone, procarbazine, and doxorubicin or vincristine, prednisone, etoposide, and doxorubicin chemotherapy; additional two or four cycles of cyclophosphamide, vincristine, prednisone, and procarbazine were added in TG2 (intermediate stages) or TG3 (advanced stages), respectively. Patients in CR (assessed by computed tomography or magnetic resonance imaging) did not undergo RT. Those with tumor volume reduction more than 75% received reduced involved-field RT with 20 Gy and an additional 10- or 15-Gy boost only for larger residuals. RESULTS: Rates of overall survival, progression-free survival (PFS), and event-free survival at 10 years were (± SE) 96.3% ± 0.6%, 88.2% ± 1.1%, and 85.4% ± 1.3%, respectively. PFS for TG1 patients without or with RT was 97.0% ± 2.1% versus 92.2% ± 1.7% (P = .214) but was unsatisfactory for nonirradiated patients in TG2 (68.5% ± 7.4% v 91.4% ± 1.9%; P < .0001), with similar but not significant results in TG3 (82.6% ± 5.4% v 88.7% ± 2.0%, P = .259). Reduction of the standard radiation dose from 25 to 20 Gy did not increase failure rate. CONCLUSION: RT can be omitted in early stage HL in so defined CR following this chemotherapy. RT with 20(-35) Gy proved to be sufficient in patients with incomplete remission following chemotherapy.

Resection alone in 58 children with limited stage, lymphocyte-predominant Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma.

BACKGROUND: Lymphocyte-predominant Hodgkin lymphoma (LPHL) is a rare, CD20-positive, good prognostic lymphoma in children. Patients with early-stage LPHL who underwent successful surgical lymph node resection alone have been reported. To clarify the optimum treatment strategy in children, European study groups were asked to report their experience of surgery alone used in the treatment of pediatric LPHL. METHODS: Data from 58 patients were collected by the French Society for Pediatric Cancers, the German-Austrian Pediatric Study Group/German Society of Pediatric Oncology and Hematology (Germany), and the Children's Cancer and Leukaemia Group (United Kingdom). In total, there were 50 boys and 8 girls, and the median age was 11 years (age range, 4-17 years). Fifty-four patients had stage IA disease, 2 patients had stage IIA disease, and 2 patients had stage IIIA disease. RESULTS: With a median follow-up of 43 months (range, 2-202 months), the overall survival rate was 100%, and the progression-free survival (PFS) rate was 57%. Fifty-one of 58 patients achieved complete remission (CR) after surgery. In the CR group, the overall PFS rate was 67% (95% confidence interval, 51-82%). All seven patients who had residual disease after initial surgery developed recurrences (P = .003). Among 18 patients with stage IA LPHL who developed recurrent disease, 11 patients had local recurrences, and 7 patients recurred in stage IIA. One patient with stage IIIA disease presented with high-grade B-cell non-Hodgkin lymphoma at 10 years of follow-up. CONCLUSIONS: When complete resection was achieved, a substantial proportion of patients with surgically treated, early-stage LPHL experienced long-term remission and actually may have been cured.

Proliferation characteristics in pediatric Hodgkin's lymphoma point to a cell cycle arrest in the G(1) phase.

This study was undertaken to determine the prognostic relevance of the proliferation rate in neoplastic cells in children and adolescents with Hodgkin's lymphoma. Paraffin-embedded biopsy specimens were immunostained with the proliferation-associated monoclonal antibodies Ki-S5 (Ki-67 antigen) and Ki-S2 (which detects the repp86 protein). Repp86 is a protein of about 100 kDa encoded by a gene located on human chromosome band 20q11.2. In contrast to the Ki-67 antigen, repp86 expression is restricted to the cell cycle phases G(2), S and M. Immunohistochemical results on diagnostic lymph node biopsy specimens from 224 patients included in two pediatric multicenter Hodgkin's trials, GPOH HD-90 and HD-95, were compared with clinical data. High Ki-67 antigen expression was a striking feature of Hodgkin's and Reed-Sternberg cells as well as lymphocytic and histiocytic cells (median: 80%, range: 20-100%), in contrast to low repp86 expression (median: 20%, range: 10-80%; P<0.001). The proliferation rate was independent of histological subtype, stage and presence of B symptoms. The probability of event-free and overall survival (+/-standard error) of all patients at 5 years was 91.6+/-2.0 and 98.1+/-1.0%, respectively. The proliferation rate of tumor cells did not influence the outcome. The difference between Ki-67 and repp86 expression in Hodgkin's and Reed-Sternberg or lymphocytic and histiocytic cells points to a possible cell cycle arrest in the G(1) phase, which may explain the obvious paradox of a highly proliferating but slowly growing paucicellular tumor. High Ki-67 expression does not seem to be an adverse prognostic factor in pediatric and adolescent patients with Hodgkin's lymphoma treated by effective risk-adapted chemo-radiotherapy regimens.