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© 2003 American Society for Clinical Oncology Primary Mediastinal Large B-Cell Lymphoma With Sclerosis in Pediatric and Adolescent Patients: Treatment and Results From Three Therapeutic Studies of the Berlin-Frankfurt-Münster Group
From the Department of Pediatric Hematology and Oncology, Medizinische Hochschule Hannover; Lymphnode Registry founded by the Society of German Pathologists, Institute of Hematopathology, Christian-Albrechts-Universität, Kiel; Department of Pediatric Hematology and Oncology, Technische Universität, Dresden; Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen; Department of Pediatric Hematology and Oncology, Universitätskinderklinik Freiburg, Germany; St. Anna-Kinderspital; and Institute of Pathology, University of Vienna, Vienna, Austria. Address reprint requests to Alfred Reiter, MD, NHL-BFM Study Center, Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Feulgenstr. 12, D-35385 Giessen, Germany; email: alfred.reiter{at}paediat.med.uni-giessen.de.
Purpose: Primary mediastinal large B-cell lymphoma with sclerosis (PMLBL) is a rare entity of non-Hodgkin’s lymphoma (NHL) arising from thymic mature B cells. Optimal treatment strategies remain to be established, especially in pediatric patients. Patients and Methods: This study analyzes clinical characteristics and treatment outcome of 30 pediatric patients with PMLBL, diagnosed in multicenter therapy NHL–Berlin-Frankfurt-Münster Group (BFM) trials. Treatment was stratified by stage and serum lactate dehydrogenase (LDH) and consisted of four to six 5-day courses of chemotherapy using steroids, oxazaphosphorine alkylating agents, methotrexate, cytarabine, etoposide, and doxorubicin. Radiation was not part of the protocol.
Results: From April 1986 to August 1999, 1,650 patients with newly diagnosed NHL were enrolled in the NHL-BFM trials; 30 patients (1.8%) had PMLBL. Median age was 14.3 years (range, 1.4 to 16.7 years); 15 patients were male and 15 patients were female. With a median observation time of 5 years (range, 1 to 12 years), probability of event-free survival (pEFS) at 5 years was 0.70 (SE, 0.08). Two patients erroneously diagnosed as T-cell NHL received non–B-cell therapy and died from progress of disease. Events in 28 patients receiving B-cell therapy included early progress during therapy (n = 1) and relapse (n = 6). Residual mediastinal masses were present in 23 patients after two courses of therapy and in 15 patients after the end of therapy. LDH Conclusion: PMLBL mainly is found in adolescents. Dose-intense chemotherapy including high-dose methotrexate yields a pEFS at 5 years of 0.70 (SE, 0.08). LDH is of prognostic value in pediatric patients with PMLBL.
PRIMARY MEDIASTINAL large B-cell lymphoma with sclerosis (PMLBL) is a pathologic and clinical entity of non-Hodgkin’s lymphoma (NHL) derived from mature thymic B cells. It was first described in 19811,2 and is now well recognized as a separate entity of aggressive B-cell NHL (B-NHL), characterized by diffuse proliferation of large cells with clear cytoplasm, invasive growth pattern, and various degrees of sclerosis leading to a typical compartmentalization pattern.3 Tumor cells are of B-cell origin, expressing CD79a, CD19, CD20, and CD22, but not CD5 or CD10. Characteristically, PMLBL cells do not show immunoglobulin G expression and are negative for CD21, which indicates that PMLBL is derived from medullary thymic B cells.4 Clinically, PMLBL is characterized by large, bulky mediastinal tumors, frequently involving adjacent mediastinal structures and lung tissue and often presenting as superior vena cava obstruction.2,5–7 The most frequent extrathoracic manifestation is in the kidney.3,6,8 However, extranodal spreading to other parenchymal organs is rare, as is bone marrow or CNS involvement. PMLBL is predominantly diagnosed in young female adults (median age at diagnosis, 28 to 35 years).6,9,10 Intensive multidrug chemotherapy followed by radiotherapy proved to be efficacious in the treatment of adult patients with PMLBL.10–12 Only a few studies exist on the frequency and presentation of PMLBL in childhood.13,14 PMLBL seems to be a rare entity of NHL in pediatric patients, with a still-uncertain prognosis.13,15 In the multicenter-therapy NHL–Berlin-Frankfurt-Münster (BFM) trials, nearly all pediatric patients with newly diagnosed NHL from Germany, Austria, and parts of Switzerland are enrolled. The present study aims at describing frequency, clinical characteristics, treatment, outcome, and prognostic factors in a group of 30 pediatric patients with PMLBL, prospectively enrolled into three consecutive NHL-BFM trials from April 1986 to August 1999.
Patients Children and adolescents up to 18 years of age with newly diagnosed NHL were eligible for the NHL-BFM trials. Exclusion criteria were as follows: human immunodeficiency virus infection, severe immunodeficiency, posttransplantation lymphoma, NHL as a second malignancy, previous cytostatic treatment, and pre-existing disease prohibiting chemotherapy. From April 1986 to August 1999, 1,650 eligible patients were enrolled from 90 centers in Austria, Germany, and Switzerland in three consecutive trials: NHL-BFM 86, 90, and 95 (Table 1  ). Patients registered in the BFM study center during the interim phase between NHL-BFM 90 and NHL-BFM 95 were also included. The study protocols were approved by the local ethical committee of the study chairmen (H.R. for NHL-BFM 86; A.R. for NHL-BFM 90 and 95). Informed consent was obtained from all patients’ parents or guardians. The study population was subdivided according to NHL subtype into three groups with different therapy strategies: patients with lymphoblastic lymphoma or peripheral T-cell lymphoma, patients with B-NHL and acute lymphocytic leukemia, and patients with anaplastic large-cell lymphoma. We report here on treatment and results of 30 patients with PMLBL. The patients with PMLBL of NHL-BFM 86 and NHL-BFM 90 were included in previous reports.
Diagnosis Diagnosis of PMLBL was based on histopathology and immunohistochemistry according to the updated Kiel classification and the World Health Organization classification for NHL.16,17 Biopsy material was obtained by open biopsy. Tumor slides of all patients were reviewed by central reference pathologists (M.T., R.P.). Immunohistochemistry on conventional paraffin sections was performed using avidin-biotin-peroxidase complex or alkaline phosphatase antialkaline phosphatase18 techniques and paraffin-resistant monoclonal antibodies, established in the authors’ laboratory (R.P.) or purchased from DAKO (Hamburg, Germany) or Dianova (Hamburg, Germany). Monoclonal antibodies to CD20, Ki-B5, and CD3 were used for the detection of B and T cells; Ki-M1P and antilysozyme were used to detect macrophages.18,19 CD30 was visualized using the monoclonal antibody BER-H2.20
Staging
Therapy
In NHL-BFM 86, seven of nine patients were treated in therapy branch B-RG (for stage III B-NHL). These patients received six courses of chemotherapy (including methotrexate [MTX] 0.5 g/m2) as described previously.23 Two patients were treated in therapy group non–B-NHL (therapy for lymphoblastic lymphoma) because of erroneous diagnosis of mediastinal T-cell NHL.23
In NHL-BFM 90 as well as in the interim phase (with a duration of 1 year) between NHL-BFM 90 and NHL-BFM 95, patients with PMLBL were stratified into therapy branches R2 (stage III, no abdominal disease or LDH < 500 U/L) and R3 (stage III abdominal disease and LDH > 500 U/L, and stage IV). Of 13 patients with PMLBL (eight patients from NHL-BFM 90 and five patients from the interim phase), 10 patients were stratified into therapy branch R2, and three patients were stratified into therapy branch R3. If tumor regression was incomplete after two courses of chemotherapy (residual tumor on CT scan or magnetic resonance imaging), patients were to receive intensification course CC (Fig 1
In NHL-BFM 95, patients with PMLBL were treated in therapy branch R2/95 (stage III, LDH < 500 U/L), R3/95 (stage III and IV, LDH > 500 to 1,000 U/L), and R4/95 (stage III or IV, LDH > 1,000 U/L). Of eight patients with PMLBL treated in NHL-BFM 95, one patient was stratified into branch R2/95, four patients were stratified into branch R3/95, and three patients were stratified into branch R4/95 (Fig 1
Therapy elements and dosages of NHL-BFM 95 are given in Table 2
Response Criteria Tumor response was evaluated after each course of therapy. Follow-up studies were performed at 4- to 6-week intervals during the first 1.5 years after diagnosis. Treatment success was determined by event-free survival (EFS). Events were defined as death resulting from any cause, tumor progression or relapse, or second malignancy.
Analysis of pEFS (probability of EFS) was performed using the Kaplan-Meier method, with differences compared by the log-rank test; SE was calculated according to Greenwood.25,26 pEFS was calculated from the date of diagnosis to the first event (death from any cause, tumor progression, or second malignancy) or to the date of last follow-up. Differences in the distribution of different parameters were examined using the
Of a total of 1,650 pediatric patients with newly diagnosed NHL, 30 patients had PMLBL, accounting for 1.8% of pediatric NHL (Table 3 ).
Histopathology All patients exhibited the characteristic histopathology described for this lymphoma entity, with large pleomorphic B cells intermingled with small reactive lymphocytes. The lymphoid cells were irregularly arranged in compartments typically produced by branching stripes of interstitial fibrosis. A corresponding immunophenotype (with the tumor cells invariably expressing CD20, Ki-5B, and partially also CD30 in a few patients, but not CD5 or CD10) confirmed the morphologic diagnosis.
Clinical Features The most frequent presenting clinical symptom was pleural and/or pericardial effusion in 15 patients (50%). Four patients presented with clinical signs of obstruction or thrombosis of large thoracic vessels; one patient experienced severe acute pancreatitis as the first sign of PMLBL. Impaired renal function (determined by elevation of serum creatinine two times greater than the age-related normal value) was not present in any patient.
Treatment Results
Three of 30 patients with PMLBL did not respond to chemotherapy and died. Six patients relapsed after a median time of 10.3 months from initial diagnosis. Three of these relapsed patients are alive after autologous (n = 2) or allogeneic (n = 1) blood stem-cell transplantation. In four of six relapsed patients, relapse occurred locally and exclusively in the mediastinum. In two patients, additional sites were involved (lung, n = 1; cervical lymph nodes, n = 1).
Events according to study and therapy branches are given in Table 4
The course of the 28 patients receiving B-cell therapy is depicted in Fig 4 . One patient did not show any response to chemotherapy. Second-look surgery after three courses of chemotherapy and local irradiation (50 Gy) showed vital tumor tissue; this patient died of additional disease progress despite intensification of therapy. Five patients showed complete tumor regression after two courses of chemotherapy; two of these patients subsequently experienced local relapse. Twenty-two patients showed good but incomplete tumor regression after two courses of chemotherapy. In five of these patients, second-look surgery was performed after two to three courses of therapy, showing nonviable tumor remnants in all patients. None of these patients relapsed. Seventeen of 22 patients with incomplete tumor regression after two courses of therapy did not undergo second-look biopsy and continued with chemotherapy. In two of these patients, residual masses had disappeared by the end of chemotherapy; one of these patients relapsed locally. Fifteen patients had local tumor remnants after the end of chemotherapy. In three of these patients, second-look surgery was performed after the end of therapy, showing necrotic tissue in all cases. One of these patients experienced relapse (local plus new sites). Of 12 patients without second-look surgery, two patients experienced local relapse.
Radiotherapy was not part of the therapy protocol. However, three patients without response to chemotherapy received local irradiation; all of these patients subsequently experienced disease progression. Furthermore, three of 22 patients with incomplete tumor regression after three courses of chemotherapy received additional local radiotherapy with 30 (n = 2) and 25 (n = 1) Gy after the end of chemotherapy, which was based on the decision of the physician in charge (Fig 4  ). All three irradiated patients remained free from disease progression.
Prognostic Factors
Data and results from NHL-BFM trials on pediatric patients with PMLBL represent the largest series of uniformly treated pediatric patients with PMLBL at present.13–15 In the majority of reports on pediatric NHL, patients with PMLBL are not analyzed as a separate entity, but are included in the group of either large B-cell lymphomas or large-cell lymphomas of the mediastinum.29,30 These categories represent rather heterogenous groups of NHL entities of biologically different types of NHL. PMLBL, however, is a distinct entity of NHL derived from mature thymic B cells.1–4 Data from the NHL-BFM trials regarding frequency and presentation of NHL entities may be considered population based and epidemiologically representative, inasmuch as more than 90% of all pediatric patients with newly diagnosed NHL in Germany and Austria are registered in the NHL-BFM trial.31 According to our data, PMLBL is a rare entity of NHL in the pediatric population, accounting for less than 2% of the NHL-BFM study population. Median age of pediatric patients with PMLBL is significantly higher compared with the remaining study population exhibiting NHL entities (14.3 v 9 years; P = .0001). These data are consistent with findings from adult series, which describe PMLBL mainly as a tumor of young-adult age.5–7,9,11,32 However, 50% of patients with PMLBL registered in the NHL-BFM trials were younger than 14 years, indicating the necessity of careful diagnostic and immunohistochemical evaluation of all pediatric patients with a mediastinal mass. In contrast to previous reports from series with adult patients with PMLBL, data from the NHL-BFM trials did not show the previously described female predominance; 50% of all pediatric patients with PMLBL were male.6,9,10 Similar to previous reports on adult patients, in the present study, PMLBL presented most frequently as a large mediastinal mass. Presenting symptoms were respiratory distress, pleural and pericardial effusions, and compression of large thoracic vessels. The frequency of renal and lung involvement seems to be similar in pediatric and adult patients.3,6,8 In contrast to other entities of NHL in childhood, PMLBL does not seem to cause impairment of renal function even if both kidneys are infiltrated; none of the seven patients with renal involvement in our series showed elevated creatinine levels at diagnosis.33,34 Chemotherapy alone, according to protocol NHL-BFM for mature B-NHL, seems to be efficient in the treatment of PMLBL in childhood, yielding a pEFS of 0.75 (SE, 0.08). pEFS of the 28 patients with PMLBL treated according to the B-NHL strategy was not significantly inferior to pEFS of patients with stage III of other subtypes of childhood B-NHL. It is not possible to compare treatment outcome of our patients with PMLBL with that of other therapeutic trials on pediatric NHL because of the above-mentioned fact that PMLBL of childhood are not analyzed separately as a distinct entity of NHL in any other published study. In the reports of the French LMB studies, patients with PMLBL are included in the broader category with large B-cell lymphomas.29 In a retrospective analysis of 20 children with large-cell lymphoma of the mediastinum (only nine of 20 patients were evaluated for immunophenotype) from four Children’s Cancer Group studies, a 5-year pEFS of 75% was reported.30 However, these 20 children were treated according to four different treatment protocols. In addition, eight of these 20 patients received local irradiation of different dosage, varying from 20 to 30 Gy.30 In adult series, which analyzed patients with PMLBL separately, intensive multidrug chemotherapy for B-NHL proved to be efficacious in the therapy of adult PMLBL.5,10–12,35,36 However, most adult therapy protocols for mediastinal B-NHL include local radiotherapy. Some recently published studies not only report an improvement of outcome for irradiated patients with residual mediastinal tumors, but also for irradiated patients without residual tumor at the end of chemotherapy.12 The NHL-BFM trials did not include radiotherapy during first-line therapy for B-NHL. Even patients with residual mediastinal masses after the end of chemotherapy were not supposed to be irradiated according to the protocol. Only three patients in the present series received radiotherapy at the end of chemotherapy as a result of the individual decisions of the physician in charge. Mediastinal radiotherapy remains a critical issue in pediatric and adolescent patients. Published data on the increased incidence of breast cancer in young women who had received mediastinal radiotherapy in adolescence have enhanced skepticism toward mediastinal radiotherapy in pediatric patients.37 Answering the question of who could possibly benefit from additional radiotherapy is therefore important for future therapy trials in pediatric PMLBL. According to our data, the presence of residual tumor after chemotherapy does not seem to be a useful criterion to discriminate patients with especially high risk of failure who could possibly benefit from additional radiotherapy: Only three of 15 patients with residual masses subsequently experienced progressive disease; on the other hand, two of five patients with complete tumor regression after two courses of chemotherapy experienced relapse. Positron emission tomography (PET) scan and gallium-67 single positron emission computed tomography (67Ga-SPECT) may be appropriate diagnostic tools for predicting the risk of failure by evaluating metabolic activity of residual mediastinal masses.12 However, only limited experience exists with the use of 67Ga-SPECT in pediatric patients. Furthermore, the phenomenon of thymic rebound growth and enhanced metabolic activity after chemotherapy in pediatric patients is well known and might jeopardize the reliability of mediastinal PET and 67Ga-SPECT in pediatric patients. Additional studies and standardization of these imaging studies in the pediatric patient population are required before PET scan or 67Ga-SPECT could qualify as diagnostic criterion in the critical question of whether mediastinal radiotherapy is suitable for pediatric PMLBL. In our series, serum LDH more than 500 U/L at diagnosis was associated with an increased risk of failure (pEFS, 0.40; SE 0.15). Very early in the course of the disease, this easily accessible parameter might define a subset of approximately one third of patients who could benefit from treatment intensification including local irradiation.
Principal investigators: R. Mertens, Aachen; A. Gnekow, Augsburg; G. Henze, Berlin-Charité; J. Krause, Chemnitz; G. Weißbach, Dresden; G. Weinmann, Erfurt; D. Beck, Erlangen; W. Havers, Essen; B. Kornhuber, Frankfurt; C. Niemeyer, Freiburg; K. Welte, Hannover; B. Selle, Heidelberg; N. Graf, Homburg-Saar; M. Rister, Koblenz; P. Thomas, Krefeld; U. Mittler, Magdeburg; J. Haas, C. Bender-Götze, München; H. Jürgens, Münster; R. Geib, Saarbrücken; D. Niethammer, Tübingen; J. Kühl, Würzburg, Germany; C. Urban, Graz, Austria; and F. Niggli, Zürich, Switzerland. Contributing pathologists: H. Mittermeyer, Aachen; R. Backmann, Augsburg; H. Stein, Berlin; J.O. Habeck, Chemnitz; E.W. Schwarze, Dortmund; M. Müller, Dresden; V. Becker, Erlangen; L.D. Leder, Essen; S. Falk, Frankfurt; N. Böhm, Freiburg; A. Georgii, Hannover; F. Otto, Heidelberg; K. Remberger, Homburg/Saar; F. deLeon, Koblenz; O.M. Gokel, Krefeld; A. Roessner, Magdeburg; K. Wurster, P. Meister, München; G. Grundmann, Münster; H. Mitschke, Saarbrücken; P. Kaiserling, Tübingen; H.K. Müller-Hermelink, Würzburg; C. Schmid, Graz, Austria; and T. Stallmach, Zürich, Switzerland. Reference laboratories for histopathology and immunophenotyping: R. Parwaresch, M. Tiemann, Lymph Node Registry founded by the Society of German Pathologists, Institute of Hematopathology, University Kiel, Kiel; H.K. Müller-Hermelink, Institute of Pathology, University Würzburg, Würzburg; H. Stein, Institute of Pathology, Free University Berlin, Berlin; A. Feller, Institute of Pathology, University Lübeck, Lübeck, Germany; and I. Simonitsch, Institute of Pathology, University Vienna, Austria.
We thank E. Odenwald for expert work in cytological diagnosis, and U. Meyer for excellent data management. We especially thank all doctors and nurses in participating hospitals for their continuous care for sick children and their excellent cooperation with the NHL-BFM study center.
Supported by the Deutsche Krebshilfe, Bonn, Germany, grant no. M 109/91/Re1; T 12/96Re I.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
500 U/L was associated with increased risk of failure in multivariate analysis. 
2 or Fisher’s exact test. Prognostic relevance of different parameters was examined by stepwise Cox regression analysis.
