Prognostic Significance of CD20 Expression in Classical Hodgkin Lymphoma: a Clinicopathological Study of 119 Cases1

Vol. 9, 1381–1386, April 2003 Clinical Cancer Research 1381

Prognostic Significance of CD20 Expression in Classical Hodgkin Lymphoma: A Clinicopathological Study of 119 Cases1

Alexandar Tzankov,2 Jens Krugmann, INTRODUCTION Falko Fend, Martina Fischhofer, Richard Greil, HRS3 cells represent the neoplastic population of cHL. and Stephan Dirnhofer Recent immunological and molecular studies have shown that Institute of Pathology [A. T., J. K.] and Department of Hematology HRS cells originate from mature germinal center B cells that and Oncology and the Tyrolean Cancer Research Institute [M. F., have undergone clonal immunoglobulin gene rearrangement, R. G.], University of Innsbruck, A-6020 Innsbruck, Austria; Institute but have crippling mutations or other molecular alterations, of Pathology, Klinikum Rechts der Isar, Technical University of preventing immunoglobulin transcription (1–7). Although cHL Munich, Munich, Germany [F. F.]; and Institute of Pathology, University of Basel, Basel, Switzerland [S. D.] is genotypically considered a B-cell lymphoma, the classical B-cell marker CD20 is expressed only in ϳ20–30% of such cases. Moreover, CD20 is the only marker of B-cell differenti- ABSTRACT ation that can be repeatedly and reproducibly detected on HRS Purpose: Recent evidence has demonstrated that classi- cells in paraffin sections (7–9). CD20 is a membrane-embedded, cal Hodgkin lymphoma (cHL) originates from mature ger- nonglycosylated, phosphorylated protein (10, 11) that appears minal center B cells. However, only ϳ25% of cHLs express on the B-cell surface after immunoglobulin light chain rear- the classical B-cell marker CD20. There is very little, and rangement and before expression of intact surface immunoglob- controversial, information on the prognostic significance of ulin (12). CD20 resembles a Ca2ϩ ion channel (11, 13) and is CD20 expression in cHL with regard to failure-free (FFS) involved in signal transduction for B-cell differentiation and and overall survival (OS). proliferation (14), as well as for G0-G1 cell cycle transition (15). Experimental Design: CD20 expression was investigated Clinically established prognostic factors in cHL are stage, in a series of 119 cases of cHL treated at a single institution age, presence of B-symptoms, bulky disease, hemoglobin con- where complete clinical follow-up was available. The results centration, erythrocyte sedimentation rate, and serum levels of were correlated to FFS and OS by the Kaplan-Maier ␤ albumin, lactate dehydrogenase, 2-microglobulin, and interleu- method and uni- and multivariate analyses. kin-10 as well as association with HIV (16–20). The prognostic Results: Hodgkin and Reed-Sternberg cells expressed significance of CD20 expression in cHL is controversial and a CD20 in 20% (24 of 119) of the cases based on a cutoff of matter of ongoing debate (19–23). The German Hodgkin Study 10% positivity. Within a mean follow-up period of 12 years, Group reported that the CD30ϩ/CD20ϩ immunophenotype of univariate analysis revealed a significantly higher frequency HRS cells has a positive but statistically insignificant impact on of disease relapses in the CD20-negative group (30 of 95; FFS in cHL (20). In the same study, however, CD30Ϫ/CD15Ϫ/ 32%) compared with CD20-positive tumors (2 of 24; 8%; CD20ϩ cHL had an inferior clinical outcome. In a recent -Compared by the log-rank test, the mean FFS in investigation, Rassidakis et al. (19) found no association be .(0.022 ؍ P CD20-negative cases (202 months) was considerably shorter tween CD20 status and FFS or OS in patients with stages I–IV ؍ than in the CD20-positive cases (286 months; P 0.0195). In cHL treated by at least seven efficacy-equivalent chemotherapy a multivariate analysis, CD20 expression was an independ- regimens. In line with these findings, Molot et al. (22) reported ent positive prognostic factor for FFS in cHL patients no prognostic role for CD20 expression in Hodgkin lymphoma, ؍ treated from 1974 to 1980 (P 0.035). This effect disap- whereas the group from Memorial Sloan-Kettering Cancer Cen- ؍ peared in the period from 1981 to 1999 (P 0.266). ter (23) found an inferior clinical outcome in CD20-positive Conclusion: CD20-positive cHL shows a trend for bet- cHL patients. ter FFS and OS. However, improved treatment modalities To further assess the prognostic significance of CD20 seem to abolish these differences. expression in cHL, we performed a retrospective single institutional study of 119 cases with a mean clinical follow-up of 12 years.

Received 8/19/2002; revised 11/15/2002; accepted 11/15/2002. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to 3 The abbreviations used are: HRS, Hodgkin and Reed-Sternberg; indicate this fact. cHL, classical Hodgkin lymphoma; FFS, failure-free survival; 1 This study was supported by the Austrian National Bank (Project OS, overall survival; EBV, Epstein-Barr virus; LMP-1, latent 5621) and by the Krebshilfe Tirol. membrane protein-1 of Epstein-Barr virus; ABVD, adriamycin- 2 To whom requests for reprints should be addressed, at Institute of bleomycin-vincristine-dacarbatine; COPP, cyclophosphamide-vin- Pathology, University of Innsbruck, Mu¨llerstrasse 44, A-6020 Inns- cristine-procarbazine-prednisone; BEACOPP, bleomycin-etoposide- bruck, Austria. Phone: 43 512 507 36 92; Fax: 43 512 58 20 88; E-mail: adriamycin-cyclophosphamide-vincristine-procarbatine-prednisone; [email protected]. LPHL, lymphocyte-predominant Hodgkin lymphoma.

Table 1 Antibodies and antigen retrieval techniques used Antibody Antigen retrieval Dilution Incubation Source CD15 Pressure cooker; 5 min; 121°C 1:400 30 min; 20°C DAKO CD20 Microwave oven; 10 min; 800 W 1:700 30 min; 20°C DAKO CD30 Pressure cooker; 5 min; 121°C 1:50 30 min; 20°C DAKO LMP-1 0.1% pronase; 4 min 1:1000 30 min; 20°C DAKO

Fig. 1 Expression of CD20 in Hodgkin cells of cHL. Cells are stained with immunoperoxidase stain. Magnification, ϫ400.

PATIENTS AND METHODS used as chromogen. For positive control staining, tonsils with Patients. We analyzed 119 formalin-fixed, paraffin-em- follicular hyperplasia and with paracortical hyperplasia from bedded samples from cHL cases from the files of the Depart- patients with florid infectious mononucleosis were used. For ment of Pathology at the University of Innsbruck, diagnosed negative controls, the primary antibodies were omitted. A case between 1974 and 1999 (24). All cases were reclassified ac- was considered CD20-positive if there was specific membra- cording to the updated WHO classification (8). Clinical data nous staining in Ͼ10% of the HRS cells (Fig. 1). The staining were obtained by reviewing the charts and contacting the treat- intensity of small B lymphocytes within the cHL infiltrates ing physicians. Treatment was either standard or consistent with served as internal control. Taking into account previous studies the investigational protocols active during the time the patients investigating the expression pattern of CD20 in cHL and its were diagnosed. In brief, patients were staged surgically in association with clinical outcome (19–21), we considered a stages I and II when radiotherapy was administered as the sole cutoff value of 10% the most appropriate. treatment modality. Otherwise, patients were staged clinically Statistical Analysis. Statistical analysis was performed and mostly treated with risk-adapted treatment strategies ac- using the Statistical Package of Social Sciences (SPSS). FFS cording to the protocols of the German Hodgkin Study Group. was analyzed with the Kaplan-Maier method and compared by 2 In advanced stages, radiotherapy was used only for treatment of the log-rank test. The Pearson ␹ test was applied to demonstrate residual disease or primary bulky disease (24). Disease remis- correlations between expression of CD20 and relapse rate as sion was defined as absence of disease for at least 1 month as well as different clinical and laboratory parameters. To compare determined by laboratory and imaging studies as well as phys- differences for patients treated before and after 1980, we used ical examination. Disease relapse was defined as disease pro- the independent sample t test. Multivariate analysis for the effect gression occurring at least 1 month after achieving disease of expression of CD15 and CD20 as well as for age, sex, Ann remission. Treatment failure was defined as disease relapse or Arbor stage, EBV association, B-symptoms, and histological primary treatment resistance. subtype was performed using a general linear model. P Ͻ 0.05 Immunohistochemistry. The primary antibodies used in was considered significant. this study and types of antigen retrieval performed are listed in Table 1. Standard immunoperoxidase techniques were used with RESULTS an automated immunostainer (Nexes; Ventana, Tucson, AZ) Clinical Data, Histopathology, and OS Analysis. Our exactly as described previously (25). Diaminobenzidine was study group consisted of 65 (55%) male and 54 (45%) female

Table 2 Clinicopathological characteristics of cHL patients with respect to CD20 expression All patients CD20-positive (n) cases, n (%) Histology Nodular sclerosis 70 11 (16) Mixed cellularity 39 9 (23) Lymphocyte depleted 3 1 (33) Lymphocyte rich 7 3 (43) Sex M 65 14 (22) F 54 10 (19) Ann Arbor stage I–II 68 17 (25) III–IV 42 5 (12) Age (years) Ͻ45 86 13 (15) Ͼ45 33 11 (33) Therapy Radiotherapy 24 6 (25) Chemotherapy/Radiochemotherapy 84 16 (19) ABVD 27 6 (22) COPP 15 1 (7) COPP ϩ ABVD or BEACOPP 42 8 (19) B-Symptoms 51 11 (22) Fig. 2 FFS of cHL patients correlated with the expression of CD20. Total 119 24 (20) CD20ϩ versus CD20Ϫ was compared by the log-rank test.

patients. The mean ages were 40.4 years (range, 14–83 years) patient characteristics of CD20 expression are summarized in for the men and 34.3 years (range, 16–77 years) for the women. Table 2. Eighty-six of the 119 patients (72%) were younger than 45 years Statistical Analysis of the Prognostic Significance of of age. Histopathologically, this group included 70 cases with CD20 Expression. CD20 expression was asymmetrically dis- nodular sclerosis, 39 with mixed cellularity, 7 with lymphocyte- tributed in the age groups (15% CD20-positive cases in patients rich cHL, and 3 with lymphocyte-depleted cHL. According to Ͻ45 years of age, 33% in patients Ͼ45 years; P ϭ 0.027). There the Ann Arbor classification, 12 cases presented in clinical stage was no correlation of CD20 expression with EBV infection of I, 56 in stage II, 27 in stage III, and 15 in stage IV; 31 cases HRS cells (P ϭ 0.7). Univariate analysis revealed a significantly (26%) were associated with EBV, as assessed by the expression higher frequency of disease relapses in the CD20-negative of LMP-1. Fifty-four patients were treated with combined ra- group (30 of 95; 32%) compared with the CD20-positive group diochemotherapy, 30 were treated with chemotherapy, and 24 (2 of 24; 8%; P ϭ 0.022). Compared by the log-rank test, the were treated with radiotherapy alone. Of the 84 patients treated FFS was worse in the CD20-negative than the CD20-positive with combined radiochemotherapy or chemotherapy alone, 18 group; P ϭ 0.0195; Fig. 2). received ABVD ϩ COPP, 24 received BEACOPP, 27 received We then evaluated relapse rates in CD20-positive and ABVD, and 15 received COPP chemotherapy regimens (Table -negative cases within the different patient groups, using as 2). Within the median follow-up period of 127 months (range, criteria treatment regimens, including the different types of 0.2–331 months), OS was 59%, and the average time to first chemotherapy; age; sex; disease stage; histological subtypes; relapse was 52 months (range, 5.7–186 months). Disease re- LMP-1; and CD15-positive and -negative clusters as well as the lapses were observed in 32 patients (27%). During the course of presence or absence of B-symptoms. When we applied the our study, there were seven malignancy-related deaths, six at- log-rank test, CD20 expression appeared to be a statistically tributable to disease relapse and one attributable to primary significant prognostic factor for FFS in all groups except for age refractory disease. In addition, 11 patients died from cardiovas- and stage, where it was of borderline significance (P ϭ 0.052 cular and pulmonary diseases, 6 from the development of a and 0.057, respectively; Table 3). For the different types of second malignancy, and 1 from trauma. During the course of chemotherapy, the unequivocal trend for a better FFS of CD20- this study, FFS in the whole collective increased from 45% for positive patients remained; however, because there were too few patients treated from 1974 to 1980 to 65% for patients treated cases in each group, this appeared not to be statistically signif- from 1981 to 1999 (P ϭ 0.007). icant. Multivariate analysis revealed that therapy regimens (P ϭ Immunohistochemistry. All cHLs in our study group 0.013), different types of chemotherapy applied (P ϭ 0.011, were CD30-positive, and 113 of 119 (95%) were also positive with patients receiving BEACOPP showing the best and ABVD for CD15. CD20 was expressed in 20% (24 of 119) of the cases the worst results), B-symptoms (P ϭ 0.014), and age (P ϭ (Table 2). With regard to therapy regimens, CD20 was ex- 0.042) were independent prognostic factors for OS and that pressed in 9 of 54 (17%) patients treated with combined radiotherapy regimens (P ϭ 0.0005) and stage (P ϭ 0.013) were chemotherapy, in 7 of 30 (23%) treated by chemotherapy, and in independent prognostic factors for FFS. CD20 did not appear to 6 of 24 (25%) treated by radiotherapy. The clinicopathological be an independent positive prognostic factor for FFS or OS in

Table 3 Relapses in CD20-positive and -negative cHLs within different patient groups Treatment failures n (%) P Grouping variable CD20ϩ cases CD20Ϫ cases Subgroups Whole collectives Treatment period 1974–1980 0/5 (0) 13/22 (57) 0.016 0.019 1981–1999 2/19 (11) 18/73 (25) 0.15 Therapy Radiotherapy 1/6 (16) 9/18 (50) 0.15 0.018 Radiochemotherapy 0/9 (0) 8/45 (17) 0.17 Chemotherapy 1/7 (14) 11/23 (48) 0.11 Stage I–II 2/17 (12) 11/53 (21) 0.37 0.057 III–IV 0/5 (0) 17/37 (46) 0.049 B-Symptoms No 1/11 (9) 17/48 (35) 0.12 0.043 Yes 1/11 (9) 11/40 (28) 0.2 Histology Nodular sclerosis 0/11 (0) 17/59 (29) 0.041 0.024 Mixed cellularity 1/9 (11) 12/30 (40) 0.02 Lymphocyte depleted 0/1 (0) 0/2 (0) Lymphocyte rich 1/3 (33) 1/4 (25) 0.8 LMP-1 Positive 1/7 (14) 6/24 (25) 0.5 0.030 Negative 1/17 (6) 24/71 (34) 0.017

this cHL study group, but the P for FFS was of borderline Interestingly, the prognostic value of CD20 expression for significance (P ϭ 0.058). Finally, malignancy-related mortality FFS in our series, although significant for the treatment period was exclusive to CD20-negative cases (n ϭ 7), although this 1974–1980, disappeared in the period 1981–1999. van Spronsen was not statistically significant. et al. (26) made the same observation for the prognostic signif- When analyzed separately for patients treated in the period icance of histopathological grading in nodular sclerosing cHL. 1974–1980, CD20 expression appeared to be of independent Thus, for the first time in cHL, we demonstrate that the signif- prognostic significance for both OS (P ϭ 0.004) and FFS (P ϭ icance of an immunohistochemically determined prognostic 0.035). The prognostic significance of CD20 disappeared in the marker can be neutralized by improved therapy regimens. period 1981–1999 because of better FFS in the CD20-negative Our results are at variance with the few studies investigat- group (75% for 1981–1999, compared with 43% for 1974– ing the association of CD20 expression with clinical outcome in 1980; P ϭ 0.005; Table 3). Comparisons with the t test revealed cHL (19–23). The German Hodgkin Study Group reported an no significant differences in disease stages, B-symptoms, age, inferior FFS and OS in 21 patients of 1286 who were classified EBV association, and CD20 status between patients treated in as cHL but expressed only CD20 (CD30Ϫ/CD15Ϫ/CD20ϩ the period 1974–1980 and those treated during 1981–1999, cHL; Ref. 20); however, it is not clear whether these cases may ϭ except for the specific therapy regimens applied (P 0.003). in part represent other entities, such as nodular LPHL or T-cell- After 1980, the proportion of patients treated by radiotherapy rich large B-cell lymphomas, or borderline cases, setting them alone was low (25% for 1981–1999, compared with 41% for apart from true cHL. The German Hodgkin Study Group also 1974–1980), but the proportion of patients treated by combined indicated that these tumors might represent lymphomas other ϩ radiochemotherapy or chemotherapy who received ABVD than cHL and recommended histopathological reevaluation in COPP or BEACOPP chemotherapy regimens was high. these cases, the results of which have not yet been reported. Interestingly, in the same study, CD30ϩ/CD15Ϯ/CD20ϩ cHL DISCUSSION cases had a better FFS than did CD30ϩ/CD15Ϯ/CD20Ϫ cases, In this single institutional study of 119 cases of CD30- in agreement with the results of our study. These differences did positive cHL with a mean follow-up period of 12 years, we not appear to be statistically significant (20), but the mean demonstrate that the disease immunophenotype CD30ϩ/ follow-up period was shorter than in our study. CD15Ϯ/CD20ϩ (20) is associated with a favorable clinical Donnelly et al. (23) from the Memorial Sloan-Kettering outcome. This was true for all histological subtypes and Ann Cancer Center described an association of CD20 expression in Arbor disease stages, CD15Ϯ and LMP-1Ϯ cases, male and cHL with worse clinical outcome. Unfortunately, their data have female patients from both age groups, patients with and without been published only as an abstract, and it is not clear what cutoff B-symptoms, and for all treatment regimens (Table 3). In a value was used to define CD20 positivity. CD20 was detected in multivariate analysis of all these factors, CD20 was not an only 9% (16 of 181) of cHL cases, and the follow-up period was independent prognostic factor for FFS. However, the P was of considerably shorter than in our study. borderline significance (P ϭ 0.058), indicating that analysis of Recently, Rassidakis et al. (19) analyzed 598 previously a larger patient population is warranted and will likely produce untreated cHL patients for the prognostic significance of CD20 significant conclusions. expression. CD20 was expressed by HRS cells in 22% of

patients but was not associated with different FFS after treat- in our group, there was no association between EBV infection ment with equivalent regimens. The discrepancy with our find- and expression of CD20. ings might be explained by differences in the follow-up period. The mean follow-up period in the study of Rassidakis et al. (19) ACKNOWLEDGMENTS was 65 months versus 144 months in our study, and we observed We thank A. Zimpfer for excellent technical assistance. 11 late relapses that occurred after follow-up month 65 in the CD20-negative group. REFERENCES Finally, in the study of Molot et al. (22), who reported no effect of CD20 expression on clinical outcome, only patients 1. Kamel, O. W., Chang, P. P., Hsu, F. J., Dolezal, M. V., Warnke, R. A., and van de Rijn, M. 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Alexandar Tzankov, Jens Krugmann, Falko Fend, et al.

Clin Cancer Res 2003;9:1381-1386.

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