Originally published as JCO Early Release 10.1200/JCO.2006.06.5342 on September 5 2006

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Prognostic Significance of T-Cell or Cytotoxic Molecules Phenotype in Classical Hodgkin’s Lymphoma: A Clinicopathologic Study

Naoko Asano, Aya Oshiro, Keitaro Matsuo, Yoshitoyo Kagami, Fumihiro Ishida, Ritsuro Suzuki, Tomohiro Kinoshita, Yoshie Shimoyama, Jun-Ichi Tamaru, Tadashi Yoshino, Kunio Kitamura, Hisashi Fukutani, Yasuo Morishima, Shigeo Nakamura

From the Department of Pathology and Molecular Diagnostics, Division of Epidemiology and Prevention, and Department of Hematology and Chemotherapy, Aichi Cancer Center; Department of HSCT Data Management, Department of Hematology, and Department of Pathology and Clinical Laboratories, Nagoya University, Nagoya; Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto; Department of Pathology, Saitama Medical Center, Saitama Medical School, Kawagoe; Department of Pathology, Faculty of Health Sciences, Okayama University, Okayama; Department of Internal Medicine, Ichinomiya Municipal Hospital, Ichinomiya; and Department of Internal Medicine, Aichi Hospital, Aichi Cancer Center, Okazaki, Japan

Address reprint requests to Naoko Asano, MD, Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan; e-mail: nasano{at}aichi-cc.jp

	ABSTRACT

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PURPOSE: Classical Hodgkin’s lymphoma (CHL) is characterized by Hodgkin’s and Reed-Sternberg (H-RS) cells, most of which are derived from germinal-center B cells. Nevertheless, one or more markers for T cells and follicular dendritic cells (FDC) may be expressed in a minority of H-RS cells in some CHL patients, although the clinical significance of this remains controversial. The aim of this study was to clarify the association between phenotypic expression and clinical outcome in CHL.

PATIENTS AND METHODS: Participants were 324 consecutive CHL patients, comprising 132 patients with nodular sclerosis (NS), 35 patients with NS grade 2 (NS2), and 157 patients with mixed cellularity (MC). We evaluated the presenting features and prognosis of patients on categorization into four phenotypically defined groups: B-cell (CD20⁺ and/or CD79a⁺; n = 63), T-cell and/or cytotoxic molecules (CD3⁺, CD4⁺, CD8⁺, CD45RO⁺, TIA-1⁺, and/or granzyme B⁺; n = 27), FDC (CD21⁺ without B-cell marker; n = 22), and null-cell types (n = 212). Other potential prognostic factors were examined.

RESULTS: The T-cell and/or cytotoxic molecules group showed a significantly poorer prognosis than the other three groups (P < .0001). This finding was seen consistently in multivariate analyses. Morphologic subtyping (NS/NS2/MC) and Epstein-Barr virus positivity were not identified as independent prognostic factors.

CONCLUSION: The presence of T-cell and/or cytotoxic antigens in H-RS cells may represent a poor prognostic factor in CHL, even if their expression is not regarded as lineage specific. Examination of T-cell and/or cytotoxic molecules phenotype in CHL patients is recommended as a routine pathologic practice.

	INTRODUCTION

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The recent availability of a large number of monoclonal antibodies for leukocyte surface markers has provided further evidence for the B-cell origin of Hodgkin’s and Reed-Sternberg (H-RS) cells in many but not all patients.^1,2 The application of molecular methods, single H-RS cell analysis,³ and comparative genome expression analysis⁴ has provided additional definitive evidence that H-RS cells of classical Hodgkin’s lymphoma (CHL) are derived from germinal-center B cells.^5-7 Nevertheless, a small number of patients with CHL are immunoreactive for T-cell antigens,^8,9 and rare occurrences of CHL are even derived genotypically from T cells.^10,11 Adding to this complexity, we reported previously nine patients with CHL with a follicular dendritic cell (FDC) phenotype without other B-cell or T-cell markers.¹² These phenotypic analyses were interpreted variously to suggest the distinct cellular origin (B cells, T cells, or FDCs) of H-RS cells, notwithstanding that the expression of these cell-associated antigens was found to lack clear lineage specificity. Of note, the association between the expression of these markers and clinical outcome in CHL has been controversial.

In this study, we investigated comprehensively 324 patients with CHL to clarify their clinicopathologic features and survival, with special reference to phenotypic properties (four phenotypes: B cell, T cell and/or cytotoxic molecules [T/CM], FDC, and null cell) and positivity for Epstein-Barr virus (EBV) on H-RS cells.

	PATIENTS AND METHODS

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Patient Samples
A total of 324 consecutive patients with CHL diagnosed between April 1982 and March 2005 at Aichi Cancer Center Hospital (Nagoya, Japan) were selected from patient records. Approval for the study was provided by the Institutional Review Board of Aichi Cancer Center.

For the diagnosis of CHL, all patients in this study were negative for human T-cell leukemia virus type 1 antibody in sera. The tumor cells showed no sinusoidal spread and grew separately from each other in all areas of the biopsies to exclude Hodgkin’s-like anaplastic large cell lymphoma (ALCL) under the Revised European-American Lymphoma classification.¹³ Patients with nodular lymphocyte-predominant Hodgkin’s lymphoma, which is now termed B-cell neoplasm, also were excluded.

Each patient case was reviewed independently by two pathologists (N.A. and S.N.), who used a combination of morphologic review and immunostaining to assign each patient case to one of the categories of the modified WHO classification scheme.¹⁴ Controversial determinations were reassessed jointly by the two pathologists until a consensus was reached. Morphologically related entities, such as Hodgkin’s-like ALCL and peripheral T-cell lymphoma with Reed-Sternberg–like cells, were ruled out by three external lymphoma experts (T. Yoshino, Okayama, Japan; K. Ohshima, Kurume, Japan; and Y. Matsuno, Tokyo, Japan), who were blinded to the phenotype and clinical course of the patients.

Tissue Specimens and Histology
Tissue samples were fixed in 10% formalin and embedded in paraffin, then sectioned at 5-µm intervals and stained with hematoxylin and eosin. Imprint smears of surgically rejected specimens were stained with May-Grünwald-Giemsa stain.

Immunohistochemistry
Formalin-fixed paraffin sections were subjected to immunoperoxidase studies using the avidin-biotin peroxidase complex method. Monoclonal antibodies used were CD3, CD8, UCHL-1/CD45RO, L26/CD20, 1F8/CD21, Ber-H2/CD30, CD79a, and ALK1 (DAKO, Glostrup, Denmark); CD4 (Novocastra Laboratories, Newcastle, United Kingdom); LeuM1/CD15 (Becton Dickinson, Sunnyvale, CA); TIA-1 (Coulter Immunology, Hialeah, FL); and granzyme B (Monosan, Uden, the Netherlands). All antibodies were first heated in a microwave, then the antibodies were used. Reaction for the reagents was considered positive when more than 5% of the H-RS cells stained, although in practice many of the positive samples showed marking in more than 10% of cells.

In Situ Hybridization Study
The presence of EBV small RNAs was determined by in situ hybridization using EBV-encoded small nuclear early-region oligonucleotides on formalin-fixed, paraffin-embedded sections as described previously.¹⁵

Statistical Analysis
Differences in characteristics between the two groups were examined by the ² test, Fisher’s exact test, Student’s t test, and Mann-Whitney U test as appropriate. Patient survival data were analyzed by the Kaplan-Meier method. Differences in survival were tested by the log-rank test. Survival for this study was evaluated in terms of disease-specific survival (DSS), measured from the date of diagnosis until the date of death as a result of a lymphoma-related cause. In DSS analysis, patients were censored at the time of death if this was from a cause unrelated to lymphoma, and deaths from treatment-related causes were classified as death from lymphoma. Univariate and multivariate analyses were performed with Cox proportional hazards regression models. Results are expressed as hazard ratios (HRs) and 95% CIs. All data were analyzed with the aid of STATA software (version 9.0, STATA Corp, College Station, TX).

	RESULTS

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Clinicopathologic Characteristics
Patient characteristics are summarized in Table 1. There were 223 male and 101 female patients with a median age of 48 years (range, 4 to 89). Histopathologically, they included 132 patients with nodular sclerosis (NS; median age, 31 years; range, 12 to 84 years, male-to-female ratio, 1.36), 35 with NS grade 2¹⁶ (NS2; median age, 50 years; range, 5 to 88 years; male-to-female ratio, 2.89), and 157 with mixed cellularity (MC; median age, 57 years; range, 4 to 89 years, male-to-female ratio, 3.36). On comparison, patients with NS showed a significantly younger age at onset (P = .0001) and a higher ratio of females (P = .001). Patients with NS2 were associated significantly with several aggressive clinical parameters, namely advanced clinical stage in 22 patients (63%; P = .023) and anemia (hemoglobin < 10.5 g/dL) in 11 patients (48%; P = .031).

Phenotypic Distribution of CHL
Based on the immunohistochemically recognizable features of the H-RS cell, the present series of CHL patients were delineated into four phenotypic groups, as summarized in Table 2. The first group included 63 patients with the B-cell phenotype with expression of CD20 or CD79a. The second group included 27 patients with the T/CM phenotype with expression of CD3, CD4, CD8, CD45RO, and/or CMs such as TIA-1 and granzyme B (Fig 1), but not CD20, CD79a. The third group included 22 patients with the FDC phenotype with expression of CD21, but not any of the other B- or T-cell markers. The fourth group included 212 patients with the null-cell phenotype without expression of the B-cell, T-cell, or FDC-related markers. In the T/CM group, the expression of CMs was found in 20 patients, five of whom lacked the other T-cell markers. All patients in this T/CM group were also negative for ALK1 by additional immunohistochemical staining.

View larger version (89K): [in this window] [in a new window]   Fig 1. Classical Hodgkin’s lymphoma (CHL) with T-cell and/or cytotoxic molecule expression. (A) T-cell and/or cytotoxic molecule–positive CHL patient sample shows fibrous collagen bands dividing the lymph node into nodules and is categorized as nodular sclerosis (original magnification x40). (B) Reed-Sternberg cells are present (original magnification x400) and (C) are immunoreactive for granzyme B (original magnification x400).

EBV Distribution in CHL
EBV was detected in 149 of 314 (47%) patients, with no association seen with histopathologic group. The EBV-positive group was characterized by a higher ratio of males and an older age of onset than the EBV-negative group. CD20 expression was more frequently detected in the EBV-positive group (P = .025).

Therapeutic Response
A total of 183 patients received combination chemotherapy consisting of first-line treatment regimens as follows: doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 146 patients); cyclophosphamide, vincristine, procarbazine, and prednisone (15 patients); bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (six patients); and cyclophosphamide, doxorubicin, vincristine, and prednisone (16 patients; Table 3). Ninety-four patients received radiation therapy, and 88 received both chemotherapy and radiation. In 106 patients with stage I/II disease, 78 patients (74%) received ABVD-based chemotherapy and six underwent radiation therapy only. No significant differences in treatment types were seen among phenotypic subgroups. In total, 77% patients (134 of 174) with CHL achieved a complete response with the initial therapy. Notably, the T/CM group showed a lower complete response rate (58%) and a higher no response rate (16%) than the other three groups.

Survival
DSS curves of the NS, NS2, and MC patients showed no significant differences among them. In Figure 2A, however, the DSS curves of the four phenotypic groups based on immunohistochemical evaluation revealed a significant difference (P = .0041). In the 139 patients who received ABVD-based chemotherapy, the survival rate of the T/CM-positive CHL patients was significantly poorer than that of the others (P < .0001; Fig 2B), and five patients showed an aggressive clinical course within 24 months of diagnosis. Median survival of stage I and II patients was 55 and 27 months, respectively. Two patients with stage I/II disease expressing the T/CM phenotype died within 12 months. Survival of the B-cell group tended to be relatively inferior to that of the null-cell group, but without statistical significance (data not shown). Finally, patients with EBV-positive CHL showed a tendency to poor prognosis compared with EBV-negative patients, but without significance by the log-rank test (P = .11).

View larger version (16K): [in this window] [in a new window]   Fig 2. Survival data for four subgroups by phenotypic differentiation (B cell, T cell and/or cytotoxic molecules [T/CM], null cell, follicular dendritic cells [FDC]) in classical Hodgkin’s lymphoma. (A) Disease-specific survival according to four phenotypic groups. (B) Prognosis of patients with the T/CM phenotype (———) is significantly poorer than that of those without this phenotype (–– ––) in classical Hodgkin’s lymphoma patients who received chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine.

	DISCUSSION

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Our study in 324 consecutive patients with Hodgkin’s lymphoma had three major findings. First, among the four phenotypic subclassifications (B-cell, T/CM, FDC, and null-cell groups), the T/CM group had a significantly poorer prognosis in uni- and multivariate analyses. To our knowledge, this is the first study to report the prognostic significance of this factor. Second, among the histopathologic groups (NS, NS2, and MC) of CHL, no significant differences were found in clinical features, except age at onset and sex ratio. Finally, EBV positivity was more prevalent in MC, occurred mostly in older men, and was not identified as an independent prognostic factor.

T-cell marker and/or CM expression has been demonstrated immunohistochemically on H-RS cells in approximately 5% to 20% of CHL patients, although there is little information in the literature regarding the clinicopathologic significance of their expression. In our series, T/CM marker expression was detected in 27 (8%) of 324 CHL patients, and was significantly associated with an adverse prognosis.

Genotypic evidence from several groups has indicated that the expression of T-cell phenotype on H-RS cells is aberrant.^10,17 Consistent findings regarding T-cell marker positivity and its prognostic significance have been reported.¹⁷ In one report, however, the proportion of T-cell marker expression was low.¹⁰ Conversely, CM positivity was reported in 10% to 18% of CHL patients.^18,19 Our relatively lower percentage (6%) of cytotoxic phenotype in CHL patients might have been influenced by the exclusion of borderline cases, which posed a problem in differential diagnosis from Hodgkin’s-like ALCL under the Revised European-American Lymphoma classification.¹³

We reported previously that CM expression has an independent prognostic impact associated with unfavorable survival in nodal peripheral T-cell lymphoma, unspecified.¹⁵ Moreover, TIA-1 and/or granzyme B expression on Hodgkin’s-like ALCL was significantly associated with an adverse prognosis (Asano et al, submitted for publication). These data suggest that the expression of CMs may be predictive of the overall survival of CHL patients. The case of a CHL patient with evidence of clonal T-cell receptor (TCR-) gene rearrangement who had considerably shorter disease-specific survival has been reported.¹⁷ Studies of TCR- rearrangement in H-RS cells have been technically challenging. A clonal TCR- chain gene was undetected in any of the patients with successful amplification of DNA by polymerase chain reaction analysis. This finding indicates that few patients with the T/CM phenotype have CHL of possible T-cell origin, although problems may have existed in the sensitivity of TCR- gene detection. The biologic significance of T/CM expression in CHL without genetic evidence of T-cell origin remains to be elucidated. These issues warrant additional investigation.

According to the WHO classification, histopathologic grouping in CHL is made in consideration of background inflammatory cells, including lymphocytes, plasmacytes, histiocytes, and eosinophils. In this study, we compared these morphologic groups (NS, NS2, and MC) in terms of clinical characteristics and survival, but found no significant differences among them, except for a younger age at onset and higher ratio of females in NS. As reported previously,¹⁴ the present MC group was characterized by a higher ratio of positivity for EBV compared with the NS group.

The clinicopathologic significance of EBV as a prognosticator in CHL patients is still controversial.^20-26 Several recent studies have documented a marked survival disadvantage in older EBV-positive CHL patients compared with EBV-negative patients.^21,22 In our study, however, no significant survival difference was seen between EBV-positive and -negative patients. These results conflict with those reported by others, but the clinical features of our EBV-positive patients were compatible with those reported previously.^20,23,24

The prognostic significance of B-cell or FDC marker in CHL is also controversial.²⁷ In this study, the expression of B-cell and FDC markers was detected in 20% and 7% of CHL cases, respectively. The B-cell group showed a relatively unfavorable clinical course compared with the null-cell group, whereas that of the FDC group was relatively favorable. These results may be in keeping with a recent report which identified the FDC marker as an independent favorable prognostic factor for overall survival in patients with diffuse large B-cell lymphoma.²⁸

Clinical prognostic factors for CHL have been studied by Hasenclever et al.²⁹ They showed that the IPFP score is useful in determining the prognosis of advanced CHL, and in clinical decision making for individual patients. In the present study, and consistent with other findings,³⁰ the IPFP score was found to have prognostic significance in CHL. Moreover, among patients with early-stage (I/II) CHL, those with an IPFP score of 3/4 showed a poorer prognosis than those with low-risk score (< 3), although there were no patients with a high IPFP score (5 or more) in the stage I/II patients (data not shown). One notable consideration is that T-cell or cytotoxic phenotype remained a significant prognostic factor even after adjustment for IPFP score.

Compared with Western CHL reports, the patients in this study were characterized by a low NS rate, low CD15 positivity, and poor prognosis.^14,27,31 According to these findings, the patients may have included far fewer NS cases with a favorable prognosis and CD15⁺ CD30⁺phenotype than in these Western studies. However, the T/CM phenotypic appearance of H-RS cells is present in Western as well as Japanese patients,^10,17-19 possibly indicating that the T/CM phenotype in CHL carries a poor prognosis in both Western and Asian patients.

In conclusion, we demonstrated that patients with CHL with the T/CM phenotype have a significantly poorer prognosis than those with the other phenotypic groups. Examination of T-cell markers in CHL patients is recommended as a routine pathologic practice.

	Appendix

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The following institutions provided patient clinical data and specimens: National Sapporo Hospital; Health Sciences University of Hokkaido; Asahikawa-kosei General Hospital; Akita University School of Medicine; Nagano Red Cross Hospital; Iida Municipal Hospital; Fukui Red Cross Hospital; Hamamatsu Medical Center; Seirei Mikatahara General Hospital; Toyohashi Municipal Hospital; Fujita Health University School of Medicine; Okazaki Municipal Hospital; Tousei Hospital; Japanese Red Cross Nagoya First Hospital; Nagoya Ekisaikai Hospital; Nagoya Memorial Hospital; Yokkaichi Municipal Hospital; Suzuka Chuo General Hospital; Mie University School of Medicine; Kyoto Prefectural University School of Medicine; Hyogo Medical Center for Adults.

	Authors’ Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Naoko Asano, Shigeo Nakamura Administrative support: Yasuo Morishima, Shigeo Nakamura Provision of study materials or patients: Naoko Asano, Aya Oshiro, Yoshitoyo Kagami, Tomohiro Kinoshita, Yoshie Shimoyama, Kunio Kitamura, Hisashi Fukutani, Yasuo Morishima, Shigeo Nakamura Collection and assembly of data: Naoko Asano, Aya Oshiro, Jun-Ichi Tamaru, Tadashi Yoshino, Shigeo Nakamura Data analysis and interpretation: Naoko Asano, Keitaro Matsuo, Fumihiro Ishida, Ritsuro Suzuki, Shigeo Nakamura Manuscript writing: Naoko Asano, Keitaro Matsuo, Shigeo Nakamura Final approval of manuscript: Naoko Asano, Aya Oshiro, Keitaro Matsuo, Yoshitoyo Kagami, Fumihiro Ishida, Ritsuro Suzuki, Tomohiro Kinoshita, Yoshie Shimoyama, Jun-Ichi Tamaru, Tadashi Yoshino, Kunio Kitamura, Hisashi Fukutani, Yasuo Morishima, Shigeo Nakamura

 

View larger version (9K): [in this window] [in a new window]   Fig A1. Survival data for three subgroups by histologic differentiation (nodular sclerosis [NS] v mixed cellularity [MC] v nodular sclerosis grade 2 [NS2]) in classical Hodgkin’s lymphoma. No significant difference in survival was observed among NS (dotted line), MC (heavy black line) and NS2 (red line) patients.

View larger version (9K): [in this window] [in a new window]   Fig A2. Survival data for two subgroups by Epstein-Barr virus (EBV) -positivity or -negativity in classical Hodgkin’s lymphoma. The EBV-positive subgroup (solid line) shows no significant difference when compared with the EBV-negative patients (dotted line).

View larger version (6K): [in this window] [in a new window]   Fig A3. Survival data for two subgroups by International Prognostic Factor Project (IPFP) score in early-stage classical Hodgkin’s lymphoma (CHL). Among patients with early-stage (stage I/II) CHL, those patients with an IPFP score of 3/4 showed a poorer prognosis than those with a low-risk score (< 3).

	ACKNOWLEDGMENTS

	NOTES

 
published online ahead of print at www.jco.org on September 5, 2006.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted March 9, 2006; accepted July 27, 2006.

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