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Originally published as JCO Early Release 10.1200/JCO.2005.03.6327 on April 24 2006 © 2006 American Society of Clinical Oncology. Marker Expression in Peripheral T-Cell Lymphoma: A Proposed Clinical-Pathologic Prognostic Score
From the Institute of Hematology and Clinical Oncology "L. and A. Seràgnoli," Hematology and Hematopathology Units, St Orsola-Malpighi Hospital, University of Bologna, Bologna; Hematology Unit, S. Croce and Carle Hospital, Cuneo; Institute of Pathology, Perugia University in Terni, Terni; Institute of Hematology, Perugia University, Perugia; Division of Pathology, Spedali Riuniti di Bergamo, Bergamo; Anatomy Pathology Section, Department of Human Pathology, University of Pavia, Pavia; Division of Hematology, University of Modena, Modena, Italy; University of Basel, Basel, Switzerland; and the Intergruppo Italiano Linformi Address reprint requests to Stefano A. Pileri, MD, and Pier Luigi Zinzani, MD, Pathology and Lymphoma Unit, Institute of Hematology and Clinical Oncology "L. and A. Seràgnoli," St Orsola-Malpighi Hospital, University of Bologna, Via G. Massarenti 9, 40138 Bologna, Italy; e-mail: pileri{at}med.unibo.it
PURPOSE: Although peripheral T-cell lymphoma, unspecified (PTCL/U), is the most common T-cell tumor in Western countries, no study to date has been based on the application of a wide panel of markers to a large series of patients and assessed the impact of phenotype on survival. We evaluated the expression of 19 markers in 148 PTCLs/U and 45 PTCLs of the angioimmunoblastic type (AILD). PATIENTS AND METHODS: The analysis was performed on tissue microarrays by immunohistochemistry and in situ hybridization. Clinical data were available in 93 PTCL/U patients, most of whom had been included in a previous study proposing a prognostic index (PIT).
RESULTS: An aberrant phenotype with frequent loss of CD5 and/or CD7 was typical for PTCLs, irrespective of whether they were U or AILD. Aberrantly expressed proteins rarely included CD20, CD15, and CD30. Positivity for Epstein-Barr virus–associated small RNAs and CD15 expression emerged as adverse prognostic factors. Among PTCLs/U, the proliferation-associated protein Ki-67 turned out to be prognostically relevant and was integrated in a new predictive score, incorporating age (> 60 years), high lactate dehydrogenase, poor performance status, and Ki-67 CONCLUSION: Our retrospective analysis shows a wide range of protein expression in PTCLs and proposes a new prognostic index. The latter represents one of the first examples of mixed score (including patient- and tumor-specific factors) applied to malignant lymphomas and may be the basis for future prospective therapeutic trials.
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of tumors that the WHO classification basically subdivides into specified and unspecified (U).1 In Western countries, they represent 15% to 20% of aggressive non-Hodgkin's lymphomas,2-4 and more often present in middle-aged/elderly patients in stage III to IV, with nodal and/or extranodal locations,5-7 who die rapidly despite aggressive therapies.8,9 Morphology does not correlate with outcome,10 and the significance of the international prognostic index (IPI) is controversial,11 although several investigators agree on its relevance.2,5,12 Recently, a clinical score has been proposed to improve prognostic stratification of PTCL/U patients.11 More refined diagnostic/prognostic criteria are certainly needed.13 In contrast to peripheral B-cell lymphomas, PTCLs have been the object of a few gene expression profiling studies.14-16 Immunohistochemical analysis shows that PTCL/U generally carries aberrant T-cell marker expression.17,18 Patients with nodal disease are more often CD4+, whereas the patients with extranodal are frequently CD8+.10 The exclusive positivity for CD4 or CD8, respectively, sometimes has been identified with monoclonality. The appearance of more rarely expressed molecules, such as CD15, can cause diagnostic difficulties. This study intends to clarify the antigen expression profile of PTCLs and correlate it with clinical presentation and follow-up.
Tissue Collection and Tissue Microarray Construction Paraffin blocks of 300 PTCLs, originally diagnosed at disease presentation as either U or the angioimmunoblastic type (AILD), were obtained from Intergruppo Italiano Linfomi centers, covering the period 1989 to 2001. Ninety-five samples were excluded from the present study because of one or more of the following reasons: insufficient amount of tissue spared, suboptimal tissue fixation, and no confirmation of the original diagnosis. The 205 selected samples were reclassified according to the criteria of the WHO Blue Book.1 For tissue microarray (TMA) construction, a slide stained with hematoxylin and eosin was prepared from each paraffin block, and representative tumor regions were morphologically identified and marked on each slide. Tissue cylinders with a diameter of 1.0 mm were punched from the marked areas of each block and brought into a recipient paraffin block using a precision instrument, as previously described.19 Four-µm thick sections were cut from each recipient block and used for Giemsa or immunohistochemical stains.
Immunohistochemistry
Patient Data Clinical data were available in 93 patients with PTCL/U, who were enrolled previously onto an Intergruppo Italiano Linfomi trial.11 The clinical data included age, sex, CBC, lactate dehydrogenase (LDH) level, and serum beta2-microglobulin level, Ann Arbor stage, IPI, number and sites of extranodal disease, bone marrow involvement, systemic symptoms, bulky disease, performance status (PS; ambulatory [Eastern Cooperative Oncology Group PS 0 to 1] v nonambulatory [Eastern Cooperative Oncology Group PS  2]), date of diagnosis, date of last follow-up, status (alive or dead), and if dead, date and cause of death. Bulky disease was defined as a mass with 10 cm diameter. Systemic symptoms were defined as recurrent fever (> 38°C), night sweats, or loss of more than 10% of body weight. Anemia was defined as a hemoglobin value less than 12 and 10 g/dL in men and women, respectively. Informed consent was obtained from all patients and each institutional ethical committee approved the tissue collection. If available, the original immunohistochemical stains on conventional sections were compared with the corresponding results on TMAs.
Statistical Analysis
One hundred ninety-six PTCLs were brought into a TMA format, of which 148 were U and 45 were AILD. After TMA immunohistochemical analysis, the three remaining samples were reclassified as anaplastic lymphoma kinase–positive (ALK+) anaplastic large cell lymphoma and excluded from additional evaluation. Morphologically, PTCLs of both U and AILD types fulfilled the criteria of the WHO classification1 (representative examples are shown in Figs 1A to 1C). Because of array tissue selection, the reactive component generally was scarce: it included small lymphocytes, eosinophils, plasma cells, histiocytes, and sometimes residual follicles (Fig 1D). Epithelioid elements were rarely abundant. Scattered Hodgkin's-Reed-Sternberg (HRS) –like cells were sometimes present within the atypical cellular milieu.
Protein Expression in PTCLs/U and PTCLs/AILD The number of analyzable samples varied for the 19 investigated markers due to TMA-related difficulties (ie, lack of tumor cells in the arrayed tissue or missing tissue (empty spots). Still, in 133 samples (68%), the entire set of markers was available. The T-cell receptor ß-chain (ßF1) was detected in 96% of all assessable samples, including those with CD56 and/or CD57 positivity and CD4/CD8 double-negativity (Fig 2A). Regarding conventional markers, CD3 was found in 86% of PTCLs/U and CD2 was found in 100% of PTCLs/AILD. In most PTCLs, at least one of the CD2, CD3, CD5, or CD7 antigens was lost, most frequently CD5 or CD7. An overview of marker expression is listed in Table 2. If we take into consideration the positivity for each single marker, CD4 was more frequently expressed than CD8 (46% v 15% and 42% v 19% among PTCLs/U and AILD, respectively; Table 2).
When CD4 and CD8 expression was evaluated in individual patients (Figs 1E to 1H and Fig 3), double-negative and double-positive tumors accounted for 55% of samples in both subgroups of PTCL. No correlation between CD4 and CD8 expression and that of cytotoxic markers (T-cell intracellular antigen 1 [TIA-1], granzyme B [GB], CD56, and CD57) was found. CD10 positivity was detected in two of 143 PTCLs/U and in 17 of 43 PTCLs/AILD (Table 2). Regarding the latter, the amount of neoplastic cells stained varied from sample to sample (5% to 60%; Fig 2B), and was equivalent on TMAs and conventional sections. EBER-positive tumor cells were detected in 5% of PTCLs/U (Fig 2C) and 3% of PTCLs/AILD. Notably, CD15 was seen in five PTCLs/U, and in three together with CD30. These three samples showed neither HRS cells nor anaplastic morphology on microscopic examination (Figs 2D and 2E).28,29 A high tumor cell proliferation was seen in 11% and 5% of PTCLs/U (Fig 2F) and AILD, respectively. Finally, the search for aberrant B-cell marker expression displayed CD20 positivity in 1% of the evaluated PTCLs. In samples with previously available immunostains, the results on conventional sections paralleled those on TMAs (data not shown).
Survival Analysis Of 93 PTCL/U patients with clinical information available, 44 died as a result of their disease (Fig 4A). Detailed clinical data are listed in Table 3. In the univariate analysis of DSS relative to the investigated proteins, expression of Ki-67 (relative risk, 2.831; 95% CI, 1.161 to 6.904; log-rank P = .0158), EBER (relative risk, 2.848; 95% CI, 0.993 to 8.168; log-rank P = .0398), and CD15 (relative risk, 3.584; 95% CI, 1.250 to 10.280; log-rank P = .0104) significantly correlated to the lowest survival rates. Patients with CD57-expressing tumors tended toward shorter survival times (log-rank P = .0864). All other immunohistochemical markers had no significant impact on survival. When CD4 and CD8 were combined, the CD4+/CD8– tumors had a better, but still not significantly different prognosis (P = .0646). Clinical factors associated with a worse survival were as follows: systemic symptoms (relative risk, 2.076; 95% CI, 1.146 to 3.760; log-rank P = .0130), age older than 60 years (relative risk, 2.011; 95% CI, 1.100 to 3.674; log-rank P = .0197), nonambulatory PS (relative risk, 2.416; 95% CI, 1.253 to 4.656; log-rank P = .0062), LDH higher than institutional upper level (relative risk, 1.868; 95% CI, 1.006 to 3.469; log-rank P = .0424), and bulky disease (relative risk, 2.826; 95% CI, 1.330 to 6.004; log-rank P = .0044). Ann Arbor stage was also significantly associated with survival (log-rank P < .0001), but some subgroups were small (Table 4). There was no significant association of survival with sex, anemia, number of nodal sites at presentation, IPI, elevated beta2-microglobulin, or bone marrow involvement. Notably, the IPI was not significant in univariate analysis of survival (P = .1), whereas the Prognostic Index for PTCL/U (PIT) score had prognostic value (P = .0043; Table 4).
On the basis of these findings, a multivariate analysis was carried out: CD15, EBV, and Ann Arbor stage were not considered due to the insufficient number of samples (Tables 2and 4). In this analysis, none of the remaining factors (age, PS, bulky, LDH, "B" symptoms, and high Ki-67 score) emerged as significant. When analyses were performed by including five of the above-mentioned six parameters (an attempt made in light of the relatively limited number of events), Ki-67 emerged as a significant risk factor (relative risk, 3.100; 95% CI, 1.210 to 7.947; P = .0185), whereas the PS (P = .0510) and LDH (P = .0730) were near the level of statistical significance.
Prognostic Index
The phenotypes, prognostic factors, and treatment options for PTCLs are still matter of debate, and these tumors are viewed as a wastebasket category, as was the diffuse large B-cell lymphoma before intensive gene expression profiling allowed its subdivision into subgroups.36,37 This TMA-based study focuses on the molecular characteristics of 148 and 45 PTCLs, U and AILD, respectively, by expanding the spectrum of information provided by the WHO Blue Book.1
The ßF1 antibody reacted with 96% of our samples. Matched with the remaining immunostains, this finding rules out the possible inclusion of natural killer/large granular lymphocyte tumors in our series. In contrast, the six ßF1-negative samples might exhibit a Within this context, the variable expression of CD4 and CD8 is noteworthy. In our hands, neoplastic cells of PTCL/U more commonly expressed CD4 than CD8 (46% v 15%), a figure largely in line with previous reports.10,13,38,39,41 In contrast to results reported by Geissinger et al,38 no association was seen between CD4 or CD8 expression and the proliferation activity. Interestingly, we found 32% of PTCLs/AILD to be CD8 positive, which is in the upper range of values reported in previous publications.42-56 In contrast, the incidence of CD4 positivity (42%) was much lower than expected. In fact, Lee et al57 suggested that most if not all PTCLs/AILD are derived from CD4+/CD8– mature T-helper cells. The observed variation might be due to methodologic differences, given that Lee et al57 used a sophisticated approach including double and triple immunohistochemical stains, which is not applicable to the daily routine. Our observation of a huge number of PTCLs/U and PTCLs/AILD (55%) that were either CD4/CD8 double-negative or, more rarely, double-positive, is of significant interest. Such profiles that are usually observed during intrathymic T-cell development,1 have been reported previously in isolated PTCL patients58,59 and a proportion of cutaneous T-cell tumors,60 making this, to the best of our knowledge, the first demonstration that PTCL/U and PTCL/AILD can carry such aberrancies, which may be diagnostically relevant. The expression of CD56 and CD57 rarely has been studied in PTCL/U. The former marker is seldom expressed in normal T-lymphocytes, and is usually associated with spontaneous cytotoxicity restricted to non–major histocompatibility complex.61 Thus, CD56-positivity suggests a malignant phenotype and has been reported in several nodal and extranodal specified PTCLs.1,62 In our study, a CD56+/ßF1+ phenotype was detected in 5% of PTCLs/U, and it is interesting that only three of these samples coexpressed TIA-1 and none coexpressed GB. CD57 was seen in 10% and 5% of our PTCLs, U and AILD, respectively. Although CD57+ normal T lymphocytes increase with age, we observed no correlation between patient age and CD57 expression.63 Other aberrantly expressed markers, such as CD15 (recorded in 4% of our patients), CD30 (6%), and CD20 (1%), may cause diagnostic difficulties. In particular, we found expression of CD20 in only two PTCLs/U that were both negative for CD79a, in keeping with previous observations of CD20 positivity in isolated PTCLs/U, and CD79a aberrant expression in specified PTCLs.64-66 Coexpression of CD15 and CD30 raises the question of how to differentiate between PTCL and Hodgkin's lymphoma, as discussed by Barry et al,28 who described CD15+/CD30+ PTCLs with and without HRS-like cells. In agreement with Gorczyca et al,29 our three CD15/CD30 double-positive samples contained no HRS-like cells. Interestingly, the reports of Barry et al28 and Gorczyca et al29 were based on highly selected series, whereas our study represents the first opportunity to assess randomly the prevalence of such marker association. The fact that only three of 183 assessable patients (1.6%) showed CD15/CD30 double-positive neoplastic cells demonstrates the rarity of this phenotypic aberration. Finally, our data are in line with previous observations that CD10 positivity is characteristic of PTCL/AILD.23,24 Notably, in our series only 39% of AILD tumors were CD10 positive, even by adopting a low cutoff value, and these results did not vary between TMAs and conventional sections. This prompts us to verify further the exact incidence of such findings in future studies. The patient subgroups enrolled in the course of clinicopathologic trials should be as homogeneous as possible to avoid interpretation bias and identify effective therapies. In particular, markers capable of assessing individual risk at disease presentation must be easily detectable and should stratify patients reliably based on their combination. In our collection, the following biopathologic factors were associated with the worst outcome in PTCL/U: high Ki-67 expression, EBV positivity, and CD15 staining. The latter finding has not been recognized as an adverse parameter in previous studies and needs confirmation in the light of the limited number of positive tumors in our series. EBV has been proposed as a negative prognosticator in PTCL/U,67 and is more commonly detected among Asian patients.68 We found EBV positivity in 5% and 3% of PTCLs, U and AILD, respectively, and confirmed its unfavorable impact on survival. No other immunohistochemical marker alone or in combination was associated with a poor outcome, although patients with tumors expressing CD57 or CD4+/CD8– phenotype showed a tendency for a better outcome; the possible prognostic relevance of the latter have also been proposed by others.10,60 The optimal approach to predicting patient prognosis integrates more than one factor, and ideally should incorporate both patient- and tumor-specific characteristics. In PTCL/U, the IPI, originally developed to predict the course of aggressive lymphomas,69 is most commonly used, and is associated significantly with survival according to several reports.70-72 That this finding has not been confirmed in our study is likely due to a bias in our patient mix (ie, only one patient was designated as stage I and died early in the course of the disease). Recently, a new prognostic index tailored for PTCL/U (PIT) was proposed by Gallamini et al,11 based on a retrospective multicentric clinical analysis of 385 patients, which included bone marrow involvement, age, PS, and LDH. If these four variables are combined in four groups, the PIT can identify patient subgroups with different outcomes. However, PIT does not include tumor-specific factors and is based on a series lacking systematic histologic review.
On the basis of our controlled collective and previous experience in the literature,11,30-35 a new score was developed that integrates both patient- and tumor-specific characteristics (age, PS, LDH, and Ki-67 marking
The following clinicians and/or pathologists, listed according to their respective institutions, also contributed to the study: Francesco Zaja, Carlo A. Beltrami (Department of Pathology, University of Udine School of Medicine, Italy); Maurizio Martelli, Carlo D. Baroni (Institute of Pathology, University of Roma "La Sapienza," Italy); Luigi Rigacci, Simonetta Di Lollo (Department of Human Pathology and Oncology, University of Firenze, Italy); Alberto Comino (Division of Pathology, S. Croce and Carle Hospital, Cuneo, Italy); Paolo Coser, Vito Colombetti (Division of Pathology, Hospital of Bolzano, Italy); and Massimo Federico, Marina Milani (Institute of Pathology, University of Modena, Italy).
The authors indicated no potential conflicts of interest.
We thank Roberto Arcese, Silvia Asioli, Renzo Barbazza, Arrigo Bondi, Pierluigi Bontempo, Carlo Bordi, Giuseppe Brandi, Marco Cardarelli, Stefania Damiani, Stefania Discepoli, Fabio Facchetti, Giorgio Gardini, Raffaella Gentile, Giuseppe Lanzanova, Vladimiro Mambelli, Pietro Muretto, M. Kat Occhipinti-Bender, Lapo Alinari, Giuseppe Pizzicannella, Flavia Renda, Luca Riccioni, Simona Righi, Paolo Rinaldi, Federica Sandri, Ariele Saragoni, Vincenzo Suma, Mauro Truini, and Luigi Tucci.
Supported by grants from Associazione Italiana per la Ricerca sul Cancro (Milan), Fondazione Cassa di Risparmio in Bologna, Fondazione della Banca del Monte e Ravenna, and BolognAIL; P.W. was supported by the Niklaus & Bertha Burckhardt-Bürgin Stiftung and the Krebsliga beider, Basel, Switzerland. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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ABSTRACT
INTRODUCTION
2 analyses. Survival curves were plotted according to the Kaplan-Meier method.
) in the arrayed spot of a PTCL/U (Giemsa stain; x250, x40, x400, x500, x125); (E and F) CD4/CD8 double-positivity (x250); and (G and H) double-negativity (x125).
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nature; however, this fact is irrelevant to our analysis. Both U and AILD PTCLs demonstrated a frequent loss of CD5 and CD7; CD3 was the most common conventional marker expressed in the former, and CD2 was the most common conventional marker expressed in the latter. Although the high frequency of CD3 positivity is in keeping with previous studies,
