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Maarten H. Vermeer, MD; Cornelis P. Tensen, PhD; Petra M. van der Stoop; Hans W. van Oostveen, PhD; Marianne Lund; Rik J. Scheper, PhD; Rein Willemze, MD, PhD

Arch Dermatol. 2001;137:901-905.

ABSTRACT
Background  Previous studies demonstrating that the neoplastic cells in Sézary syndrome and tumor stage mycosis fungoides express interleukin 4 (IL-4), IL-5, and IL-10 have resulted in the concept that cutaneous T-cell lymphomas are derived from CD4⁺ T cells with a T_H2 type cytokine profile.

Objective  To determine the cytokine profile in CD30^- primary cutaneous large T-cell lymphomas, which represent a subgroup of cutaneous T-cell lymphoma with an aggressive clinical behavior (5-year survival rate of 15%).

Design and Methods  Seven biopsy specimens were taken from 4 patients with CD30^- primary cutaneous large T-cell lymphomas and studied for the expression of T_H1 (IL-2 and interferon ) and T_H2 (IL-4, IL-5, IL-10) cytokines using a reverse transcription–polymerase chain reaction technique. Skin biopsy specimens from patients with Sézary syndrome, mycosis fungoides, atopic dermatitis, or psoriasis were included as controls.

Results  In the 7 CD30^- primary cutaneous large T-cell lymphomas showing an almost pure population of large tumor cells (>90%), no expression of IL-4 was found, and IL-5 was only found in 1 of 7 cases. In control biopsy specimens, expression of IL-4 and/or IL-5 was demonstrated in atopic dermatitis (3/3), tumor stage mycosis fungoides (2/2), and Sézary syndrome (3/3), but not in plaque stage mycosis fungoides.

Conclusion  Our results demonstrate that CD30^- primary cutaneous large T-cell lymphomas do not produce T_H2 cytokines, illustrating that not all cutaneous T-cell lymphomas have a T_H2 cytokine profile.

INTRODUCTION

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CUTANEOUS T-cell lymphomas (CTCLs) are a heterogeneous group of T-cell lymphoproliferative disorders that clinically originate in the skin.¹ In most CTCLs, the neoplastic cells have the phenotype of skin homing CD3⁺, CD4⁺, CD8^-, and CD45RO⁺ memory T cells. In mice 2 distinct subsets of CD4⁺ T lymphocytes are distinguished on the basis of different patterns of cytokine secretion, ie, T_H1 cells producing interleukin 2 (IL-2), interferon (IFN-), and tumor necrosis factor (TNF-) and T_H2 cells producing IL-4, IL-5, and IL-10.² The cytokines produced by these 2 T-cell subsets have opposing effects. Thus, IL-2 and IFN- stimulate the proliferation of T_H1 cells but inhibit the proliferation of T_H2 cells, whereas IL-4 stimulates the proliferation of T_H2 cells and both IL-4 and IL-10 inhibit T_H1 cell growth and function.^3-4 Based on these observations in murine CD4⁺ T cells, several groups have started to evaluate cytokine profiles of the neoplastic CD4⁺ T cells in CTCL. Studies in Sézary syndrome (SS), a leukemic form of CTCL, demonstrated increased IL-4 and IL-5 and low IL-2 and IFN- production by peripheral blood mononuclear cells^5-6 and increased expression of IL-4 and IL-5 messenger RNA (mRNA) within lesional skin.⁷ Subsequent studies in lesional skin of mycosis fungoides (MF), the most common subtype of CTCL, demonstrated the presence of IL-4 and IL-5 mRNA in tumor stage MF but not in the early patch stage, whereas IL-2 and IFN- were detected in all stages.⁸ These observations resulted in the concept that the neoplastic T cells in MF and SS produce IL-4 and IL-5 (T_H2 cells), whereas the reactive inflammatory cells are the source of IL-2 and IFN- (T_H1 cells). This model implies that in the early stages of MF, in which the neoplastic T cells represent only a minority of the cellular infiltrate, the expansion of neoplastic T_H2 cells is inhibited by IL-2– and IFN-–producing reactive T_H1 cells. With progression of disease, as the malignant cell population expands, increased production of IL-4 may impair the T_H1 cell–mediated host antitumor response.⁹

This concept of CTCL as neoplasms of IL-4– and IL-5–producing T_H2 cells also gave an explanation for various immune abnormalities associated with the advanced stages of MF and SS and provided a rationale for treatment with biologic response modifiers as IFN-, retinoids, IFN-, and IL-12, aimed at potentiating a T_H1 antitumor response.^10-13

From a clinical point of view, it is important to know whether this new immunopathogenic concept and, more important, the therapeutic consequences derived from it also hold true for CTCLs other than MF and SS. In this respect, CD30^- primary cutaneous large T-cell lymphomas (PCLTCLs) are the most important group, since these lymphomas do not or insufficiently respond to currently available therapies, including multiagent chemotherapy (5-year survival rate of 15%).¹ In the present study, patients with a CD30^- PCLTCL were investigated for the expression of T_H1 and T_H2 cytokines using reverse transcription–polymerase chain reaction (RT-PCR). Skin biopsy specimens from patients with plaque or tumor stage MF, SS, psoriasis, lichen planus, and atopic dermatitis were included as controls.

MATERIALS AND METHODS

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PATIENTS

Seven skin biopsy specimens were obtained from 4 patients with a CD30^- PCLTCL. At the time of diagnosis, staging procedures did not reveal any evidence of extracutaneous disease. From 2 patients additional biopsy specimens obtained during follow-up were available for examination. In all biopsy specimens the histologic findings showed a diffuse infiltration of medium and large pleomorphic T cells. Detailed immunohistochemical studies demonstrated that in all cases the neoplastic T cells made up more than 90% of the infiltrate; CD8⁺-reactive T cells, CD1a⁺ dendritic cells, CD68⁺ macrophages, and CD20⁺ B cells were few or absent and together never exceeded 10% of the total number of infiltrating cells. Despite multiagent chemotherapy, all patients had diseases that ran a progressive clinical course and all patients died of systemic lymphoma 6 to 55 months (median, 8 months) after diagnosis (Table 1).

View this table: [in this window] [in a new window] Table 1. Clinical Characteristics and Follow-up Data of CD30- Primary Cutaneous Large T-Cell Lymphoma Included in This Study*

Biopsy specimens from 8 patients with CTCL, including plaque stage MF (n = 3), tumor stage MF (n = 2), and SS (n = 3), were included as controls. The diagnoses in these cases were based on clinical, histological, and immunophenotypic criteria, as described previously.¹ In all CTCL, except for the patients with SS, extensive staging procedures had failed to demonstrate extracutaneous disease at the time of presentation. In addition, skin biopsy specimens from untreated skin lesions of patients with psoriasis (n = 5), lichen planus (n = 2), and atopic dermatitis (n = 3) were included as benign control groups.

EXTRACTION OF RNA, PERFORMANCE OF RT-PCR, AND ANALYSIS OF CYTOKINE mRNA EXPRESSION

Four-millimeter punch biopsy specimens were snap frozen in liquid nitrogen and stored at -196°C until use. Total RNA was extracted from ten 10-µm cryostat sections using RNAzol B (Campro Scientific, Veenendaal, the Netherlands). The integrity and amount of isolated RNA were verified by running one fifth of the isolated RNA on a 1.5% Tris-borate-EDTA (TBE) agarose gel stained with SYBR green II RNA gel stain (FMC, Rockland, Me). Next, after denaturing for 10 minutes at 70°C, half of the remaining RNA was reverse transcribed by incubating for 60 minutes at 42°C in a cocktail containing 200 U of Superscript II reverse transcriptase (Gibco-BRL, Breda, the Netherlands), deoxynucleotide triphosphates (10mM each), 0.5 µg of oligo d(T12-16) (Gibco-BRL), and 10mM dithiothreitol in a total volume of 20 µL. As a negative control, the other half of the isolated RNA was incubated with an identical cocktail but lacking Superscript II reverse transcriptase. Immediately following reverse transcription, samples were diluted to 100 µL with deionized water. A total of 5 µL of this diluted complementary DNA (cDNA) was amplified using PCR with sense and antisense primers selected with the primer selection program PC Gene (Table 2). To prevent amplification of genomic DNA, only intron-spanning primers were used. The integrity of cDNA was verified by including control amplification of cDNA encoding U1A (U1 small nuclear ribonucleoprotein–specific protein A). Because the U1A protein regulates the production of its own mRNA, an advantage of this control is the equal and low abundant expression in most tissues.¹⁴ Polymerase chain reaction was carried out using 0.2 U of SuperTaq (Sphaero Q, Leiden, the Netherlands) in a buffer supplied by the manufacturer with 2mM magnesium chloride, 500µM deoxynucleotide triphosphate, 10 pmol of each of the sense and antisense primers, and deionized water to a total volume of 25 µL. The cDNA was amplified in a thermocycler (Omnigene; Hybaid, Middlesex, England) for 40 cycles, where a single cycle consisted of 94°C for 40 seconds, 60°C for 50 seconds, and 72°C for 60 seconds. Before cycling, samples were denatured for 5 minutes at 94°C, and after cycling, an extra incubation for 5 minutes at 72°C was performed. To avoid carryover contamination, strict physical and procedural precautions were observed. Furthermore, a negative control water blank was included in each PCR amplification experiment. Following amplification, a 10-µL sample of the PCR product was size analyzed on a 1.5% agarose TBE gel, stained with ethidium bromide, and compared with molecular weight markers. To confirm the identity of the PCR product, samples were blotted on Qiabrane membranes (Diagen, Dusseldorf, Germany) and hybridized with specific phosphorus 32 end-labeled oligonucleotide probes (Table 2). On each sample of cDNA, all PCRs and hybridization of PCR products were performed in duplicate.

View this table: [in this window] [in a new window] Table 2. Oligonucleotide Primers Used for PCR or as Hybridization Probe*

RESULTS

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CYTOKINE EXPRESSION IN CD30^- PCLTCL

Initially, 4 cases containing an almost pure population (>90%) of large pleomorphic T cells were investigated (Table 3). Based on the concept that CTCL represents a proliferation of CD4⁺ T_H2 cells, a strong IL-4 mRNA expression was expected. However, IL-4 mRNA could not be demonstrated in any of these 4 biopsy specimens and IL-5 mRNA was demonstrated in only 1 of these (Figure 1). Because of these negative results, 3 additional biopsy specimens were analyzed from 2 of these patients (patients 2 and 3), either at the same time (patient 3) or during progression at 4 and 5 months after diagnosis (patient 2). Also, in these additional biopsy specimens, IL-4, IL-5, and IL-10 mRNA were not detected, whereas the presence of U1A confirmed the presence of intact mRNA. Expression of the T_H1 cytokines IFN- and IL-2 was detected in 5 of 7 and 4 of 7 biopsy specimens, respectively.

View this table: [in this window] [in a new window] Table 3. Expression of Cytokine Messenger RNA in CD30- Primary Cutaneous Large T-Cell Lymphoma*

View larger version (25K): [in this window] [in a new window] Representative example of a reverse transcription–polymerase chain reaction (RT-PCR) analysis of T-helper (TH) cytokine messenger RNA (mRNA) in peripheral blood mononuclear cells (PBMCs; control) and CD30- primary cutaneous large T-cell lymphoma (CD30- PCLTCL), demonstrating the absence of typical TH2 cytokine mRNAs (interleukin 4 [IL-4], IL-5, and IL-10) in CD30- CTCL. M denotes DNA marker; sizes in base pairs are given on the right. IFN- indicates interferon . Bands in the upper part of the gels (most prominent in -RT samples) most likely result from residual genomic DNA in the RNA samples.

CYTOKINE EXPRESSION IN MF AND SS

In plaque stage MF, IFN- and IL-2 mRNA were detected in 3 of 3 and 2 of 3 cases, respectively, whereas IL-4 and IL-10 mRNA were not found (Table 4). In contrast, both cases of tumor stage MF expressed IFN-, IL-2, IL-4, and IL-10, whereas IL-5 was expressed in 1 of 2 cases. Thus, IL-4 was only found in MF lesions showing a predominance of neoplastic T cells. In the 3 skin biopsy specimens from patients with SS, IL-4 and IL-5 mRNA were demonstrated in 2 and 3 cases, respectively (Table 4).

View this table: [in this window] [in a new window] Table 4. Frequency of Cytokine Messenger RNA Expression in Skin Biopsy Specimens of CD30- PCLTCLs, MF, SS, and Benign Control Groups*

CYTOKINE EXPRESSION IN PSORIASIS AND ATOPIC DERMATITIS

In psoriasis, which is widely considered a T_H1-mediated disorder,¹⁵ IFN- and IL-2 were detected in all 5 biopsy specimens, whereas IL-4 and IL-5 were found in 1 of 5 and 1 of 3 cases, respectively (Table 4). Interleukin 10 mRNA was detected in 4 of 5 psoriatic skin lesions. In atopic dermatitis, IL-2, IFN-, and IL-5 were found in 3 of 3 biopsy specimens. Interleukin 4 was detected in 2 of 3 biopsy specimens, whereas IL-10 mRNA–derived cDNA could not be detected (Table 4).

COMMENT

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In the present study, we investigated T_H1 and T_H2 cytokine profiles in CD30^- PCLTCL. Because previous studies in MF and SS suggested that the neoplastic T cells in CTCL are derived from T_H2-producing CD4⁺ T cells and all biopsy specimens contained more than 90% neoplastic T cells, expression of IL-4 and IL-5 mRNA was expected.

However, in the initial skin biopsy specimens of all 4 patients with a CD30^- PCLTCL, IL-4 mRNA was not detected, whereas IL-5 mRNA was detected in only 1 of 4 biopsy specimens. These results suggested that the neoplastic T cells in these CD30^- PCLTCLs do not produce T_H2 cytokines. Additional evidence for this conclusion is provided by the absence of IL-4 and IL-5 mRNA in 3 additional biopsy specimens from 2 of these 4 patients, as well as the presence of IL-4 mRNA in control biopsy specimens, run in parallel, from patients with tumor stage MF (2/2), SS (3/3), and atopic dermatitis (2/3), which is consistent with the results of recent literature.^{8, 16} Moreover, all PCR and hybridizations of PCR products were performed in duplicate, and controls for the integrity of isolated mRNA and transcribed cDNA were positive in all cases. The expression of IFN- and IL-2 found in 5 of 7 and 4 of 7 biopsy specimens, respectively, may be attributed to a few scattered CD8⁺ T cells (always less than 5%), but it cannot be excluded that these cytokines are produced by the tumor cells.

In SS and advanced MF, the production of IL-4 and IL-5 has been associated with a constellation of immune abnormalities, such as an increased serum IgE level, decreased T-cell response to antigens, impaired cellular cytotoxicity, and peripheral eosinophilia.^{9, 17} It is of interest that increased IgE levels and eosinophilia are generally not observed in CD30^- PCLTCL and consistently were not present in the 4 patients studied. In addition to these immune abnormalities, IL-4 and IL-5 have been considered to be responsible for the more aggressive clinical behavior of SS and advanced-stage MF by impairing T_H1 cell–mediated antitumor responses.⁹ On the other hand, the production of IFN- in early stage MF by the reactive T-cell infiltrate can be an important factor responsible for the indolent course of early patch and plaque stage disease by inhibiting IL-4 production. Thus, in this model competing T_H1 and T_H2 cytokine effects may be important in disease progression of MF and SS.

This concept may explain at least in part the beneficial effects of IFN- and retinoids, both of which have T_H1 response–augmenting activities, in the treatment of MF and SS.^{10, 18-20} In addition, it provides a rationale for treatment with still experimental biologic response modifiers, such as IFN- and IL-12, the mean inducer of IFN-.^11-12 In vitro studies have already demonstrated that the excess IL-4 production in peripheral blood mononuclear cells from patients with SS can be inhibited by IL-12, IFN-, and IFN-.^{5, 12} In phase 2 studies with IFN-, partial responses were observed in approximately 30% of patients with CTCL.¹¹ In a phase 1 study in MF and SS, subcutaneous IL-12 resulted in complete or partial responses in 4 of 5 MF plaques, 2 MF tumors, and 1 of 2 patients with SS.¹³ In addition to an inhibitory effect on T_H2 cells, IFN- may induce the production of the CXCR3-targeting chemokines IFN-inducible protein 10 (IP-10), monokine induced by IFN- (MIG), and IFN-inducible protein 9/IFN-inducible T-cell -chemoattractant.^21-23 These chemokines specifically attract CXCR3-bearing activated T cells^24-25 and are considered to play an important role in the antitumor responses.²⁶ In accordance, both biopsy specimens in which IFN- was not detectable by RT-PCR were also negative for IP-10 as determined by in situ hybridization.²³

Because recent studies demonstrated that p53 protein can downmodulate IL-4 gene expression²⁷ and overexpression of p53 protein was found on neoplastic cells in 4 of 8 CD30^- PCLTCLs,²⁸ the expression of p53 could be a factor in the absence of IL-4 in these lymphomas.

Expression of IL-10 in CTCL is of interest because in MF an increased expression of IL-10 mRNA is associated with tumor progression.²⁹ However, in this study IL-10 mRNA was detected in only 1 of 7 CD30^- PCLTCL biopsy specimens, making it unlikely that production of IL-10 is an important mechanism in the pathogenesis of CD30^- PCLTCL.

Previous studies established that in the group of PCLTCLs, expression of the CD30 antigen on most tumor cells is the most important prognostic parameter. Thus, whereas CD30⁺ PCLTCLs have an excellent prognosis (5-year survival rate of >90%), the prognosis of CD30^- PCLTCL is poor (5-year survival rate of <15%). The molecular and genetic mechanisms underlying these differences in clinical behavior are as yet unexplained. A study on a small number of CD30⁺ PCLTCLs suggested that this type of CTCL is characterized by production of IL-4 and IL-10.³⁰ Our observations demonstrating lack of T_H2 cytokine mRNA expression in CD30^- PCLTCL provide another biological difference with CD30⁺ PCLTCL and suggest differences in the regulation of tumor cell proliferation by the cytokine network.

Cytogenetic studies in CTCL have identified structural chromosomal abnormalities in MF, including 1p, 2p, 6q, 10q, and gene alterations in p16^INK4a.^31-36 Multiple chromosomal abnormalities and alterations of p16^INK4a were found to be associated with tumor progression and a poorer prognosis. In contrast, no data are available on the genetic alterations in CD30^- PCLTCL, and investigations in this field are clearly warranted.

In conclusion, the results of the present study suggest that, in contrast to SS, MF, and CD30⁺ PCLTCL, the neoplastic T cells of CD30^- PCLTCL do not or rarely express IL-4 and IL-5 mRNA and thus do not display a T_H2 cytokine profile. This observation contrasts with the current concept of CTCLs as lymphomas producing IL-4 and IL-5 and demonstrates heterogeneity of the cytokine profile in CTCL.

AUTHOR INFORMATION

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Accepted for publication February 6, 2001.

We thank K. Thestrup-Pedersen, MD, PhD, for critical reading of the manuscript and helpful discussion.

Corresponding author: Maarten H. Vermeer, MD, Department of Dermatology, LUMC, Albinusdreef 2, 2300 RC Leiden, the Netherlands (e-mail: m.h.vermeer{at}lumc.nl).

From the Departments of Dermatology (Drs Vermeer, Tensen, van Oostveen, and Willemze and Ms van der Stoop) and Pathology (Drs Tensen, van Oostveen, and Scheper), Free University Hospital, Amsterdam, the Netherlands; and Department of Dermatology, Marselisborg Hospital, Aarhus, Denmark (Ms Lund).

REFERENCES

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