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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3077-3083
By
From the Departments of Dermatology, Internal Medicine
(Immunoallergology and Respiratory Disease Unit), and Human Pathology
and Oncology, University of Florence Medical School, Florence, Italy;
and the Department of Pathology-Section of Hematopathology, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, MA.
Primary CD30+ cutaneous T-cell lymphomas (CTCLs)
represent a spectrum of non-Hodgkin's lymphomas (NHLs) that have been
well defined at the clinical, histologic, and immunologic level. This group, which includes 2 main entities (large cell lymphoma and lymphomatoid papulosis [LyP]) and borderline cases, is characterized by the expression of CD30 antigen by neoplastic large cells at presentation, possible spontaneous regression of the skin lesions, and
generally favorable clinical course. Although the functional relevance
of CD30 and its natural ligand (CD30L) expression in most cases of NHL
is presently undefined, previous studies indicate that CD30L is likely
to mediate reduction of proliferation in CD30+ anaplastic
large-cell NHL. No information is currently available concerning the
expression of CD30L in primary CD30+ CTCLs. In this
study, we investigated the immunophenotypic and genotypic expression of
CD30 and CD30L in different developmental phases of skin lesions
(growing v spontaneously regressing). By immunohistochemistry,
CD30L expression was detected in regressing lesions only; by molecular
analysis, the expression of CD30L was clearly higher in regressing
lesions than in growing ones. CD30L, while expressed by some small
lymphocytes, was most often coexpressed by CD30+
neoplastic large cells, as demonstrated by 2-color immunofluorescence and by immunohistochemistry on paraffin sections. Taken together, these
data suggest that CD30-CD30L interaction may play a role in the
pathobiology of primary cutaneous CD30+
lymphoproliferative disorders. In particular, CD30L (over)expression might have a major role in the mechanism of self-regression of skin
lesions, the most distinctive clinical feature of this cutaneous lymphoma subtype.
RECENTLY, DIFFERENT FORMS OF cutaneous
T-cell lymphoma (CTCL) other than mycosis fungoides (MF) have been
defined on the basis of well-defined clinical, histologic, immunologic,
and molecular features.1-3 This group includes a spectrum
of diseases known as CD30+ lymphoproliferative disorders of
the skin4-7: primary cutaneous CD30+ large
T-cell lymphoma (CD30+ large-cell CTCL) and lymphomatoid
papulosis (LyP). CD30+ large-cell CTCL is characterized
clinically by presentation with solitary or localized skin lesions,
possible spontaneous regression (partial to complete), good and rapid
response to local radiotherapy, and favorable prognosis, despite
frequent cutaneous relapses. LyP, historically defined as "a
continuing, self-healing eruption, clinically benign, histologically
malignant,"8 is characterized clinically by an
intermittent or continuous eruption of usually multiple, papulonodular
lesions, with ulceration, crusting, and self-healing, sometimes with
scarring and/or depigmentation. CD30+ atypical cells occur
in a background of inflammatory cells.3,4,6,7 It is worthy
of emphasis that CD30 expression by neoplastic T cells has a special
diagnostic and favorable prognostic significance when expressed at
presentation and correlated with the above typical clinicopathologic
features.2,5,7 Conversely, CD30 expression occurring in the
transformation of MF into large-cell lymphoma tumor stage does not
influence the prognosis, which is invariably poor.9
CD30 antigen is a member of the tumor necrosis factor (TNF) receptor
superfamily,10,11 which was identified as a cell surface antigen on primary and cultured Hodgkin's and Reed-Sternberg cells by
the monoclonal antibody Ki-1.12,13 CD30 antigen is normally expressed by a subset (15% to 20%) of CD45RO+ T cells
after activation by a variety of T-cell stimuli.14 CD30 is
also expressed at variable levels in different non-Hodgkin's lymphomas
(NHLs), as well as in several virally transformed T- and B-cell
lines.15,16 In particular, CD30 is a specific marker of a
subset of peripheral T-cell NHL, ie, anaplastic large cell (ALC) lymphoma.17 More recently, CD30 preferential
expression has been detected on subset of tissue and circulating
CD4+ or CD8+ T cells producing type 2 T-helper
(Th2) cytokines in healthy and immunoreactive
conditions.18,19 The biologic significance of CD30 molecule
is related to the existence of a natural ligand (CD30L), a member of
the TNF ligand superfamily recently identified in murine T cells and in
human peripheral blood T cells and mainly expressed on activated T
cells and monocytes and, constitutively, on granulocytes and some
Burkitt-like lymphoma cell lines.10,20,21 CD30 and CD30L
are involved in the regulation of cell proliferation, activation, and
differentiation, including control of cell survival or death by
apoptosis or cytotoxicity.21
Recent data demonstrate pleiotropic biologic activities of CD30L on
different CD30+ lymphoma cells lines and indicate that a
CD30-CD30L interaction might have a pathophysiologic role in Hodgkin's
lymphoma and in specific subsets of NHL, particularly ALC
lymphoma.20,21 CD30L is capable of transducing signals
leading to either cell death or proliferation through its specific
cognate molecule CD30. Although previous studies indicate that CD30L
plays a key role as a paracrine- or autocrine-acting surface molecule
in the pathophysiology of Hodgkin's lymphoma16 and in
CD30+ NHL,22 no information is currently
available concerning the expression of CD30L in primary cutaneous
lymphomas. By the combined use of different methods, including
immunohistochemistry and 2-color immunofluorescence,
reverse-transcriptase polymerase chain reaction (RT-PCR), quantitative
PCR, and Southern blot, we have analyzed the phenotypic and genotypic
expression of CD30 and CD30L in cutaneous lymphoproliferative
CD30+ disorders, to investigate the correlation between
CD30 and CD30L expression in different developmental phases of skin
lesions (growing v spontaneously regressing) and its possible
significance in the pathophysiology of clinical regression of skin
lesions in these disorders.
Patients and Skin Samples
Immunohistochemistry
Two-Color Immunofluorescence
RNA Isolation and Reverse Transcriptase Total mRNA was extracted from skin biopsies by a commercial kit (Ambion, Austin, TX). All samples used in these experiment clearly gave 18S and 28S bands in 0.8% agarose gels, indicating the integrity of RNA. Following extraction, 1 µg of RNA was reverse-transcribed from an oligo (dT) primer using a M-MLV reverse transcriptase (GIBCO-BRL, Gaithersberg, MD).Competitive PCR for Beta-Actin Competitive PCR for beta-actin was performed by using PCR MIMIC Protocol (Clontech Lab, Palo Alto, CA) according to manufacturer's instructions. In this method, a competitor control fragment (PCR MIMIC) is used together with sample cDNA in the reaction mixture; sample and control cDNA are amplified with the same primers in the same reaction, but they are distinguished on gel electrophoresis by differences in length. By knowing the amount of PCR MIMIC added to the reaction, it is possible to determine the amount of target cDNA, and thus the initial mRNA levels. Each sample was subject to 25 cycles of amplification according to the manufacturer's instructions. This method allowed us to use a constant number of molecules of mRNA for beta-actin for each of the following experiments.PCR Different amounts of cDNA for each sample (corresponding to the same amount of mRNA molecules for beta-actin) were amplified in a 10-µL volume of final reaction mix in an Idaho Technology (Idaho Falls, ID) thermal cycler with capillary glass with 0.25 U of Taq DNA polymerase (Perkin-Elmer-Cetus, Branchburg, NJ) and 10 pmol/L of primers specific for CD30 (sense, 5'-TGA CAA GGC TGT CAG GAG GTG CTG TTA CCG, region 333-362 and antisense, 3'-CCT CGT CAG TTT AGA AGC AGC TTC CTG GGC, region 852-823), CD30L (sense, 5'-CCC CTC AAA GGA GGA AAT TGC TCA GAA GAC, region 353-382, and antisense, 3'-ATT GAC TGA TAT GGT GGT GTT GAC CTG CAG, region 748-719), and beta-actin (sense, 5'-ATC TGG CAC CAC ACC TTC TAC AAT GAG CTG CG, region 294-324, and antisense, 3'-CGT CAT ACT CCT GCT TGC TGA TCC ACA TCT GC, region 1131-1100). Primers for CD30 and CD30L were selected using Oligo Primer Analysis Software Version 5.0 (National Bioscience, Plymouth, MN) and were purchased from Genset (Paris, France); primers for beta-actin were purchased from Clontech Laboratories. PCR conditions for CD30 and beta-actin were 30 seconds at 94°C, followed by 30 cycles of 10 seconds at 96°C, 20 seconds at 67°C, and 30 seconds at 72°C. PCR conditions for CD30L were 30 seconds at 94°C, followed by 30 cycles of 10 seconds at 96°C, 20 seconds at 66°C, and 30 seconds at 72°C. After the last cycle, samples were incubated for 50 seconds at 72°C to ensure completion of the final extension step. To monitor for carry-over contamination, a negative control (without template) was included in each PCR amplification. Following amplification, the PCR cocktail was sized in a 1.5% agarose gel at 100 V for 1 hour and counter-stained in a ethidium bromide solution (10 mg/mL). The gel was visualized under UV light and the size of any bands present was compared with molecular weight markers run in a parallel lane.Analysis of Amplified DNA by Southern Blot for CD30L An aliquot (5 or 10 µL) of the amplified DNA was fractionated on a 1.5% agarose gel and transferred to a nitrocellulose membrane filter as described by Southern.26 Blots were washed twice for 1 hour at 65°C in 1x SSPE (0.15 mol/L NaCL, 10 mmol/L NaH2PO4, l mmol/L EDTA) containing 0.1% sodium dodecyl sulfate. Southern blot analysis was performed with an internal probe designed to recognize intervening sequence between primers (sense, 5'-CCT ACC TCC AAG TGG CAA AGC ATC TAA ACA, region 426-455, and antisense, 3'-GTG TTT CGT TTG CAT TCC AGA CTC ACA CAC, region 683-653). This probe were obtained by PCR amplification. Primers were selected using Oligo Primer Analysis Software Version 5.0 and were purchased from Genset. The DNA fragment obtained by PCR was subcloned using the p-GEM-T Vector System (Promega, Madison, WI) according to the manufacturer's instructions, and sequenced. Sequencing of the subcloned product was performed using the Sequenase version 2.0 DNA Sequencing kit (USB, Cleveland, OH). Southern blot was performed as previously described.26 The probe was labeled with (32P)dCTP using the Megaprime DNA labeling System (Amersham, Buckinghamshire, UK).Image Analysis (quantitative analysis) The intensity of bands obtained by Southern blot was measured by a CCD video camera (C3077/01; Hamamatsu Photonics, Hamamatsu, Japan) connected to a video frame-grabber M4476 (Hamamatsu Photonics), in a Macintosh computer Iisi (Apple Europe, Korch, Holland). Acquisition of the image was obtained with Imagequest IQB software by Hamamatsu Photonics. Image processing and analysis was performed with the free software IMAGE by Wayne Rasband, National Institutes of Health Research Services Branch, NIMH, version 1.28.
Immunohistochemistry Frozen sections. CD30+ cells, invariably of the T-helper cell phenotype (CD3+, CD4+), were found in all examined specimens in different proportions (Table 1). In particular, CD30+ cell numbers were greater than 75% in samples no. 2, 5, and 12 (CD30+ large-cell CTCL, growing lesions); 40% to 75% in samples no. 1 and 13 (LyP, growing lesion), and in 4, 6, and 7 (CD30+ large-cell CTCL, regressing lesions); and 15% to 40% in samples no. 3 and 8 (LyP, regressing lesion). CD30L+ cells were found in regressing lesions only (Table 1). By step-section analysis, CD30L+ cells showed a distribution similar or identical to that of CD30+ neoplastic cells. Paraffin sections.
Three LyP cases with regressing lesions studied in paraffin sections
showed 10% to 20% CD30+ cells (Fig
1a and b). Most of the same large cells and
some of the smaller cells, including mast cells, also stained for CD30L (Fig 1c).
Two-Color Immunofluorescence CD30L expression was not detected in the 3 biopsies from growing lesions. On the contrary, CD30L expression was found in all biopsies (5/5) from regressing lesions. The expression of CD30L was mostly restricted to cells expressing CD30 antigen (Fig 2a and b). CD30+ cells coexpressed Fas and FasL in all examined specimens, independent of regression (data not shown).
RT-PCR and Southern Blot for CD30L At partial variance from immunohistochemistry, molecular analysis demonstrated the presence of CD30L expression in all samples examined (Fig 3). Nevertheless, the image analysis of the intensity of bands obtained by Southern blot showed a different level of expression of CD30L, despite the same amount of target cDNA, relative to the same mRNA levels obtained for beta-actin (quantitative PCR). Our results indicate that the intensity of bands from regressing lesions is clearly higher than that from growing lesions (Fig 4). In particular, this was evident in 2 samples (growing v regressing lesions) obtained from the same patient (Fig 3, lanes 1 and 3, respectively, growing and regressing lesion of the same patient).
Summary of Results In this study, we have analyzed the phenotypic and genotypic expression of CD30 and CD30L in this typical CTCL subset, in order to investigate CD30-CD30L interaction in different developmental phases of skin lesions (growing v spontaneously regressing). At the immunohistochemical level, CD30L expression was detected in regressing lesions only, whereas it was not found in growing ones. The 2-color immunofluorescence analysis of frozen tissue showed that CD30L was mostly coexpressed by CD30+ neoplastic cells. Colocalization of CD30L with CD30 was also demonstrated by immunohistochemistry on paraffin sections from an additional 3 LyP patients, in which some smaller lymphocytes also appeared to express CD30L. Molecular analysis by PCR and Southern blot demonstrated the presence of CD30L expression in all samples. Nonetheless, the intensity of bands shown by image analysis of Southern blots from regressing lesions was clearly higher than that from growing lesions. In particular, this was evident in 2 samples (growing v regressing lesion) obtained from the same patient. Although the significance of the above findings (higher expression of CD30L in regressing v growing lesions) could be hampered by the obvious consideration that small reactive cells are much fewer in growing lesions as compared with regressing ones, it has to be stressed CD30L staining was totally negative in growing lesions, irrespective of the presence of small cells. In fact, growing lesions from patients with LyP notwithstanding they always contained small cellsdid not stain for CD30L. In contrast, the expression of CD30L was mostly restricted to large CD30+ cells in regressing lesions, where a few small cells
also stained for CD30L.
Recently, several studies have indicated that CD30L plays a key role as a paracrine- or autocrine-acting surface molecule involved in the pathobiology of Hodgkin's lymphoma and NHL.15 It has been shown that the interaction of CD30L with its cognate receptor is able to induce either a proliferative or nonproliferative effect, depending on the cell type and/or on different intracellular signaling pathways.27-29 In particular, it has been demonstrated that recombinant CD30L exerts a potent antiproliferative effect on CD30+ ALC lymphoma cell lines.21 Primary cutaneous CD30+ lymphoma, characterized by frequent regression of skin lesions, seems a suitable in vivo model for the investigation of a possible pathophysiologic role of CD30/CD30L interaction. Indeed our results, showing CD30L at higher levels in regressing than nonregressing skin lesions, suggest that CD30L may be a key mediator of tumor regression in the spectrum of CD30+ cutaneous lymphomas.
Submitted March 16, 1999; accepted June 29, 1999.
Supported by grants from the bank Cassa di Risparmio dl Firenze S.p.A., Florence, Italy (Skin Tumor Project), from the Italian Ministry of University and Scientific and Technologic Research (University funds, 60%), from the Associazione Italiana per la Ricerca sul Cancro (AIRC), and from the Italian Ministry of Health (MPI 40% Oncology).
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
Address reprint requests to N. Pimpinelli, MD, PhD, Institute of Dermatology and Venereology, University of Florence Medical School, Via degli Alfani 37, I-50121 Firenze, Italy; e-mail: pimpi{at}cesit1.unifi.it.
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  T. Nijsten, C. Curiel-Lewandrowski, and M. E. Kadin Lymphomatoid Papulosis in Children: A Retrospective Cohort Study of 35 Cases Arch Dermatol, March 1, 2004; 140(3): 306 - 312. [Abstract] [Full Text] [PDF]
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 A. Younes and M. E. Kadin Emerging Applications of the Tumor Necrosis Factor Family of Ligands and Receptors in Cancer Therapy J. Clin. Oncol., September 15, 2003; 21(18): 3526 - 3534. [Abstract] [Full Text] [PDF]
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 J. Willers, R. Dummer, W. Kempf, T. Kundig, G. Burg, and M. E. Kadin Proliferation of CD30+ T-Helper 2 Lymphoma Cells Can Be Inhibited by CD30 Receptor Cross-Linking with Recombinant CD30 Ligand Clin. Cancer Res., July 1, 2003; 9(7): 2744 - 2754. [Abstract] [Full Text] [PDF]
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 M. Steinhoff, M. Hummel, I. Anagnostopoulos, P. Kaudewitz, V. Seitz, C. Assaf, C. Sander, and H. Stein Single-cell analysis of CD30+ cells in lymphomatoid papulosis demonstrates a common clonal T-cell origin Blood, June 28, 2002; 100(2): 578 - 584. [Abstract] [Full Text] [PDF]
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 M. E. Kadin Regulation of CD30 Antigen Expression and Its Potential Significance for Human Disease Am. J. Pathol., May 1, 2000; 156(5): 1479 - 1484. [Full Text] [PDF]
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TOP
ABSTRACT
INTRODUCTION
80°C until sectioning and preparing for immunohistochemistry
(APAAP method). A portion of biopsies from 6 skin lesions were prepared
for molecular analysis. Each tissue specimen was put in RNase-free
microfuge and immediately frozen in liquid nitrogen until RNA
extraction. All skin biopsies were taken after informed consent was
obtained.
, negative
control.
; CD30L,
). The intensity of CD30L bands from regressing lesions is clearly
higher than that from growing lesions. In particular, this is evident
in 2 samples (1 v 3, growing v regressing lesions)
obtained from the same patient (see also Fig