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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Departments of Immunobiology, Pathology,
Biostatistics and Medical Informatics, and Dermatology, Hospital
Henri-Mondor, Assistance Publique-Hôpitaux de Paris, and
University Paris XII, Créteil, France, and the Department of
Dermatology, Center of Extracorporeal Photochemotherapy, Hospital
Avicennes, Assistance Publique-Hôpitaux de Paris, and University
Paris XIII, Bobigny, France.
It is now widely accepted that polymerase chain reaction (PCR)
analysis of cutaneous T-cell clonality is of diagnostic value in
cutaneous T-cell lymphomas (CTCLs) and most helpful in the diagnosis of
mycosis fungoides (MF). However, the diagnostic and prognostic value of
circulating clonal T cells remains unclear. We studied T-cell clonality
in the peripheral blood (PB) and the cutaneous lesion, sampled at the
same time, in 363 consecutively seen patients with a clinical suspicion
of cutaneous lymphoma. Using a PCR technique providing a specific
imprint of T-cell clones (PCR The recent development of molecular techniques for
routine hospital work has led to the definition of new diagnostic and
prognostic variables. For example, in a patient presenting with a
clinical suspicion of cutaneous T-cell lymphoma (CTCL), it is now
accepted that the identification by polymerase chain reaction (PCR) of a dominant T-cell clone in a cutaneous lesion supports the diagnosis of
CTCL.1-2 Most reported PCR techniques identified a
dominant cutaneous T-cell clone in 45% to 70% of cases of mycosis
fungoides (MF).3-6 Previously, we reported that the
presence of a dominant T-cell clone in the cutaneous infiltrate in
patients with MF decreases the probability of remission induction after
topical treatment, and we therefore proposed that this variable be
included as a prognostic factor in clinical trials in such
patients.7
The clinical extent of both cutaneous and extracutaneous lesions
remains the main prognostic factor in MF.8 It has long been known that dissemination to the peripheral blood (PB) indicates a
poor prognosis.9 However, the techniques that have been
used are either not sensitive (cytogenetic analysis) or not specific (cytologic analysis and electron microscopy). Initial molecular studies
used Southern blot analysis, which improved the specificity of
disease-extension studies and confirmed the poor prognosis associated
with circulating tumor cells.9-11 However, Southern blotting is laborious and expensive and is thus not suitable for routine hospital work. Analysis of T-cell clonality by PCR and migration of PCR products on a denaturing gradient gel, ie,
PCR- The aim of this study was to determine the frequency and
diagnostic value of circulating tumor cells as detected by
PCR- Patients
Histologic diagnosis
Patients with a histologically established diagnosis of non-CTCL disease were divided into 2 groups. The first group consisted of patients with well-defined benign dermatoses, such as contact dermatitis, drug-induced dermatoses, lichenoid reactions, benign follicular mucinosis, psoriasis, folliculitis, benign panniculitis, vasculitis, prurigo, sarcoidosis, Jessner-Kanof infiltration, discoid lupus erythematosus, granuloma annulare, pityriasis lichenoides, dermatophytosis, cutaneous lymphoid hyperplasia (ie, lymphocytoma), and benign tumors. The second group consisted of patients with non-CTCL malignant disease (non-CTCL MD). In some patients with persistent plaques or erythroderma, MF or SS was clinically suspected but it was not possible to confirm the diagnosis on skin biopsy. The specimens from these patients were divided in 2 categories: uncertain MF and nonspecific lesions. Uncertain MF was defined as a linear subepidermal lymphocytic infiltrate with few Sézary cells and focal epidermotropism. Lesions were considered nonspecific if the lymphocytic infiltrates were patchy and perivascular and had neither Sézary cells nor epidermotropism. T-cell receptor gene rearrangement analysis by GC-chain clamp
multiplex PCR-  -chain gene rearrangements were studied by using a GC-clamp multiplex PCR--DGGE procedure as previously
described.14 Briefly, 4 oligonucleotides matching the 4 V segment families and 4 oligonucleotides matching the J junction
segments were used in a single 50-µL PCR reaction (multiplex PCR) in
a thermal cycle (model 480 thermocycler; Perkin Elmer, Foster City,
CA). To avoid contamination by the amplification products, deoxyuridine
triphosphate nucleotides were substituted for deoxythymidine
triphosphate in the amplification reaction mixture and samples were
first subjected to uracil-DNA glycosylase activity. After 40 PCR
cycles, 30 µL of amplified products were run on a 6.5%
polyacrylamide gel containing a linearly increasing 10% to 60%
denaturing gradient (DGGE). The use of oligonucleotides matching all
V and J functional segments, combined with DGGE, allows creation
of a migration profile specific for each T-cell clone.14
Three positive controls were added in each series: the Jurkat cell line
with a biallelic VIJI and VIVJI rearrangement, and 2 samples from
patients with dominant T-cell clones with VIIJP/VIIJP and
VIIIJP/VIIIJP1 rearrangements. The PCR results were considered positive (PCR-+) when a dominant T-cell clone was
detectable and negative (PCR- ) when a polyclonal
pattern of T-cell infiltration was observed. In the latter case, the
presence of a smear on the gel ensured that T-cell DNA was present and amplified.
The sensitivity of this technique depends on the type of V Because the patients with CTCL were assumed to have a primary cutaneous
lymphoma, tumor cells in their skin were characterized by their
PCR-
Exceptionally, 2 dominant clones from 2 patients seemed to comigrate on the 10% to 60% DGGE gel, particularly when monoallelic rearrangements were amplified. However, the 2 rearrangements could be easily distinguished by loading the PCR products on a discriminating 30% to 50% denaturing gradient gel. Statistical methods Comparisons of categorical data were done by using the 2 test or, when appropriate, the Fisher exact test.
Patient characteristics We studied a biopsy specimen from a skin lesion in 363 consecutively seen patients in whom a clinical diagnosis of cutaneous lymphoma was initially considered. The histologic diagnoses and the ages of the patients with those diagnoses are shown in Table 1. There were 88 patients with MF, 22 with SS, 28 with PTCL, and 14 with LyP, for a total of 152 patients with CTCL. The benign dermatoses (n = 72) were 55 reactive dermatoses, 7 benign tumors, and 10 cases of cutaneous lymphoid hyperplasia. Non-CTCL MD was diagnosed in 27 patients (24 cases of CBCL, 1 of Merkel cell carcinoma, 1 of true histiocytic lymphoma, and 1 of myelomonocytic proliferation). The uncertain MF (n = 27) group and the nonspecific (n = 85) group included the patients in whom the diagnosis of MF could not be supported by the histologic data from the biopsy. These prospective findings confirm that a dominant monoclonal T-cell population is detected in cutaneous lesions of CTCL (all histologic subtypes) in 70% of cases4 and in 62.5% of patients with MF2 (Table 1). Also, we found that 17 of 72 patients in whom CTCL was initially considered in the differential diagnosis, despite benign histologic characteristics, had a dominant T-cell clone in the skin (Table 1).
Detection of an identical cutaneous and circulating T-cell clone is associated with the diagnosis of CTCL The biopsy specimen of the skin lesion and a simultaneously obtained PB sample were analyzed for T-cell clonality. Use of PCR--DGGE allowed the identity of 2 dominant clones detected in the
2 samples to be established. Among the 363 patients, 46 (13%) had the
same dominant clone in the PB and skin (Table 1). Detection of an
identical clone in the PB and skin occurred significantly more often in
the 152 patients (22%) with histologically confirmed CTCL than in the
211 patients (6%) in the non-CTCL group (P < .001). This
difference remained significant (P < .02) when the 22 patients with SS were not taken into account because a high proportion
of them, as expected, had circulating tumor cells (Table 1).
Detection of circulating tumor cells is infrequent in patients with MF Analysis of the 88 patients with MF (Table 1) showed that 55 had a dominant clone in the skin. Eleven of these 55 patients (20%) ie, 12.5% of the 88 patients with MFalso had a circulating tumoral clone. When we examined the influence of disease stage on the
finding of circulating tumor cells (Table
2), we found that circulating tumor cells
were infrequent in nonerythrodermic stages of MF; the proportions were
4%, 15%, and 0%, respectively, in patients with stage Ia, stage Ib,
and stage IIa or IIb. Circulating tumor cells were detected more
frequently in the 12 MF patients with erythroderma (stage III) (42%;
P = .003).
Most patients with identical circulating and cutaneous T-cell clones had erythroderma Remarkably, among the 46 patients who had the same dominant clone in the PB and skin, 26 (57%) had erythroderma at presentation. As expected, the 15 patients with SS were among these 26, but there were also 11 patients who did not have SS (35%): 5 had MF and 6 had non-CTCL skin lesions (Table 3).
The high frequency of circulating T-cell clones not detected in the skin is similar in all histologic groups The frequency of circulating dominant T-cell clones that were not detected in the skin was assessed in 2 ways. Thus, the patients in whom the circulating clone was different from the dominant cutaneous clone were considered separately from the patients who did not have a dominant cutaneous clone and in whom, therefore, the meaning of the dominant circulating clonal population remained uncertain. Overall, such clones were detected in 33% of patients with MF and there were no differences (P = .99) among the 8 clinicohistologic groups analyzed in the frequency of a circulating clone that was not found in the skin (Table 4).
Circulating T-cell clones not detected in the skin were more frequent in patients older than 60 years The frequency of a circulating T-cell clone that was not detected in the skin was significantly greater in patients aged 60 years or older (76/194) than in patients under 60 years of age (38/169; P = .002; Table 5). This age-related difference remained significant when only the 152 patients with CTCL were analyzed (P < .01). In contrast, detection in the PB of a T-cell clone identical to that in the skin, which was associated with a diagnosis of CTCL, was not influenced by the age of the patient (P > .5).
We conducted a prospective study comparing T-cell clonality in the
skin lesion and a simultaneously obtained PB sample in 363 consecutively seen patients in whom cutaneous lymphoma was clinically
considered in the differential diagnosis. On histologic assessment, 152 of these patients were found to have CTCL and 88 of these 152 had MF.
The study confirms that 70% of patients with CTCL and 62% of patients
with histologically proven MF have a dominant T-cell clone in the
cutaneous lesion that is detectable by PCR- At first, it may appear that the 24% positive samples found in the group considered to have non-CTCL on the basis of histologic analysis represent a high percentage. However, previous studies using molecular techniques found dominant T-cell clones in patients with various benign dermatoses, eg, in 22% of patients with cutaneous lymphoid hyperplasia,13 14% with contact dermatitis,18 14% with drug-induced dermatoses,19 14% with pseudolymphoma,5 and in individual cases of pityriasis lichenoides20 and benign follicular mucinosis.21 To compare the results in our non-CTCL group with those in true control groups in previous reports (namely, patients with ascertained clinicopathological diagnoses),3-6,13 the final diagnosis was considered at the end of the study. The final diagnoses, based on clinical presentation and outcome, repeated biopsy evaluations, and biologic data and available for 325 patients, were 182 cases of CTCL, 14 of large-plaque parapsoriasis, 26 of unclassified cutaneous inflammation, and 103 of non-CTCL. In the 103 patients with non-CTCL, 18% still had a detectable T-cell clone in the skin. It remains possible that CTCL would have developed in these patients during a longer follow-up period. Wood et al13 suggested that "clonal dermatitis" is a subgroup of histologically nonspecific dermatitis in which patients are at increased risk of development of CTCL. This is consistent with the fact that 30 patients in our study were finally reclassified as having CTCL and half of these patients had a detectable T-cell clone in the skin lesion. The current findings further illustrate that a dominant T-cell clone detectable in the skin supports a diagnosis of CTCL. Because PCR- In the group of 88 patients with MF, detection of circulating
tumoral cells was rare (12.5% of cases). This detection rate is
similar to that obtained by Southern blot analysis,9 a
technique with specificity and sensitivity in PB assessments similar to that of the PCR- It is of note that more than half (57%) of the patients with a circulating clonal population identical to the dominant cutaneous T-cell clone presented with erythroderma. Although this was expected for patients with SS (who, by definition, have circulating tumor cells and erythroderma), among the group of patients with MF, the frequency of a circulating tumoral population was significantly greater in those with the erythrodermic forms (42%; P = .003). Remarkably, in the non-CTCL group, 6 of 13 patients with an identical circulating and cutaneous clone had erythroderma. When the final diagnosis in these patients was considered, 4 of them did in fact have CTCL (3 patients with SS and 1 with erythrodermic MF) and 2 continued to be considered to have unclassified cutaneous inflammation. This is in keeping with the finding that nonspecific histologic findings are compatible with the diagnosis of CTCL.24-25 The nosologic distinction between erythrodermic MF and SS is not currently clear. In the EORTC classification,17 erythrodermic MF is not defined; rather, EORTC recommends reserving the label of MF for classic disease with progression through the patch, plaque, and tumor stages. SS is characterized by the triad of erythroderma, generalized lymphadenopathy, and the presence of tumoral T cells (Sézary cells) in the skin, lymph nodes, and PB. Recent reviews of MF and SS8,26 did not categorize erythrodermic MF as a separate entity, although the distinction between the 2 conditions appears to have prognostic importance. Thus, lymph node involvement and the presence of more than 5% Sézary cells, which distinguish SS from erythrodermic MF, were 2 factors indicative of a poor prognosis in a series of 106 patients with erythroderma and a histologic diagnosis of epidermotropic cutaneous lymphoma.27 In another series, the absence of circulating tumor cells was a good prognostic factor for overall survival in patients with erythrodermic CTCL treated by total skin irradiation.28 Biologically, SS is defined by the number of circulating Sézary cells (> 15% of leukocytes in this study). However, there is no consensus regarding how these cells should be identified and the percentage required to make the diagnosis. None of the current techniques (cytologic analysis, electron microscopy, or immunophenotyping) are specific for a tumoral population. The monoclonal nature of the Sézary cell has been demonstrated in studies using molecular techniques; however, most of these studies also found a small percentage of patients with SS who did not have a detectable circulating monoclonal population on either Southern blot analysis10,29,30 or PCR.31,32 Altogether, on one hand, nearly 50% of patients with erythrodermic MF
have circulating tumor cells and, on the other hand, a small subgroup
of patients with SS do not have a detectable clone. The prognostic
value of a circulating tumoral population detected by PCR- In addition to circulating tumoral clones, a dominant T-cell
clone in the PB not found in the skin was detected in 30% of patients
with CTCL. The importance of these circulating clones remains unknown,
although 3 hypotheses can be considered. First, in MF, some clones
could correspond to genuine tumor cells not detected in the skin
because the cutaneous clone is diluted in a reactive infiltrate.
However, this situation must be rare because the frequency of
circulating dominant clones (30%) was the same in the group of 72 patients with documented benign disease. Moreover, among the patients
with MF who had a dominant T-cell clone in PB that was not detectable
in skin lesions, none subsequently had lesions positive for the
circulating clone. Second, these circulating clones could be reactive
to the cutaneous tumor, as suggested recently for small-plaque
parapsoriasis.33 Our results do not support this
hypothesis, however, because a similar frequency (between 30% and
40%) of circulating T-cell clones not detected in the skin was found
in all clinicopathologic categories studied. Third, these circulating
dominant clones might be related to the clonal T-cell expansions in
elderly patients, which were originally characterized in the
CD8+ CD28 In conclusion, our prospective study of PB T-cell clonality in patients
with a clinical suspicion of cutaneous lymphoma showed that detection
of a dominant clone in the PB identical to that in the skin provides
additional evidence for the diagnosis of CTCL with respect to the
demonstration of T-cell clonality in the skin alone. This study found
that half of the patients with an identical T-cell clone in the PB and
skin had erythroderma. The prognostic value of circulating tumor cells
detected by PCR-
We thank Samir Agrawal for rereading the manuscript.
Submitted December 27, 1999; accepted June 22, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Marie-Hélène Delfau-Larue, Service d'Immunologie Biologique, Hôpital Henri-Mondor, 51 av du Marechal de Lattre de Tassigny, 94010 Créteil, France; e-mail: marie-helene.delfau{at}hmn.ap-hop-paris.fr.
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© 2000 by The American Society of Hematology.
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  J. Guitart and C. Magro Cutaneous T-Cell Lymphoid Dyscrasia: A Unifying Term for Idiopathic Chronic Dermatoses With Persistent T-Cell Clones Arch Dermatol, July 1, 2007; 143(7): 921 - 932. [Abstract] [Full Text] [PDF]
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 Y. Sandberg, E. J. van Gastel-Mol, B. Verhaaf, K. H. Lam, J. J.M. van Dongen, and A. W. Langerak BIOMED-2 Multiplex Immunoglobulin/T-Cell Receptor Polymerase Chain Reaction Protocols Can Reliably Replace Southern Blot Analysis in Routine Clonality Diagnostics J. Mol. Diagn., October 1, 2005; 7(4): 495 - 503. [Abstract] [Full Text] [PDF]
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T. Juarez, S. N. Isenhath, N. L. Polissar, D. E. Sabath, B. Wood, D. Hanke, C. L. Haycox, G. S. Wood, and J. E. Olerud Analysis of T-Cell Receptor Gene Rearrangement for Predicting Clinical Outcome in Patients With Cutaneous T-Cell Lymphoma: A Comparison of Southern Blot and Polymerase Chain Reaction Methods Arch Dermatol, September 1, 2005; 141(9): 1107 - 1113. [Abstract] [Full Text] [PDF]
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J. de Quatrebarbes, E. Esteve, M. Bagot, P. Bernard, M. Beylot-Barry, M. Delaunay, M. D'Incan, P. Souteyrand, L. Vaillant, N. Cordel, et al. Treatment of Early-Stage Mycosis Fungoides With Twice-Weekly Applications of Mechlorethamine and Topical Corticosteroids: A Prospective Study Arch Dermatol, September 1, 2005; 141(9): 1117 - 1120. [Abstract] [Full Text] [PDF]
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C. Querfeld, S. T. Rosen, T. M. Kuzel, K. A. Kirby, H. H. Roenigk Jr, B. M. Prinz, and J. Guitart Long-term Follow-up of Patients With Early-Stage Cutaneous T-Cell Lymphoma Who Achieved Complete Remission With Psoralen Plus UV-A Monotherapy Arch Dermatol, March 1, 2005; 141(3): 305 - 311. [Abstract] [Full Text] [PDF]
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F. Vega, R. Luthra, L. J. Medeiros, V. Dunmire, S.-J. Lee, M. Duvic, and D. Jones Clonal heterogeneity in mycosis fungoides and its relationship to clinical course Blood, October 16, 2002; 100(9): 3369 - 3373. [Abstract] [Full Text] [PDF]
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E. Dippel, D. Klemke, M. Hummel, H. Stein, S. Goerdt, and M.-H. Delfau-Larue T-cell clonality of undetermined significance Blood, July 1, 2001; 98(1): 247 - 248. [Full Text] [PDF]
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Top
Abstract
Introduction
-gene rearrangements in the peripheral blood of patients with mycosis fungoides.
Arch Dermatol.
1992;128:1602-1607
T-cell receptor genes in mycosis fungoides and Sézary syndrome.
Cancer.
1991;68:1572-1582
-thalassemia