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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3376-3380
Prognostic Significance of a Polymerase Chain Reaction-Detectable
Dominant T-Lymphocyte Clone in Cutaneous Lesions of Patients With
Mycosis Fungoides
By
Marie-Hélène Delfau-Larue,
Sophie Dalac,
Eric Lepage,
Tony Petrella,
Janine Wechsler,
Jean-Pierre Farcet, and
Martine Bagot
From the Service d'Immunologie Biologique, Unité
d'Information Médicale, Département de Pathologie, Service
de dermatologie du Pr Revuz, Hôpital Henri-Mondor, Créteil,
France; the Service de Dermatologie du Pr Lambert, Hôpital du
Bocage; and the Département de Pathologie, CHU de
Dijon, Dijon, France.
 |
ABSTRACT |
Although mycosis fungoides (MF) is considered to be an indolent
lymphoma, survival is highly influenced by TNM stage. At diagnosis, most MF patients present with early stage disease and a high
probability of long-term survival. Treatment is generally directed
towards skin lesions, and achievement and duration of complete
responses are variable. A dominant T-cell clone is detectable in the
cutaneous lesions of 60% of patients. The aim of this study was to
determine whether the presence of a T-cell clonal population influences the clinical course of the disease after topical therapy. Cutaneous biopsies from 68 patients were histologically diagnosed as MF and
T-cell clonality was analyzed by in vitro amplification of TCR-
chain gene rearrangements (polymerase chain reaction [PCR]). After a median follow-up of 48 months,
response to treatment was clinically assessed. Age, sex, duration of
symptoms before diagnosis, type of cutaneous lesions (T stage), TNM
stage, and PCR were evaluated as predictive factors of response to
treatment in univariate and multivariate analyses. Univariate analysis
demonstrated that T1 cutaneous lesions (P = .05) and PCR
negativity (P = .007) were associated with a higher complete
remission rate. Using multivariate analysis, T stage
(relative risk, 3.13; P = .06) and PCR (relative risk,
4.4; P = .01) remained independent significant predictive parameters of response. In conclusion, T stage and cutaneous PCR at
diagnosis are the two predictive parameters of treatment response for
MF. Therefore, the cutaneous PCR findings should be considered in
the analysis of future therapeutic trials.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
MYCOSIS FUNGOIDES (MF) is the most common
subtype within the group of cutaneous T-cell lymphomas
(CTCL).1 The natural history of MF is characterized by an
indolent yet orderly progression through four stages: patch, plaque,
tumor, and visceral involvement. The characteristic lesions of this
disease begin as macular lightly erythematous patches that subsequently
evolve into well-demarcated scaling plaques. These plaques may then
progress to tumor lesions and subsequently spread to the viscera, but
this progression is not necessarily seen in all patients (reviewed in
Lorincz2).
Among patients with MF, the prognosis is highly variable. MF is
classified into clinical stages using the TNM classification and the
staging system established at the National Cancer Institute (Bethesda,
MD) (Table 1).3,4 Previous studies of
prognostic indicators have shown consistently that the skin (T) stage
and the presence or absence of extracutaneous disease are the most important determinants of outcome.5-7 Patients with limited
skin involvement (T1) have a favorable prognosis,8 whereas
patients with erythrodermic MF (T4) or tumor (T3) have an unfavorable
prognosis.
Numerous therapeutic strategies have been tried in MF (reviewed in
Diamandidou et al9). Treatment regimens in early MF are
generally directed towards skin lesions, ie, psoralen and ultraviolet A
(PUVA), topical chemotherapy (nitrogen mustard), and electron beam
therapy. Each approach produces similar response rates, and there are
no randomized trials demonstrating the superiority of one regimen over
another.
The diagnosis of CTCL relies on histopathological examination of skin
biopsies.10 The T-cell receptor chain gene (TCR) rearrangement provides a convenient genetic marker for the study of
clonality in cutaneous mature T-cell infiltrates (reviewed in Wood et
al11 and Volkenandt et al12). Like other
investigators, we have reported that the frequency of detection by
polymerase chain reaction (PCR) of a dominant T-lymphocyte clone in
lesions histologically typical of MF (regardless of stage) is
60%.13-16 The presence or absence of a detectable dominant
T-cell clone is identical in different lesions of the same type
(patch/plaque, tumor, erythroderma) from the same
patient.17 In 89% of cases, the PCR(+) or
PCR( ) nature of the cutaneous lesions is maintained during
the course of the disease after therapy. When the samples are positive,
the clonospecific imprint of the tumoral population also remained
stable with time.17
To study the influence of a dominant monoclonal T-cell population in
cutaneous lesions of MF on the clinical course of the disease after
topical therapy, we studied the effect of clonality on the achievement
of complete remission in 68 patients.
| |
MATERIALS AND METHODS |
Patient selection and staging.
From December 1, 1988 until August 31, 1994, a cutaneous biopsy was
performed for histological and molecular studies on all patients with a
clinical picture suggestive of MF. The criterion for including patients
in this study was the existence of lesions histologically typical of
MF, ie, band-like subepidermal infiltrates, the presence of Sezary
cells, and single-cell epidermotropism and/or clusters of
cell-forming Pautrier's microabscesses.10 Patients were
excluded if they had more than 15% circulating Sezary cells or if
clinical data were not available. Sixty-eight patients were eligible.
Staging at presentation was performed according to the modified
TNM classification of cutaneous T-cell
lymphomas3,4 (Table 1). After diagnosis, all
patients received topical treatment consisting of either
mechlorethamine (33 patients), total skin electron beam irradiation
(TSEB; 25 patients), PUVA therapy (5 patients), topical steroids (4 patients), or local electron beam irradiation (1 patient). The type of
treatment administered was not influenced by the PCR results.
Evaluation criteria.
Patients were classified in two categories according to their clinical
status at the time of the last clinical update: complete remission
(CR), ie, no clinically detectable lesion; or no CR, ie, presence of
lesions with either a stable clinical stage or progression.
TCR gene rearrangement analysis by GC clamp multiplex
PCR-denaturing gradient gel electrophoresis (DGGE).
DNA was extracted from frozen 4-mm punch biopsy samples by standard
proteinase K digestion and phenol/chloroform precipitation. Various
amounts of DNA (from 250 ng up to 1 µg) were assayed. Two hundred
fifty nanograms of DNA was chosen because results were similar to those
with 1 µg DNA and it allowed DNA banking. Thus, during patient
follow-up, DNA specimens from the diagnostic biopsies could be assessed
concurrently with DNA from new biopsies for comparison. TCR
chain gene rearrangements were studied using a GC clamp multiplex
PCR/DGGE procedure, as previously described.18 Briefly,
four oligonucleotides matching the four V segment families and four
oligonucleotides matching the J junction segments were used in a
single 50 µL PCR reaction (multiplex PCR) in a thermal cycler (Perkin
Elmer 480; Perkin Elmer, Norwalk, CT). After 40 cycles, 30 µL of amplified products was run on a 6.5% polyacrylamide gel
containing a linearly increasing 10% to 60% denaturing gradient (DGGE). The use of oligonucleotides matching all the V and J functional segments combined with DGGE allows the achievement of a
migration profile specific for each T-cell clone.18
The sensitivity of the technique depends on the type of V-J
rearrangement present in the tumoral population and the intensity of
the reactional infiltrate in the pathological skin biopsy. We
determined the range of sensitivity of our technique by diluting DNA
from the Jurkat T-cell line in DNA extracted from normal
skin15 or from reactive lymph nodes.18 Jurkat
cells possess a rearrangement often used by normal T cells (VIJI) on
one allele and a rarer rearrangement on the other allele (VIV-JI). We
found the sensitivity to be 0.1% for the rare rearrangements in a
poorly cellular infiltrate and 5% for the more frequent rearrangements
hidden by dense reactional infiltrates. This means that one or two
discrete bands will be visible when a dominant T-cell clone constitutes
from 0.1% to 5% or more of the total cell
population.15,18
Results of PCR were expressed as positive [PCR(+)] when a dominant
T-cell clone was detectable and negative [PCR()] when a
polyclonal pattern of T-cell infiltration was shown. In the latter
case, the presence of a smear on the gel ensured that T-cell DNA was
present and amplified.
Statistical methods.
Complete response rates according to pretreatment prognostic factors
and PCR results were compared by  2 or Yates
2 test. All parameters found to be significant at the
0.1 level in the univariate analysis were included in a logistic
regression analysis of response. The study was stopped on February 1, 1998, 41 months after inclusion of the most recent patient. The tests were regarded as significant if the two-sided P value was less than .05.
| |
RESULTS |
Initial patient features.
Table 2 summarizes the clinical
characteristics of the 68 patients included in this study and the
number of PCR(+) patients for each characteristic. Seventy-one
percent of patients presented in early stage disease with
patch/plaque-type cutaneous lesions (IA, IB, and IIA). Among the 68 patients studied, 62% had cutaneous lesions histologically typical of
MF that were PCR(+). The PCR(+) rate was independent of sex, age
at diagnosis of MF, and duration of cutaneous symptoms before
diagnosis. There was no correlation between the detection of a dominant
T-cell clone and either the cutaneous or extracutaneous extension of
the lesions (Table 2). The only direct link between clinical features
of the disease and clonality was the absolute relationship between the
tumoral lesions and the presence of a dominant T-cell monoclonal
population; 100% of tumoral lesions were PCR(+).
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Table 2.
Patient Characteristics and Presence of a Dominant
T-Cell Clone Detected by GC Clamp Multiplex PCR-DGGE in Cutaneous
Lesions
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|
Patient clinical features at the last clinical update.
After a median follow-up of 48 months, 33 of 68 patients (48%) were in
clinical CR as assessed by the absence of cutaneous lesions.
Sixteen patients died during the follow-up period. The initial
characteristics of these patients are shown in
Table 3. For 10 of them, the cause of death
was attributable to MF. All patients who died of their MF had a
dominant clonal population in the initial cutaneous lesion. By
contrast, no PCR() patients died of MF during the same
follow-up time (P < .01).
Nineteen patients were alive but not in CR at the last clinical update.
Two had relapsed after an initial complete response, whereas the
disease staging remained stable in the others, either without extension
of the lesions (15/19) or an increase in the number of cutaneous
plaques (2/19).
Factors that influence the CR rate.
We studied the influence of the clonality of cutaneous lesions at the
time of diagnosis on the CR status after treatment. In univariate
analysis, two parameters were associated with a higher CR rate: T1
cutaneous lesions (P = .05) and PCR() lesions (P = .007). The age of the patient at time of diagnosis (65 v >65 years), the sex, the duration of symptoms before the
diagnosis of MF (120 v >120 months), and the TNM staging
showed no prognostic value (Table 4). A
multivariate regression analysis including T stage (T1 v T2 to
T4) and PCR demonstrated that PCR negativity was a significant
independent predictor of CR after treatment (relative risk, 4.4;
P = .01; Table 5).
| |
DISCUSSION |
The study of factors influencing survival in MF have enabled three
groups of patients to be identified.5 Good-risk patients are those with patch/plaque skin disease, a negative peripheral blood
smear, and no evidence of visceral disease or nodal disease (stages IA,
IB, and IIA). This subgroup has a median survival of greater than 12 years.5-8 Poor-risk patients are those with visceral
disease or effaced lymph nodes (stage IV), with a median survival of
2.5 years. The intermediate-risk group (stages IIB and III) has a
median survival of 5 years. At diagnosis, the majority of patients
belong to the good-risk group.5,6,19 In this group, most of
the treatment regimens are directed towards skin lesions (for review,
see Diamandidou et al9). The relapse rate after treatment
and the disease-free interval are very variable from one patient to
another and, at present, no predictive criterion of therapeutic
efficacy has been demonstrated. To study the influence of a
detectable T-cell clone on the treatment response, patients were
classified into two groups according to whether or not they were in CR
at the last clinical update. Median follow-up was 48 months. A
statistical univariate analysis identified a factor influencing the CR
rate that was already known to influence survival,5,19 ie,
localized patch/plaque type disease. In addition, this study demonstrated the independent predictive value of dominant T-cell clone
detection in the skin lesions. PCR() patients more frequently achieved CR than those with a detectable dominant T-cell clone [PCR(+)].
The technique used in this study for the analysis of TCR gene
rearrangements detected the presence of a dominant monoclonal T-cell
population in 62% of lesions histologically typical of MF (Theodorou
et al15 and this study). This result contrasts with the
90% positivity reported by Wood et al.20 When we modified our technique to make it one log more sensitive by studying the various
possible VJ combinations separately (monoplex PCR), we also found
that 90% of MF lesions had a detectable dominant monoclonal or
oligoclonal T-cell population. However, 20% of the chronic eczematous
lesions studied were also positive (data not shown). We decided to
preserve the specificity of our test rather than to increase its
sensitivity, and the GC clamp multiplex PCR and DGGE methodology was
used.
Previously, we have shown that, in the same patient, whether positive
or negative, the PCR result of different lesions biopsied on the
same day or during the course of the disease was homogeneous and
remained constant in 90% of cases. When the PCR was positive, the
clonospecific imprint of the dominant population was identical in the
various cutaneous lesions.17 Thus, whether positive or negative, the PCR result appears to be a patient-dependent feature rather than a lesion-dependent feature. This finding is critical in
studying the predictive value of PCR.
The relationship between the T-cell clonality in cutaneous lesions and
the clinical staging of the MF patients points to the tumoral form as a
peculiar form of the disease. The clinical observation that a minor
subset of patients progresses to a tumoral stage of the disease, even
after several decades, supports this hypothesis. Indeed, a dominant
T-cell clone is detected in 100% of tumoral cases, whatever the
technique used, including Southern blot, which is less sensitive than
PCR (reviewed in Wood21). This result may, at first, appear
to be discordant with previously published data showing that the PCR
result is patient-dependent and not lesion-dependent. However, the
rarity of tumoral forms (~10% of MF, of which some are tumoral at
presentation) and the fact that 38% of early forms of MF are
PCR() mean that the probability of a patch/plaque
PCR() lesion evolving into a tumoral PCR(+) lesion is low
(3.8% at the most). Moreover, patients who are PCR(+) at diagnosis,
who less frequently achieve a CR, may progress more often to a tumoral
form than patients who are PCR(). This possibility will be
studied by the long-term follow-up of patients included at an early
stage of disease. In the tumoral form, the prognosis is most often
unfavorable not only with respect to treatment response, but also with
respect to survival.2 This finding suggests that, in the
initial population of malignant cells, one or more additional genetic
events may occur in a single cell leading to a growth advantage for
this cell, to a clinical presentation with a tumoral stage, and to a
high malignant cell/reactive cell ratio and therefore a positive
PCR. Previous studies have demonstrated the presence of multiple
cytogenetic abnormalities in tumoral
lesions.1,22
Data reported in the literature suggest that the cytokines produced by
the malignant T-cell clone may have a role in the in situ recruitment
of an inflammatory infiltrate.20,21 Furthermore, numerous
reactive nonmalignant lymphocytes have been shown to infiltrate
patch/plaque-type MF lesions.21,23 If the ratio of clonal
tumoral cells to reactive polyclonal cells is lower than the clonality
detection threshold, the PCR will be negative. In this context, two
elements could explain the association between a PCR() result
and the higher probability of achieving CR. On the one hand, the
tumoral mass in PCR() lesions may be less than that of the
PCR(+) lesions. On the other hand, the polyclonal reactive cells,
which represent the majority of cells in PCR() lesions, might
play a role in the control of tumor growth. This hypothesis is in
concordance with the data reported by Hoppe et al,24 who
demonstrated that, in patch/plaque-type lesions (T1/T2), the actuarial
survival of patients is correlated with the percentage of
CD8+ lymphocytes infiltrating the lesion.
An analysis of the patients who died during the follow-up period of the
study showed that the number of patients who died due to their MF in
the PCR(+) group (10/42) was significantly greater than in the
PCR() group (0/26) (P < .01). In our series, 48 patients had an initial clinical presentation with a good prognosis in
terms of survival (stages IA, IB, and IIA). Only 1 of these patients
died of his/her disease during the study period. Among the 20 patients
with a poorer prognosis (stages IIB, III, and IV), 9 have died.
Multivariate analysis, including the staging and PCR, found that the
predominant factor for survival was the staging (data not shown). A
recent report has suggested that, in the group of stage IA patients, a
lower CR rate might be associated with disease
progression.8 A longer follow-up of our patients could help
to clarify the influence of PCR on survival in the good prognosis
group.
In conclusion, using GC clamp multiplex PCR-DGGE, the detection of a
dominant monoclonal T-cell population in the cutaneous lesions of a
patient with histologically documented MF decreases the probability of
achieving a CR after treatment. Thus, PCR distinguishes two subsets
of patients and should be part of the initial staging of MF patients.
It should be included as a predictive criterion in the analysis of
therapeutic trials.
| |
FOOTNOTES |
Submitted July 9, 1997;
accepted June 21, 1998.
Supported by aid from the Ligue contre le Cancer de l'Yonne.
Address reprint requests to Marie-Hélène Delfau-Larue,
MD, Service d'Immunologie Biologique, Hôpital
Henri-Mondor, 51 av du marechal Delattre de Tassigny, 94010 Créteil, France.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors are indebted to Samir Agrawal for helpful discussion and
re-reading of the manuscript. We thank Prof P. Saiag (CHU Ambroise
Paré, Paris, France), Dr N. Franck (CHU Cochin Tarnier, Paris,
France), and Dr P. Brunet (Hopital Joffre, Corbeil, France) for their help in follow-up data collection.
| |
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February 1, 1999;
135(2):
200 - 202.
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Abstract
Introduction
Abstract