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Junctional CD8+ Cutaneous Lymphomas With Nonaggressive Clinical Behavior
A CD8+ Variant of Mycosis Fungoides?
Reinhard Dummer, MD;
Jivko Kamarashev, MD;
Werner Kempf, MD;
Andreas C. Häffner, MD;
Monika Hess-Schmid, MD;
Günter Burg, MD
Arch Dermatol. 2002;138:199-203.
ABSTRACT
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Objective To evaluate the clinical and prognostic features in primary cutaneous
CD8+ T-cell lymphomas, which are rare and considered to be aggressive
cutaneous lymphoproliferative disorders.
Design Single-center retrospective study.
Setting Lymphoma clinic (referral center) of a university hospital.
Patients Three patients presented with CD8+ cutaneous lymphoma characterized
by a patchlike pattern and hyperpigmentation.
Results Histological analysis revealed a CD3+, CD8+ small-cell
infiltrate showing a remarkable affinity to the dermoepidermal junction zone.
Clonality for the T-cell receptor  chain was detected by polymerase
chain reaction followed by denaturing gradient gel electrophoresis. The clinical
presentation lasted several years (6 and 9 years, respectively) before the
correct diagnosis was made. Treatment with nontoxic approaches (UV-B and local
steroids) was successful. Aggressive clinical behavior was not observed.
Conclusions Our 3 cases of junctional CD8+ cutaneous T-cell lymphomas
were characterized by hyperpigmentation and nonaggressive clinical behavior.
This type of lymphoma, which can be considered a CD8+ mycosis fungoides
variant, must be distinguished from other types of cutaneous CD8+
lymphomas so that overtreatment can be avoided.
INTRODUCTION
MOST CUTANEOUS T-cell lymphomas (CTCLs) have the phenotype of T-helper
memory lymphocytes (CD3+, CD4+, and CD45R0+).1-2 Only a minority of cases present with
other phenotypes, such as CD3+, CD4-, CD8-, or CD3+CD8+,3-4
or with the spectrum of CD56+ lymphomas.5-7
The primary cutaneous lymphomas with the phenotype of cytotoxic/suppressor
(CD8+) T cells have been of significant interest in the recent
literature.8-12
The detailed analysis of histological and clinical features in several cases
has led to the conclusion that CD8+ T-cell lymphomas represent
a distinct type of CTCL with an aggressive clinical behavior.4, 12
Within the last 3 years, we have seen 3 cases that have fulfilled the
criteria of an CD8+ epidermotropic T-cell lymphoma with a remarkable
affinity of the CD8+ cells to the dermoepidermal junction zone.
The patients in all 3 cases presented with hyperpigmented lesional skin. In
2 cases, the period between the appearance of the first skin symptoms and
the diagnosis was extremely long (6 and 9 years, respectively). None of the
patients developed progressive disease during the observation period.
PATIENTS AND METHODS
PATIENTS AND STAGING PROCEDURES
Our study included 3 patients who were seen in the outpatient lymphoma
clinic of the Department of Dermatology, University of Zurich, Zurich, Switzerland.
The patients underwent a clinical examination, routine blood cell counts and
chemistry studies, chest x-radiographic investigation, and ultrasound examination
of the abdomen and lymph nodes. Also, serological immunoparameters were investigated,
and a fluorescent activated cell sorter was used to analyze circulating peripheral
blood lymphocytes.
HISTOPATHOLOGIC EXAMINATION
Each patient underwent a biopsy at first presentation. Skin sections
were partly fixed in paraffin and partly snap frozen for molecular biological
analysis. Paraffin-embedded material was extensively studied using a panel
of monoclonal antibodies (Table 1).
Immunoreactivity was visualized using a standard alkaline phosphatase, anti–alkaline
phosphatase technique (Dako Diagnostics AG, Zug, Switzerland).13
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Table 1. Clinical Presentation and Outcome of the 3 Patients
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MOLECULAR BIOLOGICAL ANALYSIS
Snap-frozen material was used to extract DNA. Using previously described
primers, the T-cell receptor chain locus was amplified, and denaturing
gradient electrophoresis was used to detect clonal populations.14-17
EPSTEIN-BARR VIRUS IN SITU HYBRIDIZATION
In situ hybridization for Epstein-Barr virus RNA was performed using
a commercial kit and an Epstein-Barr virus–encoded small nuclear RNA
probe (Dako Diagnostics AG).
RESULTS
CLINICAL FEATURES
The clinical presentations of the patients are summarized in Table 1 and shown in Figure 1). All 3 patients were in good condition and free of general
symptoms. The lesions, which were confined to the trunk and the proximal aspect
of the extremities, consisted of discrete, reddish brown patches, several
centimeters in diameter, with minimal desquamation. The hyperpigmented aspect
of the patches was prominent in all 3 patients and was not associated with
a particular phototype (Table 1).
In 2 patients, the lesions were asymtomatic. Patient 2 had an 8-year history
of severe pruritus and urticaria factitia, both of which were refractory to
therapy. Imaging did not reveal any extracutaneous involvement.
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Figure 1. Clinical presentation in cases
1 (A), 2 (B), and 3 (C), characterized by extended hyperpigmented patches.
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The findings of routine blood and urine laboratory tests were noncontributory.
Fluorescent activated cell sorter analysis demonstrated a normal number of
circulating CD4+ and CD8+ lymphocytes (CD4/CD8 ratios:
patient 1, 5.0; patient 2, 2.3; and patient 3, 1.0). In cases 1 and 3, the
levels of soluble interleukin 2 receptor,18
neopterin, and  2-microglobulin19
were within normal ranges. They were not determined in case 2.
HISTOLOGICAL AND IMMUNOHISTOLOGICAL ANALYSIS
The histological findings in the 3 cases were similar. The epidermis
showed a slightly compact horny layer or slight parakeratosis. The rete ridges
were thin and elongated, resulting in a psoriasiform appearance. Single-cell
exocytosis was evident. Beneath the epidermis, there was a moderate, bandlike
lymphocytic infiltrate lining up directly opposite of the dermoepidermal junction,
as well as prominent single-cell epidermotropism, but there were no Pautrier
collections. Deeper in the middle dermis, there were discrete perivascular
infiltrates, which were composed of small lymphocytes and histiocytes. Melanin
incontinence was quite pronounced. Immunohistochemical analysis revealed that
the lymphocytes at the dermoepidermal junction were CD3+, CD4-, and CD8+ (>80%), while the perivascular lymphocytes
in the middle dermis were predominantly CD3+, CD4+,
and CD8- (>80%) (Figure 2), and that the CD8+ cells also expressed TIA-1 but not
CD7. Detailed results of the immunohistochemical investigations are presented
in Table 2. In all cases, additional
cytotoxic molecules and natural killer cell receptors were present.20
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Figure 2. Histological (stained with hematoxylin-eosin
[H&E]) (A) and immunohistological (B-D) features in a representative biopsy
specimen (case 1). Note the junctional preference of the small CD3+,
CD8+, and CD4- lymphocytes (original magnification
x200).
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Table 2. Immunohistochemistry Results on Paraffin-Embedded Tissue*
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MOLECULAR BIOLOGICAL ANALYSIS
Polymerase chain reaction–denaturing gradient gel electrophoresis
detected clonal T-cell populations in snap-frozen skin biopsy specimens in
all 3 cases. In 2 cases, the clonal population showed a rearrangement of V
1-8 and J 1/2.
The other patient showed a rearrangement of V 1-8 and JP
1/2.14 Peripheral blood mononuclear cells did
not contain clonal populations according to the results of polymerase chain
reaction–denaturing gradient gel electrophoresis in cases 1 and 2; however,
an identical clonal T-cell rearrangement was detectable in samples of skin
and blood in case 3. The results of Epstein-Barr virus RNA in situ hybridization
were negative in all 3 cases.
CLINICAL COURSE
In all 3 cases, the disease had a benign chronic course and was controlled
with nontoxic and conservative therapy, including antihistamines, topical
corticosteroids, and UV-B or psoralen–UV-A.The lesions in cases 1 and
2 responded to these mild therapies. The recalcitrant pruritus in case 2 posed
a significant therapeutic problem. Different modalities, including a combination
of psoralen–UV-A and systemic retinoids, with or without interferon
alfa, were used to try to relieve the pruritis, without success. The overall
duration of disease has been lengthy in patients 1 (9 years) and 2 (10 years),
with no sign of progression or extracutaneous involvement. During the 10 months
of follow-up in case 3, the clinical presentation of the disease has improved
with local steroid treatment (betamethasone, 3-5 times a week).
COMMENT
Cutaneous T-cell lymphomas with a suppressor/cytotoxic (CD8+)
phenotype are rare lymphoproliferative disorders. They are not categorized
separately by recent lymphoma classifications.21-23
We report 3 cases of CD8+ CTCL. All 3 cases were diagnosed
as low-grade lymphomas because of the clinical features, the course of the
disease, and the findings of histological and molecular biological analysis.
All of them showed clonality on polymerase chain reaction–denaturing
gradient gel electrophoresis and a junctional homing preference for small-cell
CD8+ T lymphocytes. Therefore, all 3 cases fulfilled the criteria
for CD8+ epidermotropic cytotoxic T-cell lymphomas as defined in
an earlier publication,4 as well as for CD8+ patch-stage mycosis fungoides.22
All 3 patients had more or less extensively hyperpigmented, flat skin
lesions, resulting in the clinical differential diagnosis of superficial morphea,
lichen sclerosus et atrophicus, or ashy dermatosis. In 2 cases, it was several
years before the correct diagnosis was finally made.
In lymphoproliferative disorders, the clinical features might be helpful
in making the correct diagnosis. We encourage additional studies to see whether
hyperpigmentation is more frequent in CD8+ CTCL, as the bruiselike,
contusiforme appearance, which we described previously5
and which has been observed by other investigators,6-7
is a common feature in CD56+ natural killer cell lymphomas.
After diagnosis, our patients clearly responded to mild and nonaggressive
treatment, including the use of local steroids, psoralen–UV-A, retinoids,
and UV-B phototherapy. One case was complicated by very severe pruritus with
urticaria factitia that could not be controlled by any antipruriginous agent.
This clinical behavior is in contrast to that described by Berti et al,4 who reported an aggressive course and median survival
time of 32 months in 17 cases. In 2 of our cases, the disease course was protracted
over 9 and 10 years, respectively, and in all 3 cases, there was no tendency
for extracutaneous involvement, which agrees with the chronic subtype reported
by Agnarsson et al in 1990.10 All 3 of our
cases showed a CD7 loss, similar to Agnarsson and colleagues' cases. In view
of the clinical descriptions in earlier publications, we are convinced that
this variant of CD8+ lymphoma might also have been noticed earlier
by other groups.
Because of the clinical presentation and the benign behavior in our
3 cases, we think that this type of CD8+ T-cell lymphoma has to
be differentiated from other cytotoxic lymphoproliferations, as it appears
to have a good prognosis, similar to patch-stage mycosis fungoides. It remains
to be determined whether the expression of CD8 by the tumor cells has any
prognostic implications at all. However, today, there is a tendency toward
aggressive treatment of CD8+ lymphomas, which is not always justified.
Therefore, all physicians involved in the care of patients with CTCL have
to be aware that CD8+ positivity alone has no clear prognostic
value.
AUTHOR INFORMATION
Accepted for publication June 18, 2001.
We wish to thank Beatrix Müller for histochemical and immunohistochemical
analysis, Markus Bär and Maggi Johnson for the photographic documentation,
and Marion Lüthi for the preparation of the manuscript for this article.
Corresponding author and reprints: Reinhard Dummer, MD, Department
of Dermatology, University Hospital, Gloriastrasse 31, CH-8091 Zürich,
Switzerland (e-mail: dummer{at}derm.unizh.ch).
From the Department of Dermatology, University of Zurich Medical School,
Zurich, Switzerland.
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