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The Clonal Nature of Pityriasis Lichenoides
Jeffrey M. Weinberg, MD;
Leonard Kristal, MD;
Lillian Chooback, PhD;
Paul J. Honig, MD;
E. Michael Kramer, MD;
Stuart R. Lessin, MD
Arch Dermatol. 2002;138:1063-1067.
ABSTRACT
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Background Pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis
lichenoides chronica (PLC) are benign lymphocytic infiltrates of the skin
that classically present as either a recurrent papulonecrotic eruption (PLEVA)
or a persistent, scaling, papular eruption (PLC). Observations of both types
of lesions present on individual patients have led to speculation that both
entities are related. Previous studies evaluating the DNA of biopsy specimens
from patients with PLEVA and PLC revealed clonal T-cell receptor  gene
rearrangements.
Objective To analyze and compare the T-cell populations between lesions of PLEVA
and PLC.
Design Retrospective and prospective analysis of patient tissue samples, classified
by histologic analysis. Extracted DNA from 13 skin biopsy specimens with the
diagnosis of PLC and 14 skin biopsy specimens with the diagnosis of PLEVA
was analyzed by polymerase chain reaction/denaturing gradient gel electrophoresis
(PCR/DGGE).
Setting Molecular diagnostic laboratory at an academic medical center.
Patients Twenty-seven tissue samples were obtained from patients with a histologic
diagnosis of PLEVA or PLC. These samples were analyzed by PCR/DGGE.
Main Outcome Measure The presence or absence of T-cell receptor gene rearrangements on PCR/DGGE
analysis corresponding to a clonal population of T cells.
Results Of 14 PLEVA specimens, 8 (57%) demonstrated monoclonal T-cell receptor
gene rearrangements; 1 (8%) of 13 PLC specimens showed a gene rearrangement
(P = .008, Fisher exact test).
Conclusions Our results demonstrate the polyclonal nature of the lymphocytic infiltrate
found in almost all of the PLC specimens, which contrasts with the monoclonal
nature found in most of the PLEVA specimens. These differences may represent
different stages of the clinical evolution of a single entity that results
from varying host immune responses to pathogenic factors. Specifically, we
propose that PLEVA is a benign clonal T-cell disorder in which the clone arises
from a subset of T cells in lesions of PLC. The host immune response to this
clone determines the clinical and histologic findings in PLEVA.
INTRODUCTION
PITYRIASIS LICHENOIDES is characterized by papulosquamous to papulonecrotic
lesional morphology, a chronic and recurrent clinical course, and, as demonstrated
by histopathologic analysis, a lichenoid infiltrate with variable dermal hemorrhage
and keratinocyte necrosis. Pityriasis lichenoides and its principal variants
were identified and reported in a series of articles published in the late
19th and early 20th centuries.1 It was first
described by Neisser2 and Jadassohn3 in separate reports in 1894; both included cases of
what would now be considered acute and chronic variants of the disease.4 Juliusberg5 redescribed
the chronic form of pityriasis lichenoides in 1899 and designated it as a
separate entity, introducing the term pityriasis lichenoides
chronica (PLC). Brocq6 later included
PLC in his classification of parapsoriasis as guttate parapsoriasis. In 1916,
Mucha7 redescribed the acute form of pityriasis
lichenoides, distinguishing it from both PLC and other diseases. This entity
was termed pityriasis lichenoides et varioliformis acuta (PLEVA) by Habermann8 in 1925. Accordingly,
PLEVA is also known as Mucha-Habermann disease.
Observations of both acute and chronic lesions present on the same individual
have led to speculation that both entities are related to and may be a part
of a continuous disease spectrum.9 The term pityriasis lichenoides can be used to encompass both acute
and chronic presentations that are characterized by papulosquamous lesions
located primarily on the trunk or extremities. The papules in PLEVA develop
immediately and heal spontaneously with central necrosis. The acute episodes
are recurrent and persistent. The maculopapular lesions of PLC develop less
quickly with an adherent scale and resolves spontaneously with residual pigmentary
changes. Both lesions histologically show similarities. The lesions of PLEVA
reveal a superficial and deep perivascular lymphocytic infiltrate accompanied
by lymphocytes that obscure the dermoepidermal interface, where there are
also extravasated erythrocytes and necrotic keratinocytes. The lesions of
PLC have a bandlike lymphocytic infiltrate with a few extravasated erythrocytes
in the papillary dermis and vacuoles and necrotic keratinocytes at the dermoepidermal
interface.
The etiology of these disorders remains unknown. Immunohistochemical
analysis has found similarities in both entities.10
Molecular characterization of the infiltrating cells in a small series of
patients with PLEVA indicated that the lymphocytic infiltrate is lymphoproliferative
in nature11 and demonstrated a monoclonal population
of T cells by Southern blot analysis of T-cell receptor (TCR) gene rearrangement. In addition, Panhans et al12 described the case of a 7-year-old boy with atypical
CD30-positive cells and a clonal TCR gene rearrangement
by polymerase chain reaction (PCR) of TCR
genes. Recently, Dereure et al13 reported a
study of T-cell clonality in PLEVA using PCR of TCR
gene rearrangements. An analysis of 13 of 20 PLEVA biopsy specimens revealed
the presence of a dominant T-cell clone. Despite its lymphoproliferative nature,
PLEVA is a clinically benign entity with no significantly documented association
with malignant lymphoma,9 except for a few,
poorly documented case reports.14
Another recent study evaluated clonality in cases of PLC15:
6 cases of PLC were analyzed using a frozen section–immunoperoxidase
technique and PCR/denaturing gradient gel electrophoresis (PCR/DGGE). Of these,
3 demonstrated a monoclonal gene rearrangement. The purpose of the present
study was to analyze and compare the T-cell populations, by TCR gene rearrangement analysis, in lesions of PLC and PLEVA in an
attempt to develop a model of the clonal relationship between the 2 disorders.
To our knowledge, our study is the first to directly compare both entities.
MATERIALS AND METHODS
PATIENT SAMPLES
In the present study, 27 biopsy specimens were analyzed: 13 from patients
with PLC and 14 from patients with PLEVA. Of the 27 cases, 6 (4 PLC and 2
PLEVA) were analyzed prospectively, and 21 (9 PLC and 12 PLEVA) were studied
retrospectively from archived tissue specimens. Informed consent and approval
by the institutional review board of the University of Pennsylvania, Philadelphia,
was obtained to study unused portions of diagnostic samples. In the retrospective
arm of the study, questionnaires were mailed to the patients' primary dermatologists
to obtain the following information: patient age at biopsy, duration of eruption
prior to biopsy, location of eruption, and follow-up.
HISTOPATHOLOGIC ANALYSIS
All hematoxylin-eosin–stained skin biopsy specimens were reviewed
by one of us (E.M.K.) in a blinded fashion to establish uniform diagnosis.
All 27 skin biopsy specimens included in this study were assigned a diagnosis
of either PLEVA or PLC. Histologic diagnosis was based on the following 4
criteria: (1) density of the lymphocytic infiltrate, (2) degree of epidermal
necrosis, (3) number of extravasated erythrocytes, and (4) number of necrotic
keratinocytes.
DNA EXTRACTION
Genomic DNA was extracted from snap frozen samples (6 prospective cases)
as previously described.16 Genomic DNA from
formalin-fixed paraffin-embedded blocks (21 retrospective cases) was extracted
in the following manner. Ten 10-mm sections were cut from each block, deparaffinized
in xylene, rinsed with 95% ethanol, dried, resuspended in tris-EDTA (10mM
Tris–hydrochloric acid and 1mM EDTA, pH 7.8) and incubated with proteinase
K (Sigma-Aldrich Corp, St Louis, Mo) at 37°C overnight. Samples were heated
for 10 minutes at 95°C (inactivate proteinase K), spun, and supernatants
were phenol-chloroform extracted and ethanol precipitated. Dried DNA was resuspended
in sterile water and used for PCR.
PCR/DDGE ANALYSIS OF TCR GENE REARRANGEMENTS
AND STATISTICAL ANALYSIS
We used the method of Wood et al17 to
perform PCR/DGGE analysis of TCR gene rearrangements.
Genomic DNA was PCR-amplified using 2 sets of TCR-V and TCR-J
consensus oligonucleotide primers (primers V1-8 and J1-2; primers
V9 and J1-2) in 2 separate PCR reactions. To detect clonality,
PCR products were analyzed by DGGE using a DGGE System (CBS Scientific Company
Inc, Del Mar, Calif) according to manufacturer's specifications. Our detection
sensitivity of TCR PCR/DGGE analysis of skin biopsy specimens18 is at the 1% level and comparable with others reports.17 Two-by-two comparisons were made between cases of
PLEVA and PLC with and without detection of T-cell clonality by the Fisher
exact test using StatView II software (Abacus Concepts Inc, Berkeley, Calif).
RESULTS
CLINICOPATHOLOGIC CORRELATION
Of the 27 specimens analyzed, 13 were classified as PLC and 14 as PLEVA
based on the histologic criteria outlined in the "Materials and Methods" section. Figure 1 illustrates the histologic findings
of PLC: a sparse, superficial perivascular lymphocytic infiltrate associated
with a few extravasated erythrocytes in the papillary dermis and some vacuoles
and necrotic keratinocytes at the dermoepidermal junction. Figure 2 demonstrates a dense superficial and deep lymphocytic infiltrate
that obscures the dermoepidermal interface, where there are also extravasated
erythrocytes and necrotic keratinocytes. This is consistent with a diagnosis
of PLEVA.
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Figure 1. Low-power photomicrograph of pityriasis
lichenoides chronica illustrating a sparse, superficial perivascular lymphocytic
infiltrate associated with a few extravasated erythrocytes in the papillary
dermis and some vacuoles and necrotic keratinocytes at the dermoepidermal
junction (hematoxylin-eosin, original magnification x100).
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Figure 2. A dense superficial and deep lymphocytic
infiltrate obscuring the dermoepidermal interface, where there are also extravasated
erythrocytes and necrotic keratinocytes, which is consistent with a diagnosis
of pityriasis lichenoides et varioliformis acuta (hematoxylin-eosin, original
magnification x100).
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Prospectively, one of us (L.K.) evaluated 6 cases of pityriasis lichenoides
in a pediatric population. Initially, 3 patients were given the clinical diagnosis
of PLC based on the clinical appearance of small scaling macules, and 3 patients
were clinically diagnosed as having PLEVA based on the predominance of small
scaling and/or crusted papules. Histologic examination correlated with the
clinical diagnosis in 5 of the 6 cases. One of the clinical PLEVA cases was
reclassified as PLC (PLC patient 13) after histologic examination demonstrated
changes most consistent with PLC. Even in this small prospective survey of
patients, it was evident that clinical observation could not perfectly predict
histologic findings. Additionally, in the 21 archival cases that were reviewed,
several cases clinically thought to have PLC or PLEVA were reclassified based
on histologic analysis, further suggesting a spectrum of disease.
CLINICAL COURSE
Table 1 lists the characteristics
of the patients, including sex, age, duration of skin lesions prior to diagnosis,
and body location. For most patients, follow-up is provided. Follow-up was
available for 9 PLC patients and 10 PLEVA patients. Clinical course was characterized
by either persistent or worsening disease, intermittent recurrences, improvement,
or total clearing. Follow-up ranged from 2 months to 7 years. In the PLC group,
there was an average follow-up of approximately 2.2 years: 4 patients were
clear, 3 had disease, 1 had intermittent recurrences, and 1 noted improvement.
For the patients with PLEVA, with an average follow-up of approximately 4.4
years, 5 were clear, 4 had intermittent recurrences, and 1 noted worsening
disease. Our follow-up data suggest no clear differences in the clinical courses
of PLEVA and PLC cases.
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Data Summary of Patients With PLC and PLEVA*
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TCR GENE REARRANGEMENT STUDIES
The results of TCR gene rearrangement analysis
by PCR/DGGE from patients with PLC and PLEVA are summarized in Table 1. Of the 13 patients with PLC, a clonal population of T cells
was detected in the skin biopsy specimen of 1 patient (8%) by TCR PCR/DGGE
analysis. In contrast, 8 (57%) of the 14 patients with PLEVA demonstrated
a detectable monoclonal TCR gene rearrangement
(P = .008, Fisher exact test). Figure 3 shows the results of PCR/DGGE analysis of representative
patients with PLC and PLEVA.
COMMENT
To our knowledge, our analysis is the first to examine the clonal nature
of both PLEVA and PLC. We obtained tissue samples from previously defined
specimens, and obtained DNA for molecular analysis. Clinical information and
follow-up was obtained from these patients. Our results indicate a distinction
in the biological nature between these 2 entities. Although most of our cases
of PLEVA displayed evidence of the presence of monoclonal T-cell populations
by molecular analysis, only 1 of the patients with PLC showed evidence of
such populations, with nearly all the results indicating the presence of reactive,
polyclonal T cells. These differences may represent different stages of the
clonal evolution of a single entity that results from varying host immune
responses to pathogenic factors. Larger series will be necessary to validate
our findings.
Recently, Dereure et al13 reported the
results of a study of T-cell clonality in PLEVA using heteroduplex analysis
of TCR gene rearrangements. In an analysis of 20
PLEVA biopsy specimens, 13 (65%) revealed the presence of a dominant T-cell
clone. This corresponds to our findings of a clone in 57% of PLEVA samples.
Dereure et al concluded that their findings provided further evidence for
the presence of dominant T-cell clone in skin lesions of some patients with
PLEVA and supports the hypothesis that PLEVA is part of the spectrum of clonal
T-cell cutaneous lymphoproliferative disorders. They did not analyze any cases
of PLC. Shieh et al15 evaluated the clonality
of lesional lymphocytes in PLC. They found that 3 of 6 cases involved monoclonal TCR gene rearrangements. Their finding of a clone
in 50% of cases varies significantly from our detection of a clone in 8% of
cases. It is unlikely that the differences in clonal detection resulted from
differing assay sensitivities. It is possible that small sample sizes contributed
to these differences. In addition, this finding may correspond to the different
characteristics of the populations under study. The mean age in our patients
with PLC was 7 years, while the patients of Shieh et al15
ranged in ages from 39 to 64 years. The clonal evolution from PLC to PLEVA
and individual immune responses may differ in childhood and adult populations.
In our study, histologic criteria were used to categorize biopsy specimens
into a particular diagnostic group based on the degree of features listed
in the "Results" section. The histologic findings were not always in agreement
with the clinical impression, such as in PLC patient 13. Whereas we were able
to separate specimens into 2 groups, it must be remembered that with a spectrum
of disease and tremendous overlap such divisions are observer dependent. Therefore,
histologic analysis in this instance is not totally reliable to make an accurate
diagnosis.
The clonal relationship between PLC and PLEVA is further supported by
immunohistologic findings. In the study by Wood et al,10
the only immunohistologic difference observed between PLEVA and PLC was the
trend toward a predominance of CD8+ T cells in PLEVA, especially
within the epidermis. They argued that a subset of infiltrating cells may
be the primary target, with epidermal destruction representing a secondary
event. In addition, in the recent study by Shieh et al,15
all PLC cases showed a mild to moderate superficial and deep infiltrate composed
primarily of CD4+ T cells.
Taken together, our findings may be useful in understanding the pathogenesis
of pityriasis lichenoides and support a model of a clonal spectrum of the
disease. We speculate that in PLC a clonal population of CD8+ T
cells infiltrates the skin in small numbers, usually below the detection threshold
of PCR. With a greater influx of clonal CD8+ T cells, the clinical
manifestations of PLEVA become evident. At this point, a T-cell clone can
be most frequently detected (Figure 4).
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Figure 4. Model of the clonal evolution
of pityriasis lichenoides. In pityriasis lichenoides chronica (PLC), a clonal
population of CD8+ cells infiltrates the skin in small numbers,
below detection of polymerase chain reaction. With a greater influx of CD8+ cells, the clinical manifestations of pityriasis lichenoides et varioliformis
acuta (PLEVA) become evident. At this point, a clone can be detected. Shaded
cells are CD8+ cells.
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In summary, our data underscore the clinicopathologic similarity between
acute (PLEVA) and chronic (PLC) variants of pityriasis lichenoides. The increased
frequency of the detection of a monoclonal T-cell population in individual
lesions of PLEVA compared with PLC lesions supports a model in which PLEVA
and PLC may represent different stages of evolution of a single entity. The
monoclonal T cells detected in lesions of PLEVA may arise from a subset of
T cells in lesions of PLC as a result of a variable host immune response to
pathogenic factors. Further analysis will be necessary to fully elucidate
the clonal evolution of pityriasis lichenoides. Analysis of both PLEVA and
PLC lesions obtained from the same patient will be helpful in further defining
the precise clonal evolution of these entities.
AUTHOR INFORMATION
Accepted for publication December 17, 2001.
This study was supported by grant K24 AR 02102 from the National Institutes
of Health, Bethesda, Md (Dr Lessin).
Corresponding author: Jeffrey M. Weinberg, MD, Department of Dermatology,
St Luke's–Roosevelt Hospital Center, 1090 Amsterdam Ave, Suite 11D,
New York, NY 10025 (e-mail: jwein{at}bway.net).
From the Department of Dermatology, University of Pennsylvania (Drs
Weinberg, Chooback, and Lessin), the Children's Hospital of Philadelphia (Drs
Kristal and Honig), and Thomas Jefferson Medical College (Dr Kramer), Philadelphia,
Pa. Dr Weinberg is now with the Department of Dermatology, St Luke's–Roosevelt
Hospital Center, New York, NY, and Dr Lessin is now with the Fox Chase Cancer
Center, Philadelphia.
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