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From the Institute of Dermatologic Science and IRCCS
Ospedale Maggiore,*
Milan, Italy; the Department of
Dermatology,
Ospedale Busto Arsizio, Italy;
and the Departments of Dermatology and
Pathology,
Free University Hospital,
Amsterdam, The Netherlands
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/
T cells. Nine
of 17 cases showed the characteristic clinical and histological
features as well as clinical behavior of well defined types of
CTCL, such as mycosis fungoides (2 cases), pagetoid
reticulosis (2 cases), lymphomatoid papulosis (2
cases), and CD30+ large T cell lymphoma (2
cases), all of which usually express a CD4+ T cell
phenotype, and 1 case of subcutaneous panniculitis-like T cell
lymphoma. The other 8 cases formed a homogeneous group showing a
distinctive set of clinicopathological and immunophenotypical
features, not consistent with that of other well defined types
of CTCL. Clinical characteristics included presentation with
generalized patches, plaques, papulonodules,
and tumors mimicking disseminated pagetoid reticulosis; metastatic
spread to unusual sites, such as the lung,
testis, central nervous system, and oral
cavity, but not to the lymph nodes; and an aggressive course
(median survival, 32 months). Histologically, these
lymphomas were characterized by band-like infiltrates consisting of
pleomorphic T cells or immunoblasts, showing a diffuse
infiltration of an acanthotic epidermis with variable degrees of
spongiosis, intraepidermal blistering, and necrosis.
The neoplastic cells showed a high Ki-67 proliferation index and
expression of CD3, CD8, CD7, CD45RA,
ßF1, and TIA-1 markers, whereas CD2 and CD5 were
frequently lost. Expression of TIA-1 pointed out that these lymphomas
are derived from a cytotoxic T cell subset. The results of this and
other studies reviewed herein suggest that these strongly
epidermotropic primary cutaneous CD8+ cytotoxic T cell lymphomas
represent a distinct type of CTCL with an aggressive clinical
behavior.
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Introduction |
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In the present study we discuss the clinical, histological,
immunohistochemical, and molecular features of 17 cases of CD8+
CTCL. To characterize the derivation and functional status of the CD8+
neoplastic T cells, they were further investigated for the presence of
cytotoxic proteins such as perforin (PF), granzyme-B (g-B), and
T-intracytoplasmic antigen (TIA)-1/granule membrane protein
(GMP)-17.19-22
In + T cells and natural killer (NK)
cells these cytotoxic proteins (CGPs) are expressed irrespective of
their functional state.23
In 
ß+ cytotoxic T cells
(CTL) TIA-1/GMP-17 is expressed constitutively,21
whereas
PF and g-B are detectable at protein level only after antigenic
stimulation.24,25
The ultimate goal of our study was to find out whether distinct clinicopathological entities could be recognized in this group of CD8+ CTCL.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The study described 17 patients with a CD8+ CTCL registered
in the files of the Institute of Dermatological Sciences of the
University and IRCCS (Milan, Italy) and of the Dutch Cutaneous Lymphoma
Working Group (Amsterdam, The Netherlands). Only one of these cases was
previously reported.2
Criteria for inclusion were 1)
presentation with skin lesions and no evidence of extracutaneous
disease at the time of diagnosis, 2) expression of CD8 antigen together
with other T-cell-associated antigens by the neoplastic T cells, 3)
negative staining for mAbs against NK cells (CD16, CD56, CD57) and
T-lymphocytes (TCR-1), and 4) HIV negativity and absence of
any immunosuppression. Staging procedures, including routine blood
counts and chemistry, chest radiograph, computed abdominal tomography,
and bone marrow biopsy and aspirates had failed to demonstrate other
than cutaneous disease. Clinical records and follow-up data were
obtained from patients' charts. Clinical parameters
evaluated were age, gender, extent of disease, type of skin
lesions at presentation, spontaneous regression, progression of
disease, treatment, and follow-up (Table 1)
.
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Skin biopsies obtained from each patient both at onset and,
whenever possible, during progression of disease were reviewed. Skin
sections had been fixed in 10% buffered formalin or Bouin's liquid
and embedded in paraffin; 3-µm-thick sections were stained with
hematoxylin/eosin (H&E) and Giemsa stain. Histological parameters
evaluated are presented in Table 2
.
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Immunohistochemical stainings were performed in all cases on
paraffin-embedded tissues and, in 15 of 17 cases, on frozen tissue
sections by using the panel of antibodies shown in Table 3
. Three mAbs were used to detect CGPs:
clone 2G9 identifying TIA-1/GMP17 protein,21
clone
G-925
recognizing PF, and clone GrB-726
specific for g-B. A standard alkaline-phosphatase
anti-alkaline-phosphatase (APAAP) (Dako, Glostrup, Denmark) technique,
according to the method of Cordell,27
was performed.
Microwave cooking technique was according to previously described
method,28
using EDTA buffer, pH 8.0, for antigen retrieval
on paraffin sections before incubation with mAbs (anti-CD2, -CD3, -CD4,
-CD5, -CD8, -CD30, -g-B, -PF, -ßF-1/T-cell receptor (TCR)-ß,
-BCL-2, and -Ki-67). For CGPs staining was considered positive when
more than 50% of tumor cells showed cytoplasmic granular positivity
for specific mAbs. Proliferation index (Ki-67) was evaluated by a
semiquantitative method.
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TCR gene rearrangement was evaluated in 15 of 17 cases by a
polymerase chain reaction assay coupled with nondenaturing
polyacrylamide gel electrophoresis according to a method previously
described.29
The amplification of the TCR- chain locus
V-J junctional region was performed by using the oligonucleotide
specific primers for J1/2 coupled with V2a, V9, and V10.
Fifteen microliters of amplified material were then run overnight on
12% nondenaturing polyacrylamide gel electrophoresis in
Tris-borate-EDTA buffer at 70V. Heteroduplex patterns were
finally revealed by ethidium bromide staining. The presence of a
nongermline band, compared with previously identified positive and
negative controls, was indicative of rearrangement of TCR- chain.
Additionally, 15 of 17 cases were analyzed for the presence of Epstein-Barr virus (EBV)-1 genome respectively with nested polymerase chain reaction in 13 cases and by in situ hybridization (ISH) in the remaining two (cases no. 7 and 8). Specific oligonucleotide primers targeted to EBNA-2 gene were used according to a published protocol30 and 1 mg DNA was tested for each specimen. Amplified products were resolved by standard horizontal agarose gel electrophoresis and visualized by W-light exposure after ethidium bromide staining. ISH to detect the presence of EBV small encoded RNA (EBER) was performed on formalin-fixed, paraffin-embedded sections of tumoral lesions. Briefly, a cocktail of fluorescein isothiocyanate (FITC)-labeled EBER-1 and EBER-2 was used (Dako, Glostrup, Denmark). The RNA-ISH protocol was performed according to a previously published method.31 To evaluate the specificity of the signal, paraffin-embedded tissue sections were treated with 2Q-1-DNase (Pharmacia, Uppsala, Sweden) or hybridized with irrelevant anti-sense or sense RNA probes according to standard procedures. A known EBV-positive tumor served as positive control.
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Results |
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Our group included 7 females and 10 males with a median age of 53
years (range, 8–91 years). Patients no. 1–8 showed similar clinical
presentation and course, suggesting they can be recognized as a
distinct group. These patients showed a generalized eruption of
erythemato-scaling patches, plaques, and verrucous or
hemorrhagic papulonodular and tumoral lesions (Figure 1, a and b
, and Table 1
), sometimes
showing a spontaneous central resolution (Figure 1d)
. Specific
involvement of the oral cavity was observed during the course of the
disease in cases no. 1, 2, and 5. Follow-up data for patients no. 1–8
showed metastatic involvement of the testis (no. 6), lung (no. 4), and
central nervous system (CNS) (no. 1 and 4), sparing of lymph nodes, and
a rapidly fatal course with a mean survival time of 32 months. In
patients no. 1–8, despite the therapeutic regimens used, only partial
remission with short disease-free periods were achieved. Furthermore,
at relapse, all patients showed signs of progressive disease, and in 3
of 8 cases (no. 2, 3, and 6) worsening of the disease was observed
during interferon- (IFN-) or photochemotherapy (PUVA) treatment.
In none of the cases was the development of the CD8+ CTCL preceded by
long-standing precursor lesions as commonly seen in MF. One patient
(no. 1) had a history of nodular sclerosis Hodgkin's disease, stage
IIA, 6 years before the appearance of a CD8+ cutaneous lymphoma. She
was treated with polychemotherapy and local radiation therapy with a
good result and no relapse of Hodgkin's disease.
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). Only case no. 9 showed a peculiar if not
distinct clinical course (see Discussion).
Histology (Table 2)
The histological features are summarized in Table 2
.
Cases with aggressive clinical behavior (no. 1–8) showed
characteristic if not distinct histological features. Very early
lesions showed intraepidermal pagetoid spreading of atypical
lymphocytes. Fully developed lesions were characterized by a
band-like/lichenoid infiltrate (Figure 1c)
consisting of atypical
small/medium (cases no. 1, 3, 4, and 5) and medium/large (cases no.
6–8) pleomorphic lymphocytes (Figure 2, a
-c) or immunoblasts (case no. 2) (Figure 2d)
, with a diffuse
infiltration of an acanthotic or hyperplastic epidermis (Figures 1c, 2a, and 2b)
. Intercellular edema, blistering, and necrosis were
frequently detected in the central part of the lesion (Figure 1c)
,
whereas a pagetoid spreading of lymphocytes at the border of the
lesions was seen (Figures 1c and 2d)
. Extensive keratinocyte necrosis
was observed only in cases no. 1 and 5 (Figure 2b)
. A diffuse
epidermotropic infiltrate was observed also in tumoral stage (Figure 2, a and d)
. Sweat glands and hair follicles were frequently involved
(Figure 1c)
, sometimes forming a lymphoepithelioid pattern (Figure 2c)
;
a perivascular distribution of neoplastic cells (Figure 1c)
without
signs of angioinvasion and angiodestruction was seen; nerves were
spared by infiltration. A variable number of reactive macrophages and
dendritic cells, rare eosinophils, and plasma cells was observed. The
other 9 cases showed the characteristic histological features of MF
(nos. 9–10), pagetoid reticulosis (nos. 11 and 14), LyP (nos. 15 and
16), CD30+ PC-LCL (nos. 13 and 17), or panniculitis-like SC-TCL (no.
12).
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The neoplastic cells showed a peripheral T cell phenotype (Table 3)
. The phenotypical profile of cases no. 1–8 was ßF-1/TCR-ß+,
CD3+, CD8+ (Figure 3a)
, TIA-1/GMP17+
(Figure 3b)
, CD45RA+ (7/8) (Figure 3c)
, CD7+ (6/7). The pan T cell
markers CD2 (Figure 3d)
and CD5, granzyme-B, and perforin were
expressed in only 2 cases; HECA 452 was negative in 7/8 cases and weak
in case no. 8; all showed high proliferation index using Mib-1. The
complete immunophenotype of the other 9 cases is also reported in Table 3
. In contrast to the aggressive cases, neoplastic T cells of this last
group were often CD45RO+ and HECA-452+. It is noteworthy that no
significant differences were observed in the expression of GCPs between
these two groups.
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Successful amplification of DNA was obtained in 14 of 15 analyzed
cases. Rearrangement of the TCR- gene by heteroduplex analysis was
demonstrated in 13 cases, while only one case (no. 11) showed germline
configuration of the TCR- gene (Table 2)
. It was not possible to
evaluate the TCR- gene rearrangement in the archival cases, nos. 4
and 14. Nested polymerase chain reaction analysis for EBNA-2 genes
yielded negative results in all of the tested cases. Neoplastic cells
in case nos. 7 and 8 were negative by RISH for EBER-1/2.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and retinoids, nor with more aggressive
treatments like total skin electron beam irradiation, polychemotherapy,
or allogenic bone marrow transplantation (Table 1)
. All eight patients
died with disseminated disease 14 to 50 months (median, 32 months)
after diagnosis. Histologically, these cases showed a band-like,
lichenoid, strongly epidermotropic lymphoid infiltrate involving the
appendages, mimicking in some cases the lymphoepithelioid pattern
observed in gastrointestinal lymphomas.32
Cytologically 4
cases were classified as small/medium size pleomorphic T cell lymphomas
(PTCL), 3 as medium/large size PTCL, and one as immunoblastic T cell
lymphoma. Unlike most cases of MF, epidermotropism was noted in all
stages of the disease. When only these histological features are
considered, differentiation between these aggressive CD8+
epidermotropic cytotoxic T cell lymphomas and other types of CTCL, such
as transformed MF or pagetoid reticulosis, may be difficult or even
impossible. However, when the clinical features, the proliferation
index (Ki-67+), and the phenotypic profile are taken into account as
well, these CD8+ epidermotropic cytotoxic T cell lymphomas can easily
be recognized also in early stage. The neoplastic T cells had a
characteristic ßF1+, CD3+, CD8+, CD7+, CD45RA+, TIA-1/GMP-17+
immunophenotype, suggesting bona fide derivation from CD8+ cytotoxic T
cell subset,33
although only 3 cases also expressed PF
and/or g-B (which are, for their well established biochemical role,
more reliable markers of cells with activated cytotoxic
function).24,25
The absence or the weak expression (case
no. 8) of the cutaneous lymphocyte antigen, an epitope expressed
by memory T lymphocytes (CD45RO+) in the context of P-selectin
glycoprotein ligand-1/CD162 molecule,34
and
of the CD103/HML-1+ (specific homing of the intraepithelial lymphocytes
of the gut, observed only in case no. 1), confirms that different
mechanisms could play a role in this disease.
Review of the few case reports and small series of patients with a CD8+
CTCL published thus far revealed cases with very similar
clinicopathological features,15,18
including presentation
with a generalized skin lesions that often mimic disseminated pagetoid
reticulosis,34
metastatic spread to unusual anatomical
sites, such as the spleen,11
lungs,13,14,17
liver,13
CNS,13
and oral
cavity,15,18
but rarely to peripheral lymph
nodes,15
unresponsiveness to or even worsening during
specific CTCL treatment,15,16,18
and poor prognosis. The
histological features of these cases, showing marked infiltration of
medium/large pleomorphic T cells into an acanthotic epidermis with
variable degrees of spongiotic alterations and blistering, are very
similar to what we observed in our own cases. With respect to the
immunophenotype, Agnarsson et al15
suggested that cases
with fatal outcome were CD2- and CD7+. The loss of the CD2 pan T cell
marker was also noted in other reported cases16,18
and was
detected in 5 of 7 tested aggressive cases of our group. The CD7+
reactivity was detected in most of our CD8+ aggressive cases (7/8), but
had been also reported in several cases of extranodal lymphomas of NK
or / T cell derivation,36-40
and also in our CD8+
pagetoid reticulosis, LyP, and MF-like cases (Table 3)
. Interestingly,
we detected CD45RA positivity in 7/8 of the aggressive cases, although
the last case was CD45RA-/RO- (Table 3)
. CD45RA expression has also
been noted in other aggressive lymphoproliferative cutaneous disorders
of / T cell derivation.41
The loss of leukocyte
common antigen CD45 and their isoforms was previously reported on
atypical lymphocytes in the localized and disseminated pagetoid
reticulosis.42
Only Urrutia et al had used these markers
and described a CD45RA-/RO- aggressive case.16
The results of our own study, as well as data available from the literature, strongly suggest that these strongly epidermotropic CD8+ CTCL represent an aggressive and distinct disease entity.
The expression of TIA-1 molecules and CD45RA in these cases suggests derivation from CD8+ cytotoxic T cells. By investigating the expression of CGPs, the cytotoxic origin of a broad range of lymphoproliferative disorders has been demonstrated.36-40,43-51 Interestingly, some of these disorders can involve the skin at both onset36-40,43-46,48 and relapse.36-40,43,46,49-51 Gastrointestinal cytotoxic T cell neoplasms have a very similar T cell phenotype,47 whereas NK/T cell lymphomas of the nasal type are angiocentric and predominantly CD16+ and CD56+.36-39 Consistently, unlike nasal NK/T cell lymphomas, primary cutaneous epidermotropic CD8+ CTCL were not associated with EBV-1.
In addition to this well defined group of CD8+ CTCL, the other 9 CD8+
cases showed the clinical and histological features of well defined
types of CTCL, included as separate entities in the EORTC
classification for primary cutaneous lymphomas. This group included 2
cases with MF-like lesions, 2 cases of pagetoid reticulosis, 2 cases of
LyP, 2 cases of CD30+ PC-LCL, and 1 case of panniculitis-like SC-TCL.
Whereas SC-TCL may often have a CD8+ cytotoxic T cell
phenotype52-53
and shows an aggressive clinical course,
the other conditions normally have a CD4+ T cell phenotype. The
specific phenotype is reported in Table 3
; in contrast to patients no.
1–8, CD45RO and HECA-452 markers were frequently positive. The
clinical presentation and behavior of these CD8+ cases was very
similar, as reported for CD4+ cases.1
Only one of
these patients (no. 9) showed a bimodal clinical course. This patient
presented with MF-like lesions in 1984 and PUVA treatment resulted in
complete remission. However, after 8 years the disease relapsed, and
the patient died in a short time of disseminated disease involving
skin, oral mucosa, and CNS, similar to the CD8+ aggressive variant. In
7 of these 9 cases the neoplastic T cells expressed TIA-1, with
simultaneous expression of g-B and PF in two of them, suggesting that
most of these cases are also derived from cytotoxic CD8+ T cells.
Taken together, the results of this and other studies suggest that perhaps three aggressive groups of CTCL-expressing a CD8+ phenotype can be distinguished. First, we reported the existence of a strongly epidermotropic type, which demonstrates an aggressive clinical behavior and can be considered as a distinct type of CTCL. Second, recent studies suggest that most cases of panniculitis-like SC-TCL have a CD8+ cytotoxic T cell phenotype and should be considered, according to the REAL classification,54-55 as a distinct disease entity. Third, it is well known that CD8+ T cell lymphomas are reported in case of congenital or acquired immunodeficiency.56 Additionally, well defined types of CTCL such as MF, pagetoid reticulosis, LyP, and CD30+ PC-LCL can demonstrate a CD8+2-9 , 57-58 rather than a CD4+ T cell phenotype in a minority of cases. Current evidence suggest that these CD8+ cases have the same clinical behavior and prognosis as the more common CD4+ cases.
Delineation of these aggressive groups of CD8 cytotoxic CTCL may have
important therapeutic implications. Recent evidence suggests that most
CD4+ CTCL, including classical MF, SS, and CD30+ lymphoproliferative
disorders, may have a Th2-like cytokine profile.59-61
This might explain why therapies that augment Th1 responses, like
retinoids and IFNs, have a beneficial effect on these conditions. It
might be expected that the neoplastic cells in these CD8+ aggressive
CTCL have a Th1-like (Tc1) cytokine profile (IL-2, IFN-, TNF-ß).
According to our data and some literature reports,15,16,18
treatment with Th1-augmenting therapies might be counterproductive and
could result in deterioration rather than amelioration of the disease.
Thus, the derivation of neoplastic clones from cells with different
immunological functions must always be considered for a correct
approach to these disorders and we suggest including CD8 and TIA-1 mAbs
in the panel of reagents used for routine evaluation of primary CTCL to
facilitate early recognition of CD8+ CTCL.
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Acknowledgements |
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Footnotes |
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Accepted for publication April 28, 1999.
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References |
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/ T cells. J Exp Med 1991, 173:449-502 gene rearrangements for diagnosis and monitoring of cutaneous T-cell lymphomas. Blood 1994, 83:3271-3278/ T-cell origin. Blood 1996, 88:4265-4274/ T-cell lymphoma presenting as disseminated pagetoid reticulosis. J Invest Dermatol 1991, 96:718-722[Medline]
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receptor ß chain). Blood 1996, 88:1383-1389This article has been cited by other articles:
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