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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1723-1731
Nonhepatosplenic   T-Cell Lymphoma: A Subset of Cytotoxic
Lymphomas With Mucosal or Skin Localization
By
Bertrand Arnulf,
Christiane Copie-Bergman,
Marie-Hélène Delfau-Larue,
Anne Lavergne-Slove,
Jacques Bosq,
Janine Wechsler,
Michel Wassef,
Claude Matuchansky,
Bernard Epardeau,
Marc Stern,
Martine Bagot,
Felix Reyes, and
Philippe Gaulard
From the Département de Pathologie and EA2348, Service
d'Immunologie Biologique, CHU Henri Mondor, Créteil;
Département de Pathologie, Hôpital Lariboisière,
Paris; Département de Pathologie, Institut Gustave Roussy,
Villejuif; Service de Gastroentérologie, Hôpital Saint
Lazare, Paris; Département de Pathologie, Service de Pneumologie,
Hôpital Foch, Suresnes; Service de Dermatologie and Groupe
d'étude Français des Lymphomes Cutanés; and Service
d'Hématologie Clinique, CHU Henri Mondor, Créteil, France.
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ABSTRACT |
Human   T lymphocytes represent a minor subset of T cells in
the peripheral blood, which exhibit a limited diversity and a
tissue-restricted repertoire in contrast to their broad specificity. Most postthymic neoplasms that arise from this T-cell subpopulation belong to the hepatosplenic lymphoma entity. Only a few cases of
nonhepatosplenic lymphomas have been described in detail previously. This study presents the clinicopathologic features of 11 consecutive cases of nonhepatosplenic lymphoma. All were characterized by mucosal or skin initial involvement: nasal cavity (n = 3), gastrointestinal tract (n = 3), skin (n = 3), lung
(n = 1), larynx (n = 1). Most patients presented with B
symptoms (eight of 11), without peripheral lymphadenopathy and bone
marrow involvement. A past history of chronic antigen exposure was
noted in six cases, and four patients had features of immune
deficiency. On histology, they were classified as pleomorphic tumors.
Features of epitheliotropism and angiocentrism was observed in most
cases. Tumor cells had a CD2+, CD3+, T-cell
receptor (TCR) 1+,  F1 phenotype.
They were CD5 (9 of 10) and
CD4/CD8 (9 of 10) or CD8+
(1 of 10). A clonal -chain gene rearrangement was detected in all
tested cases (9/9). All cases had an activated cytotoxic T-cell intracellular antigen-1 (TIA-1)+, Granzyme
B+ phenotype. Epstein-Barr virus (EBV) sequences were
detected in six cases by in situ hybridization (ISH). Despite an
aggressive clinical course, complete remission was obtained in three
patients, and one of the latter required a peripheral blood stem-cell
transplantation. Nonhepatosplenic peripheral T-cell lymphoma can
be regarded as a model of activated cytotoxic lymphoma, occurring in
mucosae or skin. These appear to be derived from the subpopulation of tissue-restricted lymphocytes, which are involved in the host epithelial surface surveillance. The role of chronic antigen exposure in the pathogenesis of these rare lymphomas can be suggested, in view
of the past history observed in at least some patients.
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INTRODUCTION |
LYMPHOCYTES THAT EXPRESS the
T-cell receptor (TCR) represent a small subset compared with T cells
that bear the  TCR.1,2 Although the overall structure
of the TCR is similar to the TCR with variable, joining,
and constant regions (-chain) and additional diversity regions in
the chain, T cells exhibit a more limited diversity and a
tissue-restricted repertoire.1-4 Human T cells
account for 1% to 15% of peripheral blood lymphocytes (PBL) and,
throughout the peripheral lymphoid tissues, show a predilection for the
red pulp of the spleen (up to 30% of the whole T-cell population) and
the gastrointestinal tract.1-2,4-6 The precise functions of
T cells are not completely understood. However, mouse models
indicate a role for the T-cell subset in host epithelial surface
control and early-stage engagement in immune response against pathogens
(viruses, bacteria, and parasites), before the recruitment of T
cells.4,7-9 T cells are able to react with antigens
both in a major histocompatibility complex (MHC)-restricted and
MHC-unrestricted fashion, and have a broad antigen specificity from
heat-shock proteins to nonpeptidic phosphorylated metabolites.8,10,11 Thus, T cells appear to be early
effectors in the immune response, providing a first line of defense in
the epidermal and epithelial linings.8,11 These functions
are mediated by cytokine production, and include the capacity to
stimulate B cells for immunoglobulin production and to develop direct
cytolytic activity, as well as antibody-dependent cellular
cytotoxicity.8,11
T cells have rarely been implicated in neoplastic
lymphoproliferative disorders. Among peripheral T-cell lymphomas, we have identified hepatosplenic T-cell lymphoma as a distinct entity,12,13 which is now recognized by
others.14-16 This lymphoma is a rare disease with
distinctive clinicopathologic features characterized by its extranodal
hepatosplenic presentation and the sinusal/sinusoidal tropism of the
neoplastic T cells. Clinically, typical presentation consists in
young men with hepatosplenomegaly and frequent systemic symptoms in
contrast to the absence of peripheral lymphadenopathy. Initial
examination of the blood smears often reveals a decreased platelet
count without circulating lymphoma cells. Survival analysis of the rare
reported cases reflects the aggressive course and the poor prognosis of
this disease.12,15 Several cases of nonhepatosplenic
T-cell lymphoma have recently been reported.15,17-26 Most
of them are cutaneous T-cell lymphomas with predominant
epidermal and/or subcutaneous tissue
involvement.15,17-22 Rare cases of nasal T-cell
lymphoma have also been reported,23,24 as well as an
individual case of T-cell lymphomas of the thyroid gland.25 Only one patient with a nodal presentation has
been described.26
In the present study, we report 11 consecutive cases of peripheral
T-cell lymphomas that displayed a TCR phenotype. All were
characterized by an initial site of involvement in mucosal tissues or
skin: nasal cavity (n = 3), gastrointestinal tract (n = 3), skin
(n = 3), lung (n = 1), and larynx (n = 1). These lymphomas
probably originate from the normal T cells that are present or
can be induced by inflammatory states in different mucosa-associated
lymphoid tissues (MALT), as well as in the skin. Given the potential
role of the T cells in the immune response, their capacity for
developing cytolytic activity, and their peculiar relationship with
epithelial cells, some mechanisms of tumorigenesis are discussed.
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MATERIALS AND METHODS |
Patient selection.
This series includes all patients with nonhepatosplenic
peripheral T-cell lymphoma diagnosed between February 1986 and February
1997, using immunohistochemistry on frozen material, in three
Departments of Pathology (Hôpital Henri Mondor, Créteil; Hôpital Lariboisière, Paris; and Institut Gustave Roussy,
Villejuif, France). All biopsy specimens had the histology of lymphoma
on hematoxylin-eosin-stained sections. On frozen sections, lymphoma cells expressed at least the CD2 and CD3 T-cell antigens, and all were
positive with TCR-1 antibody, but negative with F1. The clinical
and biologic records of each patient were reviewed for types and
duration of symptoms, initial and other sites of involvement found
during the course of disease, and outcome. Parts of clinical and
phenotypic features of two patients (cases no. 1 and 4),
as well as the cytotoxic profile in six cases, have been reported
elsewhere.13,23,27-29
Tissue specimens.
Biopsy specimens from initial sites of involvement (sinonasal tract,
skin, stomach, lung, larynx, and intestine) were fixed in buffered
formaldehyde or Bouin's fixatives and paraffin-embedded for
histopathologic analysis. A portion of each biopsy was snap-frozen in
liquid nitrogen for phenotypic and genotypic studies.
Histologic studies.
Paraffin-embedded tissue sections were stained with hematoxylin-eosin,
periodic acid-Schiff (PAS), and/or Giemsa for histologic studies. Lymphomas were classified according to the updated Kiel classification.30 Each case was independently examined by
two pathologists. The presence of necrosis, epitheliotropism,
angiocentrism, and angioinvasive features was carefully investigated.
Immunohistochemical staining.
Cryostat sections were evaluated for T-, natural killer (NK)-, and
B-cell differentiation antigens using the alkaline
phosphatase/anti-alkaline phosphatase (APAAP) method.31
The following mouse monoclonal antibodies were used: Leu-5/CD2,
Leu-4/CD3 and Leu-3/CD4, Leu-1/CD5, Leu-9/CD7, Leu-2/CD8 (Becton
Dickinson, Mountain View, CA), Ber-H2/CD30, LMP-1 (Dako SA, Glostrup,
Denmark), CD19, NKH1/CD56 (Coulter, Hialeah, FL), F1 and TCR-1,
TCS-1, V2, and V3 (T-Cell Diagnostics, Woburn, MA). F1
recognizes a nonpolymorphic epitope of the chain of the TCR
heterodimer. TCR-1 recognizes a nonpolymorphic epitope of the chain of the TCR heterodimer. TCS-1 antibody is directed
against a conformational epitope of the human V1/J1 junction,
whereas V2 and V3 monoclonal antibodies recognize an epitope of
the human V2 and V3 regions of the chain, respectively. CD3 polyclonal, L26/CD20, and Ber-H2/CD30 monoclonal antibodies (all
from Dako SA) were also used in paraffin-embedded sections. Cytotoxic
cell proteins were detected using monoclonal antibodies that recognize
T-cell intracellular antigen-1 (TIA-1) (clone TIA-1; Coulter), perforin
(clone delta G9; T-Cell Diagnostics), and Granzyme B (clone GrB-7;
Monosan, Uden, The Netherlands). Expression of perforin was evaluated
on frozen tissue sections, whereas the mouse monoclonal antibodies
TIA-1 and GrB-7, which recognize formalin-resistant epitopes of TIA-1
and Granzyme B, respectively, were used in paraffin-embedded tissue
sections. For a better detection of TIA-1 and Granzyme B, a
pretreatment with microwave oven heating (two cycles of 5 minutes in
0.01 mol/L citrate buffer, pH 6) was performed, as previously
described.29 Optimum labeling for granzyme B was obtained
by twice repeating the bridge and APAAP complex. Rabbit antimouse
immunoglobulin and APAAP complexes were obtained from Dako.
Genomic study.
DNA was extracted from lymphoma tissues by a standard proteinase K
digestion, phenol/chloroform precipitation procedure; 250 ng was used
for each experiment. TCR -chain gene rearrangements were studied
using a guanine-cytosine (GC) clamp multiplex polymerase chain reaction (PCR)/denaturing gradient gel electrophoresis (DGGE) procedure, as previously described.32 The use of
oligonucleotides that match all of the V and J functional
segments, combined with DGGE, allowed the achievement of a migration
profile specific to each T-cell clone. The highly heterogeneous PCR products of polyclonal reactive T cells result in a smear on DGGE,
whereas a clonal rearrangement of TCR genes results in one
(monoallelic) or two (biallelic) bands on DGGE.
In situ hybridization study.
The in situ hybridization (ISH) procedure for the detection of EBER
transcripts was performed using the fluorescein-conjugated Epstein-Barr
virus (EBV; EBERs 1 and 2) oligonucleotides (Dako) complementary to
nuclear RNA portion of the EBER 1 and 2 genes that are actively
transcribed in latency infected cells. Details of the procedure have
been previously reported.23 Briefly, deparaffinized sections were rehydrated and preparated with proteinase K, dehydrated, air-dried, and hybridized for 2 hours at 37°C with the fluorescein isothiocyanate-conjugated (FITC) EBER oligonucleotides in
hybridization solution. After washing in Tris-buffered saline (TBS)
that contained 0.1% Triton X-100, the following
immunohistochemical detection method was used: mouse anti-FITC, rabbit
antimouse immunoglobulin, and APAAP complexes (Dako). Visualization of
the reaction was performed by incubation in a solution that contained
bromochloroindolylphosphate (BCIP) and nitroblue tetrazolium (NBT)
(Dako). The slides were briefly counterstained with methyl green. As
positive controls for ISH, one case of EBV-positive Burkitt lymphoma
was run in parallel.
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RESULTS |
Clinical features.
The main clinical features are summarized in Table
1. The median age of the patients was 48 years (range, 14 to 88). Eight of 11 patients were male and three were
female. All patients presented initially with mucosa or skin
involvement of the nasal cavity (three cases), the gastrointestinal
tract (small bowel in cases no. 10 and 11, stomach in case no. 9), the
skin (cases no. 6, 7, and 8), the lung (case no. 4) and the larynx
(case no. 5). B symptoms were present at presentation in eight
patients. Initial staging was similar in the 11 patients, since none of
them had lymph node, liver, spleen, or bone marrow involvement.
Biologic findings on peripheral blood were unremarkable, except for
mild anemia and lymphopenia in case no. 4. Platelet count was normal in
all patients at presentation. Laboratory liver tests were also unremarkable. The lactic dehydrogenase (LDH) level was elevated in four
patients (cases no. 2, 3, 7, and 8). Hypogammaglobulinemia was noted in
three patients (cases no. 2, 4, and 7). Antibodies against human
immunodeficiency virus (HIV) and human T-cell lymphotrophic virus type
1 (HTLV-1) were not detectable in all but one patient (no. 9), who had
an HTLV-1-positive serology. In this case, HTLV-1 was not clonally
integrated into the malignant cells.
A significant past history was present in six patients: chronic
sinusitis in the three patients with nasal lymphoma (cases no. 1, 2, and 3), opportunistic pulmonary infections (cytomegalovirus, Pneumocystis carinii pneumonia) related to
hypogammaglobulinemia and T-cell deficiency in patient no. 4 with
pulmonary lymphoma, chronic Strongyloidiasis and Helicobacter
pylori-associated gastritis in an African HTLV-1-seropositive
patient (case no. 9) with gastric lymphoma, and celiac sprue disease in
patient no. 11 with intestinal lymphoma. Ten patients received an
anthracycline-containing polychemotherapy regimen, whereas patient no.
5, an elderly male, received oral chemotherapy. In seven patients, the
clinical outcome consisted of poor response or refractory state. Most
patients had an early aggressive course, with local recurrence
(n = 5) and/or systemic (n = 5) or other mucosal (n = 2)
localizations. The median follow-up duration was 18 months (range, 1 to
96). Six patients died of disease within 2 to 17 months. Two patients
(no. 3 and 9) with nasal and gastric lymphoma, respectively, responded
well to first-line (case no. 3) or second-line (case no. 9)
chemotherapy. Patient no. 9, who received a second-line rescue regimen
and a peripheral blood stem-cell transplantation following total-body
irradiation and high-dose cytarabine with melphalan, has no evidence of
disease 24 months after diagnosis. Patient no. 8, with epidermotropic T-cell lymphoma who received polychemotherapy and radiotherapy, was alive after 8 years, with skin recurrence.
Histopathology.
The histologic findings are summarized in Table
2. All cases disclosed a diffuse infiltrate
of atypical lymphoid cells, and were classified as pleomorphic medium
and large-cell (PML) (seven cases), pleomorphic large-cell (PL) (two
cases), and pleomorphic small-cell lymphomas (PSC) (two cases).
Three cases (cases no. 1 to 3) were located in the nasal cavity. The
neoplastic infiltrate consisted of medium and/or large pleomorphic lymphoid cells (Fig 1)intermingled with variable numbers of small lymphoid cells, plasma
cells, eosinophils, and histiocytes. Features of angiocentrism and
angioinvasion, epitheliotropism, and areas of necrosis were observed in
all three cases. Patient no. 4 presented with disease restricted to the
lung and an open-lung biopsy was available. The neoplastic infiltrate
was composed of large atypical lymphoid cells and was predominantly
interstitial without extensive destruction of the normal architecture.
Features of angiocentrism, angioinvasion, and epitheliotropism were
present (Fig 2A and B). Case no. 5 involved
the larynx, extending to the piriform sinus, the ventricle, and the
arytenoid. One month later, the lymphoma disseminated to the
subcutaneous tissue in the spinal region and biopsy specimens from both
sites were available. The neoplastic cells were medium and large, with
abundant clear cytoplasm and slightly irregular nuclei with dense
chromatin. Epitheliotropism was present in the larynx mucosa. Small
foci of necrosis and angiocentrism were seen without angioinvasion.
Three patients presented with cutaneous disease. Cases no. 6 and 7 were
comparable, as both histories started with necrotic subcutaneous
nodules of the thigh, which on histologic analysis were characteristic
of cytophagic histiocytic panniculitis without evidence of
lymphoma (Fig 3A). Second excisional
biopsies of cutaneous nodules obtained 7 and 5 months later,
respectively, showed characteristic features of lymphoma in both cases
(Fig 3B). However, in case no. 6, skin biopsy specimens showed an
epidermotropic PML lymphoma extending to the dermis and the
subcutaneous tissue, whereas in case no. 7, the neoplastic infiltrate
consisted of a PSC confined to the subcutaneous tissue, admixed with
benign histiocytes that showed phagocytosis. Patient no. 8 presented
with recurrent skin lesions with spontaneous remission over a period of
10 years. The initial skin biopsies demonstrated an intense
epidermotropic neoplastic infiltrate that extended to the superficial
and deep dermis composed of atypical PML cells. All cutaneous cases
displayed features of angiocentrism, but angioinvasion was observed
only in case no. 6 and foci of necrosis in cases no. 6 and 8.
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| Fig 1.
Pleomorphic large-cell T-cell lymphoma (case no.
3) (nasal biopsy specimen with hematoxylin-eosin stain).
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| Fig 2.
Pulmonary pleomorphic large-cell T-cell lymphoma
(case no. 4). (A) Atypical lymphoid cells involve the bronchiolar wall and epithelium; (B) features of angioinvasion; note the preservation of
alveolar structures (lung biopsy specimen with hematoxylin-eosin stain); (C) neoplastic cells strongly express TCR .
(Immunohistochemical staining on frozen sections with anti-TCR1
antibody, APAAP technique.)
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| Fig 3.
Subcutaneous T-cell lymphoma (case no. 6). (A)
Initial biopsy sample shows characteristic features of cytophagic
histiocytic panniculitis without evidence of lymphoma cells; (B) second
biopsy performed 7 months later demonstrates involvement of the
subcutaneous tissue by a pleomorphic T-cell lymphoma
(hematoxylin-eosin stain).
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The last three cases involved the gastrointestinal tract. In case no.
9, the tumor was initially localized to the antrum of the stomach and
consisted of a diffuse lymphomatous infiltrate that involved the lamina
propria and was composed of atypical PSC without epitheliotropism.
H pylori-like microorganisms were found. Cases no. 10 and 11 were located in the ileum, and both cases displayed features of PML
that involved the entire mucosa, intermingled with variable numbers of
eosinophils and plasma cells. In case no. 10, a small-cell component
confined to the lamina propria was observed, which displayed some
degree of epitheliotropism. Although patient no. 11 had celiac disease,
no villous atrophy could be seen, but a marked increase of
intraepithelial lymphocytes was present. All gastrointestinal cases
displayed features of angiocentrism, but angioinvasion was found only
in case no. 10 and necrosis in cases no. 10 and 11.
Immunophenotypic studies.
Complete immunophenotypic characterization was available for all cases
on frozen and paraffin sections (Table 3).By definition, all cases expressed TCR (TCR1+)
(Fig 2C), but were negative for TCR (F1). In
all cases, the neoplastic cells expressed the T-cell-associated markers CD2 and CD3, and most cases lacked the CD5, CD7, CD4, and CD8
antigens. Only one case (no. 9) demonstrated CD5 positivity, which was
confirmed by immunostaining on paraffin sections. An additional case
was positive for CD7. One case expressed the T-cell suppressor-cell
antigen CD8, and the remaining cases were
CD4/CD8 or not interpretable for CD4. Ten
cases were studied using the anti-TCS1, anti-V2, and anti-V3
monoclonal antibodies, which react with variable epitopes of the chain. The tumor cells were shown to express the V2-encoded epitope
in seven cases, whereas two gastrointestinal cases expressed the
V3-encoded epitope and the pulmonary case expressed the variable
V1-encoded epitope. In these 10 cases, the patterns of TCR1 and
V epitopes stainings were similar. Expression of the CD30 activation
marker was observed on a variable proportion of neoplastic cells in
seven cases, all of which were PML or PL lymphomas. Only two cases,
both located in the nasal mucosa, expressed the NK marker CD56. All
cases were negative for B-cell-associated markers tested either on
paraffin or frozen sections.
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Table 3.
Immunohistochemical Data, Genomic Data, and EBV Status
in Patients With Skin-Mucosa-Associated T-Cell Lymphomas
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All cases were studied for cytotoxic markers. All of them demonstrated
a strong granular cytoplasmic positivity for the cytotoxic granule-associated protein TIA-1. A variable proportion of neoplastic cells were also found positive with Granzyme B (Fig 4A and B) in all
cases. Staining for perforin was performed
on frozen sections in nine cases, of which seven were positive, one was
negative, and the remaining was not interpretable.
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| Fig 4.
Granzyme B expression. (A) Strong paranuclear staining of
neoplastic cells in a nasal lymphoma (case no. 3); (B) strong
cytoplasmic staining of a few neoplastic cells surrounding intestinal
glands in an enteropathy-associated T-cell lymphoma (case no.
11). (Paraffin-embedded section, APAAP technique.)
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EBV status.
ISH studies with the EBER probes demonstrated two patterns of EBER
positivity in the tumor cells. Five cases, including the three nasal
cases, the case involving the larynx, and case no. 10 involving the
ileum, were considered as EBV-associated lymphomas, as more than 80%
of tumor cells displayed an intense nuclear staining.33 Case no. 9, which involved the stomach, displayed a pattern of positivity similar to what has been described previously as
EBV-positive lymphomas, as only a small proportion of tumor cells
(<10%) were found to be positive. Expression of the EBV-encoded
latent membrane protein (LMP)-1 was studied by immunohistochemistry in
all cases, and was found to be positive in the three cases located in
the nasal mucosa (cases no. 1 to 3) and the one case that involved the
ileum (case no. 10).
Genomic study.
All nine studied cases demonstrated TCR -chain gene rearrangement,
which provides evidence of T-cell lineage and monoclonality.
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DISCUSSION |
Among T-cell neoplasms, the proportion of TCR versus TCR
malignancies differs according to the stage of differentiation of the
tumor cells. Thus, a significant proportion of thymic (T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma) neoplasms express
TCR, rather than TCR, whereas only a small percentage of
postthymic peripheral T-cell lymphomas are of
origin.13,34 Among them, hepatosplenic T-cell
lymphoma is a distinct clinical, morphologic, and immunologic entity,
with specific sinusal/sinusoidal localization of malignant cells in
spleen, liver, and bone marrow.12-16
In the present study, we report 11 consecutive patients with a
nonhepatosplenic peripheral T-cell lymphoma of phenotype. Interestingly, none of them had a nodal presentation. In contrast, they
all presented with an initial involvement of skin- or mucosa-associated tissue. Individual cases of nonhepatosplenic T-cell lymphomas, mainly occurring in the skin, have been previously
reported.15,17-26 Two patients in the present series had
the morphologic features of subcutaneous T-cell lymphoma resembling
panniculitis.35 The or T-cell phenotype of
such lymphomas has not been extensively investigated. However, several
cases have been demonstrated to have a T-cell
origin.17-20 These were characterized by a single lesion at
presentation, a long time between initial lesions and diagnosis, and
histopathologic features of cytophagic histiocytic panniculitis
preceding the development of a morphologically detectable neoplastic
infiltrate. Thus, it appears that the so-called cytophagic histiocytic
panniculitis may represent, at least in some cases, a prelymphomatous
state of subcutaneous lymphomas. Another patient of the present
series disclosed marked epidermal infiltration, which resembled
pagetoid reticulosis and was consistent with the rare reported cases of
epidermotropic T-cell lymphoma.15,21,22 Three
patients had a sinonasal presentation, thus corresponding to the rare
reported cases of nasal T-cell lymphomas.23,24 The
other patients had a primary laryngeal, pulmonary, or gastrointestinal T-cell lymphoma, which, to the best of our knowledge, have not
yet been described.
The 11 T-cell lymphomas of this series displayed histologic
features of pleomorphic tumors. In some cases, the lymphoid infiltration of the epithelial structures resulted in features resembling lymphoepithelial lesions, as observed in B-cell MALT lymphomas36 and in the few reported cases of
skin-associated lymphoid tissue (SALT) lymphomas.37
Immunohistochemical analysis demonstrated the T-cell derivation.
Most cases were double-negative (CD4/CD8), a common phenotype observed in
most T cells, although a minor subpopulation of T cells
in peripheral lymphoid tissues expresses the CD8 antigen.38
Most cases lacked CD5, a common finding in peripheral T-cell
lymphomas, regardless of their site of
origin.12-15,17,18,24 PCR analysis for the TCR gene, which allows the detection of clonal gene rearrangements in most
T-cell lymphomas32 whatever their or
phenotype, disclosed a clonal T-cell population in all cases tested. In
addition, an exclusive V chain of the TCR was demonstrated in
the 10 cases tested. A majority of them were positive for the V2
chain, which is also found in the majority of the peripheral blood
T cells in humans.1,3
Clinical outcome was associated with short survival in most patients. A
durable remission was only observed in the three patients treated with
a heavy regimen of chemotherapy. These results are consistent with the
aggressivity of T-cell lymphoma known in the hepatosplenic
entity.12-15 Another interesting observation in the present
series was the propensity of the neoplastic cells to be
localized at presentation or at relapse in skin or mucosal sites, as
observed in eight patients. This suggests a preferential homing to the
skin- and mucosa-associated lymphoid tissues, which parallels that of
normal T cell subsets and may be related to their functions in
immune surveillance.2,6,8,11,38 Four patients had a
progression with secondary hepatosplenic involvement, consistent with
the other characteristic homing of tumor cells in the spleen, as
observed in hepatosplenic T-cell lymphomas12-15 and
in normal spleen.1,2,5
It is noteworthy that a past history of chronic tissue-restricted
antigen exposure was observed in six patients. The skin, pulmonary,
upper respiratory, and gastrointestinal tracts are continuously exposed
to a wide variety of antigens from living microorganisms to other
environmental components. Therefore, the role of antigenic stimulation
in the development of these lymphomas may be hypothesized. This is also
consistent with the putative role of normal cells in immune
surveillance of host epithelial surfaces for infected and damaged
cells.8,11
The role of EBV in the pathogenesis of at least some of these
T-cell lymphomas can be questioned. Indeed, the pattern of EBER gene
expression by ISH with EBV genomes found in virtually all tumor cells
(EBV-associated pattern) was shown in the three nasal and in the
laryngeal lymphomas, as well as in one intestinal T-cell lymphoma, and
is similar to that observed in sinonasal NK lymphomas, as well as in a
few nonhepatosplenic T-cell lymphomas.23,24,39 Although a causal relationship between EBV and T-cell
lymphomagenesis is elusive, chronic EBV infection might have
contributed to one step of proliferation and/or transformation
in at least the five EBV-associated lymphomas.33 In one of
the gastrointestinal lymphomas, the peculiar pattern of EBER genes
expression with EBV genomes found in only a few scattered large
neoplastic cells, suggests that EBV infected tumor cells after
transformation. In addition, the absence of EBV in skin and lung
lymphomas indicates, in keeping with previous studies, that the
putative role of EBV in T-cell lymphomagenesis is site-dependent,
probably related to the sites of normal reservoir of the
virus.33
T cells are cytotoxic T lymphocytes40,41 that are
known to act as a first line of defense against pathogens, before the
recruitment of cells.7,9,11,42-44 Interestingly, we extend, in the present series, results of a previous
study29 that showed the activated cytotoxic phenotype of
nonhepatosplenic lymphomas, since tumor cells expressed the
cytotoxic effector TIA-1 and Granzyme B proteins in all cases, with
expression of perforin in most cases. These results are in accordance
with the cytotoxic activity exhibited by normal T cells with
constitutive expression of TIA-1, Granzyme B, and perforin
proteins.40,41 The activated cytotoxic profile of
nonhepatosplenic cases contrasts to the finding of a nonactivated
cytotoxic profile of most hepatosplenic tumors.15,29
In the present series, at least some cases are likely to belong to
different clinicopathologic entities of extranodal
lymphomas,16 which appear to be derived from cytotoxic
lymphocytes.29,45 Concerning the nasal T/NK lymphoma entity
included in the angiocentric category of the Revised European and
American Lymphoma (REAL) classification,16 we and others
have shown that most cases are of NK origin,23,24,46,47
although rare cases have a phenotype.23,24 It
appears from the present study and from the literature that nasal T/NK
lymphomas, whatever their NK- or T-cell origin, have common
clinical and histopathologic features, are associated with EBV, and are
derived from activated cytotoxic cells, and thus most probably belong
to the same clinicopathologic entity. Intestinal T-cell lymphomas, with
or without evidence of enteropathy, are most often derived from
cytotoxic cells.45 Most of them are derived from T
cells.48 To our knowledge, a single case of
gastrointestinal lymphoma has been mentioned in one report, without
precise localization.45 We show here that intestinal T-cell
lymphomas, including some with enteropathy due to gliadin hypersensitivity, can also derive, although rarely, from T cells. These findings are in accordance with the fact that
intraepithelial lymphocytes are mostly derived from T cells, but
also include a significant proportion of T-cells (5% to
15%).6,49 Several studies have shown that intraepithelial
lymphocytes are cytotoxic cells that are in a resting state in normal
human intestine,50 and are increased and activated in
celiac disease.51-53
In the reported cases, chronic antigen exposure was associated with a
dysregulation of the immune response in six cases:
hypogammaglobulinemia, T-cell deficiency, HTLV-1 infection, and celiac
sprue. In addition, EBV infection found in six patients may also
reflect a latent immune disorder. Impairment of the immune response
following antigen-driven stimulation could have favored the
proliferation of the reactive T cells. Indeed, expansion of
T cells has been found in autoimmune diseases such as celiac
sprue, in PBL of patients with primary immunodeficiency, and in
patients with HTLV-1 infection, accounting for a proliferation of
T-cell subsets in patients with an immune
defect.54,55 It is noteworthy that expansion of T
cells has been also reported in renal allograft
recipients56 and that hepatosplenic lymphoma may occur in
such patients.57 Additional genetic alterations may
contribute to full neoplastic transformation. Further studies are
needed to investigate the presence of recurrent cytogenetic
abnormalities in these lymphomas, such as the iso 7q chromosome, as
recently described in hepatosplenic T-cell
lymphoma.15,58
In conclusion, nonhepatosplenic T-cell lymphomas can be regarded
as a model of activated cytotoxic lymphoma, preferentially occurring in
mucosae or skin. These appear to be derived from tissue-restricted
lymphocytes implicated in immune reactions and in epithelial
surface surveillance. Further studies are needed to investigate the
putative role of chronic antigen stimulation in the pathogenesis of
these lymphomas as it has been shown, using in vitro studies, in B-cell
gastric MALT lymphomas related to H pylori-mediated antigen
stimulation,34 and to understand the molecular mechanisms
of their neoplastic transformation.
| |
FOOTNOTES |
Submitted June 30, 1997;
accepted October 22, 1997.
Supported in part by Grant No. CRC95241 from the Délégation
à la Recherche Clinique.
Address reprint requests to Philippe Gaulard, MD, Département de
Pathologie, Hôpital Henri Mondor, 94010 Créteil Cedex, France.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We gratefully acknowledge the following physicians who provided
clinical data: Bertrand Godeau, Marine Divine, Corinne Haioun, Olivier
Hermine, Yves Bouhnik, Remy Marianowski, Jean-Marc Zini, Marie-France
Avril, Jose Pico, and Jean-Nicolas Munck. We are also indebted to Odile
Casiraghi, Claire Legendre for providing histopathologic findings, to
Panagiotis Kanavaros for helpful discussion, and to Marie-Laure
Boulland for kind technical assistance.
| |
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