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NCI CANCERLIT® Search: Cutaneous T-cell Lymphoma - October 2001
National Cancer Institute®
Last Modified: November 21, 2001
Table of Contents
1
UI - 20368514
AU - Railan D; Fivenson DP; Wittenberg G
TI -
Capillary leak syndrome in a patient treated with interleukin 2 fusion
toxin for cutaneous T-cell lymphoma.
SO - J Am Acad Dermatol 2000 Aug;43(2 Pt 1):323-4
2
UI - 21102696
AU - Acosta M; Teitelbaum A
TI -
Capillary leak syndrome in a patient treated with interleukin 2 fusion
toxin for cutaneous T-cell lymphoma.
SO - J Am Acad Dermatol 2001 Feb;44(2):312-3
3
UI - 21320117
AU - Glusac EJ
TI -
Of cells and architecture: new approaches to old criteria in mycosis
fungoides.
SO - J Cutan Pathol 2001 Apr;28(4):169-73
AD - Department of Pathology, Yale University School of Medicine, New Haven,
CT 06520-8059, USA. earl.glusac@yale.edu
4
UI - 21320118
AU - Guitart J; Kennedy J; Ronan S; Chmiel JS; Hsiegh YC; Variakojis D
TI -
Histologic criteria for the diagnosis of mycosis fungoides: proposal for
a grading system to standardize pathology reporting.
SO - J Cutan Pathol 2001 Apr;28(4):174-83
AD - Department of Dermatology, Northwestern University Medical School,
Chicago, Illinois 60611, USA. j-guitart@nwu.edu
BACKGROUND: The histological diagnosis of early lesions of mycosis
fungoides (MF) is often difficult for dermatopathologists and prior
studies have shown a low agreement rate among pathologists. An important
reason for such difficulty may be the lack of specific histological
criteria. METHODS: We tested a new method to interpret and report
biopsies suspicious for MF. The method is based on a grading system
reflecting the pathologist's degree of diagnostic certainty. A panel of
four pathologists independently assessed a set of 50 biopsies suspicious
for MF first without (Phase I) and subsequently with specific
histological criteria (Phase II). A third Phase was carried out after a
training session, using a new set of cases with corresponding
immunophenotyping and gene rearrangement analysis. Weighted and
unweighted kappa statistics were used to assess inter- and
intra-pathologist variation. RESULTS: The consensus rate among
pathologists improved from 48% in Phase I to 76% in Phase III. Overall
precision weighted kappas increased from 0.630 in Phase I to 0.854 in
Phase III, indicating excellent inter-pathologist agreement by Phase
III. There was a significant association between the presence of an
abnormal phenotype and/or T-cell clonality and a higher diagnostic
score. CONCLUSIONS: The use of uniform criteria and training sessions
can substantially improve the consensus rate among pathologists in the
diagnosis of MF.
5
UI - 21451295
AU - Bekkenk MW; Willemze R
TI -
[CD56-positive 'natural killer'/T-cell lymphoma]
SO - Ned Tijdschr Geneeskd 2001 Aug 4;145(31):1524-5
6
UI - 21411441
AU - Evans AV; Wood BP; Scarisbrick JJ; Fraser-Andrews EA; Chinn S; Dean A;
TI -
Watkins P; Whittaker SJ; Russell-Jones R
Extracorporeal photopheresis in Sezary syndrome: hematologic parameters
as predictors of response.
SO - Blood 2001 Sep 1;98(5):1298-301
AD - Skin Tumour Unit, St John's Institute of Dermatology, St Thomas'
Hospital, London, United Kingdom.
Data were analyzed from 23 patients with Sezary syndrome (defined by
erythroderma, more than 10% circulating atypical mononuclear cells, and
peripheral blood T-cell clone) undergoing monthly extracorporeal
photopheresis as the sole therapy for up to 1 year. The cohort showed a
significant reduction of skin scores during treatment (P =.001).
Thirteen patients (57%) achieved a reduction in skin score greater than
25% from baseline at 3, 6, 9, or 12 months (responders). Reduction in
skin score correlated with reduction in the Sezary cell count as a
percentage of total white cell count (P =.03). Responders and
nonresponders were compared. None of the measured parameters was
significantly different between the 2 groups. It was assessed whether
any of the baseline parameters predicted outcome. A higher baseline
lymphocyte count was significantly associated with a decrease in skin
score at 6 months (P <.05). A higher baseline Sezary cell count as a
percentage of total white cell count predicted a subject was more likely
to be a responder after 6 months of treatment (P =.021). No other
parameters predicted responder status. These data show that the modest
falls in CD4, CD8, and Sezary cell counts were seen in all patients and
might have resulted from lymphocyte apoptosis. This mechanism could
explain the more favorable response seen in patients with higher
percentages of Sezary cells in the peripheral blood. Alternatively,
minimum tumor burden might be required for the induction of a cytotoxic
response. Analysis of tumor-specific cytotoxic T cells is needed to
investigate these possibilities further.
7
UI - 21439117
AU - Ni X; Hazarika P; Zhang C; Talpur R; Duvic M
TI -
Fas ligand expression by neoplastic T lymphocytes mediates elimination
of CD8+ cytotoxic T lymphocytes in mycosis fungoides: a potential
mechanism of tumor immune escape?
SO - Clin Cancer Res 2001 Sep;7(9):2682-92
AD - Department of Dermatology, University of Texas, M. D. Anderson Cancer
Center, Houston, Texas 77030, USA.
Mycosis fungoides (MF) is the most common form of cutaneous T-cell
lymphoma (CTCL) and arises from the accumulation and clonal
proliferation of epidermotropic, CD4+/CD45RO+ (helper/memory) T
lymphocytes. Loss of CD8+ CTLs within MF lesions is associated with poor
prognosis and disease progression. Because T-lymphocyte apoptosis is
controlled mainly through the Fas/Fas ligand (FasL) pathway and tumor
cells may escape immune surveillance by expressing FasL, triggering
apoptosis of tumor-infiltrating T lymphocytes, we studied the role of
this system in MF. T-cell subsets, Fas/FasL expression, and apoptosis
were evaluated in normal and lesional skin biopsy specimens from 21
patients with all stages of MF and in cultured CTCL cell lines (MJ,
HUT78, and HH) using immunohistochemistry, terminal deoxynucleotidyl
transferase-mediated dUTP nick end labeling (TUNEL), and Western
blotting. MF lesions and paired, clinically "normal," uninvolved skin
showed increased numbers of both TUNEL-positive epidermal keratinocytes
(n = 13; F = 31.146; P < 0.01, ANOVA) and dermal lymphocyte infiltrates
(n = 13; F = 15.825, P < 0.01, ANOVA) compared with the normal control
skin. FasL expression was highest in lesional epidermal keratinocytes,
in CTCL tumor cell lines, and in dermal tumor lymphocytes in MF lesions
compared with uninvolved skin. FasL colocalized with CD45RO+ cells. CD8+
cells in or adjacent to CD45RO+ cells were positively labeled by TUNEL
for apoptosis. In addition, CD8+ cell numbers were decreased in areas in
which FasL+ tumor cells were abundant (2.01 +/- 0.86%) compared with
non-FasL expressing areas (13.53 +/- 3.54%; P < 0.02). These results
suggest that a potential mechanism of tumor immune escape in MF is
FasL-mediated apoptosis of infiltrating CD8+ CTLs.
8
UI - 20251395
AU - Macey WH
TI -
A primary care approach to cutaneous T-cell lymphoma.
SO - Nurse Pract 2000 Apr;25(4):82, 85-8, 91-4 passim
AD - Occupational Health Department, University of Pennsylvania Medical
Center, Philadelphia, USA.
Approximately 1,000 new cases of cutaneous T-cell lymphoma are
definitively diagnosed each year. Mycosis fungoides and Sezary syndrome
are the primary lymphomas in this group. Mycosis fungoides can begin in
the patch, plaque, or tumor stage or in a combination. Less commonly,
its initial presentation is erythrodermic. Because the initial
appearance of cutaneous T-cell lymphoma can be subtle and the
histopathologic evidence nonspecific, the disease is commonly
misdiagnosed as a common dermatologic condition such as chronic eczema.
Misdiagnosis can severely affect treatment and prognosis. Clinicians
must be able to recognize this disease and know when to include it in
the differential diagnosis. This article provides an overview of
cutaneous T-cell lymphoma, discusses differential diagnoses, and
outlines management considerations.
9
UI - 21170449
AU - Bell TJ
TI -
T-cell lymphoma products.
SO - Nurse Pract 2001 Mar;26(3):19
10
UI - 21437196
AU - Olavarria E; Child F; Woolford A; Whittaker SJ; Davis JG; McDonald C;
TI -
Chilcott S; Spittle M; Grieve RJ; Stewart S; Apperley JF; Russell-Jones
R
T-cell depletion and autologous stem cell transplantation in the
management of tumour stage mycosis fungoides with peripheral blood
involvement.
SO - Br J Haematol 2001 Sep;114(3):624-31
AD - Department of Haematology, Hammersmith Hospital, ICSM, London, UK.
e.olavarria@ic.ac.uk
Nine patients with tumour stage mycosis fungoides (MF) have been entered
into a pilot study of T-cell depletion and autologous stem cell
transplantation (SCT). Eight patients had detectable rearrangements of
the T-cell receptor (TCR) gamma-gene demonstrated by polymerase chain
reaction (PCR)/single-stranded conformation polymorphism (SSCP) in the
peripheral blood. The median age was 47 years and the median duration of
disease before SCT was 61 months; Peripheral blood progenitor cells were
mobilized using high-dose etoposide (1.6 g/m2) and granulocyte
colony-stimulating factor (G-CSF). The apheresis products underwent
rigorous T-cell depletion with immunomagnetic methods. Double
CD34-positive and CD4/CD8-negative selection achieved a median reduction
of 3.89 log of T cells. All nine patients have been transplanted.
Conditioning included carmustine (BCNU), etoposide and melphalan (BEM)
in seven patients and total body irradiation plus etoposide or melphalan
in two. Eight patients engrafted promptly and one patient died of
septicaemia. All survivors entered complete remission. Seven patients
have relapsed at a median of 7 months (2-14) post SCT. However, most
patients have relapsed into a less aggressive stage, which has responded
to conventional therapy. Four out of seven evaluable patients had
detectable TCR rearrangements in the T-cell depleted graft. A T-cell
clone was also detected in the peripheral blood before relapse in four
cases. Autologous SCT is feasible, safe and can result in complete
remission in a significant proportion of patients with tumour stage
mycosis fungoides. Despite a short relapse-free survival, most patients
achieved good disease control at the time of relapse.
11
UI - 21448750
AU - Qin JZ; Kamarashev J; Zhang CL; Dummer R; Burg G; Dobbeling U
TI -
Constitutive and interleukin-7- and interleukin-15-stimulated DNA
binding of STAT and novel factors in cutaneous T cell lymphoma cells.
SO - J Invest Dermatol 2001 Sep;117(3):583-9
AD - Department of Dermatology, University Hospital of Zurich, Zurich,
Switzerland.
On testing cutaneous T cell lymphoma cell lines and skin lesions, we
found that the transcription factors STAT2, STAT3, STAT5, and STAT6
(STAT, signal transducer and activator of transcription) were present in
the nuclei of these cells and that the binding to their specific DNA
binding sites was stimulated by interleukin-7 and interleukin-15. DNA
binding studies also revealed the presence of three additional DNA
factors in cutaneous T cell lymphoma cells that bound to the same
sequences and could also be stimulated by interleukin-7 and
interleukin-15. One of these novel factors was also present in the adult
T cell leukemia cell line Jurkat and malignant T cells from the blood of
Sezary syndrome patients, but not in normal peripheral blood
lymphocytes. It may therefore be a marker of T cell leukemia. It seems
to interfere with the binding of STAT1 to the sis inducible element,
suggesting that the DNA binding activity of STAT1 in cutaneous T cell
lymphoma cells is disturbed.
12
UI - 21448760
AU - Vonderheid EC; Bigler RD; Kotecha A; Boselli CM; Lessin SR; Bernengo MG;
TI -
Polansky M
Variable CD7 expression on T cells in the leukemic phase of cutaneous T
cell lymphoma (Sezary syndrome).
SO - J Invest Dermatol 2001 Sep;117(3):654-62
AD - Department of Dermatology, MCP Hahnemann University, Philadelphia,
Pennsylvania 19102, USA. vonder@erols.com
CD7, a molecule normally expressed on 90% of normal CD4+ T cells, is
often deficient on the malignant T cells of cutaneous T cell lymphoma.
To investigate the clinical and biologic implications of CD7 expression,
blood lymphocytes from 42 patients with the leukemic phase of cutaneous
T cell lymphoma (CD4/CD8 ratio of 10 or more with evidence of a T cell
clone in the blood) were analyzed for level of expression of CD7 by flow
cytometry. CD7 expression by cells did not clearly segregate into two
distinct subgroups that are either CD7 positive or CD7 negative as
generally thought; however, nine of 17 patients with a predominantly
CD4+CD7+ tumor population on early studies became CD4+CD7- over time
whereas the converse situation was not observed. In addition, of three
patients with evidence of large tumor cells in the blood coexisting with
smaller cells, discordant CD7 expression was observed in one instance.
In lymph node specimens, the percentage of cells expressing CD7 and
other T cell markers did not correlate with histologic evidence of
involvement. CD7 expression on blood lymphocytes also did not correlate
with patients' survival nor to serum IgE levels or blood eosinophil
counts, a finding suggesting that this marker does not identify
functional cell subsets that produce serum interleukin-4 or -5,
respectively. We speculate that the level of CD7 expression on malignant
T cells may be the effect of sustained antigen stimulation in vivo
analogous to what has been proposed to occur with normal T cells during
aging.
13
UI - 21448761
AU - Scarisbrick JJ; Woolford AJ; Russell-Jones R; Whittaker SJ
TI -
Allelotyping in mycosis fungoides and Sezary syndrome: common regions of
allelic loss identified on 9p, 10q, and 17p.
SO - J Invest Dermatol 2001 Sep;117(3):663-70
AD - Skin Tumour Unit, St John's Institute Dermatology, St Thomas' Hospital,
London, UK. juliascarisbrick@doctors.org.uk
Allelotyping studies have been extensively used in a wide variety of
malignancies to define chromosomal regions of allelic loss and sites of
putative tumor suppressor genes; however, until now this technique has
not been used in cutaneous lymphoma. We have analyzed 51 samples from
patients with mycosis fungoides and 15 with Sezary syndrome using
methods to detect loss of heterozygosity. Micro satellite markers were
selected on 15 chromosomal arms because of their proximity to either
known tumor suppressor genes or chromosomal abnormalities identified in
previous cytogenetic studies in cutaneous lymphoma. Allelic loss was
present in 45% of patients with mycosis fungoides and 67% with Sezary
syndrome. Loss of heterozygosity was found in over 10% of patients with
mycosis fungoides on 9p, 10q, 1p, and 17p and was present in 37% with
early stage (T1 and T2) and 57% with advanced disease (T3 and T4).
Allelic loss on 1p and 9p were found in all stages of mycosis fungoides,
whereas losses on 17p and 10q were limited to advanced disease. In
Sezary syndrome high rates of loss of heterozygosity were detected on 9p
(46%) and 17p (42%) with lower rates on 2p (12%), 6q (7%), and 10q
(12%). There was no significant difference in the age at diagnosis or
number of treatments received by those with loss of heterozygosity and
those without, suggesting that increasing age and multiple treatments do
not predispose to allelic loss. These results provide the basis for
further studies defining more accurately chromosomal regions of
deletions and candidate tumor suppressor genes involved in mycosis
fungoides and Sezary syndrome.
14
UI - 21448765
AU - Ramez M; Bagot M; Nikolova M; Boumsell L; Vita N; Chalon P; Caput D;
TI -
Ferrara P; Bensussan A
Functional characterization of neurotensin receptors in human cutaneous
T cell lymphoma malignant lymphocytes.
SO - J Invest Dermatol 2001 Sep;117(3):687-93
AD - INSERM U448, Faculte de Medecine de Creteil, Service de Dermatologie,
Hopital Henri Mondor, 94010 Creteil Cedex, France.
Cutaneous T cell lymphomas are a clonal proliferation of CD4+ T
lymphocytes primarily involving the skin. Mycosis fungoides is an
epidermotropic CD4+ cutaneous T cell lymphoma, and a more aggressive
form, Sezary syndrome, occurs when the malignant cells become
nonepidermotropic. The role of neuropeptides in the growth and
chemotaxis capacity of cutaneous T cell lymphoma cells remains unknown.
In this report, we found that cutaneous T cell lymphoma cells, similarly
to normal resting or activated peripheral lymphocytes, were able to bind
neurotensin. We used an interleukin-2-dependent cutaneous T cell
lymphoma malignant T cell line derived from cutaneous T cell lymphoma
lesions in order to study the role of neurotensin in the proliferation
and migration of these malignant cells. First, we determined that the
malignant cells expressed neurotensin receptors on their cell membrane.
Functional results indicated that neurotensin did not stimulate the
growth of the cell line. In contrast, this neuropeptide inhibited the
proliferation of the tumor cells in response to exogenous interleukin-2.
Furthermore, we found that neurotensin enhanced both spontaneous and
chemoattractant-induced migration of the malignant cells. This suggests
that neurotensin in skin can play a role in the disease by locally
limiting the growth of the cutaneous T cell lymphoma tumor cells in
response to cytokines and by enhancing their chemotaxis capacity.
15
UI - 21094922
AU - Russell-Jones R
TI -
Immunophenotyping of Sezary cells.
SO - Br J Dermatol 2001 Jan;144(1):2-3
16
UI - 21385366
AU - Li N; Bhawan J
TI -
New insights into the applicability of T-cell receptor gamma gene
rearrangement analysis in cutaneous T-cell lymphoma.
SO - J Cutan Pathol 2001 Sep;28(8):412-8
AD - Dermatopathology Section, Department of Dermatology, Boston University
School of Medicine, Boston, Massachusetts, USA.
BACKGROUND: Detection of clonal T-cell receptor (TCR) gamma gene
rearrangement by polymerase chain reaction (PCR) based method is a
marker for cutaneous T-cell lymphoma (CTCL) although it can be seen in
some benign dermatoses. To determine the accuracy of histologic criteria
alone as well as the adjuvant diagnostic role of TCR gene rearrangement
for the diagnosis of CTCL, we studied 100 patients with cutaneous T-cell
infiltrates by both histology and TCR gene rearrangement. METHODS: The
histologic features of the 100 patients were first reviewed by two
independent dermatopathologists and their confidence in the diagnosis of
CTCL was assigned one of four levels. Then the specimens were analyzed
for TCR gene rearrangement either on paraffin-embedded or fresh-frozen
tissue by PCR/denaturing gradient gel electrophoresis (DGGE). RESULTS:
The clonality was detected in 100% (15/15) diagnostic of, 84.6% (11/13)
consistent with, 57.6% (19/33) suggestive of CTCL. In 9 cases TCR gene
rearrangement was compared between formalin-fixed and fresh specimens of
the same individual, but with different degrees of histologic confidence
(no lower than suggestive). In all cases fresh specimens were positive.
In 5 of the cases (2-diagnostic, 2-consistent, 1-suggestive)
formalin-fixed specimens were positive as well, and in 4 cases
(1-consistent, 3-suggestive) formalin-fixed specimens were negative.
When TCR gene rearrangement was studied in eight cases on sequential
biopsies from the same patient, the clonality was detected in only one
or two biopsies in four cases in which the histologic confidence was low
(suggestive or nondiagnostic). The TCR gene rearrangement study showed
identical banding patterns in lesions from different clinical stages in
most patients. However, we observed that in one case,
oligoclonal-banding pattern was seen in initial biopsy with
histopathologic consistent with CTCL, while monoclonal banding pattern
in more advanced lesion. CONCLUSIONS: Our data have demonstrated that
TCR gene rearrangement studies by PCR/DGGE are consistently positive
regardless of tissue fixation (formalin-fixed, paraffin-embedded vs.
fresh-frozen tissue) and biopsy site when the histologic degree of
confidence is very high (diagnostic). So, it may be of less importance
as an adjuvant to histopathologic diagnosis for the cases with
diagnostic CTCL histology. However, TCR gene rearrangement studies are
particularly important in earlier cases with less conclusive histology,
which provides strong confirmatory evidence of an evolving CTCL. In
these cases, multiple biopsies may be required to establish the
diagnosis and analysis of fresh tissue is suggested to increases the
sensitivity. Moreover, our observation also suggested that some CTCL
might not be monoclonal de novo, but oligoclonal instead.
17
UI - 21385369
AU - Brown HA; Macon WR; Kurtin PJ; Gibson LE
TI -
Cutaneous involvement by angioimmunoblastic T-cell lymphoma with
remarkable heterogeneous Epstein-Barr virus expression.
SO - J Cutan Pathol 2001 Sep;28(8):432-8
AD - Department of Dermatology, Mayo Clinic, Rochester, Minnesota, USA.
INTRODUCTION: Initially described as an abnormal immune reaction, most
cases of angioimmunoblastic lymphadenopathy with dysproteinemia
(AILD)-like T-cell infiltrates are now regarded as a peripheral T-cell
lymphoma (AILD T-NHL). AILD T-NHL is characterized clinically with
constitutional symptoms, generalized lymphadenopathy,
hepatosplenomegaly, skin rash, and polyclonal hypergammaglobulinemia.
Epstein-Barr virus (EBV) is frequently detected in involved lymph nodes,
but the presence of EBV in cutaneous infiltrates of AILD T-NHL has
rarely been examined. We present a patient with AILD T-NHL with
cutaneous involvement that shows marked heterogeneity of EBV expression
in the lymph node and skin biopsies, and review the histological
findings of AILD T-NHL in the skin. METHODS: Two skin biopsies of a
diffuse maculopapular rash and a lymph node were examined and
immunophenotyped. In situ hybridization for detection of EBV in the
lymph node and skin biopsies was utilized. In order to attempt to
delineate which lymphocytes were EBV positive, skin biopsies were dual
labeled with CD3, CD45RO, CD20 and EBV. The skin biopsies and lymph node
were submitted for gene rearrangement studies by polymerase chain
reaction (PCR). Capillary electrophoresis of fluorescently labeled PCR
products was utilized for PCR product quantitation. RESULTS: The
histological features of the lymph node were diagnostic of AILD T-NHL
and a T-cell clone was identified by PCR. The skin biopsies showed an
atypical superficial and deep perivascular polymorphous infiltrate
consistent with cutaneous involvement by AILD T-NHL. Both skin biopsies
showed the same clonal T-cell receptor gene rearrangement as the lymph
node. In situ hybridization of the lymph node and one skin biopsy showed
a few scattered EBV-positive lymphocytes (<1% of the infiltrate). A
second skin biopsy revealed 40-50% of the lymphocytes as EBV positive.
Dual staining for CD20 and EBV identified a minority of EBV-infected
lymphocytes as B-cells, but most of the EBV-positive cells lacked
staining for CD3 and CD45RO. CONCLUSIONS: In our patient, the same
T-cell receptor gene rearrangement was found by PCR in all three biopsy
sites. Most cases of AILD T-NHL contain only a few EBV-positive cells,
but in our patient the extent of EBV expression ranged from <1% to
40-50% of the AILD T-NHL cutaneous infiltrate. To our knowledge, this
case is the most extensive and heterogeneous expression of EBV in
cutaneous AILD T-NHL to date.
18
UI - 21453215
AU - Vermeer MH; Bekkenk MW; Willemze R
TI -
Should primary cutaneous Ki-1(CD30)-positive anaplastic large cell
lymphoma in childhood be treated with multiple-agent chemotherapy?
SO - J Am Acad Dermatol 2001 Oct;45(4):638-40
19
UI - 21467461
AU - Thariat J
TI -
[Cutaneous manifestations of the leukemia-lymphoma of HTLV 1: apropos of
1 case]
SO - Med Trop (Mars) 2001;61(2):173-6
AD - Service de Dermatologie et Maladies Infectieuses Dr Pradinaud, Centre
Hospitalier General de Cayenne, Cayenne, Guyane Francaise.
j.thariat@libertysurf.fr
Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus
implicated in adult T-cell leukemia/lymphoma characterized by
proliferation of infected mature auxiliary T-cell lymphocytes. Cutaneous
manifestations of T-cell leukemia/lymphoma are inconsistent and variable
findings. In some patients, skin lesions are the presenting symptoms
that lead to diagnosis and in others they are secondary occurrences.
This report describes a case of T-cell leukemia/lymphoma associated with
serologically documented HTLV-1 infection in a 27-year-old black man
from Surinam. Manifestations were low-grade at the time of diagnosis and
became tumor-like at the end stage of the disease. At the time of
presentation, examination revealed plaques of infiltrated scaly
erythrematous lesions scattered over the entire body. One year later the
patient exhibited xerodema and variable-sized subcutaneous tumor-like
nodules. This case illustrates the wide range of cutaneous
manifestations that can be found in association with cutaneous T-cell
lymphoma due to HTLV-1.
20
UI - 21408244
AU - Devulder J; Lambert J; Naeyaert JM
TI -
Gabapentin for pain control in cancer patients' wound dressing care.
SO - J Pain Symptom Manage 2001 Jul;22(1):622-6
AD - Department of Anesthesia-Section Pain Clinic, Ghent University Hospital,
Ghent, Belgium.
A patient with mycosis fungoides illustrates the problem of pain
management during wound care and suggests the utility of a novel
treatment, gabapentin. Skin lesions, be they induced through necrosis of
tumor, therapy (e.g., radiotherapy), or by pressure ulceration, are
often the cause of continuous pain or acute wound dressing pain.
Optimizing the analgesic treatment in those patients is thus of major
importance. Anti-inflammatory drugs and opioids are the cornerstones in
the treatment of cancer pain but are rarely sufficient to control wound
pain. Different adjuvant techniques can be used, including topical
analgesics, psychological distraction techniques, anxiolytics, and
co-analgesics. There is growing evidence that anticonvulsants, and
sodium channel blockers in particular, are effective not only in
neuropathic but also in inflammatory pain. Gabapentin, a voltage
sensitive sodium and calcium channel blocker, was used as a co-analgesic
to supplement morphine in this case of cancer wound dressing pain.
21
UI - 21477755
AU - Edelson RL
TI -
Cutaneous T cell lymphoma: the helping hand of dendritic cells.
SO - Ann N Y Acad Sci 2001 Sep;941():1-11
AD - Yale University Comprehensive Cancer Center and Department of
Dermatology, New Haven, Connecticut 06520, USA. richard.edelson@yale.edu
Since its introduction 25 years ago, cutaneous T cell lymphoma has
become the preferred designation for clonal malignancies of those CD4
thymus-derived lymphocytes ("cutaneous T cells") that preferentially
migrate to skin. The varied cutaneous clinical presentations, dependent
on the specific features of the dominant subclones of the malignant
lymphocytes, historically led to confusing descriptive terms (mycosis
fungoides, Sezary syndrome, lymphoma cutis, leukemia cutis, reticulum
cell sarcoma of the skin). Recognition that all of these clinical
presentations are cancers of a single type of cell has permitted their
unification under the single, clarified heading cutaneous T cell
lymphoma, or CTCL. As a neoplastic amplification of the skin-homing T
cells from which it is derived, CTCL's distinctive features can be
explained. The triad of skin localization, remarkable avoidance of bone
marrow, often even in the context of extremely high leukemic counts, and
infiltration of perifollicular T cell zones of the lymph nodes and
spleen reflect the migratory pathway and homing patterns of cutaneous T
cells. The usually retained levels of serum immunoglobulins and the
resulting capacity to defend against encapsulated bacteria, often even
in advanced CTCL, are manifestations of the helper function of the
malignant T cells-that is, their functional capacity to stimulate B
lymphocytes to produce immunoglobulin in a polyclonal manner. In
contrast, the often-extreme normal T cell deficits in advanced CTCL,
equivalent to those of late-stage AIDS, probably resulting from the
production of suppressive cytokines such as IL-10, cause susceptibility
to a broad range of opportunistic infections, the most common direct
cause of death. Pautrier microabscesses, the pathognomonic feature of
epidermotropic early CTCL, hold the clues to the pathogenesis of the
cancer. These intraepidermal collections of stimulated and proliferating
malignant cells, adherent to the dendrites of intraepidermal dendritic
antigen-presenting cells (Langerhans' cells [LCs]), indicate a dynamic
communication between the two cell types. Since CTCL cells are derived
from CD4 T cells, which normally receive signaling from dendritic cells
(DCs) via presentation of antigenic peptides as part of class II major
histocompatibility complexes to antigen-specific T cell receptors
(TCRs), it seems likely that CTCL is a clonal proliferation of T cells
responding to specific antigenic stimulation from LCs. This is supported
by our recent finding that CTCL cells proliferate in vitro in response
to TCR stimulation by autologous DCs, which have previously ingested and
processed antigens from apoptotic autologous CTCL cells. In short, CTCL
may be a malignancy of T cells stimulated to proliferate against its own
tumor antigens. The most intriguing possibility is that a
yet-unidentified transforming retrovirus, harbored by LCs,
simultaneously attracts, stimulates, and transforms a single clone of
antigen-specific cutaneous T cells. Longstanding disease-free remissions
have been induced by transimmunization (via a photopheresis apparatus).
This treatment, introduced more than a decade ago by our group and the
first and still the only FDA-approved selective anticancer
immunotherapy, has been performed more than 200,000 times worldwide on
advanced CTCL, as well as in reversal/prevention of heart transplant
rejection and treatment of graft-versus-host disease and selected
autoimmune disorders. Transimmunization induces clinically relevant
suppression, and occasionally elimination, of pathogenic T cell clones.
The common denominator between these diverse groups of responding
patients is the presence of clonally distinctive TCRs on the
disease-causing malignant or autoaggressive T cell clones. In CTCL at
least one source of tumor-specific antigens is derived from the
clone-specific (idiotypic) segments of the TCR protein chains. In the
photopheresis apparatus, two synergistic phenomena are initiated:
induction of apoptosis of the CTCL cells and mass conversion of blood
monocytes to DCs. The young DCs then ingest the apoptotic CTCL cells,
process and present the CTCL antigens to responding anti-CTCL cytotoxic
T cells, and stimulate clinically important CTCL suppression. Now that
it is better understood, transimmunization may have much broader
applications in other types of cancer as well.
22
UI - 21477766
AU - Knobler R; Girardi M
TI -
Extracorporeal photochemoimmunotherapy in cutaneous T cell lymphomas.
SO - Ann N Y Acad Sci 2001 Sep;941():123-38
AD - Department of Dermatology, University of Vienna Medical School,
University of Vienna, Austria. robert.knobler@akh-wien.ac.at
Extracorporeal photochemotherapy (ECP), or photopheresis, is a widely
used treatment for cutaneous T cell lymphoma (CTCL) and other T
cell-mediated disorders, having been administered in more than 150
centers worldwide more than 200,000 times. Consistent with the theme of
this conference--that is, highlighting the potentially most productive
investigative avenues for unraveling the mysteries of CTCL in the next
decade--ECP has been futuristic since its inception in the early 1980s.
In 1988, the treatment was the first FDA-approved selective
immunotherapy for any type of cancer. Yet, the mechanism by which it
could suppress a clone of CTCL cells or inactivate multiple autoreactive
T cell clones in graft-versus-host disease (GVHD) or allograft rejection
remained obscure until quite recently. In fact, the scientific
principles necessary to begin to comprehend the basis of ECP's efficacy
were not available when the treatment was first introduced in 1982. In
the intervening years, necessary detailed knowledge of the structure and
function of the clonotypic T cell receptors, of class I major
histocompatibility complex (MHC) presentation of tumor antigens, of CTCL
tumor-specific antigens, of dendritic antigen presenting cell (DC)
biology, and of 8-methoxypsoralen immunopharmacology has been attained.
Although much remains to be learned, we now appreciate that ECP
simultaneously and efficiently induces both apoptosis of disease-causing
T cells and conversion of monocytes to functional DCs. By processing and
presenting the unique antigenic determinants of pathogenic T cell
clones, the DCs can either initiate a clinically relevant anti-CTCL
cytotoxic response or suppress the activity of autoreactive T cell
clones. This paper will review clinical trials of ECP in CTCL and
evolving scientific understanding of ECP's mechanism in the context of
exciting future directions.
23
UI - 21477768
AU - Russell-Jones R; Child F; Olavarria E; Whittaker S; Spittle M; Apperley
TI -
J
Autologous peripheral blood stem cell transplantation in tumor-stage
mycosis fungoides: predictors of disease-free survival.
SO - Ann N Y Acad Sci 2001 Sep;941():147-54
AD - Skin Tumour Unit, St. John's Institute of Dermatology, St. Thomas'
Hospital, London, United Kingdom.
Nine patients with mycosis fungoides (age range 27-67) underwent
autologous peripheral blood stem cell transplantation (PBSCT). All
patients had tumor-stage disease, and four had lymph node involvement.
Eight patients exhibited a peripheral blood T cell clone using PCR/SSCP
analysis of the TCR gamma gene, six prior to harvest and two at the time
of harvest. Mobilization of CD34+ stem cells was achieved with etoposide
and G-CSF. Harvested cells were positively selected for CD34. After
negative selection for CD4 and CD8, only two samples became PCR
negative. Conditioning prior to reinfusion of stem cells was achieved
with various combinations of total skin electron beam (TSEB), total body
irradiation (TBI), and chemotherapy, depending upon the patient's prior
exposure to radiotherapy. One patient failed to engraft and died of
candidal septicemia 15 days posttransplant. The other eight patients
achieved complete remission, but this was short-lived in four (median
disease-free survival [DFS] = 2 months) and prolonged in three (median
DFS 11 months). Those with a short DFS were distinguished by rapid tumor
onset prior to transplant but not by stage at transplant. Loss of a
detectable T cell clone after manipulation of the harvest did not
discriminate between the two groups, but rapid relapsers had been
subjected to a greater degree of T cell depletion, possibly indicating a
compromised cytotoxic response post-PBSCT. The median survival of the
cohort is four years from tumor onset, 15 months from PBSCT, and 27
months from the date a peripheral blood clone was first detected in the
presence of tumor-stage disease. Rapid relapse was associated with poor
overall survival. Our data demonstrate the value of PBSCT for inducing
remission in tumor-stage mycosis fungoides. Reinfusion of neoplastic
cells could be avoided by harvesting stem cells at an earlier stage in
the disease process, preferably before a T cell clone is detectable in
the peripheral blood. Alternatively T cell depletion should be
restricted to the CD4 subset.
24
UI - 21477769
AU - Heald P
TI -
Clinical trials and efficacy assessment in the therapy of cutaneous T
cell lymphoma.
SO - Ann N Y Acad Sci 2001 Sep;941():155-65
AD - Department of Dermatology, Yale University School of Medicine, New
Haven, Connecticut 06520, USA. peter.heald@yale.edu
The ability of clinical trials to measure cutaneous T cell lymphoma
(CTCL) has allowed physicians and regulatory reviewers to assess the
response of the disease to experimental therapies. The goals of therapy
are remission, palliation, and improvement of survival. Given the
chronic nature of the disease, surrogate markers for survival are used
in clinical trials. The surrogate markers and the validity of the
surrogate markers used to date will be compared and contrasted. Tumor
burden measurements by way of skin scoring are the parameters most
commonly used to assess the response to therapy. Skin scoring systems
have used global mapping, severity recording, or target lesions to
assess any change in response to an intervention. The advantages and
limitations of global and focal scoring are presented, along with
examples of skin scoring systems for the five most recently completed
trials for CTCL. Measures of palliation are performed via
questionnaires. General and CTCL-specific questionnaires have been
developed that assess both discrete and global manifestations of the
disease. Those measures of palliation that have been shown to correlate
with skin scoring are presented for inclusion into future studies. In
addition, study terms such as relapse and freedom from relapse can now
be defined with reproducible molecular techniques. Every stage of CTCL
warrants further clinical trials, and guidelines for future
investigations are proposed.
25
UI - 21477770
AU - Foss FM
TI -
Interleukin-2 fusion toxin: targeted therapy for cutaneous T cell
lymphoma.
SO - Ann N Y Acad Sci 2001 Sep;941():166-76
AD - Tufts New England Medical Center, Boston, Massachusetts 02111, USA.
ffoss@lifespan.org
The interleukin (IL)-2 receptor has proved an attractive target for T
cell-directed therapies. Agents including monoclonal antibodies,
single-chain antibody immunoconjugates, radioimmunoconjugates, and, most
recently, ligand fusion toxins have demonstrated activity in vitro and
in clinical trials in both hematologic malignancies and diseases
characterized by proliferation of activated T cells, such as
graft-versus-host disease. DAB389IL-2 (ONTAK) is a ligand fusion toxin
consisting of the full-length sequence of the IL-2 gene genetically
fused to the enzymatically active and translocating domains of
diphtheria toxin. DAB389IL-2 and its predecessor, DAB486IL-2, have
demonstrated activity in a variety of diseases, including cutaneous T
cell lymphoma (CTCL), psoriasis, rheumatoid arthritis, and HIV
infection. Further clinical development of IL-2 fusion toxins in CTCL
and other hematopoietic malignancies is predicated on identification of
the high-affinity IL-2 receptor complex on the malignant cells and on a
better understanding of the biological determinants of cytotoxicity of
these molecules in vivo.
26
UI - 21477771
AU - Rook AH; Zaki MH; Wysocka M; Wood GS; Duvic M; Showe LC; Foss F; Shapiro
TI -
M; Kuzel TM; Olsen EA; Vonderheid EC; Laliberte R; Sherman ML
The role for interleukin-12 therapy of cutaneous T cell lymphoma.
SO - Ann N Y Acad Sci 2001 Sep;941():177-84
AD - Department of Dermatology, University of Pennsylvania, Philadelphia
19104, USA. arook@mail.med.upenn.edu
Recent phase I and phase II trials using recombinant human
interleukin-12 (rhIL-12) for cutaneous T cell lymphoma (CTCL) have been
completed. Observations on 32 evaluable patients revealed an overall
response rate approaching 50 percent. Biopsy of regressing lesions
revealed an increase in numbers of CD8+ and/or TIA-1+ T cells. These
results suggest that rhIL-12 may induce lesion regression by augmenting
antitumor cytotoxic T cell responses. Future trials will be focused on
strategies for further immune enhancement by the concomitant use of
additional immune augmenting cytokines with rhIL-12.
27
UI - 21477772
AU - Tokura Y; Seo N; Yagi H; Takigawa M
TI -
Photoactivational cytokine-modulatory action of 8-methoxypsoralen plus
ultraviolet A in lymphocytes, monocytes, and cutaneous T cell lymphoma
cells.
SO - Ann N Y Acad Sci 2001 Sep;941():185-93
AD - Department of Dermatology, Hamamatsu University School of Medicine,
Japan. tokuray@hama-med.ac.jp
Treatment with 8-methoxypsoralen (8-MOP) and ultraviolet A light (UVA)
has been reported to modulate cytokine production in various cells. Our
study was conducted to see the effects of 8-MOP/UVA on the
expression/production of cytokines in peripheral blood lymphocytes and
monocytes in relation to the therapeutic mechanisms of extracorporeal
photochemotherapy. 8-MOP/UVA augmented the expression of mRNAs for
interferon-gamma (IFN-gamma) and interleukin (IL)-2 and reduced those
for IL-4 and IL-10 in peripheral blood mononuclear cells (PBMCs) from
normal subjects and Sezary syndrome patients. This enhancement of Th1
cytokines was caused by increment of cytokine production by Th1 cells
but not by conversion of Th2 cells to produce Th1 cytokines. The number
of IFN-gamma-secreting lymphocytes was markedly increased in
8-MOP/UVA-treated PBMCs 20 h after treatment, and its amount was
elevated in culture supernatants. However, this enhanced production of
IFN-gamma was found only until three days after 8-MOP phototreatment,
and its level was rapidly declined by five days after treatment. In
addition to this Th1-polarized action, 8-MOP/UVA-treated PBMCs produced
enhanced amounts of IL-8 upon stimulation with anti-CD3/CD28 antibodies.
Phototreated CD4+ but not CD8+ cells provided excellent T cell help for
monocytes to produce IL-8 via a direct cell-to-cell contact mechanism.
These findings suggest that 8-MOP/UVA has a transient but biologically
active Th1-skewing action in T cells, and the phototreated T cells
simultaneously stimulate monocytes to produce IL-8. It is suggested that
8-MOP/UVA exerts a beneficial therapeutic effect on malignant Th2
neoplasms as a Th1-skewing cytokine modifier and that 8-MOP-phototreated
CD4+ T cells allow monocytes to become effective tumor
antigen-presenting cells for tumor-specific cytotoxic T cells.
28
UI - 21477773
AU - Kacinski BM; Flick M
TI -
Apoptosis and cutaneous T cell lymphoma.
SO - Ann N Y Acad Sci 2001 Sep;941():194-9
AD - Department of Therapeutic Radiology and Dermatology, Yale University
School of Medicine, New Haven, Connecticut 06520, USA.
barry.kacinski@yale.edu
The most successful therapies in the treatment of cutaneous T cell
lymphoma (CTCL), which include localized X-ray therapy, total skin
electron beam therapy, total skin therapy with psoralen and UVA or other
forms of UV light therapy, topical chemotherapy, and even topical
steroids, all work by inducing T cell apoptosis. Yet, these same
malignant T cells, which readily undergo apoptosis after these
therapies, are far less likely to do so after therapy with systemic
chemotherapeutic agents that are often curative in B cell lymphomas.
Apoptosis in T cells is a normal phenotype in that only a small fraction
of nonneoplastic T cells fail to undergo apoptosis. Although we still
understand relatively little regarding the molecular biology of CTCL, it
is clear that the neoplastic cell clone or clones that predominate in
this disease have defects in normal apoptotic control mechanisms. These
can be overridden in most cases by the strong proapoptotic signals
triggered by ionizing radiation and other agents. Better understanding
of the mechanisms by which the latter occurs should help us both improve
our current therapies and devise new ones.
29
UI - 21477774
AU - Kurzrock R
TI -
Therapy of T cell lymphomas with pentostatin.
SO - Ann N Y Acad Sci 2001 Sep;941():200-5
AD - Department of Bioimmunotherapy, University of Texas, M. D. Anderson
Cancer Center, Houston 77030, USA. rkurzroc@mdanderson.org
Pentostatin is a highly lymphocytotoxic agent active in hairy cell
leukemia. Several studies also suggest significant activity in T cell
lymphomas manifested in the skin. Herein, we will review the studies of
pentostatin in these lymphomas and our most recent trial of this agent
in heavily pretreated patients with cutaneous and peripheral T cell
lymphomas. Overall, the data suggest that pentostatin has significant
antitumor activity in these patients, with response rates ranging from
33% to over 70%. Approximately one-third of the responses are complete.
The most common side effects include granulocytopenia, nausea, and renal
insufficiency. CD4 suppression occurs and may result in an increased
risk of herpes zoster infection. Although prolonged remissions have been
seen, most responses are short-lived. These observations suggest that
further exploration of this agent, in combination with other drugs
active in T cell lymphomas, is warranted in this group of diseases.
30
UI - 21477775
AU - Bouwhuis SA; El Azhary RA; Gibson LE; McEvoy MT; Pittelkow MR
TI -
The effect of insulin-dependent diabetes mellitus on the efficacy of
extracorporeal photopheresis in late-stage Sezary syndrome.
SO - Ann N Y Acad Sci 2001 Sep;941():206-9
AD - Department of Dermatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
31
UI - 21477776
AU - Wollina U; Looks A; Meyer J; Knopf B; Koch HJ; Liebold K; Hipler UC
TI -
Treatment of cutaneous T cell lymphoma stage II with interferon-alpha-2a
and extracorporeal photochemotherapy: a prospective controlled trial.
SO - Ann N Y Acad Sci 2001 Sep;941():210-3
AD - Department of Dermatology and Allergology, Friedrich Schiller University
of Jena, Germany. Wollina-Uw@khdf.de
32
UI - 21477777
AU - Wollina U; Graefe T; Kaatz M
TI -
Pegylated doxorubicin for primary cutaneous T cell lymphoma: a report on
ten patients with follow-up.
SO - Ann N Y Acad Sci 2001 Sep;941():214-6
AD - Department of Dermatology and Allergology, Friedrich Schiller University
of Jena, Germany. Wollina-Uw@khdf.de
33
UI - 21477778
AU - Wollina U; Liebold K; Kaatz M; Looks A; Stuhlert A; Lange D
TI -
Survival of patients with cutaneous T cell lymphoma after treatment with
extracorporeal photochemotherapy: a retrospective single-center
analysis.
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