Update on Cutaneous T-Cell Lymphoma (CTCL) Pathogenesis and Therapy
Tuesday, February 06, 2007
Cutaneous T-cell lymphoma (CTCL), a malignancy of activated,
typically CD4+ T lymphocytes, is characterized by three major
activities: (1) skin homing, (2) clonal dominance, and (3)
immunogenicity. CTCL tumor burden correlates with prognosis and can
be categorized as limited patch/plaque (<10% of the skin),
extensive patch/plaque (≥10% of the skin), tumor CTCL, and
erythrodermic CTCL (≥80% of the skin). Erythrodermic CTCL is often
seen in conjunction with peripheral blood involvement, as in the
Sézary syndrome (SS). An understanding of the pathogenesis of CTCL,
in conjunction with assessment of tumor burden, guides therapeutic
decision-making and identifies targets for the development of
CTCL Pathogenesis Features
CTCL cells use mechanisms of normal immunosurveillance of the
skin to migrate to and reside in the skin. Benign and malignant
skin-homing T cells express cutaneous lymphocyte-associated antigen
(CLA),1 which mediates rolling and tethering to
E-selectin on dermal post-capillary venules.2 Two
integrin ligand pairs involved in lymphocyte homing are
α4β1 and αLβ2 on the T
lymphocyte binding to VCAM-1 and the ICAM family on the
endothelium, respectively.3 In late stages of CTCL and
SS, circulating malignant T lymphocytes lose expression of α4
(CD49d), a component of lymphocyte homing.4 Chemokine
receptor interactions are essential for lymphocyte homing in the
dermal endothelium and epidermotrophism. For example, CCR4 and its
ligand CCL17 are expressed in normal skin and in lesions of CTCL
and SS.5, 6 Expression of integrin
αEβ7 on CTCL cells is important for retention
in the epidermis via interaction with E-cadherin.7
CTCL arises from clonal expansion of T lymphocytes, as
demonstrated by expression of a specific T-cell receptor
(TCR).8, 9 By displaying markers and cytokine
production characteristics of activated T cells, CTCL cells resist
apoptosis, expand, and adversely affect normal T cells. CTCL cells
commonly express several activation markers, including the
interleukin (IL)-2α receptor (CD25).10 Following IL-2
receptor stimulation, activated T cells undergo phosphorylation of
Jak/STAT intracellular signaling proteins.11-14
Activated CTCL cells may also have significant regulatory effects
on the host's normal T cells. For example, CTCL cells may produce
IL-10 or TGFβ , both of which can substantially inhibit
cell-mediated immunity.15 In addition, CTCL cells may
induce profound deficiencies within the normal repertoire of
peripheral T cells, further contributing to the immunodeficient
state of this malignancy.16 As CTCL patients often
succumb to infections or secondary malignancies, therapies that
spare toxicity to the normal lymphocytes are
CTCL cells express antigens, including the clonotypic TCR, which
may be recognized by an anti-tumor response. Prognosis and response
to therapy may be influenced by the CD4/CD8 ratio, and
immunosuppressive medications such as cyclosporine may result in
rapid disease progression. On the contrary, interventions that
stimulate the normal immune system and/or inhibit T-regulatory
(Treg) activities that may down-regulate anti-tumor immunity have a
substantial role in the therapy of CTCL.
CTCL Therapeutic Options
Treatment decisions are based on the tumor burden, patient
immune status, and the therapy reaching the malignant T cells and
their supporting environment.
Limited Patch/Plaque CTCL
Limited patch/plaque disease is treated with skin-directed
therapies, including phototherapy and topical agents. Phototherapy
(PUVA/UVB) three times per week at 90% of phototoxic dose18,
19, topical nitrogen mustard (mechlorethamine),20
carmustine (BCNU) 20-40 mg% in an ointment base daily21,
and bexarotene gel22 are effective treatments for
limited patch/plaque disease. Although there are no data on
long-term mortality, itching and pain are reduced with these
treatments, which help morbidity. Bexarotene is a member of a
subclass of retinoids that preferentially bind retinoid X receptors
(RXRs). Retinoic acid receptors (RARs) typically bind RXRs to form
RAR-RXR heterodimers that are capable of activating gene expression
of cell-surface receptors, structural proteins, and other key
mediators of cellular function. Bexarotene has direct effects on
the expanding population of malignant cells in CTCL by inhibiting
proliferation, inducing differentiation, and promoting
apoptosis.23, 24 Topical class I corticosteroids twice
daily are used in the treatment of CTCL. However, in the absence of
long-term studies, this treatment may best be viewed as a
palliative therapy or for the treatment of nondescript
lesions.25 Zackheim et al.'s study involving
large doses of clobetasol did not show as good a result as
phototherapy. Additionally, local radiotherapy may be
Extensive Patch/Plaque CTCL
Similar to limited patch/plaque disease, extensive patch/plaque
disease can be managed with skin-directed therapies such as
phototherapy and nitrogen mustard. Use of topical carmustine is
limited by systemic toxicity (cytopenia) and irritant dermatitis.
Other whole body and systemic modalities can be used, including
oral bexarotene, methotrexate, total skin electron beam therapy
(TSEBT), and alfa interferon. Oral bexarotene can produce partial
improvement of cutaneous disease across all stages of CTCL without
compromising immune status and is useful as an adjunctive
treatment.27, 28 Oral methotrexate 15-30 mg every week
can achieve partial (22%) and complete (12%) remission in patients
with extensive patch/plaque disease.29 TSEBT involves
delivering electrons with an energy of 3-9 MeV to the skin with
less than 5% traveling beyond 2 cm.30 Typically, 1-2 Gy
are delivered per treatment with greater than 20 Gy delivered over
a period of 9-12 weeks. TSEBT generates a complete response in
50-75% of patients with extensive patch/plaque disease and is also
useful in more advanced disease.31-33 Immune-stimulating
cytokine therapy with alfa interferon can be effective in extensive
patch/plaque disease as well as more advanced
Treatment of tumor stage disease utilizes treatments previously
discussed, including skin-directed therapies, TSEBT, oral
bexarotene, denileukin diftitox, and alfa interferon with the
addition of local radiotherapy for treatment of tumors.35,
36 The activated phenotype of CTCL cells with aberrant
expression of CD25 makes CTCL cells a somewhat selective target for
biologic therapy with denileukin diftitox, a recombinant fusion
protein of diphtheria toxin conjugated to IL-2.37
Erythrodermic CTCL / SS
Extracorporeal photochemotherapy (ECP, also known as
photopheresis) given every 4 weeks is an effective therapy for
erythrodermic presentations of CTCL alone or in combination with
TSEBT or alfa interferon.38, 39 ECP involves harvesting
a small portion of circulating cells, exposing them to UVA light in
the presence of 8-methoxypsoralen and a plastic surface, and
reinfusing cells to stimulate a therapeutic response.40
ECP simultaneously renders circulating malignant T cells apoptotic
and induces differentiation of peripheral monocytes to dendritic
cells,41 thereby providing the key cellular components
for a tumor cell vaccine. Thus, it is proposed that ECP may take
advantage of unique determinants on the malignant T cells,
including TCR42, 43 and other tumor antigens,44,
45 to induce an anti-tumor immune response.46 Alfa
interferon can be used as monotherapy or in combination with PUVA
or ECP for erythrodermic CTCL.47 Patients with systemic
disease may benefit from cytotoxic chemotherapy such as
chlorambucil along with prednisone.48 For advanced,
unresponsive disease with nodal or visceral involvement or
transformation to a large-cell lymphoma, allogeneic hematopoietic
stem cell transplant can be used to achieve remission and improve
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