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Cutaneous T-Cell Lymphoma: Pathogenesis and Treatment

Cutaneous T-Cell Lymphoma: Pathogenesis and Treatment

ABSTRACT: Cutaneous T-cell lymphoma (CTCL) is a malignancy of a distinctive subset of T-helper cells designated “cutaneous T cells” because of their central role in the normal functioning of the skin immune system. Guided by selective adhesion molecules, activated/memory T cells of the skin immune system normally circulate among the skin, lymph nodes, and peripheral blood. Thus, a better understanding of the skin immune system, which normally functions to provide immunosurveillance against cutaneous pathogens and other insults, has led to a better understanding of the clinical spectrum, pathogenesis, staging, and management of CTCL. This article describes the major subtypes of CTCL and provides an update on the pathogenesis and treatment of this lymphoma. [ONCOLOGY 14(7):1061-1070, 2000]

Introduction

Cutaneous T-cell lymphoma
(CTCL) is an umbrella term used to describe a spectrum of clinical
and histologic variants characterized by a malignant population of
“cutaneous T cells” that have a predilection for the skin.
As such, CTCL may be viewed as analogous to another life-threatening
cancer that commonly begins in the skin—malignant melanoma.
Whereas malignant melanoma is a cancer of melanocytes, a cell
population that normally resides in the skin to perform an important
function (eg, to protect against ultraviolet insult), CTCL is a
malignancy of a distinctive subset of T cells of the skin immune
system that normally patrol the skin’s environment (eg, to
protect against infection).

The primary dermal and epidermal infiltrating cell in the skin of
CTCL patients was first identified 20 years ago as having a T-helper
phenotype.[1] Since that time, the advancement and application of
sensitive tools of immunology and molecular biology have allowed for
the organization of CTCL variants into a more logical classification
than had previously been possible. The use of polymerase chain
reaction (PCR) to amplify T-cell receptor genes has greatly enhanced
our ability to detect the presence of a clonal population of T
cells.[2] This has allowed for an earlier and more sensitive means of
diagnosing CTCL, as well as the identification of several previously
poorly classified CTCL variants.

Here again, CTCL is analogous to malignant melanoma, which can
present with different, important-to-recognize variations, all of
which reflect the dominant cellular features of the malignant
melanocytes. Similarly, CTCL can present with a spectrum of clinical
variations—all manifestations of the features of the dominant
set of malignant “cutaneous T cells.” Nevertheless, it
should be emphasized that even the most innocuous-appearing of these
clinical variations (for example, focal patch/plaque involvement) are
malignancies of cutaneous T cells.

Despite the advent of PCR technology, it may be difficult at times to
make the diagnosis of CTCL or to pigeonhole cases into a particular
CTCL clinical variant, for several reasons. First, there exist
several clinical presentations that may demonstrate a predominant
T-cell clone by molecular analysis or immunoassay but that only
rarely progress to clear-cut CTCL. These entities have been termed
“premycotic” CTCL, and may represent a premalignant state
of CTCL.

Second, there is often clinical overlap between variants of CTCL
and/or transformation from one variant to another. This
transformation between the different clinical forms of CTCL may
represent either the natural evolution of more aggressive subclones
of the original malignant cutaneous T cell or partial reversal of
disease progression by therapeutic inhibition of the most aggressive subclone(s).

Thus, a definitive diagnosis of CTCL can be made when the lymphoma
shows evidence of T-cell clonality in addition to a clinical and
histologic picture that is highly suggestive of one or more of the
CTCL variants.

Skin Immune System and CTCL Pathogenesis

Emergence of the concept of a skin immune system[3] has shed light on
the pathogenesis of CTCL. It is now clear that, in the normal state,
T cells can circulate from the peripheral blood, through the
selective barrier of endothelial cells bearing adhesion molecules
into the dermis, to regional lymph nodes via the lymphatic vessels,
and back into the peripheral circulation through high endothelial
venules in the lymph-node cortex (Figure
1
).

The key to this skin-blood-lymph node–specific cycling appears
to be T-cell expression of the cutaneous lymphocyte antigen (CLA)
marker. Naive (ie, CD45Ra-positive) T cells that encounter their
specific antigen in draining lymph nodes of the skin differentiate
into activated/memory (ie, CD45Ro-positive) T cells and express CLA.
Once returned to the blood, CLA-positive T cells can encounter
their ligand E-selectin on dermal endothelial cells for recruitment
back into the skin during an inflammatory response.

During normal homeostasis, this system performs an immunosurveillance
function as part of the defense against cutaneous insults and
infection. However, under abnormal circumstances, CLA-positive T
cells mediate many inflammatory skin disorders, including psoriasis,
atopic dermatitis, and cutaneous graft-vs-host disease.[4] Although
often referred to as a “primary cutaneous lymphoma” to
distinguish it from, eg, Hodgkin’s disease, which may eventually
involve the skin, CTCL is perhaps more accurately viewed as a
lymphoma arising from skin-homing, CLA-positive memory T cells of the
skin immune system.

Understanding that CTCL is a malignancy of the skin immune system
helps one to better understand the pathogenesis of this lymphoma. For
example, while the insidious patch/plaque CTCL (discussed below)
usually persists for years in patients in the absence of obvious
leukemia (ie, with normal peripheral lymphocyte subset counts and
without any abnormalities present by flow cytometry) or
lymphadenopathy, it is incorrect to view this condition as a lymphoma
confined to the skin.

It is not unusual for such patients to present with multiple
cutaneous patch and/or plaque lesions. Immunohistochemical and
molecular analysis of infiltrating T cells demonstrates a common
clonal population of CD4-positive, CD45Ro-positive memory T cells in
each of the discrete lesions. (Each patch/plaque lesion of mycosis
fungoides has the same clone.) The presence of multiple lesions with
intervening normal skin is indirect evidence that, even in this
early-stage patch/plaque disease, CTCL is a lymphoma of T cells of
the skin immune system (ie, cycling among the skin, peripheral blood,
and skin-draining lymph nodes).

In patients with early patch/plaque CTCL, in whom the vast majority
of malignant T cells home to and reside in the skin, it is possible,
using PCR, to detect the same malignant clone in the peripheral blood
and lymph nodes, thus confirming that this is a “systemic”
lymphoma.[5] At this stage, skin-directed therapy (eg, psoralen plus
ultraviolet A light [PUVA], electron-beam radiation, or topical
carmustine [BCNU]) may be sufficient to prevent disease progression
or induce apparent cure. This suggests the strong tendency of the
malignant T cells to home to the skin, as well as their dependence on
the cutaneous environment to maintain their growth.

In more advanced stages of CTCL, the malignant T cells apparently
lose their dependence on the skin environment, and more of them are
found in the peripheral blood (ie, “leukemic” CTCL) and
lymph nodes. Under such circumstances, skin-directed therapies alone
are insufficient to control disease, and systemic therapy is warranted.

While the presence of a malignant clone of CLA-positive, CD4-positive
cutaneous T cells can be demonstrated in the skin of patients with
patch/plaque CTCL, it is important to note that these cells usually
represent a minority of the T-cell dermal infiltrate, which includes
other nonmalignant activated CD4-positive, as well as CD8-positive, T
cells. Several clinical findings have supported the hypothesis that
the malignant cells of CTCL are immunogenic. CD8-positive
tumor-infiltrating lymphocytes present within CTCL lesions tend to be
more plentiful in early-stage disease. Their proportion correlates
positively with improved survival, suggesting that they may exert an
antitumor host response.[6]

In addition, cyclosporine (Neoral, Sandimmune), a potent
immunosuppressive agent that is specific for T cells, can
promote rapid disease progression, possibly through the
downregulation of antitumor T cells.[7,8] Perhaps most importantly,
results of treatment of CTCL with photopheresis (discussed below) are
consistent with the stimulation of an antitumor immune response.[9]

Clinical and Histologic Features

Parapsoriasis

The terminology and delineation of the various forms of parapsoriasis
are unclear. A pattern of large, atrophic, erythematous plaques on
the trunk

with histologic features that are nondiagnostic of CTCL has been
called large-plaque parapsoriasis. Treatment of large-plaque
parapsoriasis, most effectively with PUVA, will generally clear these
lesions. The apparent progression over years of a portion of these
cases to obvious CTCL, if left untreated, and the ability to detect
clonal dominance by PCR, suggests that large-plaque parapsoriasis is,
in fact, patch/plaque CTCL from the outset, rather than a
“premaligant” condition.[10-12]

This fact notwithstanding, it appears that patients who present with
much smaller lesions, as in so-called small-plaque parapsoriasis, do
not readily progress to CTCL, although a dominant T-cell clone may be
detectable by PCR.[5,13] Since T-cell clonality may be detectable in
several other T-cell–mediated inflammatory conditions of the
skin, such as pityriasis lichenoides et varioliformis acute (PLEVA;
Mucha-Habermann disease)[14], without any evidence of progression to
CTCL, molecular testing must be interpreted in light of the clinical
and histologic findings.

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