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15
Cutaneous T-Cell Lymphoma
FRANCINE M. FOSS, MD
MARIEFRANCE DEMIERRE, MD, FRCPC
Primary cutaneous T-cell lymphomas (CTCLs) comprise a constellation of heterogeneous lymphoproliferative disorders characterized by clonal accumulation of neoplastic T lymphocytes in the skin.
Together with primary cutaneous B-cell lymphomas,
they are the second most common group of extranodal non-Hodgkin’s lymphomas, following primary gastrointestinal lymphomas. Cutaneous T-cell
lymphomas differ clinically and histologically from
nodal lymphomas of the same histology. Before
treating a CTCL, it is essential to determine that the
patient does not have cutaneous manifestations of a
primary nodal lymphoma.1
EPIDEMIOLOGY
Cutaneous T-cell lymphoma comprises approximately 80 percent of all primary cutaneous lymphomas (Table 15–1). The majority of C-TCL consist of mycosis fungoides (MF), which takes its
name from the mushroom-shaped tumor nodules
resulting from the vertical proliferation of infiltrating cells, and Sézary syndrome (SS). Anaplastic
large cell lymphomas (CD30+) comprise 25 percent,
and CD30- peripheral T-cell lymphomas comprise
10 percent.
The National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program
reports an increase in the overall incidence of CTCL
in the United States from 1973 to 1984, with a rise
from approximately 0.2 cases per 100,000 population in 1973 to 0.4 cases per 100,000 population in
1984.2 However, there was no evidence of increasing
incidence rate during the period of 1983 through
1992.3 These data included follow-up through 1994.
Overall, the incidence rate from 1973 through 1992
was 0.36 per 105 person-years. These changes in
incidence are not well understood, but it is probable
that modern diagnostic techniques, including
immunohistochemistry, electron microscopy, and
molecular analysis, contribute to the initial apparent
increase in incidence by identifying patients earlier
in the course of the disease.
Survival was noted to improve substantially over
the 20-year period of study and was unrelated to variations of age, race, gender, or marital status.4
Increased survival may be due to improvements in
treatment, changes in the biology of the disease, or the
inclusion of a proportion of biologically benign disorders, such as lymphomatoid papulosis or large plaque
parapsoriasis, which might be misclassified as MF.
Recent reports suggest a nearly normal life expectancy for patients with very early-stage disease.5,6
Although MF/SS has been reported in young
individuals, the incidence increases with age.
Median age at the time of diagnosis is 55 to 60
years. The incidence is highest in African Americans, followed by Caucasians and Asian Americans.
Table 15–1. LYMPHOMAS PRESENTING IN THE SKIN
Type of Lymphoma
Mycosis fungoides/SS
CD30+ ALCL
Peripheral T-cell CD30–
B cell (FSC, DLC)
MALT type
Incidence (%)
45
25
10
15
<5
SS = Sézary syndrome; ALCL = anaplastic large cell lymphomas; FSC =
follicular small cell; DLC = diffuse large cell; MALT = mucosa-associated
lymphoid tissue.
259
260
MALIGNANT LYMPHOMAS
Both incidence and mortality are higher among men
than among women.
Mycosis fungoides and SS are classified in the
revised European-American lymphoma (REAL)
classification as low-grade T-cell lymphomas. Other
less common types of CTCLs or lymphoproliferative disorders include the CD30+ lymphoproliferative disorders (lymphomatoid papulosis, primary
anaplastic large cell lymphoma of the skin), pagetoid reticulosis (Woringer-Kolopp disease), granulomatous slack skin, large plaque parapsoriasis, and
T-γ lymphoproliferative disorder. The intermediateor high-grade variants of T-cell lymphoma are
human T-cell lymphotropic virus type I (HTLV-I)associated adult T-cell leukemia/lymphoma, peripheral T-cell lymphoma, and CD8+ epidermotropic
cytotoxic T-cell lymphoma. This chapter addresses
only the biology and treatment of MF/SS, except
where specifically noted to the contrary.
ETIOLOGY
Many studies have attempted to demonstrate the etiology of MF/SS, but the results are contradictory and
generally inconclusive. Extensive studies of chronic
antigenic stimulation resulting from exposure to
industrial chemicals have failed to implicate these
agents conclusively.7,8 Epidermal Staphylococcus
aureus colonization and bacteremia were noted in
one series of patients, but the study design was
unable to distinguish between microbial pathogenesis and infection secondary to immunosuppression.9
Early attempts to demonstrate a viral etiology of
MF/SS, based on identification of the HTLV-I in a
single patient and observation of similarities between
MF/SS and HTLV-I-associated adult leukemia/lymphoma, produced no serologic consistency. More
recently, however, molecular analysis has revealed
the presence of portions of the HTLV-I genome in a
subset of patients with MF/SS.10–13 Nevertheless,
epidemiologic data to date fail to support a role for
HTLV-I or HTLV-II in MF/SS.14 Other investigations
are focusing on a possible role for HTLV-V.15
Cytokine-driven proliferation of T cells has been
implicated in the etiology of CTCL. Interleukin
(IL)-7 is a growth factor for Sézary cells isolated
from patients with SS. The proliferative response to
IL-7 can be abrogated by an anti-IL-7 monoclonal
antibody.16 In addition, IL-2 and IL-7 co-stimulate
CTCL cells potentially by an autocrine or paracrine
growth-stimulatory mechanism since IL-7 is
secreted by normal keratinocytes.17 These findings
suggest that cytokine mediation may be involved in
the development of SS and other CTCLs. This
hypothesis is supported by the demonstration that
transgenic mice carrying the gene for IL-7 develop
a progressive cutaneous disorder involving T-lymphocyte infiltration.18
Chromosomal abnormalities occur commonly in
CTCL,19 but they have not been shown to be specific.
Chromosome 1 is affected most frequently, followed
by chromosome 6. The region between 1p22 and
1p36 has been proposed as the site containing a gene
that encodes a protein important for either the malignant transformation or progression in MF/SS.20 A
recent study found that epidermotropic T cells from
patients with MF/SS expressed high levels of telomerase, an enzyme that replaces terminal chromosome sequences lost during serial replication.21
Telomerase has been reported to be overexpressed in
many tumors but not in normal tissue,22 suggesting
that telomerase expression may be necessary for
tumorigenesis. It is possible that telomerase inhibition may limit tumor cell growth.23,24
CLINICAL MANIFESTATIONS
Mycosis fungoides is characterized by infiltration of
the skin by atypical small T lymphocytes with hyperconvoluted cerebriform nuclei (mycosis cells) that
usually express a mature peripheral T-cell (CD4+)
phenotype. A suppressor phenotype (CD8+) is seen
infrequently. Expression of an IL-2 receptor (CD25)
is seen in approximately half of MF/SS cases. Epidermotropism or mononuclear exocytosis into the
epidermis and Pautrier’s microabscesses in the epidermis are characteristic histopathologic findings
(Figure 15–1). Cutaneous lesions can occur as
patches, plaques, or tumors, but patients may have
lesions of two or three stages simultaneously. The
patch stage consists of multiple scaly erythematous
patches that occur most frequently over the trunk and
extremities and often are associated with severe pruritis. The patch stage resembles psoriasis or eczema
Cutaneous T-Cell Lymphoma
261
Figure 15–2. Plaque-stage cutaneous T-cell lymphoma. Lesions
are raised, scaling, and erythematous and may resemble eczema or
parapsoriasis.
Figure 15–1. Skin biopsy from a patient with stage IA cutaneous
T-cell lymphoma showing exocytosis of lymphocytes into the epidermis, forming of Pautrier’s microabscesses (×40 original magnification).
and may persist for months or even years with a waxing-and-waning clinical picture before progressing to
the plaque stage. In the plaque stage, lesions are oval
or circular, well demarcated, and elevated (Figure
15–2). Patches may regress spontaneously or coalesce
into larger plaques. Dermal thickening of the skin by
T-cell infiltration may lead to an infrequent but classic appearance on the face known as leonine facies.
The differential diagnosis of plaque-stage disease is
shown in Table 15–2 and includes nonmalignant conditions such as eczema, psoriasis, and parapsoriasis.
Although MF is usually an indolent disease, the
tumor stage can be very aggressive as neoplastic
cells enter a vertical growth phase that presents clinically as expanding nodules (Figure 15–3). These are
seen most commonly on the face and in major skin
folds: the axilla, groin, and inframammary areas.
Nodules may experience central necrosis with ulceration that may lead to secondary bacterial infection
Table 15–2. DIFFERENTIAL DIAGNOSIS OF PATCHES AND PLAQUES
Differential Diagnosis
Distribution
Pathology
Atopic dermatitis
Flexural areas, hands
Spongiosis, exocytosis
Contact dermatitis
Areas of contact
Spongiosis, exocytosis, occasional eosinophilia
Fungal infection
Intertriginous areas, nails
Hyphae within stratum corneum
Psoriasis
Elbows, knees, nails
Epidermal hyperplasia, absence of granular cell layer, dilated capillaries
in papillary dermis, and PMNs in dermal papillae and epidermis
Parapsoriasis
Flanks, submammary area
Perivascular lymphocytic infiltrate with occasional epidermotropism
PMN = polymorphonuclear neutrophil leukocyte.
262
MALIGNANT LYMPHOMAS
percent have cutaneous tumors, and 12 percent have
generalized erythroderma. Palpable adenopathy is
infrequent in patients with limited plaque, but it
occurs in approximately 50 percent of patients with
extensive plaques, tumors, or erythroderma.
Sézary syndrome, the leukemic variant of MF
seen in approximately 5 percent of newly reported
cases of CTCL, shares many of the clinical and
immunohistologic features of MF. It is distinguished
from MF, however, by its characteristic triad of diffuse erythroderma, generalized lymphadenopathy,
and the presence of hyperconvoluted neoplastic T
lymphocytes (CD4+CD7-) in skin, lymph nodes,
and peripheral blood. In patients with SS, 20 percent
or more of the circulating lymphocytes are Sézary
cells. Circulating Sézary cells typically bear the
same immunophenotype as skin infiltrates, but there
may be antigen discordance, especially for the CD25
antigen, which often is absent from circulating
Sézary cells. Patients with SS may demonstrate
manifestations of scaling or fissuring of the palms
and soles, alopecia, ectropion, or loss of nails (Fig-
Figure 15–3. Skin biopsy of tumor-stage cutaneous T-cell lymphoma showing extensive dermal and epidermal infiltration with
atypical lymphoid cell infiltrate with marked pleomorphism (× 40 original magnification).
(Figure 15–4). The differential diagnosis for tumorstage CTCL includes lymphomatoid papulosis and
B-cell lymphoproliferative disorders, including
pseudolymphoma (Table 15–3). Biopsy and immunophenotypic staining are required to make a definitive diagnosis.
Recent evidence suggests that progression to the
tumor stage may involve a loss of Fas receptor
expression, enabling malignant cells to escape apoptotic signals.25 Other studies suggest a possible relationship promoter hypermethylation of p16INK4a and
both disease progression and prognosis.26 Mutations
and functional loss of the p53 tumor suppressor gene
have been reported in MF, as have mutations and
overexpression of the myc, ras, and lck oncogenes.
At diagnosis, 42 percent of MF patients have limited plaques involving 10 percent or less of total
body surface, 30 percent have extensive plaques, 16
Figure 15–4. Patient with extensive tumor-stage cutaneous T-cell
lymphoma. Cutaneous tumors may ulcerate and become secondarily infected.
Cutaneous T-Cell Lymphoma
263
Table 15–3. DIFFERENTIAL DIAGNOSIS OF SKIN TUMORS
Differential Diagnosis
Pseudolymphoma
Lymphomatoid papulosis
Leukemia cutis
Metastatic disease
Distribution
Pathology
Face, neck, mammary areas, groin
Trunk and extremities
Face, trunk, extremities
Scalp, skin overlying primary tumor
or lymphatic drainage
Infiltrate mixed, in dermis, nonclonal
Wedge-shaped infiltrate, mild perivascular interstitial infiltrate
Grenz zone between dermis and epidermis
Malignant cells infiltrating dermis and/or subcutaneous tissue
ure 15–5). Ankle edema, malaise, and weight loss
are common, as are chills and fever resulting from
impaired thermoregulation.
IMMUNOPATHOGENESIS
The immunopathogenesis of MF/SS has been
reviewed.27 Early stages of MF/SS are characterized
by epidermotropism, that is, localization of the
malignant T cell (memory helper T cell
CD3+CD4+CD45RO+) to the skin. The mechanisms for this epidermotropism are likely multifactorial. The memory T cells that home to the skin
express both cutaneous lymphocyte antigen (CLA),
a skin-homing receptor not commonly expressed on
T cells, and lymphocyte function–associated antigen
1 (LFA-1). The former interacts with E-selectin, an
adhesion molecule found on endothelial cells of
cutaneous venules. The latter, expressed by all T
cells, interacts with intercellular adhesion molecule
1, which is produced by keratinocytes in response to
interferon-γ (IFN-γ). It appears that an IFN-γ
inducible protein (IP-10), chemotactic for CD4+
lymphocytes, tumor necrosis factor-α, and a
monokine induced by IFN-γ , could be important in
the events leading to epidermotropism.28,29
The lesions in MF/SS have been shown to be Th2
cells since they secrete IL-4, IL-5, IL-6, and IL-10.27
An excess of Th2 cytokine production could account
for the histopathologic changes seen in the evolution
of early plaque to tumor or erythroderma. Several
immune abnormalities also have been noted in
MF/SS:27 decreased cell-mediated cytotoxicity,
decreased natural killer cell and lymphokine-activated killer cell activity, eosinophilia, increased levels
of immunoglobulin E and A, and decreased cutaneous
hypersensitivity. These underlying immunologic
defects contribute to the high infection rate seen in
patients with advanced MF/SS.
HISTOPATHOLOGY
The diagnosis of MF/SS is based on a combination
of clinical and histopathologic findings. In patients
with a chronic nonspecific dermatitis, generalized
erythroderma, or poikiloderma suspected to have
MF, skin biopsies are indicated. Characteristic
histopathologic findings are infiltration of the epidermis with cytologically atypical T lymphocytes
(epidermotropism) and the presence of large hyperchromatic “mycosis cells” within the dermis and epidermis.30 Clusters of these cells in the epidermis are
Figure 15–5. Hyperkeratosis of soles in a patient with Sézary syndrome. Clinical manifestations include erythroderma, extensive pruritis, and hyperkeratosis and cracking of palms and soles.
264
MALIGNANT LYMPHOMAS
known as Pautrier’s microabscesses, whereas in the
upper dermis these cells are present in bandlike infiltrates. In the early stages of MF, the histology may be
indistinguishable from benign or borderline conditions, such as parapsoriasis. If clinical suspicion of
MF cannot be corroborated by biopsy, follow-up skin
biopsies are warranted.
In the tumor stage of MF, the epidermis may be
ulcerated due to extensive infiltration. Often these
tumors clinically resemble lesions of peripheral Tcell lymphoma. However, in the latter, the epidermis
often is spared, and the infiltrate is confined to the
deep dermis. Although Pautrier’s microabscesses
may be present in the epidermis in SS, more commonly, the upper dermis shows a dense infiltrate of
lymphocytes, histiocytes, and Sézary cells.31
Immunophenotypic analysis of Sézary cells
demonstrates that they express pan-T-cell markers
CD2, CD3, and CD5 but may demonstrate loss of
CD7 in two-thirds of cases.32–34 The majority of
Sézary cells are memory cells (CD45RO+) and also
express the skin-homing protein CLA. Clonality has
been demonstrated for the T-cell receptor gene, but
this may not be diagnostic in early-stage lesions,
where the number of infiltrating cells may be
small.35,36 Monoclonal T-cell receptor rearrangements may be demonstrated in cases of large plaque
parapsoriasis as well as in lymphomatoid papulosis
and are not therefore diagnostic of MF/SS.37
PROGNOSIS AND STAGING
The staging system for MF/SS is based on the type
and extent of skin involvement in the form of
plaques, tumors, or erythroderma, the presence of
palpable lymph node involvement, and visceral disease (Table 15–4). Lymphadenopathy is present in
approximately 47 percent of all patients, with the
highest frequency occurring in tumor-state MF, and
in 80 to 90 percent of patients with erythroderma.
Visceral involvement is found most frequently in the
liver and bone marrow. At autopsy, pulmonary
involvement and bone involvement are found in 60
percent and 40 percent of cases, respectively.
Skin stage is the most important prognostic factor. A recent longitudinal study of over 450 patients
with MF demonstrated that median survival among
Table 15–4. CUTANEOUS T-CELL LYMPHOMA TNM STAGING
Stage
Characteristics
Early
IA
IB
IIA
< 10% BSA patch or plaque (T1)
≥ 10% BSA patch or plaque (T2)
T1–2, palpable adenopathy (node biopsy
negative)
Intermediate
IIB
III
IVA
Advanced
IVB
Cutaneous tumors (T3)
Erythroderma (T4)
T1–4, node biopsy positive
T1–4, visceral involvement
TNM = tumor staging according to primary tumor (T), regional nodes (N),
and metastasis (M); BSA = body surface area.
patients with limited skin plaques is the same as that
of age-matched controls (Table 15–5).38 A recent
analysis of published epidemiologic data on MF
concluded that 90 percent of patients with 10 percent or less of skin involvement survive for 15 years
or more.39 In a study of 122 patients with limited
cutaneous involvement, only 2 percent of patients
had died after 32 years, and 9 percent showed disease progression.40 A multivariate analysis of data
from 309 Dutch patients with MF found that the 5year disease-specific survival rates for individuals
with limited skin involvement and skin tumors were
100 percent and 80 percent, respectively, but that the
rate for individuals with lymph node involvement
dropped to 40 percent.41 Older data indicate that the
median survival for patients with visceral involvement is 24 to 30 months.
Five-year survival for patients with SS is generally reported as 10 percent. In a multivariate analysis of 51 patients with SS, the overall 5-year survival
was 33.5 percent. When patients were stratified for
risk based on three variables found to be adverse
Table 15–5. CUTANEOUS T-CELL LYMPHOMA
PROGNOSIS BY SKIN STAGE
Skin Stage
at Diagnosis
10-Year Relative
Survival (%)*
p Value
T1
T2
T3
T4
100
67
39
41
NS
.002
< .001
< .001
*Observed ÷ expected survival) × 100, in controls matched for age, sex,
and race.
Reprinted with permission from Zackheim HS et al. J Am Acad Dermatol
1999;40:418.
Cutaneous T-Cell Lymphoma
independent prognostic indicators (PAS-positive
cytoplasmic inclusions in circulating Sézary cells,
CD7- phenotype, and the presence of large circulating Sézary cells), those with zero or one of the indicators had a 5-year survival rate of 58 percent,
whereas those with two or three indicators had a 5year survival rate of 5 percent.42
In addition to the risk for disease progression in
MF/SS patients, there is a well-established risk for
cytologic transformation to CD30+ large cell lymphoma,43,44 the diagnosis of which is established by
the presence of at least 25 percent large cells on
biopsy.45 In one series of 150 CTCL patients, the risk
of transformation was 12 percent, with a median time
from diagnosis to transformation of 21.5 months and
median survival following transformation of 2
months.43 In another study of 115 MF/SS patients, 23
percent underwent transformation, with a median
time from diagnosis to transformation of 12 months
and median survival subsequent to transformation of
19 months. The investigators calculated a 39 percent
cumulative probability of transformation at 12 years
following initial diagnosis.44 Analysis by the French
Study Group on Cutaneous Lymphomas determined
that the median time from diagnosis to transformation
was 6.5 years and that mean survival from transformation to death was 22 months.45 A recent review article that summarized all of the published epidemiologic
literature concluded that the cumulative rate per year
and per patient of transformation from MF/SS to large
cell lymphoma is 8 to 23 percent, and that transformation is associated with poor prognosis evidenced by
mean survival ranging from 2 to 10 months.
265
Several staging algorithms have been proposed
since 1978 for establishing prognosis in individual
CTCL patients. All are based on the principal risk
factors for disease progression (extent of skin,
nodal, and visceral involvement) and on histopathologic information from lymph node and bone marrow biopsies. In 1979, the Committee on Staging
and Classification of Cutaneous T-Cell Lymphoma
proposed a system in which low, intermediate, and
high risks were determined by differentiating four
levels of skin involvement, five levels of nodal
involvement, the presence or absence of palpable
adenopathy, and the presence or absence of visceral
involvement.46 Subsequently, Sausville and colleagues proposed a simplified version based on a
multivariate analysis that demonstrated that skin
stage, histopathologic lymph node involvement, and
visceral involvement were significant prognostic
factors.47 Based on this classification system, three
survival groups were identified (Figure 15–6): lowrisk patients with skin patches or plaques and
histopathologically uninvolved lymph nodes (stages
IA and IB) had an excellent prognosis, whereas
patients with visceral disease (stage IVB) had a poor
prognosis, irrespective of skin stage. Patients with
skin tumors, histopathologically involved lymph
nodes, and erythroderma (stages IIB, III, and IVA)
had an intermediate prognosis, similar to that of
patients with follicular B-cell lymphoma.48
Bone marrow involvement was defined further in
a retrospective study in which histopathologic staging of bone marrow based on presence of lymphoid
aggregates or infiltrating lymphoma was performed.
Figure 15–6. Survival based on prognostic category. (Reproduced with permission
from Sausville E, et al. Ann Intern Med 1988;109:372.
266
MALIGNANT LYMPHOMAS
In this study, the presence of lymphoid aggregates
had no independent prognostic significance, whereas
diffuse lymphomatous infiltrates in the marrow were
associated with an inferior outcome.49,50
CLINICAL MANAGEMENT
Initial management of CTCL depends on the extent of
clinical manifestations and the impact of symptoms
on quality of life. For more advanced disease, the primary emphases are palliation and prevention or
deceleration of disease progression.51 Most patients
experience pruritus, skin pain, progressive physical
limitation, sleep deprivation, and infectious complications. Furthermore, because stigmatizing skin lesions
may occur in places that are not easily concealed,
many patients with CTCL resort to reclusive or other
antisocial behavior or may exhibit other signs of
extreme psychological distress. Quality-of-life issues
are matters of serious long-term concern, as is the
expense of treatment that may continue for decades.
Because progressive skin deterioration is characteristic of MF/SS, infection and sepsis from S. aureus,
S. epidermidis, and Pseudomonas aeruginosa are
the principal causes of morbidity and mortality.
Chronic or recurrent infection require prolonged or
repeat antimicrobial therapy. Immune deficiency
inherent to CTCL also exposes patients to potentially life-threatening fungal and viral infections.
Almost all patients with MF/SS require treatment
directed at the skin. Systemic therapies are used in
MF/SS when patients become refractory to topical
therapies or when they demonstrate signs of
advanced systemic disease in the form of lymphadenopathy or visceral involvement. The therapeutic approaches to MF based on clinical stage are
outlined in Table 15–6.
Skin-Directed Therapies
Topical corticosteroids frequently achieve good
responses, particularly in early-stage disease, providing symptomatic relief. Zackheim and colleagues
reported the largest experience with topical steroids
in 79 patients with patch/plaque MF. High-potency
steroids were used in all T1 patients. With a median
follow-up of 9 months, 63 percent of the T1 patients
achieved complete remission and 31 percent achieved
partial remission.51
Topical chemotherapy using mechlorethamine
(nitrogen mustard, HN2) has proven effective for cutaneous MF since its use was first reported in 1973.52,53
It is dissolved in tap water and applied to the entire
body surface. One topical HN2 trial reported a 51 percent complete response rate and an 88 percent overall
response rate in 43 patients with stage I patch disease,
and complete and overall response rates of 26 percent
and 70 percent, respectively, in 58 patients with stage
II plaque disease.53 A subsequent trial involving 41
patients with T1 disease and 76 patients with T2 disease reported complete remission rates after 1 year of
67 percent in the T1 group (median time to remission
= 4.4 months) and 40 percent in the T2 group (median
time to remission = 20.4 months).54 In a long-term
follow-up study in which data interpretation was confounded by multiple therapies administered to
patients, 11 percent of 331 patients treated with topical HN2 experienced complete remissions lasting
more than 8 years.52 For patients with tumor-stage
disease, topical therapy with HN2 may not be as effective and may be supplemented with local irradiation
or systemic therapies.
Topical chemotherapy using carmustine (BCNU)
yields similar results to those with HN2. Like HN2,
carmustine is mixed with water and applied daily to
the full body surface except uninvolved areas of the
face, hands, genitals, and skinfolds. In a trial involving 89 patients with patch-stage disease, there was
an overall response rate of 92 percent after 3 years,
a 5-year survival rate of 97 percent, and a median
treatment time to complete response of 9 weeks. In
Table 15–6. MANAGEMENT OF CUTANEOUS T-CELL
LYMPHOMA BY STAGE
Stage
Management
IA/IB
Topical chemotherapy, PUVA, local EBRT, topical
retinoids
PUVA, topical chemotherapy, local EBRT, oral retinoids,
IFN, methotrexate, ONTAK (refractory)
EBRT, methotrexate, IFN, ONTAK, chemotherapy, oral
retinoids
Photopheresis, IFN, ONTAK, pentostatin,
chemotherapy, retinoids
ONTAK, pentostatin, chemotherapy, retinoids,
investigational agents
IIA
IIB
III
IV
PUVA = psoralen plus ultaviolet A; EBRT = electron beam radiation therapy;
IFN = interferon; ONTAK = denileukin diftitox.
Cutaneous T-Cell Lymphoma
the same series, 83 patients with plaque-stage MF
had an overall response rate of 64 percent, a 5-year
survival of 79 percent, and a median treatment time
to remission of 12 weeks.55
Cutaneous hypersensitivity reactions occur in
approximately 30 percent of patients treated with
topical HN2, although this can be reduced to approximately 5 percent by switching from the aqueous
solution to an ointment-based preparation. Longterm HN2 therapy, especially in combination with
multiple other skin-based therapies, has been associated with an increased risk for squamous and basal
cell carcinomas.56 There is no systemic absorption
of HN2. Carmustine, in contrast, does not induce
cutaneous hypersensitivity reaction, but it is
absorbed systemically to some degree. Secondary
skin cancers are a minor risk with carmustine.
Phototherapy
Phototherapy using ultraviolet A (UVA) with psoralen or ultraviolet B (UVB) has been shown to be
effective for treating early-stage disease.57,58 In a retrospective study of 30 patients, 25 patients (83%)
achieved complete remission after a median of 5
months of UVB treatment three times per week. The
median duration of remission was 22 months.57 On
the basis of a small trial (N = 8), Clark and colleagues have shown that narrow-band TL-01 phototherapy may be as effective as UVB therapy and
may reduce the risk of long-term adverse effects.59
Photochemotherapy, which combines UVA with
a psoralen-based photosensitizing agent, is the most
commonly used form of phototherapy in MF/SS
patients. Known as PUVA therapy, this treatment
consists of oral administration of 8-methoxypsoralen (8-MOP), which is activated by exposure to
UV light in the range of 330 to 340 nm given 2 hours
later. During a clearance phase of up to 6 months,
treatments typically are given two or three times per
week depending on skin type, severity of skin reaction, and response to treatment. Subsequently, treatments are reduced to one to three times per month,
although the frequency may be increased in the
event of disease recurrence during the maintenance
regimen. The efficacy of this treatment for patch and
plaque MF has been well established over a period
of more than 20 years, with a response rate of
267
approximately 59 percent.60–63 This has been
improved to as much as 80 percent with the addition
of low-dose IFN.64 The long-term cure rate from
treating early-stage MF patients with PUVA is 15 to
20 percent. Patients with SS may require supplementation of PUVA with systemic therapies including corticosteroids, IFN, and cytotoxic chemotherapy. Potential side effects from PUVA therapy
include nausea due to psoralen ingestion, erythema,
intensified pruritis, and chronic dry skin. Psoralen
with UVA is associated with an increased incidence
of cutaneous carcinomas, especially squamous carcinomas of the skin and male genitalia.
Radiation Therapy
Radiation therapy has been the most important
modality for treating both early and advanced
MF/SS. External beam photon irradiation is effective for controlling refractory plaque areas and
reducing tumors, but the penetration of radiation by
this method is associated with myelosuppression
and radiation dermatitis. Electron beam therapy, in
contrast, can be delivered at an energy of 4 to 9 MeV
with less than 5 percent of the dose penetrating
beyond 2 cm. The target volume for most patients
does not exceed a depth of 5 mm.65 Hence, internal
organ toxicity is uncommon.
Techniques involving the scattering of electrons
generated by a linear accelerator are capable of
achieving total-skin electron beam therapy
(TSEBT). Treatment consists of a total of 30 to 36
Gy administered three or four times per week over
an 8- to 12-week period. This regimen is based on
evidence that patients who receive more than 20 Gy
have significantly better 5-year survival and longer
complete responses than do patients treated with 20
Gy or less.66 Total-skin EBT is used most commonly
in patients with diffuse plaque involvement that is
refractory to other skin-directed therapies, tumorstage MF, or SS. Complete response rates to TSEBT
range from 56 to 96 percent in patients with stages
IA to IIA disease. Patients with stage IA disease
have a relapse-free survival rate of 33 to 52 percent
at 10 years, whereas the same rate for patients with
stage IB or worse disease is 16 percent.67,68 Toxicities associated with TSEBT include erythema,
268
MALIGNANT LYMPHOMAS
desquamation, temporary depilation, and temporary
loss of fingernails, toenails, and sweat gland function. Ocular complications are possible theoretically
because lead shields are not completely effective
against electron beam irradiation.69
Several clinical trials have explored the efficacy of
supplementing TSEBT with adjuvant therapies. In a
trial in which 103 patients with early-stage MF, all of
whom underwent TSEBT, were randomized to either
conservative (topical) therapy or aggressive (multiagent systemic chemotherapy) treatment, patients
treated aggressively had significantly higher complete response rates and significantly higher toxicities. At a median follow-up of 75 months, however,
there was no significant difference between the treatment groups in disease-free or overall survival, suggesting that aggressive early treatment does not
improve prognosis.70 A study in which 14 patients
with T1 and T2 disease underwent PUVA therapy following TSEBT reported significant improvement in
disease-free survival in the PUVA group and a trend
toward improved overall survival.68 An evaluation of
44 patients with erythrodermic (T4) MF concluded
that extracorporeal photopheresis (ECP) concurrent
with or immediately following TSEBT significantly
improves both progression-free survival and causespecific survival.71 A French study evaluated combination therapy using TSEBT for plaque-stage disease
and photon beam irradiation for thick plaques,
tumors, and nodal involvement in 45 patients with
advanced MF. The overall response rates were 81 percent for T3 patients, 61 percent for T4 patients, 79
percent for N1 patients (63% of which were complete
responses), and 70 percent for N3 patients (41%,
complete responses). The 5-year overall survival rates
were 37 percent for T3 patients, 44 percent for T4
patients, and 32 percent for N3 patients.72
Extracorporeal Photopheresis
The use of extracorporeal photopheresis, which was
first reported for treating CTCL in 1987,73 is a technique in which leukopheresis mononuclear cells are
exposed to a psoralen photoactivating agent (eg, 8MOP) and ultraviolet light (UVA) ex vivo and reinfused into the patient. In essence, ECP is systemic
photochemotherapy or a technique for administering
PUVA systemically. Initially, patients are treated on 2
consecutive days once monthly until minimal clearance occurs; then they are tapered to monthly treatment for 6 months followed by treatment at 2-month
intervals before discontinuation. More recently, therapy has been administered at 2-week intervals, and
response times have shortened. The mechanism by
which ECP elicits a response is not known, but the
most probable hypothesis is that psoralen-photoactivated circulating tumor cells are damaged by UVA
and therefore stimulate an immune-mediated antitumor response following re-infusion. This hypothesis
is supported by studies that demonstrate that response
to ECP is associated with the presence of circulating
tumor cells and with increase in CD8+ cytotoxic Tcell populations during therapy. It is also possible that
photopheresis has a direct cytotoxic or antiproliferative effect to induce apoptosis in the circulating tumor
cells.74–76 Extracorporeal photophoresis has been
most effective in patients with erythrodermic CTCL.77
In the largest series of erythrodermic (T4) patients
reported, the overall response rate was 83 percent, with
20 percent being complete responses. Forty-one percent of patients experienced at least a 50 percent
improvement in their skin disease.74 In a series of
patients whose CTCL was refractory to other therapies
and most of whom had SS, ECP produced a 73 percent
response rate.75 However, in a retrospective study that
required presence of a monoclonal T-cell population in
the peripheral blood of treated patients, the median
survival among patients treated with ECP was not significantly different from that of patients not treated
with ECP.78
The addition of IFN or retinoids to ECP has
improved response rates and response durations in
some patients.79–81 In a recent pilot study, immune
activation of lymphocytes and natural killer cells using
ultra-low doses of interleukin-2 along with ECP has
been implemented and is associated in a small group
of patients with a rapid decrease in circulating tumor
cells and improvement in skin disease. Ongoing studies are exploring other potential adjuvants to ECP.
Systemic Therapies
Cytotoxic Chemotherapy
Single-agent systemic cytotoxic chemotherapy has
been used to treat patients with refractory MF. Initial
Cutaneous T-Cell Lymphoma
therapy may consist of pulse steroids, alkylating
agents, or methotrexate. Single-agent therapy can
induce complete responses in up to 30 percent of
patients, but remissions are typically of short duration.82 Methotrexate given orally twice weekly by
intravenous infusion has been reported to have activity in up to 72 percent of patients. Low-dose pulse
dexamethasone is effective in inducing symptomatic
relief in patients with severe SS.83 Gemcitabine has
demonstrated activity in a recent phase II trial
involving 44 patients with pretreated refractory or
relapsed CTCL.84
Pentostatin (deoxycoformycin), a purine nucleoside analogue, is a potent adenosine deaminase
inhibitor that is highly lymphocytotoxic.85 Encouraging clinical results in patients treated with this agent
for hairy cell leukemia led to interest in using it to
treat CTCL as well. Subsequently, there have been
multiple phase I and phase II trials using pentostatin
as a single agent and in combination with antineoplastic agents (Table 15–7). Recently, Dearden and
colleagues reported clinical data for 145 cases of
mature B- and T-cell malignancies, covering 15 years
of pentostatin treatment. They concluded that pentostatin is an effective single-agent therapy for patients
with SS (62 percent response rate).86–87 A phase II
trial conducted by the Leukemia Cooperative Group
and the European Organization for Research and
Treatment of Cancer (EORTC) demonstrated 33.4
percent complete remission and a 22.7 percent partial remission in patients treated with single-agent
pentostatin for SS and refractory MF.88
Other purine analogues have demonstrated similar activity in CTCL, albeit with more significant
toxicities. Fludarabine and 2-chlorodeoxyadenosine
have been used as single agents in phase II studies
and have demonstrated response rates ranging from
20 to 40 percent in previously treated patients.
Myelosuppression generally has been more severe
with these agents, and remission durations have
been shorter than those with pentostatin.89–91
Prednisone and chlorambucil, alone and in combination (the Winkelmann regimen), have been
proven effective in treating patients with SS. In a
recent uncontrolled pilot study, 13 patients with erythrodermic cutaneous CTCL including SS were
treated with a daily regimen of chlorambucil and
269
steroids. The mean duration of remissions was 16.5
months (median, 12 months). After a median followup of 27 months, 6 patients remained in complete
remission and 3 had stable partial remission. Four
patients had died, 2 of them from lymphoma.90
Combination systemic chemotherapy has been
associated with high response rates, but responses
generally are not durable. In a recent phase II evaluation of the EPOCH regimen (infusional etoposide,
vincristine, and doxorubicin, bolus cyclophosphamide, and oral prednisone) in 15 patients with
advanced refractory CTLC, including 6 patients
with SS, the complete response rate was 27 percent,
and the partial response rate was 53 percent. The
nonresponders were 3 patients with visceral involvement: 2 of three patients with anaplastic large-cell
morphology and 1 patient with human T-cell lymphoma virus leukemia/lymphoma. Two of 6 patients
with SS had complete disappearance of circulating
Sézary cells.92 To date, however, no phase III trial
has demonstrated a significant survival benefit for
the majority of patients from combination chemotherapy (see Table 15–7).
Interferon-α
Interferon-α is one of the most active systemic biologic therapies for MF/SS. In the first clinical trial in
these diseases in 1984,93 20 patients with advanced
disease, most heavily pretreated, had complete and
partial response rates of 15 percent and 30 percent,
respectively.94 Other trials have reported stagedependent complete response rates as high as 40
percent and partial response rates as high as 60 per-
Table 15–7. THERAPIES AND RESPONSE DURATIONS FOR
ADVANCED CUTANEOUS T-CELL LYMPHOMA
Treatment
Median Response Duration
TSEBT + CAPO70
IFN high dose93
Fludarabine122
2-CDA123
Nipent single agent85–88
Nipent + high-dose IFN102
Fludarabine + low-dose IFN99
ONTAK106
Targretin 300 mg/m2/d113
13.7 mo
8 mo
3 mo
4 mo, 3 mo
1.3–8.3 mo
13.1 mo
6.5 mo
7.3 mo
59 wk
TSEBT = total-skin electron beam therapy; IFN = interferon;
CDA = chlorodeoxyadenosine; ONTAK = denileukin diftitox.
270
MALIGNANT LYMPHOMAS
cent.95 Objective response rates as high as 88 percent
have been reported in previously untreated patients
with stage I or II disease.
A study of 53 patients determined that dose escalation improves response rates in some patients who
do not respond to low doses.94,96,97 The optimal
induction dose is 3 million U three times per week,
but doses up to 12 million U three times per week
usually are tolerable. Toxicities are dose dependent
and include fever, chills, myalgia, malaise, and
anorexia. Very high doses may induce mild
reversible cytopenias and hypothyroidism.95 Olsen
and Bunn reported that the mean time to an objective response to IFN-2α was 5.4 months, but maximum response may take much longer, as is indicated
by a range of 0.6 to 14.8 months.95,97 Treatment by
subcutaneous or intramuscular injection often is
continued in responding patients for years because
relapse generally occurs when dose reduction precedes the maximum response.
There is no evidence supporting the hypothesis
that combining interferons improves the efficacy of
IFN- 2α. Based on negative findings in trials involving other malignancies such as chronic myelogenous
leukemia, the concept has been abandoned. Several
efforts have been made to assess the clinical benefit
of combining IFN with other established therapies
for MF/SS, with inconsistent results. For example,
two trials in which IFN was combined with ECP
yielded uncompelling results.95,98 Combination
treatment using IFN-2α and fludarabine phosphate
in 35 patients with advanced or refractory MF or SS
demonstrated a 51 percent overall response rate.
Three of four complete responders were in unmaintained remission after 18 to 35 months, suggesting
that this treatment is efficacious in a subset of
patients.99 However, in three trials totaling 31
patients treated with IFN-2α plus PUVA, all but 1
patient responded, and 22 patients had complete
responses.100,101 In general, patients enrolled in these
three studies were at earlier stages of disease and
less heavily pretreated than were patients in singleagent IFN-α studies.95 In 1992, Foss and colleagues
reported results of a phase II study that supported
the activity of a regimen in which IFN-2α and pentostatin were alternated in patients with advanced or
refractory MF or SS, except in patients with visceral
involvement.102 In this study, the response rate was
41 percent, the median response duration was 13
months, and several patients remained in unmaintained response for over 8 years.
Fusion Toxins
Denileukin diftitox (DAB389IL-2, ONTAK) is a
fusion toxin that combines the active moiety of diphtheria toxin and the full-length sequence of the IL-2
gene. This chimeric protein specifically binds to
cells bearing high-affinity IL-2 receptors, thus sparing normal cells. The fusion toxin enters the cell by
receptor-mediated endocytosis, and the active fragment of diphtheria toxin is liberated in the cytosol,
where it adenosine diphosphate (ADP)-ribosylates
elongation factor 2, thus inhibiting protein synthesis. Cytotoxicity by denileukin diftitox is predicated
on the presence of high-affinity IL-2 receptors on
neoplastic T lymphocytes. Immunohistochemical
analysis of > 250 skin biopsies from CTCL patients
demonstrates that IL-2 receptor expression, as measured by CD25 immunostaining, is present in 50 to
60 percent of cases.103,104
In phase I trials of denileukin diftitox in patients
with IL-2 receptor expressing hematologic malignancies, 35 CTCL patients were enrolled, all of
whom had refractory disease. Thirty-seven percent
of patients had objective responses, and 5 patients
(14%) had complete responses. The complete
responses occurred in patients with extensive erythroderma and tumor-stage MF.105
A subsequent phase III trial of denileukin diftitox
enrolled 71 patients with biopsy-proven CTCL that
expressed CD25 on at least 20 percent of lymphocytes. Patients were assigned to one of two dose levels
(9 or 18 µg/kg/d) of denileukin diftitox administered
for 5 consecutive days every 3 weeks for up to eight
cycles. Twenty percent of patients had partial
responses, and 10 percent experienced complete
responses. The response rate and duration of response
(median, 6.9 months; range, 2.7 to 46.1 months) did
not differ significantly by dose. Flulike symptoms and
acute infusion-related events, including hypotension,
dyspnea, and chest and back pain, all were unrelated to
dose, as were capillary leak syndrome, transient elevation of hepatic transaminase levels (61% of patients
with 17 percent grades 3 and 4), and hypoalbumine-
Cutaneous T-Cell Lymphoma
mia (79% of patients with 15 percent grades 3 and 4).
There was no evidence of cumulative toxicity at either
dose.106 It remains to be determined if denileukin diftitox has a role in the treatment of early-stage CTCL.
Steroid premedication has been shown to reduce
the frequency and severity of hypersensitivity reaction and capillary leak in a study of 20 patients with
CTCL treated with denileukin diftitox.107 In this
study, the overall response rate was 60 percent, significantly higher than that observed in the prior
phase III study. Studies are under way to attempt to
enhance the response to denileukin diftitox by
immunomodulating the expression of high-affinity
IL-2 receptor on the tumor cells. A number of biologic agents including IL-2 and retinoids have been
shown to upregulate IL-2 receptor components and
sensitize cells to killing by denileukin diftitox.108
Retinoids
The retinoids have been used for CTCL since the
1980s. 13-cis retinoic acid has been reported as
inducing overall response rates of 44 percent in 25
patients with at least T2 disease109 and 68 percent in
a study of 28 patients with MF/SS.110 In a Mexican
study in which the antipsoriatic retinoid etretinate
was combined with IFN-2a, 10 of 12 patients with
heavily pretreated refractory CTCL achieved complete responses after 1 year. After a median followup of 5 years, 7 patients (58%) remained in complete remission.111
Retinoids have been combined with other therapies such as PUVA, IFN, and TSEBT, but such combinations have not been found to be significantly
better than IFN or TSEBT alone. Patients on
retinoids plus PUVA require fewer treatments and a
significantly lower dose of UVA than do patients
receiving PUVA alone.
Whereas 9-cis retinoic acid, 13-cis retinoic acid,
and all-trans retinoic acid act by binding to intracellular retinoid A receptors (RARs) that regulate transcriptional activity of target genes, a family of novel
retinoids targets the the retinoid “X” receptors
(RXRs).112 Retinoid X receptors can form heterodimers with other receptors such as RARs, vitamin D receptor, thyroid receptor, and peroxisome
proliferator activator receptors (PPARs). Bexarotene,
an RXR ligand that selectively binds and activates
271
retinoid X receptor subtypes (RXRα, RXRβ, RXRγ),
has demonstrated activity both orally and topically in
the treatment of CTCL. The exact mechanism of
action of bexarotene is unknown, but it has been
shown to induce apoptosis in selected epithelial
tumor cell lines.
To date, two phase II–III trials have reported
activity of bexarotene in CTCL. The first trial was a
randomized open-label multicenter trial to evaluate
the safety and efficacy of bexarotene in 58 patients
with histologically confirmed early-stage (TNM IA,
IB, and IIA) CTCL who were refractory to prior
therapy.113 Doses ranged from 6.5 to 650 mg per m2
per day of oral bexarotene. A dose relationship was
seen in the overall response rates and in the time to
disease progression (30 weeks at 300 mg/m2/d and
74 weeks at > 300 mg/m2/d).
In the second trial, 94 patients with advancedstage (TNM IIB–IVB) CTCL were treated at doses
ranging from 300 to 650 mg per m2 per d.114,115 A
dose relationship was again seen in the overall
response rate, complete clinical response, median
time to response, and time to progression. Significant responses were reported in patients with Sézary
syndrome, with > 70 percent clearing of skin by
week 12. Adverse events included hyperlipidemia,
hypercholesterolemia, and hypothyroidism, requiring dose reductions in most patients.
Bexarotene Gel
A phase I–II clinical trial program of bexarotene
(Targretin) gel 1 percent was conducted in 67
patients with early-stage CTCL.116 Clinical response,
defined as ≥ 50 percent clearing of cutaneous lesions
without requirement for biopsy confirmation, was
documented in 63 percent (42 of 67) of the study
subjects. Twenty-one percent achieved complete resolution of their lesions. The median time to response
(eg, ≥ 50 percent improvement) was 15 months. The
median duration of treatment was 10 months, with a
maximum duration of 55 weeks.
A subsequent phase III trial was conducted in 50
patients with refractory or persistent early-stage
CTCL. All patients had failed at least two prior
CTCL treatments, and most (68%) were either
refractory to two or more prior therapies or were
refractory to one therapy and intolerant to at least
272
MALIGNANT LYMPHOMAS
one therapy. The overall response rate (complete and
partial remissions) was 26 percent (13 of 50) and 28
percent (13 of 47) in stage IA and IB patients,
respectively, and the time from onset of therapy to
response ranged from 36 to 154 days. Among
responding subjects, 23 percent (3 of 13) experienced a relapse of the disease, with a median time to
relapse of 149 days (range, 56 to 342 days). Toxicities included rash in 56 percent and pruritis in 18
percent of patients.
ative therapies, a number of systemic treatments are
available. However, response durations are short for
most therapies, and no survival benefit has been
established for any treatment modality. A better
understanding of the pathophysiology of the disease
has directed development of novel therapeutic
approaches including immunomodulatory cytokine
therapies and targeted cytotoxics. Vaccine strategies
are under development, as are nonmyeloablative
transplant regimens, to establish a platform for longterm adoptive immunotherapy.
Other Novel Therapies
Several experimental treatment regimens for CTCL
remain under investigation. Among these are
immunomodulatory cytokine therapies. Continuous
infusion of high-dose IL-2 was associated with a 67
percent response rate in 6 MF/SS patients. Subsequent studies using low-dose IL-2 regimens have
demonstrated activity and are ongoing.117 Interleukin-12 also has demonstrated activity in patients
with early-stage MF, with a 50-percent objective
response rate reported in a phase II study.118 The
benefit of IL-12 use appears to be its potent stimulation of IFN-γ.118 In a phase II trial using IFN-γ, 31
percent of CTCL patients experienced objective
responses.119
CAMPATH-1H, an anti-CD52 monoclonal antibody, has demonstrated activity in a number of lymphomas expressing CD52. In one pilot study, 2 of 8
patients with MF had complete responses, and 2 others had partial responses.120 Another targeted therapy, 90yttrium-T101, a radioimmunoconjugate,
demonstrated activity in 3 of 8 patients with CTCL
who had partial responses.121 Other T cell targeted
therapies that have demonstrated activity in CTCL
include anti-CD3 antibodies and both unmodified
and 90yttrium anti-CD25 antibody.
CONCLUSION
Because CTCL is a relatively indolent disease in its
early stages, the goals of early treatment are symptom relief, with minimum discomfort and inconvenience for patients, and with consideration for their
quality of life. Efforts should be made to prevent or
slow disease progression. When the disease
becomes more advanced or is refractory to conserv-
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