Seminar

Mycosis fungoides and Sézary syndrome

Sam T Hwang, John E Janik, Elaine S Jaffe, Wyndham H Wilson

Mycosis fungoides and Sézary syndrome are the most common of the cutaneous T-cell lymphomas, which are a Lancet 2008; 371: 945–57
heterogeneous group of neoplasms that affect the skin as a primary site. Although the aetiologies of mycosis fungoides Dermatology Branch
and Sézary syndrome are unknown, important insights have been gained in the immunological and genetic (S T Hwang MD), Metabolism
Branch (J E Janik MD,
perturbations that are associated with these diseases. Unlike some B-cell lymphomas, cutaneous T-cell lymphomas as
W H Wilson MD), and
a group are rarely if ever curable and hence need chronic-disease management. New approaches to treatments are Laboratory of Pathology
being investigated and include biological and cytotoxic drugs, phototherapy, and monoclonal antibodies that are (E S Jaffe MD), Center for Cancer
directed towards novel molecular targets. New molecular technologies such as complementary-DNA microarray have Research, National Cancer
Institute, Bethesda, USA
the potential to increase the accuracy of diagnosis and provide important prognostic information. Treatments can be
Correspondence to:
combined to greatly improve clinical outcome without substantially increasing toxic effects in advanced disease that
Dr Sam T Hwang, Building 10,
is otherwise difficult to treat. Although present treatment strategies are generally not curative, there is hope that Room 4N115, 10 Center Drive,
experimental treatments, particularly immunotherapy, might eventually reverse or suppress the abnormalities of MSC 1500, Bethesda, MD 20892,
mycosis fungoides and Sézary syndrome to the point at which they become non-life-threatening, chronic diseases. USA
[email protected]

Introduction year from 1973 to 2002 was 6·4 cases per million.9 The
The French physician Jean Louis Alibert published the incidence of CTCLs has continued to increase over the
first description of mushroom-like skin tumours in a past three decades by 2·9 cases per million per decade,
patient with mycosis fungoides nearly 200 years ago.2 which could be a result of better diagnosis since regional
Since then, this disease has been of interest to clinicians incidence is highly correlated to high physician density
because of the unique skin tropism that malignant T cells and socioeconomic status.9 Mycosis fungoides accounted
show. Sézary syndrome was recognised in 1938 and is a for 72% of CTCL cases reported from 1973 to 2002,
T-cell lymphoma of the skin and peripheral blood. In whereas Sézary syndrome accounted for 2·5%.9,10 The
1975, Edelson and Lutzner3 first coined the term incidence of CTCL was roughly 50% greater in black
cutaneous T-cell lymphoma (CTCL), which initially people than in white people.9 Men are affected twice as
referred to mycosis fungoides and Sézary syndrome—the often as are women, and incidence increases greatly with
two most common forms of this group. The CTCLs are age. Childhood cases of mycosis fungoides, however,
now known to encompass a broad group of cutaneous have been reported.9–11
lymphomas, including primary cutaneous anaplastic
large-cell lymphoma and other rare diseases (panel 1), Genetics
which vary in histology, immunophenotype, and Changes in a number of tumour suppressor and
prognosis.4–6 Several reviews detail the clinical features apoptosis-related genes (table 1) have been recorded in
and therapy of these rare CTCLs.1,2,7 patients with mycosis fungoides and Sézary syndrome,
Recent classification systems have drawn attention to although how most of these alterations affect T-cell
the biological importance of clinical features, in addition behaviour is still not clear. In 50–85% of patients with
to tumour morphology, and have integrated them into these disorders who were tested, one frequent genetic
the pathological definition of lymphomas.1,2,5 After abnormality seems to interfere with expression of NAV3,
consensus meetings in 2002 and 2003, the most useful which might act as a tumour suppressor in T cells.12
features of the WHO classification of lymphoid Mutations in the p53, p15, p16, JunB, and PTEN genes
malignancies4 and the European Organisation for generally occur in later-stage disease, suggesting that
Research and Treatment of Cancer (EORTC) classification they are secondary genetic events and not part of disease
of cutaneous lymphomas8 were incorporated into a single
classification scheme (WHO-EORTC).1 Although Sézary
syndrome was previously often classified as a variant of Search strategy and selection criteria
mycosis fungoides, the WHO-EORTC classification lists Information in this Seminar was obtained through Medline
these two diseases as separate entities with distinctive searches of mycosis fungoides, Sézary syndrome, and skin
clinical features (panel 1).1 This Seminar will focus on lymphoma over the past 5 years, with key words “diagnosis”,
advances in the diagnosis, pathogenesis, and treatment “pathology”, “pathogenesis”, and “treatment”. The
of these two disorders. WHO-European Organisation for Research and Treatment of
Cancer classification was used for reference and as an
Epidemiology organisational guide.1 Recent advances presented at
According to a recent analysis of data from the US scientific meetings and available as abstracts on meeting
National Cancer Institute’s Surveillance, Epidemiology, websites were also included. Only references published in
and End Results, the overall age-adjusted incidence of English were included.
CTCLs (including rare entities described in panel 1) every

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 Seminar

pheral blood involvement;22 analysis of ten genes can

Panel 1: Classification of cutaneous T-cell lymphomas by identify patients with especially poor prognosis indepen-
WHO and the European Organisation for Research and dently of tumour burden.23 Although microarray analysis
Treatment of Cancer1 is not feasible in most commercial diagnostic laboratories,
Indolent clinical behaviour real-time PCR methods that are less complex can lead to
• Mycosis fungoides improved diagnostic accuracy or prognosis, or both.
• Variants and subtypes of mycosis fungoides
• Folliculotropic mycosis fungoides Clinical features
• Pagetoid reticulosis Mycosis fungoides presents in the skin with erythematous
• Granulomatous slack skin patches, plaques, and less frequently, tumours (figure 1).
• Primary cutaneous anaplastic large cell lymphoma (CD30+) Scaling is often found on patch and plaque lesions,
• Lymphomatoid papulosis (CD30+) although generally not to the degree that is seen in patients
• Subcutaneous panniculitis-like T-cell lymphoma with psoriasis. Rarely, lesions are atrophic and dys-
• Primary cutaneous CD4+ small or medium pleomorphic pigmented in a variant termed poikilodermatous mycosis
T-cell lymphoma fungoides. A patient with mycosis fungoides typically has
many lesions of long-standing duration, typically months
Aggressive clinical behaviour to years, which are usually located in areas infrequently
• Sézary syndrome exposed to sunlight (figure 1). Lesions are less commonly
• Primary cutaneous natural-killer/T-cell lymphoma, located on the face except in tumour-stage disease (figure 1)
nasal-type or with folliculotropic variants of this disease.24 By
• Primary cutaneous aggressive CD8+ T-cell lymphoma* comparison, psoriasis—a benign inflammatory skin
• Primary cutaneous gamma/delta (γ/δ) T-cell lymphoma* disorder—also presents with symmetric, erythematous
• Primary cutaneous peripheral T-cell lymphoma, unspecified plaques but usually has less variability in lesions, more
*Provisional entities. intense erythema of individual lesions, and a more general
distribution, with a predeliction for the elbows and knees,
than does mycosis fungoides. Plaques and tumours in
Percentage affected classic mycosis fibrosis occasionally ulcerate (figure 2),
p16 (INK4a) 18–73% either spontaneously or after radiation therapy, prompting
p15 (INK4b) 5–27% the need for aggressive care of the wound to prevent
p14 (ARF) 0–18% bacterial infection and sepsis.25,26
PTEN 10–45% Sézary syndrome was classically characterised by the
p53 0–66% triad of generalised erythroderma (now defined as affecting
JunB 50–91% >80% of body surface area; figure 1), lymphadenopathy
HLA-G 0–28% and other systemic manifestations, and the presence of 5%
Fas 14–59% or more malignant T cells with cerebriform nuclei (known
Fas ligand 50–83% as Sézary cells) in peripheral lymphocytes in the blood.
Nav3 50–85% However, the International Society for Cutaneous
Lymphoma (ISCL) has recently proposed that the diagnosis
Table 1: Molecular changes associated with mycosis fungoides and
of this disease be made primarily on the basis of molecular
Sézary syndrome by genetic lesion12–16
and flow cytometric evidence of a large clonal population
of abnormal T cells in the blood in addition to erythroderma.
initiation (table 1).13–17 Loss of normal apoptotic T-cell Lymphadenopathy, although usually present, is now not
pathways, including Fas expression, has also been regarded as essential to the diagnosis of Sézary syndrome.
reported.18,19 The bright red skin of these patients is often very pruritic.
Complementary DNA (cDNA)-based microarray analysis Many patients have fine scaling, and the palms and soles
holds great promise in identification of mechanisms of are often thickened, scaly, and fissured. Furthermore, these
pathobiology and new therapeutic targets in mycosis patients might develop alopecia, nail dystrophy, and eye
fungoides and Sézary syndrome, though its application is changes (eg, blepharoconjunctivitis and ectropion) with
confounded by the scarcity of malignant cells compared advanced disease.27
with healthy cells in biopsy samples of skin.20 Ten genes Some patients with mycosis fungoides develop
have been identified as being associated with signalling erythroderma, leading to a disorder termed erythrodermic
through the tumour necrosis factor receptor and mycosis fungoides.28 Collectively, Vonderheid and
anti-apoptotic activity, suggesting that these pathways colleagues28 have used the term erythrodermic CTCL to
might promote malignant T-cell growth.21 Furthermore, include any of the lymphomas of primary skin and Sézary
expression analysis of only five genes can be used to syndrome that evolve to erythroderma. Although Sézary
diagnose Sézary syndrome with great accuracy, despite syndrome and erythrodermic mycosis fungoides are
highly variable (5–99% of circulating lymphocytes) peri- sometimes difficult to distinguish clinically, patients with

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mycosis fungoides are characterised by a history of mycosis

A B
fungoides and few (if any) abnormal cells in the blood
generally. Only patients with true Sézary syndrome will
have a substantial leukaemic T-cell burden in the blood.28,29
Moreover, patients with this disease generally develop skin
and systemic signs sooner, over months rather than years,
than do those with erythrodermic mycosis fungoides.
Staging patients with mycosis fungoides and Sézary
syndrome at initial diagnosis is helpful in guiding
treatment7 and it has prognostic value.29,30 The lesions of
mycosis fungoides and Sézary syndrome are classified into
four tumour (T) groups: T1-patches and plaques affecting C D
less than 10% of body surface area, T2-patches and plaques
affecting more than 10% of body surface area, T3-presence
of tumours (ie, raised, dome-shaped lesions >1 cm in diam-
eter), and T4-erythroderma affecting more than 80% of
body surface area.31 Lamberg and Bunn32 first described the
overall staging, which is based on the tumour (T1–4),
lymph node (N0–3), visceral metastasis (M0–-1), and blood
(B0–-1) (TNMB) system. The ISCL has proposed that the B
rating within the traditional staging system be expanded to
include a B2 rating on the basis of molecular evidence of Figure 1: Clinical manifestations of mycosis fungoides and Sézary syndrome
leukaemic involvement (table 2).28,30 Since patients with (A) Patch-stage mycosis fungoides. (B) Plague-stage mycosis fungoides showing the arcuate accentuation of the
borders in the thin-plaque lesions. (C) Tumour-stage mycosis fungoides. (D) Erythroderma in a patient with
extensive mycosis fungoides lesions (T2 or T3 disease) can Sézary syndrome.
have substantial blood involvement in the absence of
erythroderma, blood assessment is needed in these
patients.
Physicians should inform patients with mycosis
fungoides that they do not invariably progress from one
T stage to another. In fact, patients with T1 disease have
an excellent prognosis and a healthy life expectancy
compared with age-matched individuals.33–35 Patients with
T2 disease have a median survival of about 10–12 years
and a 25% risk of progressing to more advanced disease.35
Some patients initially present with advanced T3 stage
disease, occupying an even greater risk category, although
prognosis will vary depending on the histology and
number of tumours. Extracutaneous (visceral)
involvement identifies patients at high risk with median Figure 2: Ulcerating plaque and tumour in a patient with mycosis fungoides
survivals of 1–2 years, whereas patients with only tumours
or erythroderma have a median survival of 4–5 years.30 Imaging with CT is routinely undertaken for patients
Nodal enlargement is common, but does not necessarily with T3–4 disease to better assess visceral and nodal
suggest pathological involvement; its effect on prognosis involvement, but is of lesser value in patients with T1–2
is overshadowed by the extent of skin disease. The disease since internal organ involvement is rare without
presence of increased numbers of CD8+ T cells in the lymphadenopathy. PET can increase the sensitivity of
skin is a favourable prognostic factor, presumably detection of affected lymph nodes and can be useful to
because this finding indicates a host antitumour response confirm response to treatment in patients with advanced
against the malignant CD4+ T cells.36 Other histological disease.39
features can be helpful in predicting which patients will
rapidly progress from early-stage patch of plaque Diagnosis
disease.37 Mycosis fungoides is characterised by the accumulation
Patients with erythrodermic CTCL have a substantially of mature (also termed peripheral) T cells in the skin.
worse prognosis than do those with patch or plaque Malignant cells typically express CD4 and do not express
disease, and their prognosis is negatively affected by factors cytotoxic protein markers,5 although a substantial subset
such as advanced age (>65 years), increased number of of neoplastic T cells has been reported to express cytotoxic
previous treatments, enlargement of peripheral lymph protein markers.40 Histologically, patches and plaques of
nodes, and greater leukaemic burden in the blood.29,38 mycosis fungoides often show band-like lymphocytic

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The diagnosis of early mycosis fungoides often needs

Clinical signs
integration of clinical, histological, and molecular
Tumour stage features since it can be confused with benign eczematous
T1 Patches/plaques <10% body surface area skin disease.47 The ISCL proposed a four-point scoring
T2 Patches/plaques >10% body surface area system (panel 2) with these components to aid the
T3 Tumours (rounded or dome-shaped lesions >1 cm in diameter) diagnosis of early disease, although its use has yet to be
T4 Erythroderma (>80% of body surface area affected) established.42 The advantage of the system is the
Nodal stage integration of four independent criteria, allowing
N0 No clinically abnormal peripheral lymph nodes, pathological findings not CTCL diagnosis in the absence of some commonly observed
N1 Clinical abnormal (palpable) peripheral lymph nodes, pathological findings not CTCL features of mycosis fungoides.
N2 No clinically abnormal peripheral lymph nodes, pathological findings positive for CTCL The histology of Sézary syndrome in the skin is variable,
N3 Clinical abnormal (palpable) peripheral lymph nodes, pathological findings positive for CTCL and histological criteria for mycosis fungoides are
Peripheral blood sometimes not met. Sézary syndrome was historically
B0 Atypical circulating cells not present (<5%) associated with the presence of large, atypical lymphocytes
B1 Atypical circulating cells present (5% or more) with convoluted nuclear, called Sézary or Lutzner cells, in
B2 Leukaemic involvement defined by absolute Sézary cell count ≥1000 cells per μL, CD4/CD8 ratio the peripheral blood. Cells that are morphologically similar
≥10 by flow cytometry, aberrant expression of normal T-cell markers, molecular evidence of to Sézary cells are found in the blood of healthy individuals
clonality, or chromosomal abnormality in a T-cell clone28
and patients with inflammatory skin disease, leading to
Visceral organs (M)
the notions that the Sézary cell is any atypical lymphocyte
M0 No visceral organ involvement
with a hyperconvoluted nuclei and that the Sézary cell is
M1 Visceral involvement with pathological confirmation
not specific for Sézary syndrome.28,29,48 Thus, the ISCL
CTCL=cutaneous T-cell lymphoma. proposed additional diagnostic criteria for this disease,
which lists objective molecular evidence of blood
Table 2: TNMB staging system for mycosis fungoides and Sézary syndrome28,32
involvement for the diagnosis and staging of Sézary
syndrome in addition to the presence of Sézary cells, which
infiltrates in the upper dermis. Atypical T cells of small to are difficult to quantify by cytological analysis alone in
regular size with irregular (cerebriform) nuclei are many institutions (table 2).28 Clonality within circulating
frequently present within the epidermis (ie, lymphocytes (as measured by studies of TCR gene
epidermotropism) (figure 3).41,42 Pautrier microabscesses, rearrangement by PCR) is a helpful criterion for
consisting of aggregates of malignant T cells and confirmation of a diagnosis of Sézary syndrome, especially
epidermal dendritic cells (Langerhans cells) in the if the same clonal population can be detected in lesional
epidermis (figure 3), are a fairly specific but insensitive skin. However, TCR clonality can also be detected in a large
histological marker for mycosis fungoides.42 Malignant proportion of patients with autoimmune diseases such as
T cells can also accumulate along the basal layer of the systemic sclerosis49 and in healthy older adults.28 Flow
epidermis, showing a distinctive effect resembling a cytometry is favoured to identify potentially malignant
string of pearls (figure 3). Since histological findings in subsets (ie, through abnormalities of pan-T-cell markers or
mycosis fungoides are often non-diagnostic, especially in recognition of subsets of T cells expressing specific TCR
patch-stage disease, serial biopsy samples are frequently Vβ epitopes) and to quantify response to treatment.28
needed for a definitive diagnosis. Tumours are composed
of dense sheets of cytologically atypical lymphocytes in Pathogenesis
the dermis, commonly without the epidermotropism Although several aetiologies have been postulated for
that is noted in patch or plaque disease (figure 3). mycosis fungoides and Sézary syndrome, their causes
Immunohistochemical staining generally shows remain unknown. Chronic antigenic stimulation by
atypical CD4+ T cells (figure 3), although CD8+ mycosis pathogens such as Helicobacter pylori and hepatitis C
fungoides does occur, particularly in children.43 Ancillary virus has been associated with the development of gastric
findings such as loss of T-cell antigens (CD2, CD3, CD5, mucosal and non-Hodgkin lymphoma, respectively.50,51
CD7, and CD26) or the presence of a clonal T-cell receptor On the basis of limited experimental and clinical data,
(TCR) gene rearrangement by PCR can be helpful but similar roles for skin-associated microbes such as
might be non-specific.44 In one large study, clonality was Staphylococcus aureus52 and Chlamydia spp53 in terms of
detected in the lesional skin of 83·5% of CTCL samples antigen stimulation of skin T cells have been postulated
by PCR methods (compared with 2·3% of samples from for mycosis fungoides and Sézary syndrome. The finding
patients with benign inflammatory skin disease).45 that patients with these disorders have a higher frequency
Although detection of T-cell clonality correlates better of specific HLA class II alleles than do the general
with the cellular density than with the T score or population lends support to the antigenic stimulation
immunophenotype,45 it can nevertheless be useful for hypothesis,54 but other definitive evidence is scarce.
assessment of minimum residual disease after Several groups have proposed a viral aetiology for
treatment.46 mycosis fungoides, beginning with reports that a

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truncated human T-cell lymphotrophic virus (HTLV)-1

A B
sequence was present in skin biopsy samples of patients
with this disease.55 Although HTLV-1 is known to cause
human adult T-cell leukaemia and lymphoma, many
studies have reported little or no association between
HTLV-1 and mycosis fungoides.56,57 Other investigators 1
have made associations between mycosis fungoides and
Sézary syndrome, and the common cytomegalovirus58
and Epstein-Barr virus.59 Despite unconvincing data for
the aetiology of mycosis fungoides and Sézary syndrome,
a large body of evidence has accumulated regarding 2
specific immune and genetic abnormalities in these
diseases, perhaps leading to novel therapies that block
the trafficking or proliferation of malignant T cells. C D

Immune abnormalities
Mycosis fungoides and Sézary syndrome represent mal-
ignancies of a skin-resident, CD45RO+ effector memory
T cells60 that have a unique expression pattern of chemo-
kine receptors and adhesion molecules (eg, cutaneous
lymphocyte-associated antigen [CLA]). Clark and col-
leagues61 calculated that 98% of normal CLA+ effector
memory T cells reside in skin. Although the bulk of normal
skin-resident T cells are of T-helper-1 (Th1) phenotype and
express chemokine receptors CCR4 and CCR6, smaller
subsets such as central memory,60 Th2, and T-regulatory
cells also exist in the skin.61 Such findings are consistent
with the notion that mycosis fungoides and possibly Sézary
cells are derived from CLA+ effector memory cells.
Evasion of immune recognition is a strategy that tumours
adopt to ensure survival. In patch-stage and plaque-stage
lesions, the malignant T cells represent a minority of Figure 3: Histopathological diagnosis of mycosis fungoides
(A) Patch-plaque stage of mycosis fungoides shows atypical cells in the epidermis (ie, epidermotropism) and a
T cells in skin. Non-malignant CD8+ T cells are often band-like infiltrate of atypical T cells, often with cerebriform nuclei (inset), in the upper dermis. (B) CD2 staining is
present and are associated with improved prognosis.36,62 used to draw attention to mycosis fungoides cells that can aggregate together to form a Pautrier’s microabscess
Expression of Fas ligand by malignant T cells can help (arrow 1). Malignant T cells might also line up along the epidermal basement membrane giving a “string of pearls”
with the clearance of Fas-expressing CD8+ T lymphocytes effect (arrow 2). (C) Histological appearance of tumour-stage mycosis fungoides after routine haematoxylin and
eosin staining. (D) Histological appearance after CD4 immunostaining. This case of tumour-stage mycosis
that are tumour specific through direct contact and could fungoides shows a substantial loss of epidermotropism.
explain the inverse relation between Fas ligand expression
of malignant cells and the number of infiltrating CD8+
T cells in skin lesions of mycosis fungoides. A link has to sustain malignant T cells from lesions of mycosis
also been noted between increased amounts of Fas ligand fungoides in vitro.64
expression and more advanced tumours, suggesting a Patients with Sézary syndrome and advanced mycosis
role in tumour progression.63 Such findings lend support fungoides are immunosuppressed, which is particularly
to the notion that a host cytotoxic T-cell response against evident in those with high-tumour burdens. Although
malignant T cells can slow disease progression. the pathobiology of the immunosuppression is probably
multifactorial,66 an important factor could be Th2-skewing
Cytokine abnormalities of T cells by interleukins 4 and 5.67,68 Evidence also
Malignant T cells in mycosis fungoides and Sézary suggests that interleukin 18, a cytokine associated with
syndrome respond to and synthesise cytokines in their atopic dermatitis (a Th2-predominant skin disease),69
local tumour microenvironment. Interleukins 7 and 18— might contribute to the Th2 bias that is noted in mycosis
but not interleukins 2, 4, 12, 13, or 15—are upregulated in fungoides and Sézary syndrome.65 The importance of Th1
the plasma and skin of patients with mycosis fungoides pathways in control of mycosis fungoides is suggested by
and Sézary syndrome.64,65 In ex-vivo culture, interleukin 7 the clinical efficacy of Th1-promoting cytokines such as
in lesions derived from mycosis fungoides was five times interferon (IFN)-γ70 and interleukin 12,71 as well as by
higher than it was in healthy skin. Furthermore, reports that aggressive cases of this disease have arisen
interleukin 7 was sufficient to enhance proliferation of after treatment with inhibitors of tumour necrosis
healthy peripheral skin-homing T cells and was necessary factor α.72

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Interleukin 15, which is overexpressed in mycosis

fungoides and Sézary syndrome,73 inhibits T-cell apoptosis Panel 2: Algorithm for diagnosis of early mycosis fungoides
after antigen exposure and promotes the expansion of Clinical criteria
CD4+ T cells74 and Sézary syndrome cells.75 Many cell Basic
types, including keratinocytes,76,77 express interleukin 15 • Persistent and/or progressive patches or thin plaques
messenger RNA, but its protein expression is tightly
Additional
regulated.78 Moreover, before interleukin 15 can bind to its
• Non-sun exposed location
receptor on T cells, this cytokine is thought to be presented
• Variation in size or shape
in trans via initial binding to the interleukin-15α chain of
• Poikiloderma
other cells, including epidermal Langerhans cells,79 which
can have several distinct roles in the pathogenesis of Scoring
mycosis fungoides and Sézary syndrome. • 2 points for basic criteria and two additional criteria
• 1 point for basic criteria and one additional criterion
Loss of T-cell repertoire Histopathological criteria
With PCR-based methods, Yawalkar and colleagues80 Basic
reported that half of patients with stage I/II disease and • Superficial lymphoid infiltrate
all those with stage III or IV disease showed substantial
reductions in T-cell receptor diversity compared with the Additional
highly diverse T-cell receptor repertoires that are expressed • Epidermotropism without spongiosis
by normal peripheral T cells in the blood. Moreover, T-cell • Lymphoid atypia*
receptor excision circles—a remnant of the initial gene Scoring
rearrangement in T cells that is used as a measure of • 2 points for basic criteria and two additional criteria
T-cell expansions—are decreased in the blood of patients • 1 point for basic criteria and one additional criterion
with CTCL at all disease stages,81 suggesting that, in
Molecular biological criteria
addition to malignant T-cell expansion, normal T-cell
• Clonal TCR gene rearrangement
populations have expanded in response to the space left
by the loss of other T-cell families. Scoring
The loss of T-cell diversity in early stage disease is • 1 point for clonality
especially noteworthy and could be connected with the Immunopathological criteria
origin of mycosis fungoides and Sézary syndrome. A • <50% CD2+, CD3+, and/or CD5+ T cells
reduction in T-cell repertoire has commonly been noted • <10% CD7+ T cells
after infection with specific viruses such as HIV-1.82,83 A • Epidermal or dermal discordance of CD2, CD3, CD5, or CD7†
narrowed CD8+ T-cell repertoire was recorded in mice
who were serially infected with two slightly different Scoring
viruses (lymphocytic choriomeningitis virus and Pichinde • 1 point for one or more criteria
virus) that shared cross-reactive MHC class I-restricted A total of four points is needed for the diagnosis of mycosis fungoides on the basis of
peptide epitopes, although this finding did not occur any combination of points from the clinical, histopathological, molecular biological,
and immunopathological criteria. *Lymphoid atypia is defined as cells with enlarged
when mice were serially infected with the same virus.84
hyperchromatic nuclei and irregular or cerebriform nuclear contours. †T-cell antigen
Although no definitive evidence exists for a specific viral deficiency confined to the epidermis. Reprinted (with slight modification) from
aetiology in mycosis fungoides and Sézary syndrome, reference 42 with permission from The American Academy of Dermatology.

narrowing of the T-cell repertoire could result from

cross-reactivity (ie, molecular mimicry) between a viral
epitope that is recognised after infection with some showed that dendritic cells lend support to the long-term
viruses and an autoantigen in the skin that sustains T-cell culture of Sézary syndrome cells, are capable of ingestion
activation. This hypothesis could account for the inability of apoptotic T cells (including Sézary cells), and can
to detect specific viral pathogens in skin lesions of present antigens that stimulate the development of
mycosis fungoides since the initial viral pathogen might immunosuppressive Forkhead box p3 (FoxP3)+, CD25+
have been effectively eradicated. T-regulatory cells. After ingestion of apoptotic cells,
dendritic cells induce Sézary cells to show characteristic
Antigen-presenting cells features of T-regulatory cells.87 The notion that Sézary
Antigen-presenting dendritic cells can have an important cells have T-regulatory activity might partially explain the
role in the pathogenesis of mycosis fungoides and Sézary immunosuppression noted in these patients, but in-vivo
syndrome, especially in maintaining the survival and evidence is scarce.
proliferation of malignant T cells.85 Presumably, dendritic
cells acquire either self-peptide or non-self-peptide Chemokine receptors and skin tropism of malignant T cells
antigen that is presented on MHC class II molecules on The cutaneous tropism of the malignant T cells in
their surface to malignant T cells. Berger and co-workers86 mycosis fungoides and Sézary syndrome can be partially

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explained by their expression of specific chemokine

receptors. Chemotactic cytokine (chemokine) receptors Epidermal chemokines C Inhibition of apoptosis
belong to a much larger family of G-protein-coupled CCL17
CCL27
receptors that span seven membranes.88 The nomenclature
Epidermis B Activation Apoptosis
of chemokine receptors and their chemokine ligands
derives from their placement in one of four related
D
families on the basis of the spacing of crucial cysteine A Homing CCR7 Chemokine-antigen
residues.
CCR4 and CCR10 and their ligands play potential parts E
in homing of malignant T cells to skin. CCR4 and CCR10 Chemokine-toxin
CCR6
are expressed by normal T cells with a skin-homing,
Dermal blood Dendritric cell
CLA+ phenotype,89,90 and are frequently present on cells Expression by MF cells vessel
of mycosis fungoides and Sézary syndrome.91–94 Notably, CXCR4
CCR7
CCL17—a major CCR4 ligand—is synthesised by CCR4
activated keratinocytes, dendritic cells, and endothelial CCR10
cells, and is increased in the serum of patients with
mycosis fungoides.95 CCR10 and its keratinocyte-derived Figure 4: Roles for chemokine receptors in mycosis fungoides
ligand, CCL27,96 have been implicated in the homing of Chemokine receptors can have important roles in the trafficking and survival of malignant T cells in the cutaneous
microenvironment. (A) Homing: activation of T-cell integrins eases T-cell adhesion to skin endothelial cells and
CLA+ memory T cells to skin under inflammatory subsequent binding to extracellular matrix proteins. T cells migrate along a gradient of chemokines (eg, CCL17 and
conditions.89,90 Similar to CCL17, CCL27 is increased in CCL27) to the epidermis. (B) Activation: chemokine receptors allow T cells to efficiently engage dendritic cells, such as
the serum of patients with mycosis fungoides and Sézary Langerhans cells, resulting in T-cell activation and release of inflammatory cytokines. (C) Inhibition of apoptosis:
syndrome and can indicate disease activity.97,98 chemokine-receptor engagement leads to up-regulation of PI3K and Akt, which are key prosurvival kinases. Activation
of downstream effectors of this pathway can allow T cells to survive and proliferate in the skin environment.
The CCL17 and CCL27 chemokines induce T-cell arrest (D) Chemokine-antigen fusion proteins can be used to target tumour antigens from mycosis fungoides cells to CCR6+
on the luminal side of blood vessels, followed by antigen-presenting dendritic cells to stimulate host antitumour immunity. (E) Chemokine-toxin molecules can target
diapedesis through the endothelium, and migration specific chemokine receptors found on mycosis fungoides cells to mediate direct killing. MF=mycosis fungoides.
along chemokine gradients produced by keratinocytes
and immune cells that are present in the skin.99 Most chemokine-antigen fusion proteins take advantage of the
chemokine receptors activate downstream prosurvival physiological endocytosis of chemokine receptors after
pathways, including phosphatidylinositol-3-kinase and ligation, ultimately enhancing presentation of the
Akt (protein kinase B), leading to increased resistance to peptides derived from antigenic tumours on the cell
apoptosis.100,101 Thus, chemokines not only change T-cell surface.106 Chemokine-toxin fusion proteins analogous to
migratory properties and promote migration to the skin, the interleukin-2-diphtheria toxin-fusion protein
but also enhance their survival (figure 4). (denileukin diftitox) could also be highly specific for
The CXCR4 chemokine receptor might also have a role some T-cell populations, resulting in endocytosis of the
in homing of Sézary cells. Loss of cell surface antigens chemokine-toxin and cell death. Such fusion molecules
such as CD7, CD26, and CD49d66 are characteristic of could prove useful as therapeutic agents in mycosis
mycosis fungoides and Sézary syndrome. Of particular fungoides or Sézary syndrome (figure 4).
relevance is the loss of CD26, also known as
dipeptidylpeptidase IV, which proteolytically cleaves and Advances in treatment
inactivates CXCL12, the CXCR4 ligand.102 Inactivation of Since mycosis fungoides and Sézary syndrome are rarely
CD26 enhances the migration of cell lines derived from curable, the goal of treatment is to control the disease while
patients with Sézary syndrome in response to CXCL12, keeping toxic effects to a minimum. Many topical treat-
whereas the addition of soluble CD26 is inhibitory.103 ments (eg, nitrogen mustard, corticosteroids, and
With the presence of CXCL12 in skin, loss of CD26 on bexarotene) and ultraviolet light-based therapies readily
the Sézary cells can help with their cutaneous migration control some patch and thin-plaque disease. Systemic treat-
or enhance survival. ment is appropriate for patients who are poorly controlled
These results suggest that targeting receptors such as by topical therapy or who have widespread plaques and
CCR4 and CCR10, which show expression on skin-homing tumours. In patients with advanced disease or those who
T cells, can block the migration or survival of malignant have failed many single-agent treatments, a combination
T cells (figure 4). Although small-molecule antagonists of or range of treatments incorporating photochemotherapy,
CCR4 and CCR10 have yet to be developed, antibodies to retinoids, and biological drugs can be beneficial.107 In
CCR4 can induce death of malignant T cells in vitro, particular, patients with Sézary syndrome might benefit
albeit through antibody-dependent cellular cytotoxicity.104 from this varied approach, which has yielded overall
Fusion proteins that consist of a chemokine and a response rates approaching 90%.108 A complete discussion
tumour-cell antigen have been used to target CCR6+, of the clinical management of mycosis fibrosis and Sézary
immature dendritic cells, leading to protective T-cell syndrome is beyond the scope of this Seminar, but
responses against lymphoma in mice.105 Such comprehensive reviews discussing therapy are provided

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elsewhere.7,109,110 We will focus on newer medical treatments interleukin 2, which alone has a modest clinical response,115
for advanced mycosis fungoides and Sézary syndrome on the basis of their ability to upregulate their respective
(summarised in table 3) and mechanisms of action. receptors and synergistically enhance T-cell or
natural-killer-cell proliferation and cytolytic function.128
Experimental therapies Recombinant IFN-α and IFN-γ can also shift the balance
Malignant T cells of mycosis fungoides and Sézary of the immune response from Th2 towards Th1 and have
syndrome can retain varying degrees of responsiveness to shown clinical activity (table 3). Of note, gene transfer of
pharmacological doses of biological drugs that blunt IFN-γ cDNA that is mediated by adenovirus has also been
normal activated T-cell activity. For this reason, agents such given intralesionally to induce tumour regression, keeping
as corticosteroids can have substantial activity, albeit systemic side-effects associated with systemic use of the
usually of short duration. Topical corticosteroids are one of recombinant cytokine to a minimum.129
several effective therapies for early mycosis fungoides that Antibodies to CD4 (zanolimumab) and CD52
is limited to the skin.125 However, other imunosuppressants (alemtuzumab) broadly target T cells and have shown
such as cyclosporine126 and TNF-α antagonists72 should be clinical responses ranging from 38% to 78% in patients
avoided in patients with these diseases because of reports with mycosis fungoides and Sézary syndrome (table 3).70,130
of rapidly progressive disease after their use. In phase II trials, alemtuzumab was effective in relieving
The overproduction of Th2 cytokines such as erythroderma and pruritus in Sézary syndrome.123 However,
interleukins 4, 5, and 10 in mycosis fungoides and Sézary immunosuppression produced by alemtuzumab has been
syndrome suggests that cytokines which promote a Th1 associated with serious infectious complications such as
phenotype might be clinically useful. Interleukin 12, which fatal mycobacterium pneumonia and generalised herpes
is a Th1-promoting cytokine synthesised by phagocytic simplex infection, especially in patients who have been
cells and antigen-presenting cells, enhances cytolytic T-cell heavily pretreated.123
and natural-killer-cell functions and is necessary for IFN-γ
production by activated T cells. In vitro, interleukin 12 and Vaccine therapy
IFN-α can inhibit synthesis of interleukin 5 by Sézary Vaccine immunotherapy for mycosis fungoides and
cells,127 and interleukin 12 has shown clinical benefit.71 Sézary syndrome is at an early stage. A scarcity of target
Interleukin 12 is also being tested in combination with antigens has hampered this work, but new antigens for

Comments
TLR agonists
CpG111 In-vitro stimulation of interferon-γ by PBMC
Imiquimod (TLR7,8)112 Clearance of plaques resistant to PUVA; induces interferon-α
CpG7909 (TLR9)113 Overall response rate of seven of 28 (25%)
Cytokine therapy
Interferon-γ70 Five of 16 (31%) partial responses
Interferon-α114 Partial responses vary from 0–60% in many trials depending on several factors
Interleukin 1271 Overall response rate five of nine (56%); increased CD8+ T cells noted in regressing
lesions
Interleukin 2115,116 Overall response rate of 18–71% depending on the study
Vaccine therapy
Th1-skewing dendritic cells loaded with autologous tumour cells117 One patient, but impressive response in a patient who had failed all other therapies
Intranodal injection of dendritic cells loaded with autologous tumour Four patients with partial response, one with complete response, five with
cells118 progressive disease
Mimotopes (non-natural peptides derived from combinatorial peptide Complete regression in two patients tested
libraries) screened for in-vitro stimulation of CD8+ T cells specific for
CTCL cells119
Histone deacetylase inhibitors
Depsipeptide120 Small trial with three partial and one complete response
Vorinostat 121 24·2% response rate based on intent-to-treat analysis in heavily pretreated patients
Other targets
AntiCD4 (zanolimumab, HuMax-CD4)122 Seven of eight patients with mycosis fungoides responded; average freedom from
progression 25 weeks; no clinical evidence of immunosuppression
AntiCD52 (alemtuzumab)123,124 Overall response rate (38–55%) in 30 patients from two trials; could be particularly
effective for patients with erythroderma (Sézary syndrome) and severe pruritus

TLR=toll-like receptor. PMBC=peripheral mononuclear blood cells. PUVA=psoralen and ultraviolet A. CTCL=cutaneous T-cell lymphoma. Th=T-helper.

Table 3: Novel agents for treatment of mycosis fungoides and Sézary syndrome

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 Seminar

these disorders are being detected by novel serological

A
screens with use of tissue cDNA libraries.131 However,
studies in animals and human beings of B-cell lymphoma
suggest that dendritic cells pulsed with idiotype proteins
(antigens) can elicit antitumour responses and tumour
regression.132,133 Cloning or synthesising the unique T-cell
receptor sequences expressed by cells of mycosis
fungoides or Sézary syndrome, analogous to the B-cell
idiotype, is technically feasible and can provide a unique
tumour target for immunotherapy.
One strategy to avoid cloning the T-cell receptor is to
load autologous dendritic cells with tumour cells or
lysates and inject them directly into a patient’s lymph B
node.118 Geskin and colleagues117 showed that
administration of autologous tumour-loaded dendritic
cells treated with Th1-priming cytokines to heavily
pretreated patients with Sézary syndrome resulted in
beneficial clinical responses. Vaccination of patients with
mimotopes, which are synthetic peptides (selected from
combinatorial libraries) that stimulate antitumour CD8+
T cells, has also shown clinical benefit.119

Histone deacetylase inhibitors

Histone deacetylase inhibitors, such as depsipeptide134
Figure 5: Clearance of erythroderma in a patient with Sézary syndrome
and vorinostat,135 which has recently been approved by (A) Before and (B) after treatment with depsipeptide.
the US Food and Drug Administration, represent a new
drug class for cancer treatment.136 Mechanistically, plasmacytoid dendritic cells might contribute to a strong
histone deacetylase inhibitors induce growth arrest in Th1 immune response and enhance cellular immunity.
conjunction with cell differentiation and apoptosis. Preliminary clinical studies of CpG oligodeoxynucleotides
Depsipeptide and vorinostat have shown notable clinical in mycosis fungoides and Sézary syndrome showed a
responses, especially in patients with Sézary syndrome response rate of 25%,113 although CpGs as a drug class are
who have had improvement in erythroderma (figure 5) probably most useful when used as adjuvants in
and pruritus, and substantial decreases in the number of immunotherapy or combined with cytotoxic drugs.140
circulating Sézary cells.135,137 Although mild electro- Imiquimod, a TLR7/8 agonist approved for use against
cardiogram changes can arise after treatment with these genital warts, has been reported to clear plaques of mycosis
drugs, they are not associated with increased cardiac fungoides that are resistant to psoralen and ultraviolet A.112
troponin I or reduced left ventricular ejection fraction.138
Treatment of the human T-cell lymphoma line, HUT78, Selected approved agents for treatment
with depsipeptide enhanced expression of interleukin 2 Bexarotene is a retinoid that modulates gene expression
receptor and was synergistic with denileukin diftitox in through selective binding to retinoid X receptors, forming
an in-vitro cytotoxicity assay.134 Conceivably, histone either homodimers or heterodimers with other nuclear
deacetylase inhibitors might be useful in combination receptors that then act as transcription factors. Bexarotene
with denileukin diftitox for more effective treatment. is approved for use in both early-stage and late-stage
disease as an oral drug for refractory disease, and as a
Toll-like receptor agonists topical gel in early-stage disease.141 The pairing of
Human toll-like receptors (TLRs) are a family of more than bexarotene-bound retinoid X receptors and other nuclear
ten highly conserved pattern-recognition receptors that receptors, such as the thyroid, peroxisome proliferator
recognise a range of pathogen-associated molecules.139 activation, and vitamin D receptors, probably contributes
TLR9 recognises unmethylated, CpG-containing nucleo- to its metabolic and hormonal toxic effects.142 Bexarotene
tide motifs and is expressed within endosomes of can be used at lower doses when combined with
plasmacytoid dendritic cells and B cells.140 These motifs are ultraviolet A light therapy, keeping common systemic
present in most bacteria and DNA viruses but are toxic effects to a minimum while achieving comparable
uncommon in vertebrates. Upon activation by CpG or improved clinical efficacy.143
oligodeoxynucleotides, plasmacytoid dendritic cells Denileukin diftitox, a fusion molecule containing the
upregulate co-stimulatory molecules and migratory interleukin 2 receptor binding domain and the catalytically
receptors, which probably promote migration to secondary active fragment of diphtheria toxin, targets the high-affinity
lymphoid organs; generation of type I interferons by interleukin 2 receptor that is found on activated T and B

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 Seminar

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