ARTICLE
Auteur(s) : M Covadonga
Martínez-González1, M Magdalena
Verea-Hernando1, M Teresa Yebra-Pimentel2,
Jesús Del Pozo1, Marta Mazaira1, Eduardo
Fonseca1
1Dept of Dermatology, Juan Canalejo Hospital, C/ Sir
John Moore S/N. 15001, La Coruña (Spain)
2Dept of Pathology, Juan Canalejo Hospital, C/ Sir John
Moore S/N, 15001,La Coruña (Spain)
accepté le 6 Octobre 2007
Imiquimod is a topically active imidazoquinoline immunomodulator
agent that is formulated as a 5% cream for application by the
patient himself/herself and has been shown be efficient in several
infectious and neoplastic dermatological diseases [1-3]. In
immunocompetent patients, imiquimod stimulates the production of
INF-α and other cytokines (such as INF-γ, TNF-α, IL-1, IL-6, IL-8,
IL-10 and IL-12), and has indirect antiviral and antitumoral
effects [3, 4]. These cytokines are believed to then drive the
activation of the adaptative immune response towards the T helper 1
(TH1) or cell-mediated pathway and inhibit the T helper 2 (TH2)
pathway [2]. Cutaneous T-cell lymphomas (CTCL) are a heterogeneous
array of disorders characterized by expansions of malignant T cells
within the skin [5, 6]. The most common variant is mycosis
fungoides (MF), which is classified as a low-grade T-cell lymphoma.
MF is considered to be a lymphoma involving CLA-positive (cutaneous
lymphocyte antigen), CD4+ memory T cells that home to skin [7]. The
clonal dominance of the malignant cells results in the predominant
expression of TH2 cytokines [6].
Because of these effects, some authors have tried imiquimod in
resistant cases of MF, obtaining good results. But so far only a
few cases have been reported in literature [8-16]. Our objective
was to assay topical imiquimod in treating early-stages of mycosis
fungoides.
Cases reports
A 70-year-old Caucasian man presented in 1994 with several
erythematous itchy plaques, of 5-6 cm in diameter, over his
trunk. A skin biopsy confirmed the diagnosis of MF. The patient was
initially treated with topical clobetasol propionate. The treatment
induced practically complete clinical clearance and the patient
voluntarily left the course. In 1999 he developed similar
disseminated lesions located on his trunk, extremities, face and
scalp. One lesion on the trunk was in tumoral phase (stage IIB MF;
T3N0M0). Since then, the patient has been treated with radiotherapy
on the tumoral lesion (with a clinical response but with secondary
radiodermatitis) and multiple current standard therapies for his
disease, including: RePUVA, topical carmustine, topical nitrogen
mustard and systemic interferon α-2a (INFα-2a), without any
evidence of a clinical response to the plaque and patch lesions.
Finally, we decided to keep INFα-2a and to introduce topical
imiquimod as compassionate therapy. Before the introduction of
imiquimod, this patient had been treated for 2 years with systemic
INFα-2a alone, without any obvious clinical response. Imiquimod 5%
cream was applied 3 times per week on several plaques (previously
selected by us): 3 on the trunk: back (figures 1A-C), abdomen
(figure 2A) and
buttocks (figure
3A); and one on the chin (figure 4C). After 1 month
of therapy, there was intense erythema and superficial ulceration
of the lesions (figure
2B), but it was not necessary to discontinue the treatment
(figure 2C).
After 3 months of therapy, the treated lesions were completely
cleared (figures 1D-E and 3B).
Some untreated lesions, nearby the treated lesions, disappeared too
and an old radiodermatitis plaque on the trunk was reactivated
(figure 4). We
chose a treated lesion on the back for biopsy, showing histological
clearance of disease (figure 1D-E). Now the
patient is on INFα-2a (3×106 IU, 3 times per week) and
topical imiquimod (3 times per week) on other lesions.
A 62-year-old Caucasian man presented in 1999 with three
erythematous grey-brown desquamative and poiquilidermic cutaneous
lesions, of 3 cm in diameter, one on the root of the left
lower extremity and two on the buttocks. A skin biopsy confirmed
the diagnosis of MF. Routine laboratory parameters, bone-marrow
biopsy, chest X-ray and abdominal scan were normal. No adenopathies
were detected. We diagnosed stage IA MF (T1 N0 M0). Topical
treatment with clobetasol propionate, hydrocortisone butyrate,
methylprednisolone and carmustine, was successively applied without
clinical response. Then, he received PUVA therapy (cumulative dose:
1737 J/cm2) with clearance of all lesions except for the
lesion on the base of his left lower extremity. In June 2005, we
initiated topical imiquimod as a compassionate therapy. It was
applied 3 times per week on the persistent plaque. After 6 weeks
there was evidence of clinical improvement, without side effects.
After 14 months of therapy, the lesion was completely cleared and a
skin biopsy showed histological remission of disease. The patient
now suffers from another lesion of MF and it is being treated with
imiquimod cream 3 times per week.
A 79-year-old Caucasian man presented in 2001 with 5 itchy,
well-demarcated, cutaneous plaques, located on both forearms and
both ankles, with a poiquilidermic aspect. A skin biopsy confirmed
the diagnosis of MF. The lesions involved less than 10% of the
patient’s body surface area, and he had no evidence of systemic
involvement (stage IA; T1 N0 M0 of MF). The patient received
treatment with topical clobetasol propionate and then with PUVA
therapy (cumulative dose: 646.5 J/cm2), without showing
any clinical improvement. In June 2005 topical imiquimod was
initiated as a compassionate therapy, applied 3 times per week on
the persistent plaques. After 6 weeks there was some evidence of
clinical improvement, especially on the ankle lesions. The itch
disappeared in all plaques. A minimal erythema was the unique side
effect. After 7 months therapy, the lesions were clinically cleared
and a skin biopsy showed a slight inflammatory infiltrate in the
dermis, with a few slightly atypical lymphocytes, without
epidermotropism. Imiquimod treatment was continued and 3 months
later the clinical remission was maintained.
A 60-year-old Caucasian woman presented in 2003 with four itchy,
well-demarcated, rounded, erythematous cutaneous plaques, located
on her right shoulder (2 lesions), right forearm and right leg. A
skin biopsy confirmed the diagnosis of MF and there was no evidence
of systemic involvement. The patient received treatment with
topical clobetasol propionate and broadband UVB (cumulated dose:
6.74 J/cm2) with poor improvement. She was later treated
with PUVA (cumulated dose: 347.20 J/cm2) with clinical
clearance of all lesions except for the one on the right forearm.
In November 2005, topical imiquimod was initiated as a
compassionate therapy. It was applied 3 times per week on the
persistent plaque. We interrupted the treatment for a week due to
intense local inflammatory response during the first few days, but
she could continue the treatment without any other problem. After 4
months therapy, the lesion was completely cleared, without evidence
of MF in the histopathological study.
Discussion
The clonal CD4 tumor-cell populations in MF display a TH2 cytokine
profile, so they are deficient in interferon signalling. The
increase of IFN transcription might help to correct the TH1/ TH2
imbalance in MF lesions. The local immune intervention also induces
systemic immune activation [17].
Imiquimod is known to be a potent inductor of endogenous
antiviral proinflamatory mediators, to have antitumoral effects and
to stimulate the specific tumoral cytotoxic response [2, 3]. Its
mechanism of action is due to its binding of Toll receptor 7
(TLR-7) present on dendritic cells, macrophages and monocytes [2].
It is known that the development of skin lesions in MF appears
associated with an increase of TLR2, TLR4 and TLR9 expression by
keratinocytes in cutaneous lesions, which could play a role in the
chronic activation of T lymphocytes in the skin [18]. Imiquimod
increases NK-cell activity, tumoral necrosis factor (TNF)
expression and improves antigen presentation by Langerhans cells.
Also, it has been postulated that imiquimod induces apoptosis via
the binding of FasR to the Fas ligand in tumoral cells [1].
Because imiquimod inhibits TH2 clonal cells, it can be effective
as a topical therapy of CTCL. Systemic interferon is effective in
the treatment of mycosis fungoides (MF) and imiquimod induces
localized interferon production, so it can prove effective as a
topical therapy of MF (in the same way as it is effective in the
treatment of some other epidermal neoplasms, such as basal cell
carcinoma) [8].
One of the four patients (case 1) showed the most spectacular
improvement (total clinical and histopathological clearance of the
four treated lesions and others without treatment close to the
first ones). The healed lesions on the chin and scalp showed
alopecia. We attribute this good and rapid response to a synergic
effect of imiquimod and systemic INFα-2a treatment. There are no
references on this topic and only Deeths et al. included a patient
with concurrent systemic INF and topical imiquimod therapy [7].
In two other patients (cases 2 and 4) we obtained a total
clinical and histopathological response, but patient 3 presented a
total clinical response with a partial histopathological response.
We think that this fact is probably due to the syringotropic
histopathological pattern of MF in this patient.
The incidence of adverse events is lower when applying the cream
3 to 5 times a week. It has been used in different locations, even
on the eyelid and on the penis [12, 13]. In our cases we observed
only well tolerated local irritation.
We think that imiquimod might be an additional treatment option
in some cases of resistant lesions of MF but to date there are only
a small number of cases and non-randomized trials. Chong et al.
carried out a double-blind placebo-controlled pilot study of 4
males with MF (stage IB), 3 patients received imiquimod cream 5% on
a daily basis for 32 weeks and all the treated lesions showed a
mean decrease in surface area of 8.9%, whereas the control lesions
showed a mean increase in surface area of 39.9% [16]. The other
reports include isolated cases or small uncontrolled groups of
patients. We show a summary of reported cases in table 1, as well as a comparison with our
findings.
Table 1 Summary of the reported cases of MF treated
with imiquimod in the literature and comparison with ours
|
Studies
|
Sex/age
|
Stage
|
Dosage
|
Clinical response
|
Histopathological response
|
Important adverse events
|
|
Suchin, 2002 [10]
|
F/52
|
IA
|
1/d,4m
|
CR
|
NS
|
NO
|
|
Dummer, 2003 [9]
|
M/65
|
IA
|
1/d,8s
|
CR
|
-
|
NO
|
|
Deeths, 2005(1) [7]
|
F/56
|
IA
|
3/w,4m
|
PR
|
MF
|
NO
|
|
Deeths, 2005 (2) [7]
|
F/41
|
IA
|
3/w,4m
|
PR
|
MF
|
NO
|
|
Deeths, 2005 (3) [7]
|
M/79
|
IIB
|
3/w,4m
|
CR
|
NS
|
NO
|
|
Deeths, 2005 (4) [7]
|
F/43
|
IB
|
3/w,4m
|
NO
|
NS
|
NO
|
|
Deeths, 2005 (5) [7]
|
F/55
|
IA
|
3/w,4m
|
PR
|
MF
|
NO
|
|
Deeths, 2005 (6) [7]
|
M/61
|
IB
|
3/w,4m
|
CR
|
NS
|
NO
|
|
Onsun, 2005 [15]
|
F/50
|
IA
|
3/w,4-6s
|
CR
|
NS
|
NO
|
|
Soler-Machín, 2006 [11]
|
M/37
|
IA
|
3/w,5m
|
CR
|
-
|
NO
|
|
Chiam, 2006 [12]
|
M/32
|
IA
|
3/w,5m
|
CR
|
-
|
NO
|
|
Ardigo, 2006 [13]
|
M/25
|
IA
|
5/w,24m
|
CR
|
NS
|
NO
|
|
Coors, 2006 (1) [14]
|
M/78
|
IA
|
3/w,16s
|
CR
|
-
|
NO
|
|
Coors, 2006 (2) [14]
|
M/43
|
IB
|
7/w,24s
|
NO
|
-
|
NO
|
|
Coors, 2006 (3) [14]
|
M/76
|
IA
|
3/w,8s
|
NO
|
-
|
NO
|
|
Coors, 2006 (4) [14]
|
M/56
|
IA
|
3/w,8s
|
CR
|
-
|
NO
|
|
Martínez-González (1)
|
M/69
|
IIB
|
3/w,3m
|
CR
|
NS
|
NO
|
|
Martínez-González (2)
|
M/60
|
IA
|
3/w,14m
|
CR
|
NS
|
NO
|
|
Martínez-González (3)
|
M/77
|
IA
|
3/w,7m
|
CR
|
PR
|
NO
|
|
Martínez-González (4)
|
F/60
|
IA
|
5/w,4m
|
CR
|
NS
|
NO
|
Conclusion
Imiquimod could be an effective therapy for an early-stage disease
of CTCL, used alone or in combination with systemic
immunomodulatory therapy (in patients with extensive disease),
specially among those for whom other therapies have been
ineffective. However, to date there are no more than a small number
of non-randomized case studies and they do not allow for a
definitive conclusion about the efficacy of topical imiquimod in
treating MF. We want to emphasize the special nature of our four
cases as there have been very few case reports so far. There is a
need for randomized, controlled and large size studies.
Acknowledgements
Financial support: None. Conflict of interest: None.
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