ARTICLE
Auteur(s) : Michael M Sachse1, Jutta
Zimmermann2, Friedrich A Bahmer2
1Department of Dermatology, (Skin Cancer Centre
Charité), Charité University Hospital, Schumannstr. 20/21, 10117
Berlin, Germany
2Department of Dermatology, Hospital Bremen-Mitte,
Sankt-Jürgen-Straße 1, 28205 Bremen, Germany
accepté le 17 Août 2005
Chronic radiation dermatitis (CRD) defines a chronic skin
inflammation caused by ionizing radiation above a critical level
[1]. The sources of radiation are numerous; they include diagnostic
and therapeutic exposure as well as accidents like that at
Chernobyl [2, 3]. CRD follows a time course consisting of
prodromal, manifestational, subacute, chronic and late stages [3].
With a latency period of about 20-30 years after exposure, radiated
areas are prone to develop precancerous and cancerous lesions, such
as radiation keratoses, Bowen’s disease, cutaneous angiosarcoma,
basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) [4,
5].Imiquimod (Aldara®) belongs to a new class of immune
response modifiers (IRM). By enhancing both innate and acquired
immune pathways, topically applied 5% imiquimod cream has been
shown to indirectly exert both antitumor and antiviral activities.
In addition to topical immunotherapy of genital warts, therapeutic
efficiency of imiquimod was also demonstrated for various skin
neoplasias [6, 7].Here we report the case of a patient with
widespread thoracic chronic radiation dermatitis and histologically
verified precancerous and cancerous lesions successfully treated
with imiquimod.
Clinical observation
A 60-year-old man presented to the Department of Dermatology for
the first time in 1997 with thoracic chronic radiation dermatitis.
At the age of 15, suffering from asthma, his parents bought a
radium-bandage for epicutaneous application from a travelling
salesman [8]. This bandage, worn for almost one year during the
night time and placed over the sternum, did alleviate the asthma
somewhat. About 20 years later, skin changes developed on his upper
chest. As these asymptomatic cutaneous manifestations had gradually
worsened over the last few years with areas of crusting and
scarring, the patient sought medical advice.
On examination, poikilodermatous skin changes with erythematous,
partly eroded and crusted areas as well as hypopigmented scars were
present on his chest with a total area of 232 square centimetres
[9]. Four biopsies taken between 1999 and 2000 disclosed Bowen’s
disease, SCC, as well as two BCCs (( figure 1 )). carbon dioxide
laser therapy as well as photodynamic therapy performed on selected
areas only temporarily improved the condition, with new lesions
continuing to appear. Thus, we decided to start treatment with 5%
imiquimod cream, applied to the whole area once daily during the
night time for 14 days. After 6 days, the patient complained of
itching, and then the treated area became inflamed with massive
erythema together with vesicles, crusts and erosions (( figure 2 )). Consequently
application frequency was reduced to 3 treatments per week.
Gradually, the inflammation subsided and the skin lesions cleared
within the next 4 weeks. The patient has now been in complete
remission for more than 2 years with only superficial scar
formation and hypopigmentation, but neither erythema and
hyperkeratosis, nor neoplasia (( figure 3 )).
Discussion
The first case of chronic radiation dermatitis was described in
1896 [10]. Ionizing radiation exposure not only causes damage to
DNA, it also alters the immunological environment such as
transforming growth factor-beta (TGF-β) [3, 11]. The main risk of
CRD is the development of neoplasia such as SCC and BCC, and,
rarely, Bowen’s disease. The progression and degree of CRD-damage
usually depends on the quality and intensity of radiation. An X-ray
dose of more than 12-15 Gy usually leads to CTD. However, it is
possible to induce long lasting tissue damage with lower but
repetitive doses [12].
Precancerous and cancerous lesions within areas of CTD may be
treated by surgery, dermabrasion or ablative lasers such as
carbon-dioxide or Erbium-YAG lasers. Larger areas require
alternative treatment options such as oral retinoids or PDT [13].
In our case, retinoids were not employed and laser as well as PDT
exerted only a temporary effect. To our knowledge there is no study
comparing the efficacy of PDT versus imiquimod for the treatment of
actinic keratoses (AKs) so far. However, one case presentation
demonstrated both therapy regimens to be equally successful in the
treatment of actinic keratoses. The authors recommended a two step
treatment of AK, starting with PDT and followed by imiquimod to
clear any remaining epidermal dysplasias [14].
The IRM imiquimod belongs to the family of imidazoquinolines and
has been shown to enhance both the innate and acquired immunologic
responses in the skin [15]. The substance activates immune cells
via the Toll-like receptor 7 and leads to a secretion of numerous
monocyte-macrophage derived proinflammatory cytokines and
chemokines [7]. According to an in-vivo study, treatment of AK with
imiquimod resulted in an increased expression of proinflammatory
cytokines such as IFN-α and IL-6 [15].
Furthermore, infiltrating natural killer cells, lymphocytes and
dendritic cells contribute to the increased IFN-α levels [11, 16].
TNF-α and IFN-γ were shown to be associated with an enhanced
antigen presentation and maturation of Langerhans cells which are
the major antigen-presenting cells of the skin [7, 17].
In addition to its proinflammatory signals, in vitro studies
have also demonstrated apoptotic and antitumorous effects of
imiquimod [17, 18]. Recently, Majewski et al. [19] reported an
antiangiogenetic effect via IL-18 formation. Though the detailed
way of action is not fully understood, imiquimod is successfully
used for the treatment of HPV associated infections as well as skin
related tumours [7].
The complete clearing rates of AK prior to treatment with
imiquimod were recently investigated in several phase III studies
and ranged between 45-57% [20, 21]. In the treatment of superficial
BCCs, histological clearance rates were demonstrated in up to 82%
of all subjects [22, 23].
Apart from the high efficacy rates in the treatment of Bowen’s
disease, there are also promising results for the use of imiquimod
in squamous cell cancer [24-26].
The long term effects of imiquimod on the adaptive immune system
as well as a possible control of field cancerization are still a
matter of debate [27]. With regard to a decreased transformation
rate of AKs into invasive SCCs, future studies may further
elucidate this hypothesis [20].
Apart from mild to moderate skin reactions, locally applied
imiquimod 5% cream is well tolerated without any report of systemic
adverse effects [6].
In our patient with CRD, the skin reaction to imiquimod 5% cream
was conspicuous but tolerable. Within the follow-up period of more
than 2 years now, the patient has remained free of any new
neoplasia. Though it is not possible from this single case to
determine whether the development of new neoplasias has been
completely stopped or only temporarily suppressed, we feel that
imiquimod may be a new therapy option with only mild to moderate
side effects. Furthermore, the substance may represent a convenient
alternative to extensive surgical procedures on an inpatient basis
or to repetitive laser sessions. This therapy offers the additional
benefit that large areas of CRD might be treated within one
session. Thus, our successful results of the treatment of CRD with
multiple neoplasias should encourage further evaluation.
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