ARTICLE
Auteur(s) : Pascale Quatresooz1, Claudine
Piérard-Franchimont1, Philippe Paquet1,
Pascale Hubert2, Philippe Delvenne2, Gérald E
Piérard1
1Department of Dermatopathology, University Hospital
Sart Tilman, Liège, Belgium
2Department of Pathology, University Hospital Sart
Tilman, Liège, Belgium
accepté le 25 Juillet 2007
Various environmental and societal factors increase skin
weathering, in particular the risks associated with exposure to
ultraviolet (UV) radiation. This situation leads to the subsequent
upsurge of skin cancer rates. In this field actinic keratosis (AK)
is variously considered as a pre-neoplastic condition, an incipient
initiated neoplasm or an already established in situ malignancy. In
any case, very few AKs progress to invasive squamous cell carcinoma
[1-4]. Some AKs, in fact, seem to resolve spontaneously. The
proportion of AKs that do transform into full-blown squamous cell
carcinoma is difficult to compute. Various estimates have been
given ranging, from 0.1% to 5.0%. Whatever the true rate, patients
with chronic solar damage need long-term and regular observation
for the treatment of new AKs and to make sure that no more serious
lesion has developed.
In recent years, a few dermatopathologists denied the existence
of AK, and preferred to name it squamous cell carcinoma [5-9]. This
concept was not rooted in an undisputable biological background of
cancer. It does not probably help the clinician and the patient [3]
very much because the treatment stratification according to the
diagnosis [10, 11] becomes blurred, and this may possibly fuel
confusing medico-legal aspects.
Epidemiological features
AKs are very common lesions in subjects of mature or older ages. In
recent decades AK prevalence has appeared to be on the rise.
Recently reported prevalence rates ranged from 6 to 26% in western
populations of the Northern hemisphere, and may reach up to 46% in
Australia [12-16]. However, these findings remain uncertain because
there was a lack of consistency in the clinical criteria, and
histological confirmation was not performed in the majority of the
epidemiological reports. Nevertheless, there is evidence that the
incidence of AK is particularly high in men of fair-skinned
phototypes. Cumulative UV radiation exposure is most likely the
most important risk factor for AK. Therefore geographical factors
(the lower “sunbelt” latitudes and higher altitude), occupational
factors (outdoor work) and lifestyle factors (e.g. recreational
activities and sun-worshippers) may have a significant impact on
the incidence of AK [14, 17, 18].
Biological features
There is strong evidence that cumulative UV exposure plays a
central role in the molecular pathogenesis of AK and most other
skin cancers as well. X-rays and radioisotopes are also causative
factors. Undoubtedly, a biological and clinico-pathological
continuum exists between the AK status and invasive squamous cell
carcinoma [2, 3, 19-22]. However, this neoplastic progression is a
multi-step process involving several distinct biological
alterations [22-26]. The essential principle of the multistage
model is that malignant transformation involves multiple genetic
and epigenetic changes that permit the preferential growth of the
altered cell and its progeny within an appropriate environment. The
discovery of genes whose function and dysfunction are directly
responsible for malignant transformation has provided tremendous
insight into the control mechanisms of cell growth and
differentiation.
Many carcinogens produce characteristic mutations that serve as
a genetic signature of the etiologic agent. Indeed, UV radiations
cause a variety of molecular changes in keratinocytes that set the
successive stages for carcinogenesis. The DNA of keratinocytes is
damaged by UV light, and the progressive accumulation of gene
mutations leads to neoplastic transformation and the development of
AK 120]. The process commonly starts on large fields of the
UV-exposed skin. It corresponds to the concept of field
cancerisation [27-30] that may remain invisible to clinical and
histological inspection for prolonged periods. AKs develop on such
a background, explaining the multiplicity of AKs on some skin areas
and the common “recurrence” of such lesions in the vicinity of a
previously treated AK. In addition, suppression of cell-mediated
immunity by UV light adversely leads to an impaired immune defence
against neoplastic cells, and subsequent possible immune tolerance
of otherwise highly antigenic skin cancers [30]. As an example,
immunosuppressed organ transplant patients suffer from an increased
risk of developing AKs, squamous cell carcinomas and other skin
malignancies [31, 32].
All cells are equipped with redundant DNA repair mechanisms
designed to remove and repair UV-induced mutations. Biological
pathways involved in the protection against skin cancer include
direct repair, base excision repair, mismatch repair,
double-stranded break repair, and more importantly nucleotide
repair. However, these mechanisms may be compromised in individuals
with an inherited loss of heterozygosity in the tumour suppressor
genes involved in these pathways, or in the presence of extensive
UV-induced DNA damage.
Mutations leading to skin cancers in otherwise normal subjects
include p53 mutations in 50-90% of non-melanoma skin cancers,
allelic and acquired patched mutations in 12-69% of basal cell
carcinomas, and mutations in the cyclin-dependent kinase inhibitor
p16 and p19 defects in 14-20% of squamous cell carcinomas and 3.5%
of basal cell carcinomas [23]. Other gene mutations linked to skin
carcinogenesis affect ras and patched mutations. H-ras is mutated
to a constitutively active form or overexpressed in its normal form
in some squamous cell carcinomas. Abnormal proliferation can also
be linked to genomic alterations leading to overexpression of a
proto-oncogene or lack of expression of a tumour suppressor gene of
normal sequence. In particular, mutations in the tumour suppressor
gene p53 are common in squamous cell carcinomas. Mutations in the
cell cycle inhibitors p16 and p19 are also relatively common in
these neoplasms [23]. In addition to their ability to arrest the G1
phase of the cell cycle, p16, p19 and p53 inhibit Akt
phosphorylation and induce the apoptotic process. Alterations in
pro-apoptotic pathways are strongly implicated in skin
carcinogenesis because the inability to turn on programmed cell
death in response to extensive UV-induced damage may allow mutant
cells to proliferate. The expression of pro-apoptotic factors Bcl-2
and Bax was reported to be higher in the atrophic AK type compared
to the hypertrophic AK type [33].
As in any other malignancy development, the first steps in
progression do not imply full-blown cancer. Hence, making a
diagnostic distinction between AK and squamous cell carcinoma
remains a sound procedure. In this respect, molecular biology does
not provide prognosticators because many genetic changes found in
AK are already present in the field cancerisation and persist in
squamous cell carcinomas. As yet, the histological differences
between these conditions are not associated with specific molecular
changes. As noted above, only differences in the proportion of
tumours are found when considering each molecular abnormality.
Clinical features
AKs usually present as skin-colored, pink or erythematous to
yellow-brown, harsh to scaly or warty macules, papules or plaques.
They develop in clusters although single lesions may occur
occasionally when the sun damage is not so severe. In any case,
field cancerisation is already present in the surrounding skin
area. They particularly involve the face, scalp, ears, neck, and
the dorsal aspect of the forearms and hands. Lesion size ranges
from a few mm to 1 cm or more in diameter. Clinical signs of
chronic actinodermatosis, including mosaic subclinical melanoderma,
solar lentigines, actinic elastosis, and a history of severe
sunburn in childhood also appear to be linked with AK [13, 16, 29].
The diagnosis of AK is usually made routinely on the basis of
clinical characteristics. In the early stages, the flat brown AK
patch may be confused with early seborrheic keratosis, actinic
lentigo or even lentigo malignant melanoma. In the later stages,
AKs may enlarge and/or may develop prominent hyperkeratosis
resembling a verrucous lesion or a horn. They may resemble
unpleasant aggressive lesions. They may also progress toward
full-blown and invasive squamous cell carcinoma. At times, AKs
cannot be clinically distinguished from squamous cell carcinomas.
Due to these uncertainties, histological confirmation is required
in the event of clinical doubt or when special forms of treatment
are being considered. In particular, it may be necessary to exclude
a squamous cell carcinoma, especially when the lesion is large,
erythematous, pruritic, bleeding, ulcerated, indurated, rapidly
growing or otherwise unusual [24, 34, 35]. This is also the case
when AK becomes inflamed and painful [36].
Histological features
Most dermatopathologists distinguish AK from squamous cell
carcinoma in situ based upon the upward extent of the keratinocyte
atypia [3]. Accordingly, AK is characterized by pleiomorphic
keratinocytes restricted to the deeper part of the epidermis,
sometimes extending up to the mid part of the stratum Malpighi. The
germinative compartment (Ki67 + cells) is restricted to this deep
portion of the epidermis. When similar atypical keratinocytes,
including Ki67 + ones are recognized throughout the full thickness
of the epidermis, the lesion is designated as an in situ squamous
cell carcinoma. Other authors use another grading of AK according
to the degree of intraepidermal involvement by atypical
keratinocytes. Accordingly, AK grade I exhibit mild atypia, AK
grade II show moderate atypia and AK grade III are characterization
by severe atypia.
Other typical features of abnormal epidermal architecture in AK
include irregularly alternating columns of hyperkeratosis and
parakeratosis, known as the “flag” sign. Indeed, there is generally
focal sparing of the openings of the cutaneous appendages at the
skin surface. The epidermis may be atrophic, but in other instances
it appears of normal thickness, or hyperplastic. Small club-shaped
buds of the atypical basal cell layer may protrude into the upper
papillary dermis resulting in an irregular outline of the
dermo-epidermal junction. Solar elastosis is a constant
feature.
Lichenoid AKs are characterized by the presence of a dense
lymphoid infiltrate abutted to the altered epidermis. Acantholytic
AKs are distinguished by a cleft separating the deep atypical
epidermis from the upper stratum Malpighi showing a few
acantholytic dyskeratotic (apoptotic) keratinocytes. Although a
variety of quite distinct histopathological variants of AK exist,
many cases display a spectrum of patterns. In addition, AKs are
commonly seen close to or contiguous with full-blown squamous cell
carcinomas [37, 38]. In such cases, the diagnosis should be a
squamous cell carcinoma developed on an AK.
AK is evidence of cumulative UV damage, and the perilesional
skin frequently exhibits minor cellular changes such as nuclear
hyperchromasia, cytoplasmic and nuclear pleomorphism, slight
architectural disarray and increased proliferation. In addition,
the adjacent morphologically normal keratinocytes commonly
overexpress the p53 mutated protein. This phenomenon is part of the
so-called “field cancerisation” [27-29]. Indeed, the broad
cancerized field contains foci of mutant clones at different stages
of transformation, and the whole area has probably the potential to
develop AKs. It is likely that some of the seemingly recurrent AKs
supervening after initial treatment represent in fact the
expression of field cancerisation. Thus, the concept of field
cancerisation has important implications for the treatment of AKs,
and indicates that a strategy focusing purely on removal or
destruction of single visible lesions is unlikely to offer a
long-term cure.
Novel pharmacological issues
AKs are superficial lesions that can be treated by a variety of
surgical, physical and pharmacological modalities [38-42]. Older
therapies, including cryotherapy and 5-fluoroouracile, are still
valid for treating AKs. In recent years, pharmacological effects on
AK have been shown with several new drugs. Since it is not
currently possible to determine clinically which AKs will soon
progress to squamous cell carcinoma, treatment of all recognized
AKs is generally recommended [40]. However, there is are
limitations in AK care programmes because patient compliance is
frequently low due to discomfort and limited treatment efficacy
contrasting with the cost of some of the available procedures.
The recent pharmacological advances in the treatments of the
AK-squamous cell carcinoma continuum have only shown clinical
efficacy against AKs. The therapeutic resistance offered by
squamous cell carcinomas to these drugs is another important
argument for clearly distinguishing the opposite poles of this
neoplastic continuum.
Anti-epidermal growth factor receptors (EGFR)
Anti-EGFR drugs (sorafenib, erlotinib, cetuximab…) have been
recently approved as chemotherapeutic agents active against some
specific internal carcinomas. Some reports have indicated that AKs
may exhibit inflammatory reactions in patients treated by these
drugs [43, 44]. It is uncertain whether to interpret inflammation
of AKs as a sign of neoplastic progression or regression [36]. In
any case, grading the severity and extension of the neoplastic
process is important to consider [35, 45, 46]. Indeed, any
inflammatory change in incipient or thin AK is of little clinical
importance in the short term because the risk of dermal invasion
and distant metastasis is minimal or absent. By contrast, the
thicker lesions about to evolve to a full-blown squamous cell
carcinoma are more problematic. Anyway, the few months of survival
time expected for patients under anti-EGFR therapy for a metastatic
carcinoma are not likely to be affected by any progression of AKs
[44].
More importantly, the effect of erlotinib on AKs and in situ
squamous cell carcinomas might be regarded as a model for the
understanding of the partial drug effect on the target internal
carcinomas. The role of the inflammatory cell infiltrate abutted to
the skin neoplasms in these therapeutic circumstances is most
likely that of a bystander. Indeed, the anti-EGFR drug is expected
to exert a primary effect on the neoplastic cells themselves. The
inflammatory cell reaction is probably limited to a secondary
reactive process to the neoplastic damages. Therefore, this
condition appears different from the immune response mounted
against neoplasms and occasionally inducing a partial or total
regression.
From these observations it appears that anti-EGFR drugs affect
the AK-squamous cell carcinoma process without inducing full
regression of the neoplasms. Peritumoral inflammation may be
strikingly boosted.
Imidazoquinoline
Imiquimod is an immune response modifier of the group of
imidazoquinolines [47, 48] that is approved by the EMEA (European
Medical Evaluation Agency) to treat AK [48-59]. The drug induces a
variety of cytokine production and release in the skin. This effect
is expected to trigger the innate and cell-mediated adaptive immune
responses to recognize some mutated cells. Another hypothetical
mechanism of action of imiquimod on AK might be the stimulation of
the immune reactivity that had been weakened by chronic sun
exposure. The activation of the Toll-like receptor-7 is one way by
which imiquimod may activate the innate immune system [49]. Effects
on the cell-mediated adaptive immune response appear to be indirect
induction of T cell cytokines, which bias a Th1 cell-mediated
response. Further additional effects are the activation of
Langerhans cells and dermal dendrocytes [60, 61], and, possibly,
stimulation of apoptosis of neoplastic cells [50, 62].
Complete clearance of AK has been reported in the majority of
patients after one course of imiquimod treatment using a once daily
application, 3 days per week for 4 weeks [57, 58]. The cure rate is
improved to three quarters of patients after a second course of
treatment. Inflammatory reactions, itching and burning sensations
at the application sites, represent the most frequent adverse
events and in some instances a significant discomfort. In our
experience, psoriatic lesions can develop at the site of
imiquimod-treated AK, similar to a Koebner phenomenon. The
recurrence rate of AK reaches about 10% within 1-year follow up and
20% within a 2-year follow up [51].
From these observations, it appears that clinically recognized
AKs do not respond uniformly to imiquimod. The diagnostic criteria
should probably be refined in order to better identify the AK most
susceptible to respond to imiquimod before treatment. With such a
type of treatment, the beneficial effect on sub-clinical AK and
field cancerisation can be important [28].
Diclofenac-hyaluronan
Topical 3% diclofenac in 2.5% hyaluronic acid is a nonsteroidal
anti-inflammatory formulation which has proven some efficacy in
treating AK [63-68]. The rationale is based on the inhibition of
cyclo-oxygenase 2 (COX-2) expression and prostaglandin E2 (PG-E2)
synthesis induced by UVB exposure [69]. Apart from its affinity to
the inducible COX-2, the drug has been demonstrated to activate
peroxisome proliferator-activated-receptor-gamma (PPAR-gamma) which
decreases cancer cell proliferation. The clinical trials suggest
that the diclofenac-hyaluronan topical treatment should be applied
twice daily for 60-90 days to treat AK [65]. Total clearance of AK
in about 40-50% of patients can be expected under such modalities
[65, 66].
Mild to moderate adverse effects can occur, including erythema,
xerosis, pruritus and dysesthesia. The recurrence rate of AK after
stopping treatment is unknown.
Methyl aminolevulinate photodynamic therapy
Photodynamic therapy (PDT) is another way to treat AK [70-72].
Methyl aminolevulinate (MAL) can be used as a topical
photosensitizer [73, 74]. Pooled data from phase III studies showed
that one MAL-PDT treatment is equivalent to, but provides better
cosmetic results, than cryotherapy [75, 76]. Red light activation
of MAL generates reactive oxygen species (ROS) resulting in
selective photochemical and photothermal destruction of the
neoplastic keratinocytes. This procedure is recognized by the EMEA
as an indication for AK. Response rates for MAL-PDT were higher in
thin AK than in thicker lesions. With 2 MAL-PDT sessions at a one
week interval, the response rate of AK grades I and II reached 91%.
Adverse events corresponding to local pain occur quite frequently
[76].
It is possible but not proven that the field cancerisation is
inhibited by MAL-PDT. Indeed, MAL absorption by UV-mutated cells
showing no cytological alteration has not been shown to be
different from unaffected cells. The long-term effect,
post-treatment by MAL-PDT, remains unsettled.
Conclusion
The diagnosis of AK in clinical practice is probably less
straightforward than it would appear at a first glance. Its
existence has even been denied. In a common sense, AKs behave
biologically as benign lesions. However, they remain difficult to
eradicate by pharmacological intervention. In many cases,
inhibiting EGFRs or boosting some aspects of antitumoral defence
mechanisms only provokes partial regression. The topical treatment
with diclofenac-hyaluronan requires twice daily applications for 2
to 3 months. Imiquimod only needs 2 to 3 applications per week for
4 to 8 weeks. MAL-PDT is valuable with 2 sessions at one week
intervals. These new modalities offered for treating AKs
undoubtedly represent progress in clinical practice.
Acknowledgements
Financial support: none. Conflict of interest: none.
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