ARTICLE
Auteur(s) : PJF
Quaedvlieg1, E Tirsi1, MRTM
Thissen1, GA Krekels2
1Department of Dermatology, University Hospital
Maastricht, P.Debyelaan 25, Postbox 5800 6202 AZ Maastricht, The
Netherlands
2Department of Dermatology, Catharina Hospital
Eindhoven, The Netherlands
accepté le 22 Novembre 2005
Actinic keratoses (AK) are the most common premalignant lesions in
humans, affecting up to 40% to 50% of the population over the age
of 40 years in Australia. This is reflective of the large
proportion of Caucasians with Fitzpatrick skin types I and II. In
the northern hemisphere the prevalence of actinic keratoses varies
from 11-25% of the population older than 40 years [1-8]. Over the
course of a year, from 20 to 25% of AK regress. It is unclear how
often spontaneous regression is permanent. Over the course of a
year, 15 percent of the prevalent AKs which regressed, later
reappeared.These AK are in-situ carcinomas of the skin, which may
evolve into true invasive carcinomas and eventually can even
metastasize and cause death [9-15]. SCC has the potential to
metastasise and may account for up to 34% of deaths from skin
cancer among persons of 65 to 84 years of age, and 56% of deaths
from skin cancer among persons 85 years and older. However it is
unclear which and to what extent individual AK become squamous cell
carcinoma (SCC) [16-22]. In the literature, rates of 0.025%-20%
have been reported so far [23, 24].In the past, risk factors such
as fair-skinned phenotype, excessive cumulative overexposure to UV
radiation, advancing age, outdoor work, or hobbies, and Sunbelt
latitudes, and use of immunosuppressive medication have been
mentioned. However less focus has been on the clinical features of
the lesion itself [8, 25-32].Ideally, the clinician would like to
be able to distinguish those individual AK at risk for invasive
tumour from those that are not. In melanocytic lesions, for
example, a clinical classification of index of suspicion for
malignancy is used [33, 34].We reviewed the literature to identify
a similar index of suspicion for actinic keratoses.
Methods
Electronic ddatabases (Medline; National Library of Medicine) were
searched from 1985 to 2004. Cited references from identified trials
and review articles were searched manually. The following key words
were used: ‘actinic keratosis’, ‘aktinic keratosis’, ‘actinic
keratoses’, ‘aktinic keratoses’, ‘solar keratosis’, ‘solar
keratoses’ in combination with ‘squamous cell carcinoma’, ‘skin’,
‘risk factor’, ‘risk factors’, ‘etiology’, ‘development’,
‘carcinogenesis’, ‘precancerous’, ‘epidemiology’, ‘premalignant
skin lesions’. English and non-English papers were included. Two
authors (PQ and GK) examined the full texts of all studies
independently. All studies were cross-checked independently by the
reviewers.
The main outcomes examined were the clinical features and
percentage of AK lesions becoming invasive carcinoma.
First we looked at the usefulness of the article.
Studies were labeled as “useful” if they met the following
inclusion criteria: reviews, retrospective studies and prospective
studies, independent of the total number of actinic lesions
described and mentioned potential and clinical features of AK to
progress into SCC.
Exclusion criteria were all other types of reports like
editorials, congress papers, case reports, letters and practical
guidelines.
Second the studies labeled as useful were labeled for their
type.
Results
875 articles were found in the electronic database of ‘Medline’.
After scanning the ‘Medline’ computer database and the references
of the relevant articles, a total number of 62 useful articles were
selected for further analysis.
Most of the selected articles were reviews (38) followed by
prospective studies (12) and retrospective studies (12). Only 15 of
these studies mentioned rates of transformation (12) and/or
clinical features (5), see flow chart ( (figure 1) )[4, 9, 16, 24,
35-40].
The rates of malignant transformation ranged from 0.025% to 20%
per year for an individual lesion. 3 studies were prospective
studies, 2 were retrospective studies and 7 studies were reviews
(table 1)( Table 1 ).
One of these studies was a prospective study of the malignant
progression of AK into SCC. The risk of malignant transformation of
a solar keratosis to SCC within 1 year was less than 0.1% for an
individual lesion of AK [38].
The second prospective study was a study on the spontaneous
remission of AK and calculated the rate of malignant progression of
AK into SCC retrospectively with the available data, which produced
a transformation rate of 0.24% for an individual AK lesion
[11].
The final study was a randomized controlled trial (RCT) on the
risk factors for SCC [16].
From this RCT it was possible to extract total numbers of
patients with AK and total numbers of patients who developed an SCC
(table 2)( Table 2 ).
Seven articles were reviews and all of these reviews referred to
the prospective studies with the reference numbers 38 or 11. Two
studies [24, 35] were retrospective studies, which also referred
with their rates to reference 11. In the first study, Dodson stated
that the theoretical risk of malignant transformation for an
average patient with AKs followed up for 10 years would be 6.1% or
10.2% depending on the study analyzed [24]. The second study
examined the relationship between basal cell carcinomas and SCC to
actinic keratosis. The presence of a coexisting actinic keratosis
was necessary for the development of an SCC [35].
Besides the rate of malignant transformation of AK into SCC, we
were especially curious about the clinical risk factors for this
malignant progression of AKs. Five articles of the 15 mentioned
these risk factors: IDRBEU, I (Induration/Inflammation), D
(Diameter > 1 cm), R (Rapid enlargement), B (Bleeding), E
(Erythema) and U (Ulceration) [24, 25, 33, 41, 42]. The first study
indicated that AKs that change (e.g., thicken or increase in
surface area) quickly or are on mucosal surfaces are more likely to
progress to SCC [24].
In the second study, 50 papular hyperkeratotic AKs on the dorsum
of the hand, wrist and arm, less than 1 cm in diameter, were
identified in 43 patients. Histologic examination showed 18 lesions
(36%) to be invasive SCC, whereas another seven (14%) were SCC in
situ (AK). Proliferative AKs were the next most common lesion
identified (26%), followed by hypertrophic (10%) and lichnoid (4%)
AKs. Clinical hyperkeratotic AK less than 1 cm in diameter on
the dorsum of the hand, wrist, or forearms of white patients have a
malignancy rate of 50%. Lesions with this clinical description
should be removed by shave biopsy [25]. Jerant described how
changes in actinic keratosis that suggest evolution to SCC include
pain, erythema, ulceration, induration, hyperkeratosis and
increasing size [33].
Fu said that the diagnosis of AK is usually made on the basis of
clinical characteristics. However a biopsy may be required to
exclude deeper involvement, especially when the lesion is large,
pruritic, bleeding, ulcerated, erythematous, indurated, or
otherwise unusual. Several histologic variants, including
pigmented, acantholytic and hyperplastic types have been described.
All these variants share the characteristic of atypical
keratinocytic proliferation in the epidermis [41].
Marks noted that if the physician detects any sign of
malignancy, such as palpability, induration, or bleeding, a biopsy
is mandatory for confirmation.
A summary of these factors is given (table 2).
Table 1 Rates of malignant progression of AK into SCC
- Number of article in reference list [ ]
- and the type of article
|
Total number of patients with AK
|
Total number of AK lesions
|
Percentage of patients with AK who develop SCC
|
Percentage of AKs which progress to SCC
|
|
[38] Prospective study
|
1689
|
21905
|
1.7% in 5 years (28 patients)
|
< 0.1%; 0.075-0.096 (16.5 or 21 lesions)
|
|
[11] Prospective study
|
613
|
4720
|
1.6% (10 patients)
|
0.24/y (11 lesions)
|
|
[16] Randomized controlled trial
|
918
|
|
14% in 5 years (129 patients with > 9 AKs)
|
|
|
[35] Retrospective study
|
|
|
|
< 1
|
|
[24] Retrospective study
|
|
|
6.1-10.2% in 10 years
|
0.23%/y
|
|
[4] Review
|
|
|
|
0.025-16 in 10 years
|
|
[37] Review
|
|
|
|
0.025-16
|
|
[39] Review
|
|
|
10.2% in 10 years (On patients with an average of 7.7 lesions)
|
0.075-0.096
|
|
[41] Review
|
|
|
|
0.075-0.096
|
|
[40] Review
|
|
|
|
0.25-1%
|
|
[36] Review
|
|
|
|
0.1/y
|
|
[23] Review
|
|
|
|
0.25-20/y
|
Table 2 Summary of risk factors associated with a
malignant progression of AK into SCC
|
Major criteria*
|
|
Induration/Inflammation [33, 41, 42]
|
|
Diameter > 1cm [24, 33, 41]
|
|
Rapid enlargement [24, 33, 41]
|
|
Bleeding [41, 42]
|
|
Erythema [33, 41]
|
|
Ulceration [33, 41]
|
|
Minor criteria
|
|
Pigmentation [41]
|
|
Palpability [42]
|
|
Pain [33]
|
|
Pruritus [41]
|
|
Hyperkeratosis [25, 33]
|
Discussion
Actinic keratoses are very common skin lesions, affecting a great
proportion of the elderly white population. In our opinion, AK is a
carcinoma in situ, which eventually may progress to become a
squamous cell carcinoma of the skin, a non-melanoma skin cancer,
which can metastasise and cause death. Currently there is some
disagreement about the frequency with which AK progress to become
invasive SCC.
Ideally the clinician would like to know what percentage and
which specific lesions of AK are likely to progress to invasive
cancer [17-21]. Although there are many prospective studies on AK,
most of them do not reveal clinical features for malignant
transformation and progression rates. A reason for the lack of
prospective studies on the risk of malignant progression of AK into
cutaneous SCC is because any attempt to perform statistical
analysis on transformation rates of AK would be very difficult.
First of all, calculating the number of AKs in persons with
significant sun damage is a problematic task. The number of these
lesions can be countless in severely sun-damaged skin or AK lesions
can be in contiguous widespread masses, such as when an entire
scalp is affected. This is perhaps the reason why, on the other
hand, there are enough studies retrospectively reporting
percentages of SCC that arise in AK. But this is a different
study-question, and should not be confused with the percentage of
AK that transform to SCC.
To be able to differentiate high risk from low risk AKs would be
very helpful. However, analyses of the reviews and retrospective
studies showed that the reported rates were based on only 2
prospective studies [15] on malignant progression of AK, dating
from respectively 1988 and 1986 [11, 38]. The first prospective
study was a study on the spontaneous remission of AK and calculated
the rate of malignant progression of AK into SCC retrospectively
with the available data, which produced a transformation rate of
0.24% for an individual AK lesion. In the other study, the risk of
malignant transformation of a solar keratosis to SCC within 1 year
was less than 0.1% for an individual lesion of AK [38].
In addition, an AK cannot at times be differentiated from a SCC,
clinically.
Ultimately, the greatest shortcoming of the studies is that they
fail to resolve the dilemma for the clinician regarding which AKs
to treat before they progress into invasive SCC. We have identified
clinical features, which may be considered as indicators of high
risk AKs.
Although the overall risk may be in the low range, the clinician
should take into account clinical parameters like I
(Induration/Inflammation), D (Diameter > 1 cm), R (Rapid
enlargement), B (Bleeding), E (Erythema) or U (Ulceration) as
discussed in the results above. In addition, other risk factors
like: immunosuppression, age, human papiloma virus, skin type,
existing degree of photo damage, previous personal or familial
history of skin cancer must be taken into account in deciding to
treat actinic keratoses and diminish the risk of malignant
transformation [32, 43]. More weight could be given to these
features if they were applied to a prospective study to validate
them as predictors of risk of transformation.
As a consequence no existing technology besides the biopsy
allows the clinician to distinguish between individual lesions of
AK that will clear, remain stable, or progress to invasive disease
[44]. Until such technology becomes available, clinicians will make
individual decisions with individual patient. We provide a list of
major and minor criteria (based on available information from the
past 20 years) to help the clinician to differentiate the good AKs
from the bad ones. We consider AK as carcinoma in situ and this
always should be treated because of risk of malignant progression.
Our opinion is that there are indeed clinical features which may
help the clinician to differentiate the good actinic keratosis from
the bad ones. Because clinical features may contribute to a higher
risk and possible to the malignant transformation of AK to squamous
cell carcinoma accurately performed longitudinal studies on
clinical features are urgently needed.
Until these parameters are studied in a prospective way it is
difficult to quantify whether there should be one or more of the
major criteria present to treat an AK or take a biopsy for
histological examination or not. Until then we recommend further
histopathological examination if there are one or more of the major
criteria present.
Conclusion
According to the literature AKs are precursor lesions of cutaneous
SCC with a transformation rate varying from 0.025% to 20% per year
for an individual lesion. The only longitudinal study [35] looking
at the incidence of malignant transformation of AK to SCC, which
dates from 1988, reports a progression rate of less than 0.1% per
lesion per year.
Risk factors regarding increased risk for malignant progression
of AK are multiple; all AKs that are changing or showing some other
reason for concern should therefore be considered as at heightened
risk for malignant progression into SCC. Besides the known risk
factors such as the fair-skinned phenotype, immunosuppression,
excessive cumulative overexposure to UV radiation, advancing age,
outdoor work or hobbies etc. we include other important clinical
features of actinic keratotic lesions that are at risk for
malignant transformation. These clinical features IDRBEU:
(Induration/Inflammation, Diameter > 1 cm, Rapid
enlargement, Bleeding, Erythema and Ulceration. We conclude that AK
is a carcinoma in situ, which should always be treated. A small
number are already invasive and could be earlier recognized
clinically with the clinical guideline IDRBEU.
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