INTRODUCTION
Pathophysiology of AK: Progression from Normal Skin to Keratinocyte Cancers
Actinic keratoses (AKs) are intraepidermal cutaneous areas of
atypical squamous transformation that develop as a result of excessive
exposure to ultraviolet (UV) radiation on sun-exposed
skin (eg, face, scalp, neck, extremities).1 Histologically, AKs are
defined by dysplasia and consist of keratinocytes with irregular,
enlarged hyperchromatic nuclei. Actinic keratoses are characterized
by disorganized growth, which disrupts differentiation and
leads to a thickened stratum corneum with retained nuclei.2
The most current pathophysiologic evidence is consistent with
the multistep model of carcinogenesis, supporting the theory
that AK is a step in the continuum of transformation from normal
skin to AK to invasive cutaneous squamous cell carcinoma
(cSCC) to metastatic SCC.2 Based on this model, a single genetic
mutation may lead to development of a precursor lesion with
a high level of genetic instability or loss of cell cycle control.
Additional mutations in other driver oncogenes allow emergence
of additional neoplastic properties, progressing through
the following stages: sun-damaged epidermis, with individual
disordered keratinocytes; AK, spontaneously regressing
keratinized patches with abnormal cell differentiation and proliferation;
carcinoma in situ; cSCC; and metastasis.2
The initial mechanism leading to genomic instability in keratinocytes
is thought to be UVB-induced inactivation of p53, a
protein that prevents normally uncontrolled cell division after
chromosomal damage and thereby stops precancerous cells.2 Mutations of p53 are found in more than 90% of human cSCCs,
indicating that dysplastic lesions have acquired the initial genetic
mutations before transforming to cSCCs.2 If the normal
response is decreased in only a single cell, UV exposure may
select for clonal expansion of the p53-mutated cell into the
AK. It is important to realize that sunlight can act twice—as a
tumor initiator and as a tumor promoter—underscoring the
importance of sun protection in the initial prevention and ongoing
management of AK.3 In addition, consideration of the
mechanisms of action (MOAs) of topical field therapies for AK
is becoming important when selecting a treatment approach.4
The rate of progression from AK to cSCC is estimated between
0.025% and 16% per year for an individual lesion.5 The typical
person with AK has 6 to 8 lesions; an individual with multiple
AKs therefore has an annual risk of developing invasive cSCC
between 0.15% and 80%.2 Results of the Department of Veterans
Affairs Topical Tretinoin Chemoprevention Trial, which included
a population at high risk for AK, showed that approximately
65% of all primary cSCCs and 36% of all primary basal cell carcinomas
(BCCs) originated from lesions previously diagnosed
as AKs. The majority of AKs regressed during the study—55%
and 70% were not present at 1 and 5 years, respectively.6 Importantly,
even a low yearly rate of transformation of a single
AK lesion into an SCC can translate into an increased risk in
patients with multiple AKs, especially when considered over
a long period of time.7 Overall, these results support current
thinking "that AKs may play a greater role in the overall burden
of keratinocyte carcinomas than previously documented."6
