histology when AKs are abutting SCC despite lack of clinically visible lesions.3-5,11,17 This could represent a slow progression into invasive SCC and field cancerization.3-5,11,17 Of note, several of the panelists disputed data that AKs can fully regress. They noted that while atypical keratinocytes with only a single p53 mutation may regress, once a cell line has acquired additional mutations, regression becomes highly improbable. In their view, although AKs may be subclinical or missed from visit to visit,11 they are not likely to revert to a more benign status and also note there are no histopathological data to support the notion that AKs can regress.
To date, there is no definitive way to clinically identify which actinic keratoses will progress into invasive squamous cell carcinomas. Although the literature has demonstrated AK's potential for progression into invasive SCC, there are no universally recognized clinical markers that can readily identify those higher risk AKs. Inflammation, erythema, diameter >1cm, bleeding, ulceration, and rapid growth have been suggested as risk factors.15 The presence of spontaneous/pressure-induced pain may suggest the lesion is in fact a SCC not an AK.23,24 Follicular extension of AKs correlate with both a history of melanoma and non-melanoma skin cancer and an increased risk of future progression into invasive SCC.25,26 This risk may be further increased in immunosuppressed individuals given an already predisposed risk to developing AKs as well as SCC.27,28
Actinic keratoses require treatment.
Given the risk of AK progression to invasive SCC and lack of clinicopathologic signs to differentiate which AKs will progress to invasive disease, these tumors should be treated to decrease unwarranted morbidity and mortality. This statement extends not only to the AKs that are clinically visible, but also includes management of subclinical lesions.
Field, lesional, and combination therapies are effective in the treatment of actinic keratoses.
Multiple studies have demonstrated that various modalities are efficacious for treating AKs. Lesion-directed therapies are often office-based, physician-conducted modalities targeted at clinically visible AKs and can include cryosurgery, surgical/ manual removal, and laser.16,29,30 Field treatments may be office-based (eg, chemical peel, photodynamic therapy (PDT)) or patient-applied medications that target atypical/dysplastic keratinocytes by inhibiting cellular replication, upregulating immune-mediated destruction or by disrupting extracellular signaling pathways.40 These field therapies are efficacious in treating both clinically visible and subclinical lesions, often with prolonged results.29-31 Studies have also demonstrated an additive effect from combining lesion-directed therapies and patient-applied field therapies.32-37 While there are limited data that suggest the specific combination of patient-applied 5-fluorouracil (5-FU) and calcipotriol produces a synergistic effect (with potentially more severe LSR), there is not yet enough evidence to determine if combinations of other patient-applied therapies is superior to mono-patient-applied therapy.38
Multiple factors, including longer duration of therapy and local skin reactions, limit patient adherence to topical therapy for actinic keratoses.
While counseling patients on the natural progression of chronic actinic damage, it is important to discuss the risk of evolution into invasive SCC and the ongoing risk of developing new AKs and skin cancers. AKs are a chronic skin disorder, with most patients requiring periodic clinical assessments and repeated courses of treatment(s).39 Ideal clinical outcomes rely on efficacious agents and patient adherence. Unfortunately, there are many potential barriers to adherence including: insurance coverage, length of treatment course, frequency of application, understanding of more complex interval regimens (eg, 2-weeks on/2-weeks off), and visible LSRs.19,39-41
Long duration and severe local skin reactions may prevent patients from completing a prescribed therapeutic course and prevent subsequent treatments.
Counseling must be provided regarding the expected severity and duration of LSRs. Up to 90% of patients may experience LSRs such as erythema, crusting, erosion and pain at treated sites with severity and duration dependent on the prescription regimen.41 These LSRs may negatively impact patients’ quality of life, especially when applied to conspicuous areas such as the face, scalp, or dorsal hands.40,41 Depending on the onset of LSR relative to duration of therapy, severe reactions may lead to early discontinuation.40 Prolonged LSRs may also dissuade patients from future treatments.40 Even if patients are able to complete the prescribed regimen, their negative experience may adversely impact the likelihood of pursuing future therapy and lead to poor long-term outcomes.40
Patients prefer topical therapies for actinic keratoses that require fewer applications.
Patients prefer AK therapies that have shorter courses. Studies have shown that patient-applied field therapies requiring less than 4 weeks of treatment have significantly increased rates of adherence compared to treatment durations requiring over 4 weeks.40 Furthermore, the chance nonadherence increases when therapy is perceived to be too long or time-consuming (OR 1.2, 95% CI 1.1–1.3).40
To date, there is no definitive way to clinically identify which actinic keratoses will progress into invasive squamous cell carcinomas. Although the literature has demonstrated AK's potential for progression into invasive SCC, there are no universally recognized clinical markers that can readily identify those higher risk AKs. Inflammation, erythema, diameter >1cm, bleeding, ulceration, and rapid growth have been suggested as risk factors.15 The presence of spontaneous/pressure-induced pain may suggest the lesion is in fact a SCC not an AK.23,24 Follicular extension of AKs correlate with both a history of melanoma and non-melanoma skin cancer and an increased risk of future progression into invasive SCC.25,26 This risk may be further increased in immunosuppressed individuals given an already predisposed risk to developing AKs as well as SCC.27,28
Actinic keratoses require treatment.
Given the risk of AK progression to invasive SCC and lack of clinicopathologic signs to differentiate which AKs will progress to invasive disease, these tumors should be treated to decrease unwarranted morbidity and mortality. This statement extends not only to the AKs that are clinically visible, but also includes management of subclinical lesions.
Field, lesional, and combination therapies are effective in the treatment of actinic keratoses.
Multiple studies have demonstrated that various modalities are efficacious for treating AKs. Lesion-directed therapies are often office-based, physician-conducted modalities targeted at clinically visible AKs and can include cryosurgery, surgical/ manual removal, and laser.16,29,30 Field treatments may be office-based (eg, chemical peel, photodynamic therapy (PDT)) or patient-applied medications that target atypical/dysplastic keratinocytes by inhibiting cellular replication, upregulating immune-mediated destruction or by disrupting extracellular signaling pathways.40 These field therapies are efficacious in treating both clinically visible and subclinical lesions, often with prolonged results.29-31 Studies have also demonstrated an additive effect from combining lesion-directed therapies and patient-applied field therapies.32-37 While there are limited data that suggest the specific combination of patient-applied 5-fluorouracil (5-FU) and calcipotriol produces a synergistic effect (with potentially more severe LSR), there is not yet enough evidence to determine if combinations of other patient-applied therapies is superior to mono-patient-applied therapy.38
Multiple factors, including longer duration of therapy and local skin reactions, limit patient adherence to topical therapy for actinic keratoses.
While counseling patients on the natural progression of chronic actinic damage, it is important to discuss the risk of evolution into invasive SCC and the ongoing risk of developing new AKs and skin cancers. AKs are a chronic skin disorder, with most patients requiring periodic clinical assessments and repeated courses of treatment(s).39 Ideal clinical outcomes rely on efficacious agents and patient adherence. Unfortunately, there are many potential barriers to adherence including: insurance coverage, length of treatment course, frequency of application, understanding of more complex interval regimens (eg, 2-weeks on/2-weeks off), and visible LSRs.19,39-41
Long duration and severe local skin reactions may prevent patients from completing a prescribed therapeutic course and prevent subsequent treatments.
Counseling must be provided regarding the expected severity and duration of LSRs. Up to 90% of patients may experience LSRs such as erythema, crusting, erosion and pain at treated sites with severity and duration dependent on the prescription regimen.41 These LSRs may negatively impact patients’ quality of life, especially when applied to conspicuous areas such as the face, scalp, or dorsal hands.40,41 Depending on the onset of LSR relative to duration of therapy, severe reactions may lead to early discontinuation.40 Prolonged LSRs may also dissuade patients from future treatments.40 Even if patients are able to complete the prescribed regimen, their negative experience may adversely impact the likelihood of pursuing future therapy and lead to poor long-term outcomes.40
Patients prefer topical therapies for actinic keratoses that require fewer applications.
Patients prefer AK therapies that have shorter courses. Studies have shown that patient-applied field therapies requiring less than 4 weeks of treatment have significantly increased rates of adherence compared to treatment durations requiring over 4 weeks.40 Furthermore, the chance nonadherence increases when therapy is perceived to be too long or time-consuming (OR 1.2, 95% CI 1.1–1.3).40
DISCUSSION
Dermatologists must be educated and aware of the variable
therapeutic MoA and how they translate to clinical outcomes
and anticipated local skin reactions, which can be explained so
they align with patients’ personal preferences. Patient-applied
topical agents function by inducing either necrosis or apoptosis
