Cryosurgical treatment of actinic keratoses and evidence-based review

BACKGROUND: Actinic keratoses are focal epithelial carcinomas in situ, which are considered precursors of squamous cell carcinoma and must therefore be treated. In the USA, cryosurgery is the most frequent surgical procedure for the treatment of actinic keratoses and considered the treatment of choice. METHODS: Our own results of cryosurgical treatment of actinic keratoses were evaluated. Original publications and reviews on the treatment of actinic keratoses with cryosurgery were retrieved from MEDLINE and classified according to their evidence level. RESULTS: Two months after the procedure, 97.0% of the lesions (n=99) were considered sufficiently treated. Local pain during and shortly after treatment (15%) and pigmentary changes (5%) were the most frequent side effects. Recurrences were detected in 2.1% of the lesions during the 1st year and in 11,5% after 3 years. In 2 further monotherapy studies recurrences occurred in 1,2-9% of the lesions after one year in 30% after 3 years. Literature data suggest that photodynamic therapy is equally or even more effective than cryosurgery after a 3-month follow-up. The cryosurgical results were strongly dependent on the attending physician. CONCLUSIONS: Cryosurgery is beneficial in the treatment of actinic keratoses. This method is equivalent to photodynamic therapy.     

European guidelines for topical photodynamic therapy part 1: treatment delivery and current indications – actinic keratoses,Bowen’s disease,basal cell carcinoma

Topical photodynamic therapy (PDT) is a widely used non‐invasive treatment for certain non‐melanoma skin cancers, permitting treatment of large and multiple lesions with excellent cosmesis. High efficacy is demonstrated for PDT using standardized protocols in non‐hyperkeratotic actinic keratoses, Bowen’s disease, superficial basal cell carcinomas (BCC) and in certain thin nodular BCC, with superiority of cosmetic outcome over conventional therapies. Recurrence rates following PDT are typically equivalent to existing therapies, although higher than surgery for nodular BCC. PDT is not recommended for invasive squamous cell carcinoma. Treatment is generally well tolerated, but tingling discomfort or pain is common during PDT. New studies identify patients most likely to experience discomfort and permit earlier adoption of pain‐minimization strategies. Reduced discomfort has been observed with novel protocols including shorter photosensitizer application times and in daylight PDT for actinic keratoses.     

Kryochirurgische Behandlung aktinischer Keratosen mit evidenzbasierter Übersicht

Background

Actinic keratoses are focal epithelial carcinomas in situ, which are considered precursors of squamous cell carcinoma and must therefore be treated. In the USA, cryosurgery is the most frequent surgical procedure for the treatment of actinic keratoses and considered the treatment of choice.

Methods

Our own results of cryosurgical treatment of actinic keratoses were evaluated. Original publications and reviews on the treatment of actinic keratoses with cryosurgery were retrieved from MEDLINE and classified according to their evidence level.

Results

Two months after the procedure, 97.0% of the lesions (n=99) were considered sufficiently treated. Local pain during and shortly after treatment (15%) and pigmentary changes (5%) were the most frequent side effects. Recurrences were detected in 2.1% of the lesions during the 1st year and in 11,5% after 3 years. In 2 further monotherapy studies recurrences occurred in 1,2–9% of the lesions after one year in 30% after 3 years. Literature data suggest that photodynamic therapy is equally or even more effective than cryosurgery after a 3-month follow-up. The cryosurgical results were strongly dependent on the attending physician.

Conclusions

Cryosurgery is beneficial in the treatment of actinic keratoses. This method is equivalent to photodynamic therapy.     

A randomized controlled clinical trial of topical photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratoses in transplant recipients

BACKGROUND: Transplant recipients have an increased propensity to develop multiple actinic keratoses, which demonstrate an increased transformation rate into invasive squamous cell carcinoma. OBJECTIVE: To evaluate the efficacy and tolerability of topical photodynamic therapy with the new highly tumour-selective photosensitizer methyl aminolaevulinate vs. placebo in the treatment of actinic keratoses in transplant recipients. METHODS: Seventeen transplant recipients with a total number of 129 mild to moderate actinic keratoses were enrolled in a prospective, randomized, double-blind, placebo-controlled study. Two lesional areas within a patient were randomized for two consecutive treatments of topical photodynamic therapy 1 week apart using either methyl aminolaevulinate or placebo cream. Sites were illuminated with 75 J cm(-2) of visible light delivered at 80 mW cm(-2) by a noncoherent light source. Complete resolution and reduction in the number or size of actinic keratoses within the lesional area relative to the initial findings were evaluated at weeks 4, 8 and 16 after treatment. RESULTS: The lesional areas treated with methyl aminolaevulinate were clinically cleared in 13 of 17 patients at 16 weeks. A partial response was recorded in a further three. No reduction in the size or number of actinic keratoses was observed in one area treated with methyl aminolaevulinate and in all placebo-treated areas. Adverse events, such as erythema, oedema and crust formation, were mild to moderate, and treatment was well tolerated by all patients. CONCLUSION: Photodynamic therapy using methyl aminolaevulinate is a safe and effective treatment for actinic keratoses in transplant recipients. It may also reduce the risk of transformation of actinic keratoses to invasive, potentially fatal, squamous cell carcinoma.     

Topical and light-based treatments for actinic keratoses

Actinic keratosis is currently believed to be an early stage in the evolution of squamous cell carcinoma. Active and intensive treatment of actinic keratosis may prevent the formation of invasive squamous cell carcinoma and potential metastases. While destructive methods of treatment of actinic keratosis remain the gold standard for the eradication of visible and palpable actinic keratoses, new medical therapies may accomplish this goal more comfortably and reliably for the patient. Newer topical medications, light therapy and photodynamic therapy are generating promising results that presage more widespread use in the future. These novel therapies for the early treatment of actinic keratosis may be administered in combination or serially, with the locus of treatment at any given time possibly restricted to a region of affected skin. Treatment of incipient or subclinical lesions may mitigate the risk of future squamous cell carcinomas lesions. Widespread actinic keratosis constitutes a persistent medical problem that requires long-term management. The role of traditional and novel treatments in the routine treatment of actinic keratosis will be determined by the efficacy, limitations and the practicality of each of these methods in individual patients. As the first stage of squamous cell carcinoma, actinic keratosis is worthy of prompt evaluation and active treatment.     

Actinic keratosis: Facts and controversies

Actinic keratoses are common lesions that are generally clinically diagnosed. Although currently most actinic keratoses are treated, whether this is truly necessary is debated. Treatment of all actinic keratoses is advocated because preliminary evidence indicates that actinic keratoses may progress to squamous cell carcinomas. Some also consider actinic keratoses equivalent to squamous cell carcinoma.     

Kutane Nebenwirkungen einer Hydroxyurea-Therapie bei Polycythaemia vera

A 68-year-old women with polycythemia vera was treated with hydroxyurea for 8 years and developed painful ulcers on her lower legs, multiple hypertrophic actinic keratoses and a squamous cell carcinoma. After discontinuing hydroxyurea therapy the leg ulcers resolved within 8 weeks. The hypertrophic actinic keratoses and squamous cell carcinoma were treated with cryotherapy and excision, respectively. Hydroxyurea induces a variety of cutaneous side effects such as painful leg ulcers and squamous cell carcinomas. Given the wide variety of adverse cutaneous side effects associated with long-term hydroxyurea therapy, the first step in management is to insure that physicians and patients are aware of the specific risks of this treatment. Patients under hydroxyurea therapy should be monitored closely by dermatologists to early detect and treat the cutaneous side effects.     

Actinic Keratosis

Actinic keratoses are hyperkeratotic skin lesions that represent focal abnormal proliferation of epidermal keratinocytes. Some actinic keratoses evolve into squamous cell carcinoma of the skin, while others resolve spontaneously. The conversion rate of actinic keratosis to squamous cell carcinoma is not accurately known, but appears to be in the range of 0.25 to 1% per year. Although there is a low rate of conversion of actinic keratoses to squamous cell carcinoma, 60% of squamous cell carcinomas of the skin probably arise from actinic keratoses. The main cause of actinic keratoses in otherwise healthy Caucasians appears to be the sun. Therapy for actinic keratoses begins with prevention which starts with sun avoidance and physical protection. Sunprotection with sunscreens actually slows the return of actinic keratoses in patients already getting actinic keratoses. Interestingly, a few studies are available that demonstrate that a high fat diet is associated with the production of more actinic keratoses than is a low fat diet. One of the mainstays of therapy has been local destruction of the actinic keratoses with cryotherapy, and curettage and electrodesiccation. A new addition to this group of therapies to treat individual actinic keratoses is photodynamic therapy with topical aminolevulinic acid and light. In patients who have numerous actinic keratoses in an area of severely sun damaged skin, therapies which are applied to the whole actinic keratosis area are used. The goal of treating such an area of skin is to treat all of the early as well as the numerous clinically evident actinic keratoses at the same time. The classical approaches for treating areas of photodamaged skin without treating actinic keratoses individually include: the use of topically applied fluorouracil cream, dermabrasion, and cutaneous peels with various agents like trichloroacetic acid. Both topically as well as orally administered retinoids have been used to treat actinic keratoses but retinoids alone are probably not an optimal monotherapy. Photodynamic therapy with topical aminolevulinic acid and light is a new therapy for actinic keratoses. Aminolevulinic acid is a precursor of protoporphyrin IX (PpIX) which is synthesized in the actinic keratosis when it is treated with aminolevulinic acid, and the PpIX photosensitizes the actinic keratosis so that light exposure can lead to its destruction. Photodynamic therapy with topical aminolevulinic acid is approved in the US to treat multiple individual actinic keratoses on the face and scalp and has similar cure rates to those reported for cryotherapy and fluorouracil therapy.     

The effect of an intralesional sustained-release formulation of interferon alfa-2b on basal cell carcinomas

Intralesional interferon alfa-2b has been proven effective in the treatment of basal cell carcinomas. Because nine injections over a 3-week period have been necessary to produce clinically significant cure rates, a sustained-release protamine zinc chelate interferon formulation has been developed. In this study, 65 basal cell carcinomas were treated in one of two dosing schedules with intralesional sustained release interferon alfa-2b (10 million IU per injection). Thirty-three patients received a single injection and 32 patients received one injection per week for 3 weeks. At study week 16, 80% of evaluable tumors treated with three injections and 52% treated with one injection were cured histologically. Two patients discontinued injections because of side effects. A sustained-release protamine zinc preparation of interferon alfa-2b shows promise as a practical, effective, and cosmetically elegant treatment for basal cell carcinoma.     

CONSIDERATION OF THE COST OF INTERFERON ALFA-2b IN THE TREATMENT OF BASAL CELL CARCINOMA

Interferon alfa-2b is an effective but expensive way of treating basal cell carcinoma. In this paper, the cost-effectiveness of interferon relative to conventional treatment is considered. Circumstances where surgery is contra-indicated and would not otherwise be performed are not considered. The cost of achieving cure by interferon alfa-2b in the form of Intron A® is compared with the cost of conventional treatment in four situations; simple lesions, lesions in which protacted healing is expected, lesions in areas where cosmetic result is important and large lesions where hospitalisation for skin grafting may be necessary. For simple lesions, treatment with interferon alfa-2b costs between $500 and $760 more per cure than conventional treatment. However, it is less expensive than conventional methods in cases that would require extensive home nursing or hospitalisation. The difference in cost in simple cases also represents the price which must be paid for the better cosmetic result achieved by interferon alfa-2b. In conclusion, interferon alfa-2b adds another effective option to the treatment of BCC but it is expensive. To exploit its advantages properly, it must be targeted on those who will benefit from it the most.     

Topical treatment of actinic keratoses with low‐dose 5‐fluorouracil in combination with salicylic acid – pilot study

Background: Actinic keratoses (AK) are carcinomas in situ and can progress to invasive squamous cell carcinomas. Treatment of actinic keratoses can be achieved by physical ablation, chemotherapeutic agents, immunomodulators or photodynamic therapy. Patients and Methods: We conducted a proof of concept study with 15 patients. Overall 66 actinic keratoses were treated with 5‐FU (0.5 %) and salicylic acid (10 %) for 4 weeks (3 times per week). Results: After 12 weeks complete response of 47 AK (77 %), partial response of 13 AK (21 %) and non‐response of 1 AK (2 %) were achieved. Conclusions: Treatment was well tolerated and efficient.     

Optimum Treatment Strategies for Actinic Keratosis (Intraepidermal Squamous Cell Carcinoma)

Actinic keratoses are superficial squamous cell carcinomas. Treatment of these lesions is indicated to prevent the cells from invading the dermis and possibly metastasizing. If a lesion exhibits evidence of possible dermal invasion, such as marked erythema, ulceration, tenderness, bleeding, and especially induration, the physician should always consider performing a biopsy. Cryosurgical destruction, the most common treatment employed, has been shown to be 98.8% effective in eliminating the lesions. Adverse reactions such as scarring, textural changes, infection, and pigmentation alteration rarely occur. Physical destruction using electrodesiccation and curettage is particularly effective when the patient has hyperkeratotic lesions. When a patient has a multitude of actinic keratoses, the use of other treatments including fluorouracil, nonsteroidal anti-inflammatory preparations, immune response modifiers, and photodynamic therapy should be considered. However, none of these treatments has proven to be as effective overall as cryosurgical destruction. If a lesion does not respond to treatment, obtaining a biopsy of the lesion should be considered to be certain that the lesion is not an invasive squamous cell carcinoma.     

Bildgebende Diagnostik der aktinischen Porokeratose mittels optischer Kohärenztomographie (OCT)

Disseminated superficial actinic porokeratosis (DSAP) is a rare, genetically heterogeneous skin disorder. We report a case of a 73-year-old female patient who was diagnosed with DSAP by optical coherence tomography (OCT) and histology. During the last 4 years prior to diagnosis, she had developed numerous (pre)malignant lesions of the skin of the lower legs including actinic keratoses, squamous cell carcinomas and Bowen's disease. DSAP lesions and actinic keratoses were resistant to topical treatment with imiquimod and retinoids, but improved with photodynamic therapy (PDT).     

Cornu cutaneum

We report on 62 cases of cornu cutaneum. In contrast to the general opinion that the majority of these lesions arise on the basis of an underlying actinic keratosis or a squamous cell carcinoma, on histological examination we found actinic keratoses in only 25% and squamous cell carcinomas in only 3.2% of cases; 58% of all lesions were identified as common warts. We therefore recommend removal of these skin lesions by the shaving technique followed by electrodesiccation of the base. This has the advantage of supplying the histopathologist with a representative specimen for histological examination and avoiding an unnecessarily large surgical excision. In the rare cases of histologically confirmed squamous cell carcinoma, these lesions can be excised in a second session.     

Disseminated superficial actinic porokeratosis: Appearance associated with photochemotherapy for psoriasis

A patient with chronic psoriasis treated with psoralens plus ultraviolet A (PUVA) developed characteristic lesions of disseminated superficial actinic porokeratosis (DSAP). Since other processes associated with ultraviolet irradiation, including epidermal dysplasia, actinic keratoses, squamous cell carcinomas, and keratoacanthomas, have been reported to result from PUVA, it is possible that her DSAP lesions were induced by this therapy.     

Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin

INTRODUCTION: After renal transplantation, the incidence of premalignant and malignant skin lesions is high. Treatment with acitretin improves the number and aspect of actinic keratoses and appears to reduce the incidence of squamous cell carcinomas, but treatment is hampered by frequent side effects. No optimal long-term dosing advice is available. METHODS: A total of 26 long-term renal transplant recipients were randomized to 1-year treatment with acitretin, either 0.4 mg/kg/d throughout the whole year or 0.4 mg/kg/d during the first 3 months followed by 0.2 mg/kg/d for the remaining 9 months. At 9 different time points, the number of actinic keratoses and tumors was counted, and erythema and thickness of the lesions, and severity of side effects were scored. Patient's judgment was recorded using visual analog scores. RESULTS: In both groups, the number of actinic keratoses decreased by nearly 50%, but the number of new malignant tumors during the study year was similar to the number of tumors in the year before the study. Thickness of the keratoses decreased significantly in both groups. Acitretin dose had to be reduced in most patients because of the frequent occurrence of mucocutaneous side effects, such as cheilitis, excessive peeling of the skin, and hair disorders. In the 14 patients randomized to continuous treatment with a dose of 0.4 mg/kg/d, this dose could be maintained in 3 of 14 patients only. Temporary interruption of acitretin therapy was necessary in 7 of 26 patients. Patients' contentment about the aspect of their skin increased significantly, with no differences between groups. CONCLUSIONS: Acitretin therapy decreased the number of actinic keratoses in renal transplant recipients at a low maintenance dose of 0.2 mg/kg/d and significantly decreased the degree of thickness of the lesions. However, the incidence of new skin malignancies remained unchanged. Despite the high incidence of mucocutaneous side effects, patient's contentment with the aspect of their skin increased significantly.     

Actinic keratoses

Actinic keratoses are defined as proliferation of cytologically atypical keratinocytes in the zone of epidermal-dermal junction in photodamaged skin. In the northern hemisphere the prevalence of actinic keratoses ranges depending on different epidemiological studies from 11% to 25% for people aged 40 or older. The main cause of actinic keratoses is exposure to UVB radiation in sunlight UVB radiation induces mutations in the telomerase gene and in the tumor suppressor gene P53, which can also be detected in invasive squamous cell carcinoma. The only histological parameter to distinguish between actinic keratoses and SCC is the level of invasiveness. The risk for actinic keratoses to develop into SCC is about 16% over lo years. For this reason and because of the high prevalence of actinic keratoses, it has been suggested to replace the term,, actinic keratosis K with intraepidermal squamous cell carcinoma' to better characterize the lesion. In the following review recent aspects of pathogenesis and therapy of actinic keratoses are discussed.     

European Dermatology Forum guidelines on topical photodynamic therapy 2019 Part 1: treatment delivery and established indications – actinic keratoses,Bowen's disease and basal cell carcinomas

Topical photodynamic therapy (PDT) is a widely approved therapy for actinic keratoses, Bowen's disease (squamous cell carcinoma in situ), superficial and certain thin basal cell carcinomas. Recurrence rates when standard treatment protocols are used are typically equivalent to existing therapies, although inferior to surgery for nodular basal cell carcinoma. PDT can be used both as lesional and field therapies and has the potential to delay/reduce the development of new lesions. A protocol using daylight to treat actinic keratoses is widely practised, with conventional PDT using a red light after typically a 3‐h period of occlusion employed for other superficial skin cancer indications as well as for actinic keratoses when daylight therapy is not feasible. PDT is a well‐tolerated therapy although discomfort associated with conventional protocol may require pain‐reduction measures. PDT using daylight is associated with no or minimal pain and preferred by patient. There is an emerging literature on enhancing conventional PDT protocols or combined PDT with another treatment to increase response rates. This guideline, published over two parts, considers all current approved and emerging indications for the use of topical PDT in dermatology, prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence.     

Die aktinische Keratose

Actinic keratoses are defined as proliferation of cytologically atypical keratinocytes in the zone of epidermal-dermal junction in photodamaged skin. In the northern hemisphere the prevalence of actinic keratoses ranges depending on different epidemiological studies from 11% to 25% for people aged 40 or older. The main cause of actinic keratoses is exposure to UVB radiation in sunlight. UVB radiation induces mutations in the telomerase gene and in the tumor suppressor gene p53, which can also be detected in invasive squamous cell carcinoma. The only histological parameter to distinguish between actinic keratoses and SCC is the level of invasiveness. The risk for actinic keratoses to develop into SCC is about 16% over 10 years. For this reason and because of the high prevalence of actinic keratoses, it has been suggested to replace the term "actinic keratosis" with "intraepidermal squamous cell carcinoma" to better characterize the lesion. In the following review recent aspects of pathogenesis and therapy of actinic keratoses are discussed.     

Chemopreventative thoughts for photodynamic therapy

The concept of skin cancer prevention with photodynamic therapy has evolved over the past few years to include large surface application of aminolevulinic acid or methyl aminolevulinate followed by light exposure to prevent the development of new lesions. Pre-clinical studies using various mouse models have shown that large surface photodynamic therapy can prevent the appearance of actinic keratoses, squamous cell carcinomas, and basal cell carcinomas. Recent clinical studies also suggest that large surface photodynamic therapy can prevent the development of actinic keratoses and possibly skin cancer.