Successful treatment of actinic keratosis with imiquimod cream 5%: a report of six cases

BACKGROUND: Actinic keratoses (AK) are premalignant lesions, which are routinely treated by destructive procedures such as cryotherapy, electrodessication or topical 5-fluorouracil. OBJECTIVES: The aim of this study is to report six cases of AK treated with a potential new topical therapy, imiquimod. METHODS: Subjects included in this study had suffered with recurrent AK for between 5 and 16 years. All six men were treated with imiquimod 5% cream three times a week for 6-8 weeks. In the event of a local skin reaction treatment was modified to two times per week. RESULTS: All the AK lesions were successfully cleared after treatment with imiquimod cream 5% for 6-8 weeks. Histologically, no apparent signs of persisting AK could be detected, and no recurrences were reported during follow up. CONCLUSIONS: This study suggests that imiquimod may be useful as a new therapy for the treatment of actinic keratoses.     

A randomized trial of topical 5% 5-fluorouracil (Efudix cream) in the treatment of actinic keratoses comparing daily with weekly treatment

BACKGROUND: Topical 5-fluorouracil (5-FU) cream is widely used in the treatment of actinic keratoses (AKs) but the optimum treatment regimen that provides efficacy while minimizing side-effects remains unclear. OBJECTIVES: A randomized trial to compare the efficacy and side-effects of daily vs. weekly application of 5% 5-FU in the treatment of AKs of the scalp and face. PATIENTS/METHODS: Twenty patients were recruited and randomized to two groups. Group 1 (13 patients) applied 5% 5-FU twice daily for 3 weeks, group 2 (seven patients) applied 5% 5-FU twice daily for 1 day per week for 12 weeks. Patients were reviewed at weeks 3, 12, 24 and 52. At each review a lesion count and lesion map were completed and patients were asked to score efficacy and inflammation. RESULTS: At week 0 the median lesion count was the same in both groups, 17.5 lesions. At 12 weeks the median lesion count in group 1 had fallen to 0 where it remained for the duration of follow-up. In group 2 the median lesion count fell to 6 at 12 weeks, 5.5 at 24 weeks and was 3 at 52 weeks. The difference in the lesion count was significant at all time points after week 0: P < 0.05 at weeks 12 and 52, and P < 0.01 at week 24. The mean inflammation score was higher in patients clear of AKs at 12 weeks compared with those who had not cleared, 3.8 compared with 1.9. This difference was statistically significant (P < 0.05) suggesting that inflammation is necessary for efficacy. CONCLUSIONS: We conclude that daily application of 5% 5-FU cream is more effective than weekly application at clearing AKs from the scalp and face. Our results also suggest that inflammation is likely to be required to achieve a therapeutic effect.     

Efficacy and safety of serial glycolic acid peels and a topical regimen in the treatment of recalcitrant melasma

Melasma is a common acquired disorder of facial hyperpigmentation. In this study we investigated the efficacy and safety of a combined treatment regimen including serial glycolic acid peels, topical azelaic acid cream and adapalene gel in the treatment of recalcitrant melasma. Twenty-eight patients with recalcitrant melasma were enrolled in a prospective, randomized, controlled trial lasting 20 weeks. The patients of the group receiving chemical peels underwent serial glycolic acid peels in combination with topical azelaic acid 20% cream (b.i.d.) and adapalene 0.1% gel (q.i.d., applied at night). The control group received only topical treatment including topical azelaic acid and adapalene. The clinical improvement was assessed with the Melasma Area Severity Index (MASI) at baseline and monthly during the 20-week treatment period. The results showed a prominent decrease in MASI scores at the end of the treatment in both groups, although the results were better in the group receiving chemical peels (P=0.048). All patients tolerated the topical agents well with minimal irritation observed in the first few weeks of the therapy. Three patients in the glycolic acid peel group developed a mild-degree postinflammatory hyperpigmentation with total clearance at the end of the treatment period. Therefore, the present study suggests that combined treatment with serial glycolic acid peels, azelaic acid cream and adapalene gel should be considered as an effective and safe therapy in recalcitrant melasma.     

Combination of microneedling and glycolic acid peels for the treatment of acne scars in dark skin

Introduction Acne scars can cause emotional and psychosocial disturbance to the patient. Various modalities have been used for the treatment of acne scars like punch excision, subcision, peels, microdermabrasion, unfractionated and fractioned lasers. The latest in the treatment armamentarium is microneedling. Acne scars commonly coexist with postinflammatory hyperpigmentation. A combination of microneedling and glycolic acid (GA) peels was found to give excellent results in the treatment of such scars. The aim was to study the efficacy of a combination of microneedling with glycolic peel for the treatment of acne scars in pigmented skin. Method Thirty patients in the age group of 20–40 years with atrophic box type or rolling scars with postinflammatory hyperpigmentation were chosen for the study. Two groups were made. The first group comprised of 30 patients in whom only microneedling was performed once in 6 weeks for five sessions. In the second group of 30 patients, a combination of microneedling and 35% GA peels was carried out. Patients from both groups were evaluated on the basis of Echelle d’Evaluation clinique des Cicatrices d’acné classification. Results Based on the objective scoring and its statistical analysis, there was significant improvement in superficial and moderately deep scars (grade 1–3). There was also improvement in skin texture, reduction in postacne pigmentation in the second group. Conclusion Microneedling is a simple, inexpensive office procedure with no downtime. It is safe in Indian skin (skin types III–IV). The combined sequential treatment with GA peel caused a significant improvement in the acne scars without increasing morbidity.     

Pharmacokinetics and safety of imiquimod 5% cream in the treatment of actinic keratoses of the face,scalp, or hands and arms

The safety and efficacy of imiquimod 5% cream is being evaluated for the treatment of dysplastic lesions of the epidermis (actinic keratoses, AK). The objective of this clinical study was to describe the pharmacokinetics and safety of topical imiquimod during multiple dosing of AK subjects. A total of 58 adult subjects with 5 to 20 AK lesions at the treatment site applied imiquimod cream three times per week for up to 16 weeks as follows: 12 males and 11 females applied 12.5 mg imiquimod to the face; 11 males applied 25 mg to the entire balding area of the scalp; and 12 males and 12 females applied 75 mg to both hands and forearms. Pharmacokinetics and safety were assessed after the first and last doses, as well as biweekly. Imiquimod and its metabolites were measured in the serum and urine using sensitive liquid chromatography/mass spectrometry methods. Less than 0.6% of the applied doses was recovered in the urine of all subjects. Serum imiquimod levels were low, reflecting minimal dermal absorption, and increased with dose, although not proportionally. Peak levels at the end of dosing were 0.1, 0.2, and 1.6 ng/ml for the face, scalp, and hands/arms groups, respectively. A two- to fourfold accumulation was seen at the end of dosing. Local application site reactions were the most common adverse event, reported by approximately 50% of the subjects in each treatment group. The small number of systemic adverse events, including flu-like symptoms, were mostly mild and did not show a dose response. Thus, minimal systemic absorption and good safety margins for topical imiquimod were seen in AK subjects with doses as high as 75 mg three times per week for 16 weeks.Abbreviations AK Actinic keratosis - 2,5-AS 25-Oligoadenylate synthetase - AUC Area under the concentration-time curve - Cmax Maximum serum concentration - IFN Interferon-alpha - IL-1RA Interleukin-1 receptor antagonist - Rmax Maximum change from baseline value     

Successful treatment of multiple premalignant and malignant lesions in arsenical keratosis with a combination of acitretin and intralesional 5-fluorouracil

A case of arsenical keratosis with multiple lesions of Bowen's disease and squamous cell carcinoma is described. The patient was successfully treated with a combination of acitretin and intralesional 5-fluorouracil. All the lesions resolved after three months of therapy with no side effects and no recurrence during four months of follow-up.     

Caspase-3在皮肤鳞状细胞癌及光线性角化病中的表达

目的：检测Caspase-3在皮肤鳞状细胞癌及光线性角化病组织中的表达。方法： 应用免疫组化法检测16例皮肤鳞状细胞癌皮损、27例光线性角化病皮损及24例正常皮肤组织中Caspase-3蛋白的表达。结果：Caspase-3在皮肤鳞状细胞癌、光线性角化病及正常皮肤组织的表达率分别为37.50%,51.85%,79.17%,其表达含量在皮肤鳞状细胞癌、光线性角化病、正常皮肤组织逐渐增加。结论：Caspase-3蛋白表达下调可能参与皮肤鳞状细胞癌及光线性角化病的发病过程。     

SGK1在日光性角化病、基底细胞癌及鳞状细胞癌中的表达

目的：检测SGK1在日光性角化病（AK）、基底细胞癌（BCC）及鳞状细胞癌（SCC）中的表达。方法：采用免疫组化SABC法检测SGK1在25例正常皮肤(NS)、25例AK、28例BCC、28例皮肤鳞状细胞癌标本中的表达。结果：NS、AK、BCC和SCC标本中,SGK1阳性细胞率分别为（40.03±14.42）%,（36.63±14.28）%,（52.82±18.73）%和（52.58±20.13）%。BCC组和SCC组分别与NS组比较,差异均有统计学意义（Ps<0.05）。各组SGK1染色阳性细胞率>50%的标本分别为6例（24%）,3例（12%）,16例（57.14%）和14例（50%）,BCC组和SCC组分别与NS组比较,差异均有统计学意义（Ps<0.05）。结论：SGK1的高表达可能与基底细胞癌及鳞状细胞癌的发病有关。     

Comparison of facial predilection sites for cutaneous squamous cell carcinoma and actinic keratosis in Japanese patients

Cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK) occur most often on the face. Ultraviolet light is apparently their most common cause. As AK is considered to be a precursor of cSCC, their distribution on the face should be similar. However, cSCC often occurs on the temple or mandibular area, whereas AK arises on the central forehead, cheek or nose. We retrospectively evaluated differences in affected site distribution for cSCC (n = 54) and AK (n = 95). We found AK to occur preferentially on the central facial area (63/95, 66%), which is the most sun‐exposed area, and cSCC to occur preferentially on peripheral areas such as the temple and mandibular area (24/54, 44%). Those distributions were significantly different (P = 0.011, Fisher's exact test). This result suggests that cSCC occurs preferentially in the peripheral area compared with the central facial area, which further implies that either other factors are needed to make AK progress to cSCC in peripheral areas, or that peripheral cSCC can occur without preceding AK. This is the first report to focus on geographic assessment of cSCC and AK in detail. Further studies are needed to elucidate the mechanism of our finding.     

Increased Fas ligand expression by T cells and tumour cells in the progression of actinic keratosis to squamous cell carcinoma

BACKGROUND: In the counterattack model of tumorigenesis, it has been proposed that tumours develop resistance to attack from Fas ligand (FasL)-expressing cytotoxic T cells by downregulating Fas (immune escape), while at the same time upregulating FasL expression to induce apoptosis in Fas-expressing T cells (counterattack). OBJECTIVES: The aim of this study was to examine Fas and FasL expression on tumour cells and infiltrating T cells during the progression of actinic keratoses (AK), the benign precursor lesion, to squamous cell carcinoma (SCC). PATIENTS AND METHODS: Samples of AK (n = 20) and SCC (n = 20) were collected from immunocompetent patients attending dermatology clinics. Double-label immunohistochemistry was performed on frozen sections using mouse monoclonal antibodies to Fas or FasL, simultaneously with a rabbit polyclonal antibody to either CD3 or cytokeratin, markers of T cells and keratinocytes, respectively. Cell densities and the optical density of tumour Fas expression were measured using image analysis. RESULTS: FasL-expressing T cells were observed in nine of 19 SCCs, compared with three of 20 AKs (P < 0.05). FasL-expressing tumour cells were found in nine of 18 SCCs, compared with only one of 20 AK specimens (P < 0.005). There was no difference in the number of Fas-expressing T cells infiltrating AK and SCC. Fas expression by keratinocytes, measured by optical density, was lower in SCC (range 0.1-40, median 17) compared with AK (range 4-62, median 25) (P < 0.05). CONCLUSIONS: These results suggest that the greater numbers of FasL-expressing T cells infiltrating into SCC compared with AK are targeting Fas-expressing tumour cells. As AK cells progress to SCC, they subvert this T-cell-mediated killing of tumour cells by downregulating their Fas expression (immune escape). Furthermore, tumour cells upregulate their expression of FasL, possibly as a counterattack measure to induce apoptosis in the increased number of tumour-infiltrating T cells. Thus changes in Fas/FasL-mediated interactions between T cells and tumour cells occur during the progression of AK into SCC.     

Treatment monitoring of 5‐fluorouracil 0.5%/salicylic acid 10% lesion‐directed therapy for actinic keratosis using dermoscopy and in‐vivo reflectance confocal microscopy

Recently, 5‐fluorouracil 0.5%/salicylic acid 10% (5‐FU/SA) topical solution has been included in the National Italian portfolio for lesion‐directed treatment of grade I/II actinic keratosis (AKs) located on the face or scalp. To describe the utility of dermoscopy and RCM in treatment response monitoring of a series of AKs treated with 5‐FU/SA as lesion‐directed therapy. Consecutive patients were prospectively treated for a maximum of 12 weeks with 5‐FU/SA for AKs located on the face or scalp. Clinical, dermoscopic, and confocal images of one index AK were acquired at each visit and pre‐specified criteria were evaluated. Clinical, dermoscopic, and confocal responses were evaluated at last follow‐up visit. Fourteen patients were enrolled, of which five were treated for 12 weeks, seven for 8, and two for 4 weeks. At a median follow up of 30 weeks, 64.3% (9/14) index AKs achieved complete clinical, 50% (7/14) complete dermoscopic and 42.9% (6/14) complete confocal clearance. Local skin reaction was mild and significantly decreased during therapy administration. Although the small number of cases, our study underlines the utility of both dermoscopy and in‐vivo RCM in 5‐FU/SA treatment response monitoring for AKs located on the face or scalp.     

Modes of action of diclofenac 3%/hyaluronic acid 2.5% in the treatment of actinic keratosis

Background: The efficacy of topically applied diclofenac 3 % in combination with hyaluronic acid 2.5 % in the treatment of actinic keratoses (AKs) has been demonstrated in several clinical studies, but the exact mode of action is still unclear. This study evaluates the potential molecular and cellular main modes of action of topically applied diclofenac in the treatment of AKs. Patients and methods: In this prospective study 20 male patients with AKs were treated for 90 days with topically applied diclofenac 3 %/hyaluronic acid 2.5 %. Before and after treatment, skin biopsies were taken from the treatment area and were investigated histologically and immunohistochemically as well as compared to healthy skin. For this purpose, markers for inflammation (COX‐2, CD3, CD8), apoptosis (p53), cell cycle arrest (p53, p21), proliferation (Ki67), and angiogenesis (CD31) were examined. Results: The immunohistochemical analysis demonstrated a significant decrease in expression of COX‐2, CD3 and CD8. Furthermore, there was a clear reduction of CD31 expression as a marker for angiogenetic processes. Additionally, there was a tendency toward a reduction in markers for proliferation and apoptosis. Conclusions: The efficacy of diclofenac 3 %/hyaluronic acid 2.5 % in the treatment of AKs is probably due to anti‐inflammatory and anti‐angiogenic effects, potentially associated with anti‐proliferative and apoptosis‐inducing underlying mechanisms.     

Photodynamic therapy with violet light and topical δ-aminolaevulinic acid in the treatment of actinic keratosis, Bowen's disease and basal cell carcinoma

BACKGROUND: Most clinical studies using photodynamic therapy (PDT) with topical application of delta-aminolaevulinic acid (delta-ALA) use red light because it allows greater depth of penetration. However, given the porphyrin-like spectrum of delta-ALA-induced photosensitivity, violet light provides a maximal overlap with the excitation spectrum of protoporphyrin IX, meaning that PDT with violet light uses less light energy to induce the phototoxic reaction. AIM: To study the efficacy of violet light in combination with topical delta-ALA PDT in the treatment of pre-malignant and malignant skin lesions. METHODS: Eight hours after 20% delta-ALA was applied topically, photoirradiation was performed with an incoherent light source (Philips HPM-10, 400 W) emitting predominantly violet light (400-450 nm). Lesions received 10-20 J/cm2 during an exposure time of 30 min. The 38 subjects treated included three with basal cell naevus syndrome with multiple (> 30) superficial and nodular basal cell carcinomas (BCCs), one subject had multiple lesions of Bowen's disease, involving 50% of the scalp, and the remaining 34 subjects presented a total of 35 superficial BCCs, 10 nodular BCCs, four large solar keratoses and five solitary lesions of Bowen's disease. RESULTS: Complete remission both clinically and histologically was seen after a single treatment in 82% of the superficial BCCs (100% after a second treatment), 50% of the nodular BCCs, one of the four solar keratosis lesions (partial remission in the other three) and 90-100% of the solitary lesions of Bowen's disease. CONCLUSIONS: delta-ALA PDT using violet light appears to be a well tolerated and effective alternative treatment for premalignant and malignant skin lesions, especially when there are multiple lesions or large patches comprising a large area of skin.     

Pitfalls in the clinical and dermoscopic diagnosis of pigmented actinic keratosis

Pigmented actinic keratosis and melanoma may exhibit overlapping clinical features, thus representing a diagnostic challenge for dermatologists. Although the differentiation between these two entities is traditionally done by histopathology, dermoscopy has been utilized as a useful additional aid for improving the clinical diagnostic accuracy of such pigmented skin lesions. We report the clinical and dermoscopic features of two pigmented actinic keratoses to discuss the difficulties in their preoperative differential diagnosis.