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PubMed2003

A broad spectrum of human papillomavirus types is present in the skin of Australian patients with non-melanoma skin cancers and solar keratosis.

BACKGROUND: Human papillomavirus (HPV) may play a role in the pathogenesis of non-melanoma skin cancer (NMSC) in epidermodysplasia verruciformis (EV) patients, but in the general population no specific HPV types have been associated with these lesions. Objectives To examine the spectrum of HPV types present in the skin and tumours of Australian patients with NMSC or solar keratosis (SK). METHODS: Biopsies from tumours, and cotton swab samples of perilesional skin and buttock skin from each of 59 Australian patients with basal cell carcinoma (BCC), squamous cell carcinoma (SCC) or SK were tested for HPV DNA by polymerase chain reaction (PCR) using HPV consensus (FAP) primers and by type-specific primers for HPV 38 and candidate HPV 92. The identification of HPV type from consensus PCR was performed by sequencing and comparison with GenBank. RESULTS: In total, 49 of 59 (83%) patients harboured HPV DNA, which was detected in 28 of 64 (44%) biopsies, 48 of 64 (75%; P < 0.001) perilesional swabs and 36 of 59 (61%; P = 0.04) buttock swabs. Forty-five different HPV types/putative types were detected: 15 were previously characterized HPV types, 17 were earlier described putative types and 13 were new putative types. In addition, six subtypes and four variants of HPV sequences were identified. HPV types within the B1 group (EV HPV types) were found in 26 of 64 (40%) lesions, 44 of 64 (69%) perilesional swabs and 35 of 59 (59%) buttock swabs. HPV 38 was detected in 23 of 59 (39%) patients, and was found in seven of 16 (43%) SKs, but was less common in SCCs [three of 23 (13%); P = 0.037] and BCCs [four of 25 (16%); P = 0.056]. Candidate HPV 92 was found in seven of 59 (12%) patients. CONCLUSIONS: A broad spectrum of HPV types, the majority from the B1 group, was found in skin of Australian patients with skin tumours. HPV 38 was found significantly more often in SK than in SCC. However, the role of cutaneous HPV infection in the pathogenesis of NMSC remains elusive.

Adult↗
PubMed2003

Enhanced expression of p16 in seborrhoeic keratosis; a lesion of accumulated senescent epidermal cells in G1 arrest.

BACKGROUND: Seborrhoeic keratosis (SK) is a common skin disease associated with skin ageing and photoageing, but only limited studies have been performed on SK and the senescence of keratinocytes. OBJECTIVES: We sought to clarify the genetic basis of SK and the senescence of keratinocytes. METHODS: Expression of p16, cyclins A, D and E, p21, p53, retinoblastoma (Rb) gene product and telomerase-associated protein 1 (TP1) in SK was examined by immunohistochemistry. DNA fragmentation in SK was detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling method. We cultured keratinocytes from SK lesions and non-lesional epidermis and examined expression of p16, observed morphology of the cultured cells by light and electron microscopy and measured survival time. RESULTS: p16, a cyclin-dependent kinase inhibitor, was expressed in all cells from SK lesions, whereas normal keratinocytes expressed p16 only in the granular cells. Other factors such as cyclins A, D and E, p21, p53, Rb gene product, and TP1, were not expressed in SK cells. These results suggest that p16 expression is a marker of SK and that p16 has a role in the pathogenesis of SK. DNA fragmentation was not detected in four of five SK tissue samples; one of the SK tissue samples showed DNA fragmentation only in the superficial upper layer of an SK lesion, suggesting that apoptosis was inhibited in SK cells. In contrast, normal epidermis showed DNA fragmentation in the granular and squamous layers. Immunohistochemical examination of cultured SK cells also revealed the presence of p16. A greater number of SK cells survived after 3 weeks of culture in comparison with normal keratinocytes. Features of senescence, such as a balloon-like appearance after lengthy culture and increased amounts of tonofilaments in cytoplasm, were observed in SK cells in culture. CONCLUSIONS: These results suggest that SK is a benign neoplasm where keratinocytes in a senescent condition and G1 arrest are accumulated.

Cell Survival↗
PubMed2002

Keratosis lichenoides chronica in childhood.

Keratosis lichenoides chronica (KLC) is a rare chronic disorder of keratinization characterized by lichenoid hyperkeratotic papules arranged in a linear pattern, erythematosquamous plaques and seborrhea-like dermatitis on the face. We report a 2-year-old girl diagnosed with KLC whose lesions, arranged in symmetrical linear fashion, improved after sunlight exposure during the summer.

Child, Preschool↗
PubMed1998

Frequency of pre-existing actinic keratosis in cutaneous squamous cell carcinoma.

BACKGROUND: Controversy over the rate of malignant transformation of actinic keratosis (AK) into cutaneous squamous cell carcinoma (SCC) has generated considerable debate regarding the importance of treating all such precancers to preclude their transofrmation. Current changes in US healthcare policy will deny many individuals access to certain simple and effective treatment modalities for precancerous lesions. OBJECTIVE: Our purpose was to determine whether there is a significant association between the presence of cutaneous SCC and pre-existing AK. METHODS: One hundred and sixty five consecutive cases of cutaneous SCC, retrieved from the files of a university-affiliated dermatopathology laboratory serving north-central Florida, were selected for review by a single dermatopathologist (D.M.). Hematoxylin and eosin stained skin tissue slides were examined under light microscopy for the presence of AK in close proximity to, or giving rise to, cutaneous SCC. RESULTS: Of the 165 cutaneous SCC cases reviewed, 82.4% (136 out of 165) were found to have concomitant AK giving rise to and/or in close proximity to SCC. Of the 136 AK-positive SCC cases, 26.7% (44) were identified as superficial SCC arising within an AK (AKSSCC) and 55.7% (92) had AK in close proximity to SCC (AK + SCC). Close proximity is defined to include AK changes located directly adjacent to (on the shoulder of) SCC, to a maximum distance of 8 mm away. CONCLUSIONS: The 82.4% prevalence of concomitant AK and cutaneous SCC in our biopsy population suggests a strong correlation between these two lesions. The fact that 26.7% of these lesions had SCC arising from AK highlights the importance of early recognition and effective treatment for AK.

Biopsy↗
PubMed1999

Lipid profile in actinic keratosis and basal cell carcinoma.

BACKGROUND: The lipid content of the skin and its changes are important in the pathogenesis of many disorders affecting the skin, particularly actinic keratosis (AK) and basal cell carcinoma (BCC). METHODS: Cholesterol, phospholipid, triglyceride, and total lipid levels were studied in paired lesional (AK and BCC) and nonlesional intact skin of 13 patients with AK and 12 patients with BCC. Serum concentrations of the same lipid fractions studied in the skin were investigated in AK and BCC patients and in 11 healthy, age-matched controls. RESULTS: Levels of all lipid fractions were increased in both AK and BCC skin. When AK and BCC skin were compared with each other, a significant increase in phospholipids (p < 0.02) and total lipids (p < 0.01) was found in BCC. Serum cholesterol (p < 0.001), phospholipid (p < 0.001), triglyceride (p < 0.05), and total lipid (p < 0.001) concentrations of AK patients were significantly higher than those of the control group. When BCC and controls were compared, a significant increase in phospholipids and total lipids (p < 0.001) was seen. Serum cholesterol in BCC patients was significantly lower (p < 0.001) and serum phospholipid levels were significantly higher (p < 0.05) than those in the AK group. CONCLUSIONS: An increase in the metabolically active serum phospholipid fraction is reflected in elevated neoplastic tissue phospholipid. This produces altered proportions between lipid fractions in tumorous areas and may result in changes in the intact nature of the cellular membrane, spread, and malignant proliferation.

Adult↗
PubMed2001

Photodynamic therapy with violet light and topical 6-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.

Administration, Topical↗
PubMed1999

A solitary cutaneous tumor with distinct areas of verruca and seborrheic keratosis-like lesion.

A single, exophytic, cutaneous tumor on the thigh of a 52-year-old man was examined by light microscopy, in situ hybridization and immunohistochemistry. It demonstrated distinct areas of verruca and of seborrheic keratosis-like morphology simultaneously. Focally, architectural abnormalities were noted in some deeper parts of the tumor, but there was no morphological evidence of malignancy. The patient has remained disease-free for two and a half years after surgery. Biotinylated full genomicDNA probes of HPV confirmed the presence of types 6/11 exclusively in the verrucous portion of the neoplasm. In the verrucous component p53 protein was overexpressed and, additionally, increased Ki-67 immunopositive signals were detected, being localized below the HPV-DNA-expressing spinous cells.

DNA, Viral↗
PubMed2000

Histopathology of incipient intraepidermal squamous cell carcinoma ("actinic keratosis").

BACKGROUND: Actinic keratoses (AKs) are proliferations of transformed, neoplastic keratinocytes confined to the epidermis induced by exposure to ultraviolet (UV) radiation in sunlight. They are extremely prevalent and are seen in most middle-aged to elderly Caucasian persons with a history of significant sun exposure. These lesions are currently termed AKs while they remain confined to the epidermis, but when they extend more deeply to involve the papillary and/or reticular dermis, they are termed squamous cell carcinoma (SCC). The term AK was developed on the basis of clinical appearance and texture of these lesions without regard to histopathology or pathobiology. METHODS: This study was based on a current and historical literature review. RESULTS: AKs and SCC represent the same disease process at different stages of evolution. Neoplastic transformation occurs in keratinocytes exposed to UV radiation manifest primarily as mutations in the p53 gene. In time, these cells proliferate in the epidermis and eventually extend into the dermis at which point metastatic spread can occur. Cytologic atypia is visible in early stages and is identical to that seen in SCC that is present in the dermis or in metastatic lesions. This sequence of events is directly analogous to that of evolving carcinoma of the uterine cervix that has been termed cervical intraepithelial neoplasia. CONCLUSION: AKs are malignant neoplasms in evolution and demonstrate histologic and molecular genetic features of malignancy. Because the name currently used to describe these lesions does not reflect the pathobiology of the process, we propose that a new, more appropriate name be given to these lesions. We propose that a classification scheme analogous to that used by gynecologists for evolving carcinoma of the uterine cervix using the terminology "keratinocytic intraepidermal neoplasia" or another term such as "solar keratotic intraepidermal SCC" be used to define these lesions and that the term actinic (solar) keratosis be eliminated.

Carcinoma in Situ↗
PubMed2002

Clinical effect of imiquimod 5% cream in the treatment of actinic keratosis.

BACKGROUND: Actinic keratosis (AK) is the earliest clinical manifestation of squamous cell carcinoma. Metastatic SCC causes the majority of the 1300 to 2300 deaths attributed to nonmelanoma skin cancer in the United States each year. Recent studies have shown that intralesional administration of interferon can be used successfully in the treatment of AK. OBJECTIVE: Imiquimod is an immune response modifier, currently approved for the treatment of genital warts. The topically applied immune response modifier acts by up-regulating interferon and other cytokines involved in the cell-mediated immune response at the site of application. The aim of this was to determine the efficacy and safety of imiquimod 5% cream for the treatment of AK. METHODS: Twenty-two patients with AK lesions were treated with imiquimod 5% cream, initially at 3 times per week for 8 weeks, or until total clearance of lesions. Patients applied imiquimod to lesions on one side of the body and vehicle cream to the other side. A total of 17 patients who completed treatment were evaluated for number of lesions and adverse reactions before treatment and at weeks 2, 4, 6, and 8 after initiation of treatment. AK lesions were also assessed 4 and 8 weeks after treatment. RESULTS: A significant reduction in the average number of lesions per patient was observed for patients treated with imiquimod. The most frequent reactions to treatment were erythema, itching, and scabbing; however, all adverse events were mild to moderate. CONCLUSION: Imiquimod 5% cream may be a promising treatment for AK.

Adjuvants, Immunologic↗
PubMed2003

Keratosis lichenoides chronica mimicking verrucous secondary syphilis.

Keratosis lichenoides chronica is a rare dermatosis of unknown etiology with a wide variety of cutaneous manifestations. We present a 47-year-old male with a history of progressive and recalcitrant hyperkeratotic and warty plaques, mimicking verrucous secondary syphilis both clinically and microscopically. We review the clinical manifestations, microscopic features, and treatment modalities for this rare and distinctive dermatosis.

Biopsy, Needle↗
PubMed2002

Vascular variant of keratosis lichenoides chronica associated with hypothyroidism and response to tacalcitol and acitretin.

Keratosis lichenoides chronica (KLC) is a rare chronic progressive cutaneous disease that is part of the heterogeneous group of lichenoid dermatoses. The typical clinical presentation is characterized by lichenoid hyperkeratotic papules and nodules arranged in a linear and reticular pattern on the trunk and extremities. Our case confirms the existence of a vascular variant of KLC. There is no consensus about its treatment, since it is refractory to many different treatment modalities. We report the effectiveness of acitretin in KLC in combination with tacalcitol. KLC is of unknown aetiology, but is perhaps associated with systemic diseases, most importantly glomerulonephritis and lymphoma. This is the second case associated with hypothyroidism.

Acitretin↗
PubMed2005

A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)-PDT in actinic keratosis of the face and scalp.

Photodynamic therapy (PDT) with topical methyl aminolevulinate (MAL) administered in two treatment sessions separated by 1 week is an effective treatment for actinic keratoses. This open prospective study compared the efficacy and safety of MAL-PDT given as a single treatment with two treatments of MAL-PDT 1 week apart. Two hundred and eleven patients with 413 thin to moderately thick actinic keratoses were randomized to either a single treatment with PDT using topical MAL (regimen I; n=105) or two treatments 1 week apart (regimen II; n=106). Each treatment involved surface debridement, application of Metvix cream (160 mg/g) for 3 h, followed by illumination with red light using a light-emitting diode system (peak wavelength 634+/-3 nm, light dose 37 J/cm2). Thirty-seven lesions (19%) with a non-complete response 3 months after a single treatment were re-treated. All patients were followed up 3 months after the last treatment. A total of 400 lesions, 198 initially treated once and 202 treated twice, were evaluable. Complete response rate for thin lesions after a single treatment was 93% (95% CI=87-97%), which was similar to 89% (82-96%) after repeated treatment. Response rates were lower after single treatment of thicker lesions (70% (60-78%) vs 84% (77-91%)), but improved after repeated treatment (88% (82-94%)). The conclusion of this study is that single treatment with topical MAL-PDT is effective for thin actinic keratosis lesions; however, repeated treatment is recommended for thicker or non-responding lesions.

Administration, Topical↗
PubMed2002

Levulan: the first approved topical photosensitizer for the treatment of actinic keratosis.

Actinic keratosis (AK) is a very common skin problem found in patients over 50 years of age, representing an in situ keratinocytic neoplasm that can progress to invasive squamous cell carcinoma of the skin. One Food and Drug Administration-approved treatment for AK of the face and scalp is photodynamic therapy (PDT) with 20% aminolevulinic acid (ALA). This advanced technology has been demonstrated in clinical trials to be effective and well tolerated by patients.

Aminolevulinic Acid↗
PubMed2003

A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study.

BACKGROUND: Actinic keratosis (AK) is a very common condition, which has the potential of progressing to squamous cell carcinoma. The present study is a prospective, randomized study comparing the lesion response, cosmetic outcome, patient satisfaction and tolerability of a new treatment modality, photodynamic therapy (PDT), using topical methyl aminolevulinate (Metvix), with the most commonly used standard therapy for AK, cryotherapy. METHODS: A total of 204 patients with clinically diagnosed AK were randomized to either cryotherapy or PDT. The PDT patients were further assigned to an active or placebo group in a random, double-blind manner. Cryotherapy was performed using liquid nitrogen spray in a single freeze-thaw cycle. PDT was performed using 160 mg/g methyl aminolevulinate cream or placebo, a 3-hour application time, red light (570-670 nm) and a total light dose of 75 J/cm(2). PDT was repeated after 7 days. Two sessions of PDT were undertaken, as a previous study had shown a single session had similar efficacy to cryotherapy. Lesion response was assessed clinically after 3 months (complete response or non-complete response). RESULTS: The lesion response rate was 91% in the methyl aminolevulinate PDT group, 68% in the cryotherapy group and 30% in the placebo PDT group. Methyl aminolevulinate PDT was statistically significantly better than both cryotherapy and placebo PDT in terms of response rates and cosmetic outcome. Most patients preferred PDT to other treatments. CONCLUSIONS: PDT with methyl aminolevulinate is an excellent treatment option, particularly for patients with widespread damage or AK lesions in cosmetically sensitive areas.

Administration, Cutaneous↗
PubMed2000

Treatment of keratosis pilaris atrophicans with the pulsed tunable dye laser.

BACKGROUND: Few therapies are currently available to treat keratosis pilaris atrophicans (KPA), a spectrum of disorders which includes ulerythema ophryogenes and atrophoderma vermiculata. OBJECTIVE: To evaluate the response of KPA to treatment with the pulsed dye laser (PDL) with regard to improvements in erythema and skin roughness, treatment tolerability, and side effects. METHODS: Treatment of all facial areas involved with KPA with the PDL at 585 nm was evaluated in 12 patients. Prior to and after each treatment skin erythema was estimated using an erythema meter, and skin roughness was analysed using micrometer evaluation of a skin surface biopsy taken from the same mapped area and analysed by computer to calculate the roughness profile. RESULTS: Patients received 2 to 8 treatments with the PDL with energies ranging from 6.0 to 7.5 J/cm2. Clinical improvement was noted in all patients with significant reduction in erythema scores. Pre-treatment scores ranged from 4 to 13 (mean 8.3) and post-treatment 0 to 8 (mean 3.1) (P < 0.05). Improvements in skin roughness were clinically apparent in all but two patients, but these were not significant on evaluation of skin surface biopsies. Treatment was generally well tolerated, and side effects other than local pain during treatment were very few. CONCLUSION: PDL treatment appears to be a safe and effective treatment for the erythema associated with KPA but does not give significant improvement in associated skin roughness.

Adolescent↗
PubMed2003

ALA/PDT in the treatment of actinic keratosis: spot versus confluent therapy.

BACKGROUND: Actinic keratosis (AK) represents commonly occurring, atypical keratinocytic proliferations confined to the epidermis. While it is the standard of care to destroy AK, few advances have been made to the traditional approaches of physical ablation (e.g. cryosurgery, curettage) and chemotherapeutics (e.g. topical 5-fluorouracil). The recent advances in photodynamic therapy (PDT) with 20% aminolevulinic acid (ALA) offer a novel, safe, and effective approach to AK therapy. OBJECTIVE: To evaluate the safety and efficacy of 20% ALA solution and blue light for the treatment of multiple facial AK. PATIENTS/METHODS: A total of 32 patients were offered either partial treatment (i.e. individual target lesions treated) or confluent treatment (i.e. entire region treated). At 15-20 hours after ALA solution application, treated areas were exposed to visible blue light for 16 minutes and 40 seconds. RESULTS: ALA/PDT treatment resulted in a rapid resolution of multiple AK lesions with a limited period of associated photosensitivity. Side effects experienced by individual patients were found to be influenced by a number of factors: use of analgesic and topical anesthetic agents, body region treated, partial versus confluent treatment, and light exposure time. CONCLUSION: Twenty per cent ALA/PDT offers a safe, effective, and cost-efficient means of managing multiple AK lesions per treatment session with a low recurrence rate. In addition to a favorable tolerability profile, most patients also achieved an improvement in skin texture.

Adult↗
PubMed1993

A quantitative immunohistochemical evaluation of lentigo maligna and pigmented solar keratosis.

Pigmented solar keratosis (PSK) is sometimes clinically indistinguishable from lentigo maligna, a form of malignant melanoma in situ. Occasionally histologic diagnosis is also difficult. Accurate diagnosis is essential, as the treatment and prognosis for each condition differs considerably. To determine whether there was a significant overlap in the number of melanocytes in these sun-damaged skin lesions, or whether immunohistochemistry might be helpful in the differential diagnosis, the authors examined skin biopsy specimens from 26 patients with obvious lentigo maligna and 15 patients with PSK using 3 monoclonal antibodies (HMB-45, NK1C3, and vimentin) and 1 polyclonal antibody (S-100 protein). Formalin-fixed paraffin sections were immunostained with each of the above antibodies, and immunopositive cells per mm2 of epidermis were counted. The difference between lentigo maligna and PSK counts was statistically significant at a level of P < .0001; furthermore, there was almost no overlap between the two groups. The sensitivity for the diagnosis of lentigo maligna was high with all antibodies. However, HMB-45 had the highest sensitivity and the lowest false-positive rate and was visually most pleasing. Using a cut-off count of 60 cells per mm2 of epidermis, HMB-45 had a sensitivity of 96% and a 0% false-positive rate. In this study, lentigo maligna was easily differentiated from PSK. The real value of immunohistochemistry in the differential diagnosis of these pigmented lesions should be tested in a prospective study using cases that are difficult to diagnose by routine light microscopy.

Adult↗
PubMed2004

Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice.

Presenilin (PS1) and (PS2) are the centers of gamma-secretase that release Abeta from APP in Alzheimer's disease (AD). They cleave signaling proteins like Notch and downregulate beta-catenin to modulate Wnt signaling. Inactivation of PS1 or PS1 and PS2 causes a prenatally lethal 'Notch phenotype,' which has hampered investigation of PS function in adulthood seriously. We have thus turned towards PS1+/-PS2-/- mice which carry the most severe reduction of PS alleles compatible with survival, to analyze the consequences of impaired PS function especially in adulthood. In these 'partial deficient' mice, PS1 protein concentration is considerably lowered, functionally reflected by reduced gamma-secretase activity and impaired beta-catenin downregulation. Their phenotype is normal up to approximately 6 months, when the majority of the mice develop an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis and vasculitis, as seen in human systemic lupus erythematosus. Besides B-cell dominated infiltrates, we observe a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies and an increased CD4+/CD8+ ratio. The mice further develop a benign skin hyperplasia similar to human seborrheic keratosis as opposed to malignant keratocarcinomata observed in skin-specific PS1 'full' knockouts. A partial reduction of PS function in PS1+/-PS2-/- mice causes a novel phenotype in adulthood unrelated to the developmental defects of full knockouts. As PS1+/-PS2+/- mice remain healthy, this points towards a sharply defined minimum of PS function. Skin and immune system appear to be especially sensitive targets of impaired PS function and may need careful monitoring if gamma-secretase inhibitors are envisaged for treating AD.

Alzheimer Disease↗