Rao N. Saladi

Ultraviolet radiation and skin cancer.

Skin cancer is the most common type of cancer in fair‐skinned populations in many parts of the world. The incidence, morbidity and mortality rates of skin cancers are increasing and, therefore, pose a significant public health concern. Ultraviolet radiation (UVR) is the major etiologic agent in the development of skin cancers. UVR causes DNA damage and genetic mutations, which subsequently lead to skin cancer. A clearer understanding of UVR is crucial in the prevention of skin cancer. This article reviews UVR, its damaging effects on the skin and its relationship to UV immunosuppression and skin cancer. Several factors influence the amount of UVR reaching the earth’s surface, including ozone depletion, UV light elevation, latitude, altitude, and weather conditions. The current treatment modalities utilizing UVR (i.e. phototherapy) can also predispose to skin cancers. Unnecessary exposure to the sun and artificial UVR (tanning lamps) are important personal attributable risks. This article aims to provide a comprehensive overview of skin cancer with an emphasis on carefully evaluated statistics, the epidemiology of UVR‐induced skin cancers, incidence rates, risk factors, and preventative behaviors & strategies, including personal behavioral modifications and public educational initiatives.

Review: Ultraviolet radiation and skin cancer

Skin cancer is the most common type of cancer in fair‐skinned populations in many parts of the world. The incidence, morbidity and mortality rates of skin cancers are increasing and, therefore, pose a significant public health concern. Ultraviolet radiation (UVR) is the major etiologic agent in the development of skin cancers. UVR causes DNA damage and genetic mutations, which subsequently lead to skin cancer. A clearer understanding of UVR is crucial in the prevention of skin cancer. This article reviews UVR, its damaging effects on the skin and its relationship to UV immunosuppression and skin cancer. Several factors influence the amount of UVR reaching the earth’s surface, including ozone depletion, UV light elevation, latitude, altitude, and weather conditions. The current treatment modalities utilizing UVR (i.e. phototherapy) can also predispose to skin cancers. Unnecessary exposure to the sun and artificial UVR (tanning lamps) are important personal attributable risks. This article aims to provide a comprehensive overview of skin cancer with an emphasis on carefully evaluated statistics, the epidemiology of UVR‐induced skin cancers, incidence rates, risk factors, and preventative behaviors & strategies, including personal behavioral modifications and public educational initiatives.

Isoflavone Genistein: Photoprotection and Clinical Implications in Dermatology

Genistein is a soybean isoflavone with diverse biological activities. It is a potent antioxidant, a specific inhibitor of protein tyrosine kinase, and a phytoestrogen. In recent years, increasing evidence has accumulated that this natural ingredient shows preventative and therapeutic effects for breast and prostate cancers, postmenopausal syndrome, osteoporosis, and cardiovascular diseases in animals and humans. In the past decade we have conducted a series of studies and demonstrated that genistein has significant antiphotocarcinogenic and antiphotoaging effects. Genistein substantially inhibits skin carcinogenesis and cutaneous aging induced by ultraviolet (UV) light in mice, and photodamage in humans. The mechanisms of action involve protection of oxidative and photodynamically damaged DNA, downregulation of UVB-activated signal transduction cascades, and antioxidant activities. In this article, we review the biological activities of genistein, as well as published and unpublished research from our laboratory. In addition, we discuss the potential application of genistein to clinical dermatology.

Protective effects of lycopene against ultraviolet B-induced photodamage.

Lycopene, an acyclic hydrocarbon carotenoid found in tomatoes and their products, is a well-established potent antioxidant, and its anticancer properties have been shown in cultured cells and animal models. We investigated the protective effects of two concentrations of topical lycopene against acute ultraviolet B (UVB)-induced photodamage. Application of lycopene dose dependently inhibited UVB-induced ornithine decarboxylase (P < 0.05) and myeloperoxidase (P < 0.05) and significantly reduced bifold skin thickness (P < 0.05). Immunohistochemical staining revealed increased active caspase-3 of apoptotic pathway in the UVB-exposed group compared with the unexposed control. Application of topical lycopene prevented the cleavage of caspase-3. UVB irradiation completely diminished proliferating cell nuclear antigen (PCNA), and the untreated skin maintained positively stained cells throughout the basal epidermis. Topical application of lycopene significantly reversed UVB-induced PCNA inhibition, and normal PCNA staining was restored in the lycopene-treated skin. Our results suggest that topical lycopene is able to exert its protective effects against acute UVB-induced photodamage. Furthermore, it may act as a preventative agent via inhibition of epidermal ornithine decarboxylase activity, reducing inflammatory responses, maintaining normal cell proliferation, and possibly preventing DNA damage as indicated by blocking the necessitating step of apoptosis following UVB injury.

The Combination of Benzo[a]pyrene and Ultraviolet A Causes an In Vivo Time-related Accumulation of DNA Damage in Mouse Skin¶

Abstract Polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), are ubiquitous environmental carcinogens. BaP is metabolized in vivo to reactive intermediates that become covalently bound to DNA and form BaP–DNA adducts, an initial event in carcinogenesis. Ultraviolet A (UVA) synergizes with BaP to significantly enhance genetic damage and accelerate carcinogenic processes. This study was initiated to investigate in vivo cellular changes related to carcinogenesis induced by repeated exposures to BaP plus UVA. Simulated chronic exposure to an environmental carcinogen and sunlight was conducted through biweekly topical application of BaP followed 2 h later by UVA exposure over a 10 week period. BaP diol epoxide (BPDE)–DNA adducts were measured in vivo by immunohistochemistry using an anti-BPDE–DNA monoclonal antibody. Oxidative DNA damage was measured by the detection of 8-hydroxy-2′-deoxyguanosine (8-OHdG) formation using high-performance liquid chromatography. Alterations in the cell cycle that were relevant to carcinogenesis were revealed by changes in p53, as identified in vivo using a polyclonal anti-p53 antibody. We found that cells containing BPDE–DNA adducts and nuclear p53 expression significantly increased between 2 and 10 weeks of BaP–UVA treatment, whereas neither BPDE–DNA adducts nor significant changes in p53 were observed in untreated skin. Using regression analysis, oxidative 8-OHdG damage also showed a parallel increase over 2–10 weeks (r = 0.80). These results indicate that genetic damage caused by exposures to BaP plus UVA accumulates with time and increases the potential for inductive events leading to carcinogenesis and tumor formation.

Effects of ultraviolet B exposure on the expression of proliferating cell nuclear antigen in murine skin.

Abstract Proliferating cell nuclear antigen (PCNA) is an active nuclear protein involved in DNA replication, recombination and repair. PCNA is found throughout the basal layer in normal skin and in all layers of the epidermis in malignancy. This study evaluates PCNAs expression after acute and chronic UV-B irradiation. Skh-1 hairless mice exposed to 1.5 and 4.5 kJ/m2 of UV-B were sacrificed at 6, 12, 24, 48, 72 and 168 h. Immunohistochemical analysis revealed PCNA expression throughout the basal layer of untreated skin, with diminished expression at 6 h, indicative of immediate UV damage, and evidenced by the observable upregulation in pyrimidine dimer formation early on. Subsequently, PCNA immunoreactivity progressively increased, demonstrating an aberrant upward epidermal migratory pattern in association with chronic exposure. The 4.5 kJ/m2 group exhibited prolonged recovery in staining and also demonstrated this altered migratory pattern with chronic exposure. Progressive reactivation of PCNA expression occurs with repair. PCNA migration to upper layers of the epidermis indicates proliferation and possibly a subsequent increased malignant potential. We conclude that PCNA can serve as a marker of DNA repair and indirectly as an indicator of UV-B–induced damage, expression being time dependent and dose related. Specific immunoreactivity patterns and the observable atypia in keratinocytes are relevant in elucidating malignant potentiation.

Combined subcarcinogenic benzo[a]pyrene and UVA synergistically caused high tumor incidence and mutations in H-ras gene, but not p53, in SKH-1 hairless mouse skin

Combined subcarcinogenic doses of benzo[a]pyrene (BaP) and UVA induced H‐ras, but not p53, gene mutations 8 weeks before tumor emergence in SKH‐1 mice. Neither UVA (40 kJ/m2) nor BaP (8 nmol) induced any tumors after mice were topically treated 3 times/week for 25 weeks. However, combined BaP‐UVA treatment synergistically increased tumor incidence and multiplicity. All tumors induced by BaP‐UVA were malignant. The epidermis was collected from mice treated for 2, 6 and 10 weeks. DNA from UVB‐ (0.3 kJ/m2) or BaP‐UVA‐(8 nmol and 40 kJ/m2‐induced tumors was isolated and screened for H‐ras and p53 mutations. Four types of point mutation, GGC→GAC, GCC, GTC and CGC, occurred in UVB‐induced tumors at H‐ras codon 13; and one type of point mutation, GGA→GAA, at codon 12. Treatment with either BaP alone or BaP‐UVA for 10 weeks caused GGA→GAA mutation at codon 12 or GGC→GAC mutation at codon 13 in nontumor skin, respectively, as well as in tumors induced by BaP‐UVA. All of the 10‐week samples treated with either BaP or BaP‐UVA showed detectable mutations at codons 12 and 13, but the genetic load was significantly higher in BaP‐UVA‐treated mice than in those exposed only to BaP. UVA alone induced mutations at codon 12 in only one‐third of samples. G→A mutations induced by BaP or BaP‐UVA at position 38 of codon 13 have not been reported previously. C→T transitions were detected in p53 hot spots of exon 8 in 2 of 19 BaP‐UVA‐induced tumors but were not found in nontumor skin.

Use of Ber-EP4 protein in recurrent metastatic basal cell carcinoma: a case report and review of the literature.

The occurrence of metastatic basal cell carcinoma (MBCC) is extremely low, ranging from 0.0028 to 0.5%. We present a rare case report of MBCC in a 57‐year‐old Caucasian male with a known history of numerous nonmelanoma cutaneous neoplasms. The patient presented with a large ulcerated right axillary mass that recurred 2 months after an initial BCC was resected from the same site. An excisional biopsy of the recurrent mass and regional lymph nodes showed atypical basaloid cells with hyperchromatic nuclei, stromal retraction and rare squamous features in the soft tissue and lymph node. The tumor cells were bcl‐2 negative and positive for Ber‐EP4. The negative expression of bcl‐2 correlates with the aggressive nature of this tumor and Ber‐EP4 confirmed the diagnosis of BCC.

Two Cases of Multiple Angiolipoma Treated with Intralesional Triamcinolone

To the Editor:Angiolipoma is a slow-growing, benign tumor containing vascular and mature adipose elements. Common treatment for angiolipomas has been surgical removal, which is often expensive and leaves undesirable scarring. A 35-year-old pregnant woman was referred to our practice for multiple subcutaneous lesions appearing on the right and left anterior thighs. Thirteen tender and painful nodules were identified ranging in diameter from 1 to 4 cm with no discoloration (figure 1). The patient denied taking any medication, ruling out the possibility of allergic reaction, and denied a family history of such a condition or any trauma to the area. Histopathologic examination of the lesion revealed a lobular mass of mature adipose cells surrounded by a thin connective tissue with the presence of small blood vessels consistent with angiolipoma. As a result of her pain, pregnancy, and multiple lesions, the patient requested a non-invasive therapy. Considering the patient request, one test nodule was selected and treated with intralesional triamcinolone 5mg/mL in bacteriostatic water, yielding dramatic positive results with the pain disappearing within 1–2 days and a noticeable decrease in the size of the lesions. Two weeks later, the remaining 12 lesions were treated yielding excellent results. One-year post-treatment, the patient reported an 85% decrease in the size and pain of the lesions. We present a similar case of a 53-year-old man with numerous fatty and intermittently painful lesions on the stomach and right arm. The patient denied a family history of the condition or that the area had experienced trauma, and he was not onmedication. As a result of themultiple lesions, the patient opted for a medical therapy other than surgery. Six of the nodules were treated with intralesional triamcinolone acetonide 5mg/kg in bacteriostatic water. One to two days posttreatment, the patient reported a significant reduction in size and a decrease in the painful irritating sensation with overall 60% improvement of the condition. One-year post-treatment, neither patient has reported a recurrence of symptoms or any complication such as atrophy. Standard treatment for non-infiltrating angiolipomas is total surgical removal. Surgical excision is curative, and there is no evidence of malignant transformation. Because of the presence of multiple lesions, and the desire to avoid scars our patients requested non-excisional corticosteroid injections. It is postulated that corticosteroid injections result in local fat atrophy, thus shrinking the lipoma. Another possible mechanism for the corticosteroid effect may be changes in endorphin levels. Triamcinolone 5mg/mL in bacteriostatic water was injected into the center of each lesion. The volume of corticosteroid injected depends on the size of the lipoma, with an average of 0.3–0.5mL of total volume administered per angiolipoma. The number of injections depends on the site and the response desired. Improvement is expected to occur within 3–4 weeks. Rare complications, which we did not see in our cases, include atrophy, skin sensitivity, hyporpigmentation, bruising, and hematoma. These side effects may be prevented

Tracking precancerous and cancerous skin lesions with a simple transparent sheet technique.

Tracking of precancerous and cancerous lesions is vital for an efficient patient follow-up and treatment in a dermatology practice. Although the successful diagnosis and elimination of any such lesions are imperative, reidentification of exact lesion location and reassessment of the treatment area remain equally essential. Often times, this follow-up becomes rather intricate because the treated area not only improves but undergoes full recuperation, especially over longer duration periods. In addition, neighboring factors such as freckles, moles, and seborrheic keratoses may shroud the cancerous lesion in question, making its reidentification even more complicated (Fig. 1).