Cutaneous markers of photo-damage and risk of basal cell carcinoma of the skin : a meta-analysis

BACKGROUND: Epidemiologic research has demonstrated that cutaneous markers of photo-damage are associated with risk of basal cell carcinoma (BCC). However there has been no previous attempt to calculate pooled risk estimates. METHODS: We conducted a systematic review and meta-analysis after extracting relevant studies published up to January 2013 from five electronic databases. Eligible studies were those that permitted quantitative assessment of the association between histologically-confirmed BCC and actinic keratoses, solar elastosis, solar lentigines, or telangiectasia. RESULTS: Seven eligible studies were identified and summary odds ratios (OR) were calculated using both random and quality effects models. Having more than ten actinic keratoses was most strongly associated with BCC, conferring up to a 5-fold increase in risk (OR: 4.97; 95% CI: 3.26, 7.58). Other factors, including solar elastosis, solar lentigines, and telangiectasia had weaker but positive associations with BCC with ORs around 1.5. CONCLUSIONS: Markers of chronic photo-damage are positively associated with BCC. The presence of actinic keratoses was the most strongly associated with BCC of the markers examined. IMPACT: This work highlights the relatively modest association between markers of chronic ultraviolet exposure and BCC.

The epidemiology of basal cell carcinoma

Basal cell carcinoma (BCC) is a skin cancer of particular importance to the Australian community. Its rate of occurrence is highest in Queensland, where 1% to 2% of people are newly affected annually. This is an order of magnitude higher than corresponding incidence estimates in European and North American populations. Individuals with a sun-sensitive complexion are particularly susceptible because sun exposure is the single most important causative agent, as shown by the anatomic distribution of BCC which is in general consistent with the levels of sun exposure across body sites. A distinguishing feature of BCC is the occurrence of multiple primary tumours within individuals, synchronously or over time, and their diagnosis and treatment costs contribute substantially to the major public health burden caused by BCC. A primary knowledge gap about BCC pathogenesis however was an understanding of the true frequency of multiple BCC occurrences and their body distribution, and why a proportion of people do develop more than one BCC in their life. This research project sought to address this gap under an overarching research aim to better understand the detailed epidemiology of BCC with the ultimate goal of reducing the burden of this skin cancer through prevention. The particular aim was to document prospectively the rate of BCC occurrence and its associations with constitutional and environmental (solar) factors, all the while paying special attention to persons affected by more than one BCC. The study built on previous findings and recent developments in the field but set out to confirm and extend these and propose more adequate theories about the complex epidemiology of this cancer. Addressing these goals required a new approach to researching basal cell carcinoma, due to the need to account for the phenomenon of multiple incident BCCs per person. This was enabled by a 20 year community-based study of skin cancer in Australians that provided the methodological foundation for this thesis. Study participants were originally randomly selected in 1986 from the electoral register of all adult residents of the subtropical township of Nambour in Queensland, Australia. On various occasions during the study, participants were fully examined by dermatologists who documented cumulative photodamage as well as skin cancers. Participants completed standard questionnaires about skin cancer-related factors, and consented to have any diagnosed skin cancers notified to the investigators by regional pathology laboratories in Queensland. These methods allowed 100% ascertainment of histologically confirmed BCCs in this study population. 1339 participants had complete follow-up to the end of 2007. Statistical analyses in this thesis were carried out using SAS and SUDAAN statistical software packages. Modelling methods, including multivariate logistic regressions, allowed for repeated measures in terms of multiple BCCs per person. This innovative approach gave new findings on two levels, presented in five chapters as scientific papers: 1. Incidence of basal cell carcinoma multiplicity and detailed anatomic distribution: longitudinal study of an Australian population The incidence of people affected multiple times by BCC was 705 per 100,000 person years compared to an incidence rate of people singly affected of 935 per 100,000 person years. Among multiply and singly affected persons alike, site-specific BCC incidence rates were far highest on facial subsites, followed by upper limbs, trunk, and then lower limbs 2. Melanocytic nevi and basal cell carcinoma: is there an association? BCC risk was significantly increased in those with forearm nevi (Odds Ratios (OR) 1.43, 95% Confidence Intervals (CI) 1.09-1.89) compared to people without forearm nevi, especially among those who spent their time mainly outdoors (OR 1.6, 95%CI 1.1-2.3) compared to those who spent their time mainly indoors. Nevi on the back were not associated with BCC. 3. Clinical signs of photodamage are associated with basal cell carcinoma multiplicity and site: a 16-year longitudinal study Over a 16-year follow-up period, 58% of people affected by BCC developed more than one BCC. Among these people 60% developed BCCs across different anatomic sites. Participants with high numbers of solar keratoses, compared to people without solar keratoses, were most likely to experience the highest BCC counts overall (OR 3.3, 95%CI 1.4-13.5). Occurrences of BCC on the trunk (OR 3.3, 95%CI 1.4-7.6) and on the limbs (OR 3.7, 95%CI 2.0-7.0) were strongly associated with high numbers of solar keratoses on these sites. 4. Occurrence and determinants of basal cell carcinoma by histological subtype in an Australian community Among 1202 BCCs, 77% had a single growth pattern and 23% were of mixed histological composition. Among all BCCs the nodular followed by the superficial growth patterns were commonest. Risk of nodular and superficial BCCs on the head was raised if 5 or more solar keratoses were present on the face (OR 1.8, 95%CI 1.2-2.7 and OR 4.5, 95%CI 2.1-9.7 respectively) and similarly on the trunk in the presence of multiple solar keratoses on the trunk (OR 4.2, 95%CI 1.5-11.9 and OR 2.2, 95%CI 1.1-4.4 respectively). 5. Basal cell carcinoma and measures of cumulative sun exposure: an Australian longitudinal community-based study Dermal elastosis was more likely to be seen adjacent to head and neck BCCs than trunk BCCs (p=0.01). Severity of dermal elastosis increased on each site with increasing clinical signs of cutaneous sun damage on that site. BCCs that occurred without perilesional elastosis per se, were always found in an anatomic region with signs of photodamage. This thesis thus has identified the magnitude of the burden of multiple BCCs. It does not support the view that people affected by more than one BCC represent a distinct group of people who are prone to BCCs on certain body sites. The results also demonstrate that BCCs regardless of site, histology or order of occurrence are strongly associated with cumulative sun exposure causing photodamage to the skin, and hence challenge the view that BCCs occurring on body sites with typically low opportunities for sun exposure or of the superficial growth pattern are different in their association with the sun from those on typically sun-exposed sites, or nodular BCCs, respectively. Through dissemination in the scientific and medical literature, and to the community at large, these findings can ultimately assist in the primary and secondary prevention of BCC, perhaps especially in high-risk populations.

Preliminary report on bottlenose dolphin (Tursiops truncatus) uterine samples for parity analysis

There have been numerous studies on various mammalian species regarding vascular changes in uterine arteries elucidating the effects of parity. In equids, vascular changes of uterine arteries have been demonstrated to occur in uniparous and multiparous mares. The severity of these arteriole changes suggests a link to previous pregnancies. Differences in the number or range of pregnancies can be ascertained through microscopic evaluation of elastin deposition in the arterioles, perivascular fibrosis, and stromal cellularity. There has been little, if any, work performed on parity in the bottlenose dolphin (Tursiops truncatus). The objective of this preliminary study was to determine the feasibility of detecting similar vascular changes in the endometrium of known-aged female bottlenose dolphins to assess parity. Archived formalin fixed samples of uterus were obtained from nine bottlenose dolphins with known age and parity. Four slides were made from each sample and individually stained with four different techniques. From our small sample pool, it appears that uteri from nulliparous animals do not develop perivascular fibrosis. Parous uteri developed perivascular fibrosis and arteriolar elastosis. These changes agree with our expectations that some degeneration (elastosis) and compensation (fibrosis) occurs as a result of uterine expansion of pregnancy. The assessment of this technique for use in bottlenose dolphins would provide an important tool in the determination of the reproductive success of dolphin populations, identify individuals who are sexually mature but nulliparous, which could indicate reproductive dysfunction or increased calving intervals, and increase our knowledge on the role contaminants play in reproductive dysfunction.

Actinic cheilitis: Clinical and histological features

Purpose: The purpose of this study was to analyze the clinical and histological features of actinic cheilitis (AC).Patients and Methods: A total of 29 patients with AC were clinically evaluated, and incisional biopsies were performed to confirm the clinical diagnosis. Histological features were analyzed, and dysplasia was classified as mild, moderate, or severe. The chi(2) test was used for the following variables: gender, age, race, and smoking habits. The degree of dysplasia was related to these variables (Fisher's test) to test for independence between them (P <.05).Results: of the patient group, 72.41% were male, 75.86% were overage 40 years, 93.10% were white, and 72.41% were nonsmokers. Clinically, all patients presented with multifocal lesions. The following manifestations were seen: dryness, atrophy, scaly lesions, swelling of the lip, erythema, ulceration, blurred demarcation between the lip vermilion border and the skin, marked folds along the lip vermilion, white spots or plaques, crusts, blotchy areas, and areas of pallor. Keratosis, granulosis, hyperplasia, acanthosis, or atrophy and dysplasia were found in the epithelial tissue; elastosis, inflammatory infiltrate, and vasodilatation were found in the connective tissue. Dysplasia was mild in 10.34% of the patients, moderate in 27.59%, and severe in 62.07%. Absence of sample homogeneity was observed in regard to gender, age, race, and smoking habits. It was not possible to reject the hypothesis of independence between mild, moderate, or severe dysplasia and gender, age, race, and smoking habits.Conclusions: Dryness, atrophy, and scaly lesions were the most common clinical findings observed. Dysplasia, inflammatory infiltrate, and vasodilatation, as well as elastosis, were the most common histological findings observed. Gender, age, race, or smoking habits were not related to the degree of dysplasia in the sample. (c) 2008 American Association of Oral and Maxillofacial Surgeons.

Detection of estrogen receptor in formalin-fixed and paraffin-embedded breast carcinoma: correlation with histological patterns.

The authors studied the expression of estrogen receptor (ER) in tissues of breast carcinomas which were previously fixed in formalin and paraffin-embedded. The ER expression was correlated with several histological findings, namely grade of differentiation, tumor necrosis, desmoplasia, lymphocytic infiltration and elastosis. The ER was detected in tissues using the avidin-biotin immunoperoxidase technique associated with the H222 monoclonal antibody from Abbott. All 39 biopsies were of infiltrating ductal carcinoma of breast and 16 of them expressed ER. The statistical analysis showed that the expression of ER was correlated with histological findings of good prognosis as well differentiated carcinomas, no tumor necrosis, absence or mild lymphocytic infiltration around the tumor cells and severe elastosis.

Considerações sobre o câncer localmente avançado de mama (CLAM) acrescidas de identificação dos receptores de estrogênios usando anticorpos monoclonais.

The effects of therapy in locally advanced breast cancer submitted to combined conventional telecobalt therapy plus chemotherapy with cyclophosphamide and 5-fluorouracil were studied in 49 patients. Associated to radical mastectomy in operable cases. Local tumor control was achieved in 86.7%. There were no local recurrences in those submitted to surgery but they reached 21.7% in inoperable patients who received only radiation therapy and chemotherapy. The median follow-up time for dead patients was 29.5 months and for living patients 79.3 months. The index of complete responses was 24.5% and the median disease free interval was 22.9 months. The overall survival rate, between three and five years, was 32.7%. Estrogen receptors were identified by using immunohistochemical assay ER-ICA and monoclonal antibody H222-SP gamma, Abbott. There were no differences in the complete response index, disease free interval and survival rates, among ER-positive and ER-negative patients, explained by the far advanced stage of the disease. ER-positivity was significantly correlated with histological features of the tumors: cell differentiation, presence of elastosis, absence of lymphocytic infiltration and absence of tumor necrosis.

A randomized and controlled trial about the use of oral isotretinoin for photoaging

Topical retinoids are used to treat photoaging; oral isotretinoin is gold standard for acne; off label indications, including photoaging, have been reported with insufficient evidence of efficacy. This is a randomized controlled phase II trial with clinical and histological assessment to evaluate efficacy and safety of oral isotretinoin for photoaging. Study population was comprised of 32 menopausal or sterilized women, aged 40-55, divided in 2 groups: A (21) received 20mg isotretinoin, 3 times per week, nightly moisturizer, and daily sunscreen, for three months; B (11) just moisturizer/sunscreen. Main outcome measures were: overall clinical assessment; profilometry, corneometer and elasticity tests in periocular regions and left forearm; before/after biopsies from left forearm in patients of B and in 10 randomly selected of A. Microscopic blinded evaluation of epidermal thickness, dermal elastosis, new collagen, p53 epidermal expression was performed by quantitative digital image analysis. All data were submitted to statistical analysis. Clinical evaluation showed slight improvement; profilometry, corneometer and skin elasticity tests presented significant difference in pre/post values (P = 0.001 to 0.028), but no differences between A/B. Histological findings and p53 expression were comparable between groups before treatment (P > 0.1); microscopic analysis showed no differences between groups for most variables, after treatment. Slight but significant difference between A/B for p53 with major reduction post isotretinoin [0.66±0.31 vs. 0.94±0.34 respectively (P = 0.04) was observed. There were minor side effects and no significant laboratory test alterations. We concluded that no significant clinical, microscopic changes but p53 epidermal expression reduction were observed. The role of ultra-violet induced p53 mutation in skin carcinogenesis reinforces retinoids chemoprevention. Oral isotretinoin seemed safe but not effective to treat photoaging. Caution should be considered for women prone to pregnancy. Further controlled studies are necessary. © 2010 The International Society of Dermatology.

Morphologic changes and the expression of alpha-melanocyte stimulating hormone and melanocortin-1 receptor in melasma lesions: A comparative study

Melasma is a common acquired symmetrical hypermelanosis characterized by irregular light- to dark-brown macules on sun-exposed skin areas. The literature shows few studies on its physiopathogeny. However, changes in α-melanocyte stimulating hormone (α-MSH) secretion and melanocortin-1 receptor (MC1-R) expression may play a role to trigger this condition. Biopsies were taken from both melasma skin and adjacent perilesional normal skin of 44 patients. The biopsies were submitted for hematoxylin and eosin and Fontana-Masson staining and immunohistochemistry with Melan-A, α-MSH, and MC1-R, and processed for transmission electron microscopy. In some cases, they were submitted to MC1-R gene expression analysis by real-time polymerase chain reaction. Increased lymphohistiocytic infiltrate and solar elastosis, higher epidermal melanin were observed in melasma skin. Electron microscopy revealed a greater number of mature melanosomes in keratinocytes and melanocytes, and more prominent cytoplasmic organelles in melasma skin. There was no difference in melanocyte number between areas. However, melanocytes were larger and more dendritic in melasma skin. Immunohistochemistry with α-MSH and MC1-R showed significant labeling in melasmic epidermis but MC1-R messenger ribonucleic acid (RNAm) did not show significant quantitative difference between melasma and normal skin. © 2010 by Lippincott Williams & Wilkins.

Histomorfometria das fibras colágenas e das fibras do sistema elástico da queilite actínica e sua relação com os níveis de atipia

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Avaliação da atividade da unidade epidermo-melânica e do dano dérmico no melasma

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Wilson's disease: an analysis of 28 Brazilian children

OBJECTIVES: Clinical-laboratory and evolutionary analysis of twenty-eight patients with Wilson's disease. METHODS: Twenty-eight children (twelve females and sixteen males) with Wilson's disease were evaluated retrospectively between 1987 and 2009, with a follow-up of 72 months (1 -240 months). The clinical, laboratory, and histologic features at diagnosis were recorded at the end of the study. RESULTS: The median age at diagnosis was 11 years (2 -18 years). Twelve patients were asymptomatic, seven had hepatitis symptoms, five had raised aminotransferase levels, three had hepatomegaly associated with neurological disorders, one had fulminant hepatitis with hemolytic anemia, and six patients presented with a Kayser-Fleischer ring. A histological analysis revealed that six children had chronic hepatitis, seven had cirrhosis, two had steatosis, one had portal fibrosis, and one had massive necrosis. The treatment consisted of D-penicillamine associated with pyridoxine for 26 patients. Adverse effects were observed in the other two patients: one presented with uncontrollable vomiting and the other demonstrated elastosis perforans serpiginosa. At the end of the study, all 26 treated patients were asymptomatic. Twenty-four of the patients were treated with D-penicillamine and pyridoxine, and two were treated with trientine and zinc sulfate. A liver transplant was performed in one patient with fulminant hepatitis, but the final patient died 48 hours after admission to the intensive care unit. CONCLUSIONS: Family screenings associated with early treatment are important in preventing Wilson's disease symptoms and potentially fatal disease progression. The study suggests that Wilson's disease must be ruled out in children older than two years presenting with abnormal levels of hepatic enzymes because of the heterogeneity of symptoms and the encouraging treatment results obtained so far.

Clinical, histopathological and immunohistochemical assessment of human skin field cancerization before and after photodynamic therapy

Background The field cancerization concept in photodamaged patients suggests that the entire sun-exposed surface of the skin has an increased risk for the development of (pre)-malignant lesions, mainly epithelial tumours. Topical photodynamic therapy (PDT) is a noninvasive therapeutic method for multiple actinic keratosis (AK) with excellent outcome. Objectives To evaluate the clinical, histological and immunohistochemical changes in human skin with field cancerization after multiple sessions of PDT with methyl-aminolaevulinate (MAL). Methods Twenty-six patients with photodamaged skin and multiple AK on the face received three consecutive sessions of MAL-PDT with red light (37 J cm(-2)), 1 month apart. Biopsies before and 3 months after the last treatment session were taken from normal-appearing skin on the field-cancerized area. Immunohistochemical stainings were performed for TP-53, procollagen-I, metalloproteinase-1 (MMP-1) and tenascin-C (Tn-C). Results All 26 patients completed the study. The global score for photodamage improved considerably in all patients (P < 0.001). The AK clearance rate was 89.5% at the end of the study. Two treatment sessions were as effective as three MAL-PDT sessions. A significant decrease in atypia grade and extent of keratinocyte atypia was observed histologically (P < 0.001). Also, a significant increase in collagen deposition (P = 0.001) and improvement of solar elastosis (P = 0.002) were noticed after PDT. However, immunohistochemistry showed only a trend for decreased TP-53 expression (not significant), increased procollagen-I and MMP-1 expressions (not significant) and an increased expression of Tn-C (P = 0.024). Conclusions Clinical and histological improvement in field cancerization after multiple sessions of MAL-PDT is proven. The decrease in severity and extent of keratinocyte atypia associated with a decreased expression of TP-53 suggest a reduced carcinogenic potential of the sun-damaged area. The significant increase of new collagen deposition and the reduction of solar elastosis explain the clinical improvement of photodamaged skin.

Melan-a-positive "pseudomelanocytic nests": a pitfall in the histopathologic and immunohistochemical diagnosis of pigmented lesions on sun-damaged skin

We encountered recently 3 cases with a histopathologic diagnosis of melanoma in situ on sun-damaged skin (male = 2, female = 1; median age: 59 years; range: 52-60 years). The diagnosis was based mainly on the finding of actinic elastosis in the dermis and increased number of melanocytes in the epidermis and was confirmed by strong positivity for Melan-A in single cells and in small nests ("pseudomelanocytic nests"), located at the dermoepidermal junction. Indeed, examination of slides stained with hematoxylin and eosin revealed the presence of marked hyperpigmentation and small nests of partially pigmented cells at the dermoepidermal junction, positive for Melan-A. The histologic and especially the immunohistochemical features were indistinguishable from those of melanoma in situ on chronic sun-damaged skin. In addition, a variably dense lichenoid inflammation was present. Clinicopathologic correlation, however, showed, in all patients, the presence of a lichenoid dermatitis (phototoxic reaction, 1 case; lichen planus pigmentosus, 1 case; and pigmented lichenoid keratosis, 1 case). Our cases clearly show the histopathologic pitfalls represented by lichenoid reactions on chronic sun-damaged skin. Immunohistochemical investigations, especially if performed with Melan-A alone, may lead to confusing and potentially disastrous results. The unexpected staining pattern of Melan-A in cases like ours raises concern about the utility of this antibody in the setting of a lichenoid tissue reaction on chronic sun-damaged skin. It should be underlined that pigmented lesions represent a paradigmatic example of how immunohistochemical results should be interpreted carefully and always in conjunction with histologic and clinical features.