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Childhood melanoma is a rare disorder which is often associated with a diagnostic delay. Worldwide, the incidence of cutaneous melanoma is rising in both adults and children. We describe three cases of childhood melanoma in the Netherlands which illustrate different aetiological aspects of the disease. The epidemiology of childhood melanoma in the Netherlands is discussed. In reviewing the literature, we wish to draw attention to important clinical aspects which may contribute to the early recognition of melanoma in children.

Background: Basal cell carcinoma (BCC) is the most common cancer in Caucasians. Trichoepithelioma (TE) is a benign neoplasm that strongly resembles BCC. Both are hair follicle (HF) tumours. HFs are hypoxic microenvironments, therefore we hypothesized that hypoxia-induced signalling pathways could be involved in BCC and TE as they are in other human malignancies. Hypoxia-inducible factor 1 (HIF1) and mechanistic/mammalian target of rapamycin (mTOR) are key players in these pathways., Objectives: To determine whether HIF1/mTOR signalling is involved in BCC and TE., Methods: We used immunohistochemical staining of formalin-fixed paraffin-embedded BCC (n = 45) and TE (n = 35) samples to assess activity of HIF1, mTORC1 and their most important target genes. The percentage positive tumour cells was assessed manually in a semi-quantitative manner and categorized (0%, <30%, 30-80% and >80%)., Results: Among 45 BCC and 35 TE examined, expression levels were respectively 81% and 57% (BNIP3), 73% and 75% (CAIX), 79% and 86% (GLUT1), 50% and 19% (HIF1α), 89% and 88% (pAKT), 55% and 61% (pS6), 15% and 25% (pMTOR), 44% and 63% (PHD2) and 44% and 49% (VEGF-A). CAIX, Glut1 and PHD2 expression levels were significantly higher in TE when only samples with at least 80% expression were included., Conclusions: HIF and mTORC1 signalling seems active in both BCC and TE. There are no appreciable differences between the two with respect to pathway activity. At this moment immunohistochemical analyses of HIF, mTORC1 and their target genes does not provide a reliable diagnostic tool for the discrimination of BCC and TE.

Background: Although effective in superficial basal cell carcinoma (BCC), the treatment effect of photodynamic therapy (PDT) in nodular BCC (nBCC) is still questionable. The relation between tumor thickness and PDT failure is unclear., Objective: We sought to compare long-term effectiveness of fractionated 20% 5-aminolevulinic acid (ALA)-PDT with prior partial debulking versus surgical excision in nBCC. The effect of tumor thickness on ALA-PDT failure was analyzed., Methods: 173 primary, histologically proven nBCCs in 151 patients were randomized to fractionated ALA-PDT (n = 85) or surgical excision (n = 88). Two PDT illuminations were performed with a 1-hour interval. Follow-up was at least 5 years posttreatment. Clinical recurrences were confirmed histologically., Results: A total of 171 nBCCs were treated and had a median follow-up of 67 months (range 0-106). At 60 months, 23 tumors had recurred in the ALA-PDT group and 2 tumors in the surgical excision group. Cumulative recurrence probabilities 5 years posttreatment were 30.7% (95% confidence interval [CI] 21.5%-42.6%) for ALA-PDT and 2.3% (95% CI 0.6%-8.8%) for surgical excision (P < .0001). Two tumors in the ALA-PDT group recurred at 72 and 91 months posttreatment. Cumulative probability of recurrence-free survival post-PDT was 65.0% (95% CI 51%-76%) for nBCC measuring greater than 0.7 mm in thickness and 94.4% (95% CI 67%-99%, P = .018) for tumors less than or equal to 0.7 mm., Limitations: Tumor thickness on punch biopsy specimen might differ from the total lesion thickness., Conclusions: In nBCC, 5-year cumulative probability of recurrence after surgical excision is lower than after fractionated ALA-PDT with prior debulking. Although surgical excision remains the gold standard of treatment, PDT might be an alternative for inoperable patients with thin (≤0.7 mm) nBCC., (Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

In Caucasians, the acrolentiginous melanoma is a rare type of melanoma and may appear on hands, feet and subungually. It has the worst prognosis of all melanomas, due to the high rate of misdiagnosis. In 30% of the patients, it presents amelanotic and may resemble for example a common wart, paronychia, ulceration or mycosis. We present 4 patients, aged 48 years and older, in whom an acrolentiginous melanoma was contemplated. One of the lesions was highly suspected of a subungual acrolentiginous melanoma, because of the presence of Hutchinson's sign. Another lesion presented amelanotic and mimicked a foot ulcer. Acrolentiginous melanoma should be considered in case of uncertain diagnosis, delay in healing, enlargement of the lesion and when a pigmented lesion is larger than 7 mm. In these situations, early histopathological examination should be performed.

Clinical and histopathological differentiation between basal cell carcinoma (BCC) and trichoepithelioma (TE) is a frequent problem. Attempts have been made to identify immunohistochemical markers helpful in differentiating them. A correct diagnosis is important because the tumours are treated differently. Recent studies showed the absence of androgen receptor (AR) expression in benign hair follicle tumours like TE. This study examines whether AR immunostaining is a useful diagnostic test to differentiate between BCC and TE. We randomly selected 75 cases with histological diagnoses of either BCC (subtypes: superficial, nodular or infiltrative) or TE (subtypes: classic or desmoplastic) from the database of the pathology department of Maastricht University Medical Centre. The available haematoxylin &#38; eosin (H&#38;E) slides were reviewed by three independent investigators using predetermined characteristics. Fifty-six slides (38 BCC and 18 TE) with unequivocal histological characteristics of either tumour were used for immunohistochemistry with AR antibodies. Any nuclear expression within the tumour was considered positive. AR expression was present in 5/8 classic TE, 0/10 desmoplastic TE, 22/23 superficial or nodular BCC and in 10/15 infiltrative BCC. Immunohistochemical stain for AR is useful to differentiate between TE and BCC; particularly in desmoplastic TE versus infiltrative BCC (specificity and positive predictive value of 100%).

Background: The type of treatment for a basal cell carcinoma (BCC) depends on the histologic subtype. Histologic examination is usually performed on incisional biopsy specimens. In primary BCC, the histologic subtype is correctly identified with a punch biopsy in 80.7% of cases. In recurrent BCC, correct identification is more difficult because of discontinuous growth caused by scar formation. Because an aggressive histologic subtype has a significantly higher risk for recurrence in these tumors, the histologic subtype is at least as important in recurrent BCC as it is in primary BCC., Objective: To investigate the correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent BCC. Furthermore, we sought to clarify how often an aggressive histologic subtype was missed, based on the punch biopsy specimen., Methods: We compared the histologic subtype in a punch biopsy specimen with the subsequent excision specimen in recurrent BCC. All BCCs were coded and judged randomly by the same dermatopathologist., Results: In 24 of 73 investigated BCCs (32.9%), the histologic subtype of the initial biopsy did not match with the histologic subtype of the subsequent excision. Of the 37 excised BCCs with an aggressive histologic subtype, 7 (19%) were missed by the initial punch biopsy., Limitations: Intraobserver variation may have affected the results of this study., Conclusions: Discriminating tumors with any aggressive growth is relevant for treatment. However, in recurrent BCC, the histology of the biopsy specimen does not always correlate with the histology of the definitive excision. This may have important therapeutic implications., (Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Basal cell carcinoma is the most common type of skin cancer and its incidence is still rising. In recent years, new treatment modalities have been developed and existing modalities refined. The aim of this article is to give a histology-based overview of the available evidence-based research. The literature was searched for randomized controlled trials from which the efficacy of investigated treatments was obtained. Where possible, treatment modalities were evaluated specifically. Selection criteria were histological subtype, primary or recurrent basal cell carcinoma and tumour localization. Although surgery remains the preferred treatment for most basal cell carcinomas, patient and tumour characteristics should be taken into account when choosing the most suitable treatment.

This paper describes the findings of a survey distributed among Dutch patients with basal cell carcinoma (BCC). The questionnaire comprised a list of questions related to demographic characteristics, features of BCC, reason for consulting a dermatologist, anxiety, type of treatment and the satisfaction with this treatment and desired benefits of treatment. In total, 220 patients completed the survey. The age of these responders varied between 27 and 89 years (mean 64.6 years). Half of the patient group had already previously experienced a BCC. Most patients (52%) indicated that the diagnosis 'skin cancer' frightened them, but that they knew it could be treated. Accordingly, most patients (70%) indicated that BCC had no or hardly any influence on their quality of life. From the patient's perspective, efficacy, low recurrence rate and no or minor scarring are important features of a BCC treatment. Surgery was the most popular therapy. The number of BCC patients is growing, which will lead to a definite burden for dermatologists in the near future. Our survey demonstrated that patients are mostly interested in the efficacy, low recurrence rates and cosmetic outcome of their therapies. Newly efficacious and non-invasive therapies, such as the recently introduced photodynamic therapy or home treatment with imiquimod, can help to overcome these concerns.

Background: Skin cancer incidence rates have been increasing for decades and this increase is expected to continue. Surgical excision (SE) is the treatment of first choice for nodular basal cell carcinoma (nBCC). Photodynamic therapy (PDT) has proven to be an effective treatment for superficial basal cell carcinoma. Its long-term efficacy in nBCC has not yet been established., Objectives: Prospectively compare the efficacy of 5-aminolaevulinic acid (ALA)-PDT and SE in terms of failure rates with long-term follow-up. Determinants of failure in the study population, such as the effect of tumour depth, were analysed retrospectively., Methods: A randomized controlled trial in 173 primary nBCCs in 149 patients. Primary nBCCs were randomly assigned either to PDT (n = 85) or to SE (n = 88). Tumours treated with PDT were illuminated twice on the same day, 4 h after application of ALA cream, 3 weeks after debulking. SE was performed under local anaesthesia with a 3-mm margin, followed by histological examination. An intention-to-treat analysis was performed., Results: In total, 171 primary nBCCs in 149 patients were treated. A 3-year interim analysis revealed that the cumulative incidence of failure was 2.3% for SE and 30.3% for PDT (P < 0.001). Tumour depth and other analysed determinants of failure were not significantly related to treatment failure., Conclusions: SE proved to be significantly more effective than treatment with fractionated illumination ALA-PDT. Therefore, in the treatment of primary nBCC, SE is preferred over PDT following this treatment regimen.

Background: Both cryosurgery, with and without prior curettage, and surgical excision (SE) are common therapeutic strategies for basal cell carcinoma (BCC)., Objective: The objective was to compare the efficacy between curettage plus cryosurgery (C&C) and SE in nonaggressive BCC of the head and neck., Materials and Methods: A randomized controlled trial was carried out, in which tumors were assigned to either C&C (n=51) or SE (n=49). C&C was performed with a double freeze-thaw cycle after prior curettage of the tumor. SE was performed with a margin of 3 mm and with delayed histologic examination., Results: Recurrences occurred 9 times after C&C (17.6%) and 4 times after SE (8.2%). The overall 5-year recurrence probability was 19.6% for C&C and 8.4% for SE (p=.10). A hazard ratio of 2.57 (95% CI, 0.79-8.34) indicated a putative, but not statistically significant, advantage of SE., Conclusion: These data reflect the outcome of the first randomized controlled trial with long-term follow-up in the treatment of BCC, comparing C&C with SE. Although not statistically significantly different, the observed differences could still be of clinical relevance. Owing to the trend toward lower recurrence rates, better cosmetic results, and reduced wound healing time, we believe that SE should be preferred to C&C in the treatment of primary, nonaggressive BCC of the head and neck.

Background: Full thickness grafts on the nose do not always heal without problems. Partial or entire necrosis of the graft is likely to lead to less favourable cosmetic results and prolonged wound care. No consensus exists as to the use of systemic antibiotics to increase the success rate of survival of a full thickness skin graft on the nose after non-melanoma skin cancer surgery., Objective: The objective of the study was to evaluate the effect of systemic antibiotics on the survival of full thickness grafts on the nose., Methods: We performed a randomized, controlled trial in which we compared azithromycin with standard treatment in 30 patients, who underwent a full thickness graft reconstruction of a surgical defect on the nose after surgery for non-melanoma skin cancer. Percentage survival of the graft was the main outcome measure., Results: A statistically significant difference in favour of the grafts treated with azithromycin was seen (P=0.002). Of all the variables analysed, only smoking had a significant negative effect on the survival of the graft., Conclusions: Systemic antibiotics with an accurate bacterial spectrum should be advised in full thickness skin graft reconstruction after surgery for non-melanoma skin cancer of the nose. Smoking should be strongly discouraged.

Aims: The reported incidence of metastasis from squamous cell carcinoma (SCC) of the skin and lip varies between 0.5% and 16%. Clinical and histopathological criteria have been proposed to identify tumours that may have an increased risk of metastasis. The aim of this study was to define such high-risk tumours, especially since the incidence of SCC of the skin is increasing., Methods and Results: Histopathological features of metastasized skin and lip tumours and a matched group of non-metastasizing tumours were reassessed. Characteristics studied were: tumour width, excision margins, histological subtype, Clark level, Breslow depth, tumour differentiation, inflammation, perineural and angio-invasive growth, ulceration and desmoplasia. Data were statistically analysed separately for skin and labial lesions. Desmoplasia, Clark level, Breslow depth, maximum diameter, angio-invasion, grading, perineural invasion, plasma cells and eosinophilic inflammatory response proved to be statistically significantly related to metastasis of skin tumours. Breslow depth, plasma cells and grading appeared to be statistically significantly related to metastasis of SCC of the lips., Conclusions: A typical metastatic SCC showed: a tumour width of at least 15 mm, a vertical tumour thickness (=Breslow) of at least 2 mm, less differentiation, presence of desmoplasia and an inflammatory response with eosinophils and plasma cells.

Background: Photodynamic therapy (PDT) for basal cell carcinoma (BCC) is a treatment modality that is increasingly used in dermato-oncology. Currently, 2 topical photosensitizers, 5-aminolevulinate (ALA) and methyl aminolevulinate (MAL) are widely used, but their efficacy in BCC has not yet been compared in a clinical setting., Objective: To evaluate the effect, degree of pain, and costs of ALA-PDT versus MAL-PDT in nodular BCC (nBCC)., Methods: Patients suffering from BCC were randomly assigned to either ALA-PDT (n=22) or MAL-PDT (n=21) in a pilot study. In each group, half of the tumors were debulked prior to PDT. Eight weeks after treatment, the therapeutic outcome was checked histologically. Pain scores were assessed using a visual analogue scale., Results: Residual tumor tissue was detected in 6 BCCs of each study group. No significant difference between ALA-PDT and MAL-PDT was found with regard to therapeutic efficacy and pain scores. Of note, however, the costs of MAL-PDT were 6-fold higher than those of ALA-PDT., Conclusions: In this study we did not observe any differences in short-term efficacy between ALA-PDT and MAL-PDT. Therefore, both ALA and MAL can be equally recommended as topical photosensitizers in PDT.

Background: Surgical excision, including Mohs micrographic surgery, is the treatment of first choice for basal cell carcinoma (BCC). Occasionally, the Mohs procedure has to be ceased prematurely for unforeseen reasons., Objective: We sought for possibilities to adjuvantly treat patients in which superficial basal cell carcinoma remained after incomplete Mohs surgery., Methods: We report 3 cases of patients in which Mohs micrographic surgery for their large basal cell carcinomas was ceased for different unforeseen reasons, with remaining superficial fields of BCC after the aggressive and deeply localized part had been removed. Three weeks after closure of the defect, adjuvant therapy for the superficial remnants of the tumor with imiquimod 5% cream was given for 6 weeks, covering at least 1 centimeter around the surgically treated area., Results: The treatment was well accepted with no serious side effects and a good cosmetic result. No recurrences were seen after a follow-up period of 20 to 34 months., Conclusion: A combination of surgical intervention for the central deeper part of the BCC and topical imiquimod 5% cream for the superficial part at the border might be a therapeutic option for those patients with multiple facial BCCs, severe sun damage, and extensive surgery in the past, in whom completion of the Mohs surgical procedure for the entire tumor is not possible for different reasons.

Although the therapeutic role of ajoene, an organosulfur compound of garlic, in cardiovascular diseases and mycology has been established, its usefulness in cancer treatment has only recently been suggested. We applied ajoene topically to the tumors of 21 patients with either nodular or superficial basal cell carcinoma (BCC). A reduction in tumor size was seen in 17 patients. Immunohistochemical assays for Bcl-2 expression in a selection of these tumors before and after treatment showed a significant decrease in this apoptosis-suppressing protein. On average, the percentage of tumor cells expressing the proliferation marker Ki-67 was not decreased, which suggests that the action of ajoene is not explained by a cytostatic effect. To obtain further insight into the mode of action of ajoene, the BCC cell line TE354T and a short-term primary culture of BCC were analyzed for apoptosis induction after treatment with the drug. Apoptosis was detected by morphology of the cells and by flow cytometry. Ajoene induced apoptosis in a dose- and time-dependent manner in these cultures. Taking together the results of the in vivo and in vitro studies, we conclude that ajoene can reduce BCC tumor size, mainly by inducing the mitochondria-dependent route of apoptosis.

Background: Imiquimod 5% cream has been investigated for non-surgical treatment of superficial and nodular basal cell carcinoma (BCC) tumours., Objectives: Two studies were conducted to examine the effect of occlusion at low dosing frequencies on the safety and efficacy of topical imiquimod 5% cream for the treatment of superficial and nodular BCC., Patients and Methods: Both open-label studies were conducted in Europe. Patients diagnosed with BCC were enrolled into either the superficial (93 patients) or nodular (90 patients) study, depending on the histological confirmation of the patient's tumour subtype. Patients were randomized to one of four groups to apply imiquimod 5% cream 2 or 3 days per week either with or without occlusion. Six weeks following a 6-week treatment period, the entire target tumour area was excised and histologically examined for evidence of residual tumour., Results: In both studies, the highest histologically complete response rate was seen in the 3 days per week with occlusion groups, with complete response rates of 87% and 65% for the superficial and nodular studies, respectively. Occlusion did not have a statistically significant effect on response rate at either dosing frequency. Response rates for superficial and nodular BCC tumours treated 3 days per week without occlusion were 76% and 50%, respectively., Conclusions: In the superficial study, the complete response rate of 87% in the 3 days per week with occlusion group was similar to that of daily and 5 days per week dosing without occlusion in a previous 12-week study and one study of daily dosing without occlusion for 6 weeks. All treatment groups had acceptable safety profiles in both studies. Occlusion did not have a statistically significant effect on efficacy for either superficial or nodular BCC tumours.

The incidence of basal cell carcinoma is rapidly increasing and a number of treatment modalities are available. Treatment of basal cell carcinoma includes both surgical and nonsurgical approaches, some of which are traditional, and others experimental. The treatment modality utilized is dependent on both the tumor type and the patient. In order to choose between therapies, evidence-based research is necessary. In an extensive review of the literature concerning treatment options for patients with basal cell carcinoma, we found that there are a limited number of comparative, prospective, randomized, long-term follow-up studies. Based on the results of the available studies, surgical excision, Mohs surgery and cryosurgery are the three standard therapies of choice. Other treatment modalities should be considered secondary choices. There are also promising new treatment options, such as photodynamic therapy, which need further investigation. Special attention is needed when treating the more aggressive subtypes of the disease, such as the micronodular, infiltrative, adenoid and morpheic forms of basal cell carcinoma, as well as bigger basal cell carcinomas and basal cell carcinoma recurrences.

The incidence of basal cell carcinomas (BCCs) is still increasing, and there is a demand for an easy, effective and selective non-invasive treatment such as topical photodynamic therapy (PDT). Twenty-three patients with 24 nodular BCCs were treated once with delta-aminolaevulinic acid (delta-ALA) PDT (100 mW cm(-2), 120 J/cm2) 3 weeks after prior debulking of the BCCs. Three months after PDT, all lesions were surgically excised and histopathologically evaluated for residual tumour. Twenty-two (92%) of the 24 nodular BCCs showed a complete response on clinical and histopathological examination. PDT for superficially abraded nodular BCCs with topically applied delta-ALA and the VersaLight as light source is an easy, effective and safe therapy, with excellent cosmetic results and no serious side-effects, in cases where non-surgical treatment of BCCs is indicated.

Objective: To systematically review the literature for studies reporting on recurrence rates of basal cell carcinomas (BCCs) after different therapies., Design: We reviewed all studies published in English, French, German, Dutch, Spanish, or Italian between 1970 and 1997 that prospectively examined recurrence rates for at least 50 patients with primary BCCs observed for at least 5 years after treatment with Mohs micrographic surgery, surgical excision, curettage and electrodesiccation, cryosurgery, radiotherapy, immunotherapy with interferon or fluorouracil, or photodynamic therapy., Setting: Department of Dermatology, University Hospital Maastricht, Maastricht, the reference center for dermatologic oncology and Mohs micrographic surgery in the Netherlands., Main Outcome Measures: The recurrence rates after different therapies for BCCs, resulting in the development of guidelines for the treatment of these disorders., Results: Of 298 studies found in several electronic databases, only 18 met the requirements and could be used for analysis. Tumors treated with Mohs micrographic surgery show the lowest recurrence rates after 5 years, followed in order by those treated with surgical excision, cryosurgery, and curettage and electrodesiccation., Conclusions: Recurrence rates for different therapies could not be compared because of a lack of uniformity in the method of reporting, so evidence-based guidelines could not be developed. We surmise that Mohs micrographic surgery should be used mainly for larger, morphea-type BCCs located in danger zones. For smaller BCCs of the nodular and superficial types, surgical excision remains the first treatment of choice. Other treatment modalities can be used in patients in whom surgery is contraindicated. Immunotherapy and photodynamic therapy are still investigative.

Objective: To determine the policy of dermatologists practising in the Netherlands in the treatment of basal cell carcinoma., Design: Written enquiry., Setting: Catharina Hospital, Eindhoven, the Netherlands., Method: All 293 dermatologists practising in the Netherlands were sent a questionnaire in May 1996 containing 15 questions about diagnosis and treatment of basal cell carcinoma., Results: Eighteen forms dropped off because of termination of the practice or joint completion in group practices. The response was 76% (208/275). The diagnosis was made usually on the basis of histological examination (71% of the respondents; 84% in a tumour recurrence). Excision was the preferred treatment for all subtypes of basal cell carcinoma; second choices were cryosurgery or curettage/electrocoagulation. Roentgen contact therapy has been practically abandoned. New methods such as photodynamic therapy and immunotherapy are being used only sporadically on an experimental basis. Most dermatologists regarded tumour recurrences as a bigger problem than primary tumours. They attempt to reduce the percentage of recurrences by giving advice about risk factors (sunlight)., Conclusion: Too little use is being made of diagnostic biopsy to enable an optimal choice of therapy of basal cell carcinomas, especially in cases of recurrence tumours.