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Summary Background The clinical recognition of lentigo maligna (LM) and LM melanoma can be very challenging due to the overlapping features it shares with other pigmented macules of the skin. Noninvasive diagnostic techniques can assist in the differential diagnosis. Objectives To identify reflectance confocal microscopy (RCM) indicators for LM through the identification of in vivo microscopic substrates of the main dermoscopic features seen in flat pigmented lesions of the face. Methods Retrospective analysis of 60 pigmented lesions (LM, invasive melanoma, solar lentigo/flat seborrhoeic keratosis, lichen planus-like keratosis, pigmented actinic keratosis) was carried out. The main dermoscopic patterns and RCM features were described. A new method for correlating RCM with dermoscopic patterns was developed. Results Pseudonetwork (37 of 60 lesions) and annular granular structures (37 of 60 lesions) were the most frequent dermoscopic patterns, followed by pigmented blotches (27 of 60 lesions). Upon RCM examination, pseudonetwork and blotches differed in melanomas and other nonmelanocytic lesions. These differences included the intraepidermal proliferation of atypical cells (predominantly dendritic-shaped with adnexal tropism) and the presence of a meshwork pattern at the junction. Also, annular granular structures exhibited dendritic cells almost exclusively in melanoma, with no difference between melanomas and nonmelanocytic lesions for the junctional and upper dermal pattern (characterized by dermal inflammation). Fingerprinting was mostly present in nonmelanocytic lesions or corresponded to an overlap with solar lentigo in melanomas. Conclusions RCM is useful for identifying the histological substrate of dermoscopic features in pigmented lesions of the face. It can provide a better definition of the lesion areas, enabling an improved diagnostic approach.

Summary Background Methionine is one of the major targets of reactive oxygen species (ROS). It is readily oxidized to methionine-S-sulphoxide and methionine-R-sulphoxide, which can be reduced by methionine sulphoxide reductase (MSR) A and B, respectively. MSR represents a unique repair mechanism in the skin antioxidant network. It functions both as a protein repairer and as a ROS scavenger. However, the expression and activity of MSR are significantly reduced in vitiligo. Objectives To investigate whether the decreased expression of MSRA is one of the reasons why melanocytes are especially vulnerable to oxidative stress in vitiligo. Methods We downregulated MSRA expression in immortalized human epidermal melanocyte cell line PIG1 by using the short interfering RNA (siRNA)-targeted gene silencing method. We checked the changes in MSRA transcript and protein level by using reverse transcriptase–polymerase chain reaction and Western blot, respectively. Then we monitored the viability of MSRA-silenced melanocytes under oxidative stress. All statistical analysis was performed by unpaired two-tailed Student’s t-test. Results The siRNA specific for MSRA successfully suppressed MSRA expression in melanocytes. The lower MSRA expression in melanocytes led to an increased sensitivity to oxidative stress, resulting in more cell death. Furthermore, a remarkable loss of viable cells was found in MSRA-silenced melanocytes even in the absence of exogenously added oxidative stress. Conclusions MSRA is crucial for melanocytes to fight against oxidative stress in vitiligo. In addition, it is also important for normal cell survival. Any means to enhance MSRA appears to have therapeutic potential for the treatment of vitiligo.

Summary Background Fewer than 5% of cases of mycosis fungoides (MF) present with a cytotoxic/suppressor CD8+ phenotype which, despite immunophenotypic similarities with CD8+ aggressive lymphomas, is regarded as a phenotypic variant of MF. Poikilodermatous MF showing a CD8+ phenotype has been reported to have a nonaggressive clinical behaviour and a good response to psoralen plus ultraviolet A treatment. Objectives To perform a retrospective study of CD8+ MF cases diagnosed in the skin lymphoma clinic of Andreas Sygros Hospital. Methods We analysed the clinical characteristics, the immunophenotypic and molecular indices, as well as the clinical course of these patients. Results Seven cases of CD8+ MF (6·5% of all cases of cutaneous T-cell lymphoma) were diagnosed during 2002–2007. One of seven patients had stage IA, five stage IB and one stage IIB disease. Clinical characteristics were variable: four of seven patients presented with poikilodermatous plaques (in one of them lesions of lymphomatoid papulosis with CD8+ phenotype coexisted), one patient with classic MF, one with plantar MF and one with follicular MF. The time period between disease onset and diagnosis was long for most patients (up to 33 years). All patients received the recommended treatment according to TNM staging. Five of seven patients had complete remission, one partial response and one stable disease. Conclusions Special clinical characteristics, such as hyperpigmentation and poikiloderma, are often noted in CD8+ MF cases. In our series CD8+ MF presented with a long-standing disease and indolent course suggesting that CD8+ cytotoxic immunophenotype may represent a marker of mild biological behaviour.

Summary Background Vitiligo is an acquired dermatological condition that is characterized by depigmentation of patches of skin. It is relatively common, occuring in about 0·38–0·50% of the general population, and can engender significant cosmetic disfigurement and psychological sequelae in the affected individual. Recent studies demonstrate that topical tacrolimus (Protopic®; Astellas, Markham, ON, Canada) is efficacious in the treatment of vitiligo. We propose that the successful treatment of vitiligo with topical tacrolimus involves the unique immunosuppressive actions of the T lymphocyte T-helper (Th) 2 cytokine, interleukin (IL)-10. Objectives We aimed to monitor clinical changes in lesions of vitiligo treated with topical tacrolimus 0·1% ointment and quantify IL-10 cytokine levels in nonvitiliginous skin, as well as lesions of vitiligo before and following topical tacrolimus therapy. Methods Clinical evaluation of lesions of vitiligo on the basis of surface area and follicular repigmentation under Wood’s lamp was performed in 20 enrolled adult patients. Biopsy specimens were obtained from nonvitiliginous skin, as well as lesions of vitiligo before and following topical tacrolimus therapy. Specimens were processed and analysed for expression of IL-10 using the method of enzyme-linked immunosorbent assay. Results A statistically significant mean ± SEM decrease in vitiligo lesion size of 41·0 ± 5·2% was observed following 3 months of treatment. A pattern of follicular repigmentation was noted by the third month of treatment for all patients completing the study. In addition, there was a statistically significant difference between IL-10 expression in vitiligo lesions following treatment for 3 months with topical tacrolimus compared with untreated vitiligo lesions (P = 0·017) and normal skin (P = 0·004). Conclusions These results confirm that topical tacrolimus is an effective treatment for vitiligo. We propose that topical tacrolimus increases IL-10 expression in vitiligo lesions, and thereby inhibits melanocyte destruction triggered by unchecked Th1 pathways in vitiligo.

Summary Background The treatment of vitiligo remains a challenge for clinical dermatologists. We have previously shown that the helium–neon laser (He–Ne laser, 632·8 nm) is a therapeutic option for treatment of this depigmentary disorder. Objectives Addressing the intricate interactions between melanocytes, the most important cellular component in the repigmentation scheme of vitiligo, and their innate extracellular matrix collagen type IV, the current study aimed to elucidate the effects of the He–Ne laser on melanocytes. Methods Cultured melanocytes were irradiated with the He–Ne laser. Relevant biological parameters including cell attachment, locomotion and growth were evaluated. In addition, the potentially involved molecular pathways were also determined. Results Our results show that in addition to suppressing mobility but increasing attachment to type IV collagen, the He–Ne laser stimulates melanocyte proliferation through enhanced α2β1 integrin expression. The expression of phosphorylated cyclic-AMP response element binding protein (CREB), an important regulator of melanocyte growth, was also upregulated by He–Ne laser treatment. Using a specific mitochondrial uncoupling agent [carbonyl cyanide m-chlorophenyl-hydrazone (CCCP)], the proliferative effect of the He–Ne laser on melanocytes was abolished and suppression of melanocyte growth was noted. Conclusions In summary, we have demonstrated that the He–Ne laser imparts a growth stimulatory effect on functional melanocytes via mitochondria-related pathways and proposed that other minor pathways including DNA damage may also be inflicted by laser treatment on irradiated cells. More importantly, we have completed the repigmentation scheme of vitiligo brought about by He–Ne laser light in vitro and provided a solid theoretical basis regarding how the He–Ne laser induces recovery of vitiligo in vivo.

Summary Background Melanoma in situ/lentigo maligna (LM) is a potential precursor of LM melanoma. It occurs most commonly in elderly individuals on sun-exposed skin of the head and neck. Although surgical excision is the treatment of choice, this may not be desirable or feasible for large lesions at functionally or cosmetically important sites. Imiquimod is a topical immunomodulator which can generate a local cytotoxic response with potentially antiviral and antitumour effects. Objectives To present our experience of LM treated with imiquimod. Methods A retrospective review was performed of all patients with facial LM treated in our unit with topical imiquimod between January 2001 and December 2006. Pretreatment diagnostic biopsies were also reviewed and histologically graded. Results Forty-eight patients were treated with imiquimod. There were 37 responders and 11 treatment failures (of whom two were ‘partial responders’). Of the 37 responders, 31 showed a clinical inflammatory response to imiquimod. One patient in whom treatment failed subsequently developed invasive disease. The mean follow-up duration was 49 months. We could not identify histological features of prognostic significance. However, the ability to develop an inflammatory reaction to imiquimod was a strong predictor of therapeutic benefit. Conclusions We consider imiquimod to have a role in the treatment of LM in patients in whom surgery may be contraindicated or for those in whom the cosmetic or functional consequences may be considerable. Until better characterized, its use should probably be confined to centres with experience in the detection and treatment of LM and melanoma.

Contains fulltext : 69033.pdf (Publisher’s version ) (Closed access) Palifermin is a human keratinocyte growth factor that is efficacious in reducing duration and severity of oral mucositis during autologous haematopoietic stem-cell transplantation for haematological cancer as well as chemotherapy for colorectal cancers. We report the clinical and histological characteristics of a series of five patients who developed flexural hyperpigmentation after treatment with palifermin. All patients showed ill-defined symmetrical hyperpigmented papillomatous plaques with slight erythema in the skin folds, especially affecting axillary and inguinal areas. The most striking histological finding was the thickened granular layer in all patients. We demonstrate that filaggrin, an essential component in the terminal differentiation of the epidermis, was upregulated in these cases. Palifermin-induced flexural hyperpigmentation is a newly defined clinical and histological entity. The possible aetiology is discussed.

Summary Background Vitiligo is a pigmentation disorder, the cause of which is complex and not yet fully understood. There is a significant change of epidermal cytokines in involved skin of patients with vitiligo compared with uninvolved skin and skin of healthy controls, thus suggesting a possible involvement of cytokines in the pathogenesis of vitiligo. Objectives To evaluate potential roles of IL10 family cytokines (IL10, IL19, IL20, IL22 and IL24) in vitiligo. Along with the selected cytokines, we investigated subunits of the receptors (IL10RA, IL10RB, IL20RA and IL22RA1) which are involved in the signalling pathway of the cytokines. Methods Quantitative real-time polymerase chain reaction was used to detect mRNA expression levels in samples extracted from skin biopsies and peripheral blood mononuclear cells and an enzyme-linked immunosorbent assay was used to measure protein concentrations in serum from patients with vitiligo and healthy controls. Results IL22 is significantly associated with vitiligo, especially with the active stage of vitiligo, as shown by results of mRNA expression and supported by results of protein level in sera. IL22 may provoke inflammation which leads to destruction of melanocytes. Conclusions The actual role of IL22 during pathogenesis of vitiligo remains to be better characterized. Signal transductions of other investigated cytokines seem to be regulated on the expression level of their receptor complex subunits.

Summary Background Vitiligo is an autoimmune disorder that occurs with greatly increased frequency in the rare recessive autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome (APECED) caused by mutations of the autoimmune regulator (AIRE) gene on chromosome 21q22·3. We have previously detected an association between alopecia areata and single nucleotide polymorphisms (SNPs) in the AIRE gene. Objectives To report the findings of an extended study including haplotype analysis on six AIRE polymorphisms (AIRE C–103T, C4144G, T5238C, G6528A, T7215C and T11787C) in vitiligo, another APECED-associated disease. Methods A case–control analysis was performed. Results Results showed a strong association between AIRE 7215C and vitiligo [P = 1·36 × 10−5, odds ratio (OR) 3·12, 95% confidence interval (CI) 1·87–5·46]. We found no significant association with the other polymorphisms individually. However, haplotype analysis revealed that the AIRE haplotype CCTGCC showed a highly significant association with vitiligo (P = 4·14 × 10−4, OR 3·00, 95% CI 1·70–5·28). To select the most informative minimal haplotypes, we tagged the polymorphisms using SNP tag software. Using AIRE C–103T, G6528A, T7215C and T11787C as tag SNPs, the haplotype AIRE CGCC was associated with vitiligo (P = 0·003, OR 2·49, 95% CI 1·45–4·26). Conclusions The link between vitiligo and AIRE raises the possibility that defective skin peripheral antigen selection in the thymus is involved in the changes that result in melanocyte destruction in this disorder.

Summary Background Surgical procedures are indicated to treat stable vitiligo, refractory to medical treatment. In addition to conventional surgical techniques, noncultured cellular grafting is gaining wider acceptance among dermatologists. Objectives To assess the efficacy of the ReCell® kit (Clinical Cell Culture, Cambridge, U.K.) and to compare it with conventional melanocyte–keratinocyte transplantation (MKT) for the treatment of vitiligo. Methods Ten lesions in five patients at the same anatomical localization (left vs. right, or two separate lesions at the same anatomical location) were treated with ReCell® and conventional MKT and repigmentation compared at 4 months post-transplantation. Results Of the five lesions treated with ReCell® two lesions showed 100%, one 65% and one 40% repigmentation, and one lesion failed to repigment. Of the five lesions treated by conventional MKT three showed 100% and one 30% repigmentation and one failed to repigment. Conclusions ReCell® may be an effective method to treat vitiligo. Studies on larger series of patients are required to confirm its efficacy. Further research is required to establish the effective dilution of the cell suspension.

Summary Background Skin imaging devices to aid melanoma diagnosis have been developed in recent years but few have been assessed clinically. Objectives To investigate if a spectrophotometric skin imaging device, the SIAscope, could increase a dermatologist's ability to distinguish melanoma from nonmelanoma in a melanoma screening clinic. Methods Eight hundred and eighty-one pigmented lesions from 860 patients were prospectively assessed clinically and with the aid of the spectrophotometric device by a dermatologist. Assessment before and after spectrophotometric imaging was made and compared with histology, where available, or with the clinical diagnosis of a dermatologist with 20 years of experience. Results One hundred and seventy-nine biopsies were performed, with 31 melanomas diagnosed. Sensitivity and specificity for melanoma diagnosis before and after spectrophotometry were 94% and 91% vs. 87% and 91%, respectively, with no significant difference in the area under the receiver operating characteristic curves (0·932 and 0·929). Conclusions Our study provides no evidence for the use of SIAscope by dermatologists to help distinguish melanoma from benign lesions.

Summary Background Melasma is a hyperpigmentation disorder predominantly affecting sun-exposed areas in women, which is often refractory to treatment. Most commercially available treatments incorporate inhibitors of tyrosinase, a key enzyme in melanin production within the melanocyte. In general, however, the efficacy of these therapies is somewhat limited. Recent studies have identified other enzymes that play an important role in melanogenesis, including tyrosinase-related protein-1 (TRP-1), which catalyses the oxidation of the melanogenetic intermediate 5,6-dihydroxyindole-2-carbolylic acid. Rucinol (4-n-butylresorcinol) has been shown to inhibit the activity of both tyrosinase and TRP-1. Objectives To assess the efficacy of rucinol serum 0·3% vs. the corresponding vehicle as a treatment for melasma. Secondary objectives were to evaluate local and general tolerability and to assess the skin acceptability of rucinol serum in the target population. Methods In this prospective, single-centre, double-blind, randomized, vehicle-controlled, bilateral (split-face) comparative trial, 32 women with melasma were provided with two identical tubes containing rucinol serum 0·3% or vehicle. The products were each applied to one-half of the face, according to the randomization scheme, twice daily for 12 weeks (phase 1). A broad-spectrum sunscreen (sun protection factor 60) was also applied daily. Assessments at baseline, 4, 8 and 12 weeks included clinical evaluations by a dermatologist, chromametry, ultraviolet and standard photography, and assessments of skin acceptability and tolerability. After 12 weeks, patients were given the option of an additional 3-month treatment period of open full-face rucinol treatment, with reviews at 16, 20 and 24 weeks (phase 2). Results Twenty-eight patients completed phase 1 and 26 patients completed phase 2. After 12 weeks, the clinical pigmentation score for rucinol-treated skin was significantly lower than for vehicle-treated skin (P = 0·027). During phase 2, rucinol induced a significant reduction in mean pigmentation score on the half of the face previously treated with vehicle. There was also a further, significant improvement on the rucinol-treated side of the face. Chromametry measurements showed that skin was significantly lighter and less yellow, with a strong trend towards reduced redness, following rucinol therapy compared with vehicle. Rucinol serum showed good tolerability and acceptability and was considered to have good or fair efficacy by 78% of the patient population. Conclusions Rucinol serum was shown to have significant efficacy compared with vehicle alone in improving melasma after 3 months of treatment, according to clinical and objective assessments of skin colour.

Knowledge of the accurate margins of a lentigo maligna melanoma (LMM) is crucial in the presurgical evaluation of the patient. Towards this end clinicians have utilized the Wood's lamp and dermoscopy to help delineate the borders of the LMM. However, many LMMs arise on photodamaged skin, making it difficult to determine the border of the LMM and separate it from the background lentiginous skin. We present a case of a patient with a recurrent LMM on the scalp that developed in a background of photodamage with diffuse melanocytic atypia and lentigines, making it virtually impossible to determine the precise margins of the LMM by clinical, Wood's lamp or dermoscopic examination. To avoid subjecting the patient to multiple staged excisions we attempted to determine the margins of the LMM by utilizing in vivo confocal laser scanning reflectance microscopy. Using this, it was apparent that there were increased numbers of atypical/dendritic intraepidermal melanocytes in all layers of the epidermis within the LMM. In contrast, skin not involved with the LMM, as viewed under confocal laser examination, had normal honeycomb architecture and no abnormal melanocytes. The confocally determined border was further confirmed by obtaining multiple punch biopsies that were evaluated by haematoxylin and eosin histology and immunohistochemistry. Based on this information, the presurgical margins were marked and the tumour excised accordingly. The excised tissue was examined with multiple-step sections and the margins were determined to be clear. There has been no evidence of tumour recurrence after 1 year. In conclusion, this case illustrates that confocal reflectance microscopy, in conjunction with other in vivo optical instruments, can be utilized to enhance the accuracy for the presurgical margin mapping of LMM.

We demonstrate the utility of the Wood's light in a practice that specializes in the evaluation of pigmented lesions. The Wood's light assisted the physician in locating the site of a completely regressed primary cutaneous melanoma, determining the clinical borders of a lentigo maligna melanoma, differentiating between agminated naevi and a naevus spilus and detecting the recurrence of pigmentation after the excision of a dysplastic naevus, and also proved useful in monitoring a large segmental speckled atypical lentiginous naevus for change. Despite the availability of many 'high-tech' imaging and diagnostic devices designed to evaluate skin lesions, the relatively simple Wood's lamp continues to be of great value. We encourage physicians not to abandon the use of the Wood's light in their clinical practice.

Xeroderma pigmentosum (XP) is a rare autosomal recessive inherited disorder caused by a defect in the normal repair of DNA of various cutaneous cell types damaged by exposure to ultraviolet radiation. We present our 7-year experience with 36 XP patients who either visited the Department of Dermatology or were seen in the medical camps arranged in remote areas for patients' welfare, from 1995 to 2001. For ease of discussion we classified all cases into the following subgroups on clinical grounds only: mild, those with light brown freckles on the face alone; moderate, those with dark brown freckles with burning on the face, neck, ears, chest, hands and photophobia but without other associated obvious cutaneous and ocular changes; severe, those with extensive dark brown freckles with burning on the exposed parts as well as on the unexposed parts of the body, i.e. the chest, back, abdomen and arms including other associated cutaneous and ocular changes such as ulcers and malignancy. Of 36 patients, three (8.3%) were classified as mild, nine (25%) moderate and 24 (66.7%) severe; there were 18 males and 18 females, age range 2-30 years (mean 8.9 years). Seventeen patients had cutaneous changes: actinic keratosis, keratoacanthoma, fissures and ulcerative nodules on the exposed parts of the body. Four patients had wide ulcers, along with mass formation and severe pigmentation on the face, neck and head. Twenty-nine patients developed ocular symptoms: photophobia, conjunctivitis, corneal keratitis and lid ulcer. One patient had complete loss of vision. Histopathological findings revealed that six patients had squamous cell carcinoma (SCC) on the face, head, ear or lip. More than one sibling (two to four) was affected in four families. The majority of cases (20/36, 55.6%) were from the Brohi tribe (skin type III), while the remaining cases (16/36, 44.4%) were from the Sindhi population (skin type IV). The large number of XP patients seen in those with skin type III (Brohi tribe) compared with skin type IV (Sindhi population) indicates that the skin type and the race has a considerable value in the pathogenesis of XP. Furthermore, 24 of 36 patients were in the severe group and six of these had SCC. Moreover, no neurological abnormalities were observed in our patients. All patients were treated according to disease severity by prescribing oral antibiotics, local steroids, sunscreens and/or chemotherapy followed by irradiation in malignant cases. Two patients died because of extensive SCC.

Summary Background Xeroderma pigmentosum (XP) is a rare disorder produced by a genetic defect in the repair of DNA damage caused by ultraviolet radiation. The early diagnosis of malignant skin tumours is crucial in the survival of patients with XP, but this is not easy even for experienced dermatologists due to the presence of a high number of actinic lesions. Dermoscopy is a new diagnostic method that increases the diagnostic accuracy for skin tumours. Objectives To describe the clinical and dermoscopic features of different benign and malignant lesions [focusing on malignant melanoma, basal cell carcinoma (BCC) and benign melanocytic naevi] in two patients with XP. Methods Three dermatologists with experience in pigmented skin lesions and dermoscopy examined two siblings with XP over a period of 54 months. Diagnosis of skin tumours was obtained using clinical examination and dermoscopy with 10-fold magnification and digital images. All the tumours with criteria of malignancy were excised for further histopathological analyses. Results Multiple skin tumours showing some degree of pigmentation were detected in the patients. Clinical and dermoscopic examination allowed the discrimination of four melanomas (three of them in situ), 26 BCCs and five dysplastic naevi from other pigmented skin lesions. The features and parameters previously described for dermoscopy were shown to be appropriate for the recognition of tumours in our patients with XP. Generalized actinic lentigos were distinguished from BCCs by the presence of a delicate brown pigmented network. Fine vessels from poikiloderma were differentiated from the arborizing telangiectasia of BCC. Conclusions The dermoscopic findings in the tumours were similar to those previously described in patients not affected by XP. Diagnosis by dermoscopic pattern analyses allowed a correct classification of malignant tumours in these cases.

Up until now, only lesions selected on the basis of their clinical atypia or which appear equivocal on naked eye examination have been shown to benefit from the use of dermoscopy. In our experience, dermoscopic evaluation of lesions located on the face may require a different approach, as a histopathological diagnosis of malignancy is not uncommon in clinically trivial lesions (i.e. lesions lacking the ABCD criteria for clinical suspicion). Moreover, at this site dermoscopy reveals specific criteria according to the particular histological architecture shown by sun-damaged skin. We report four cases of lentigo maligna (LM) of the face whose identification depended on dermoscopic examination which was performed routinely on all facial lesions, as the lesions did not show ABCD clinical criteria for malignancy. In our experience, the identification of early signs of malignancy by dermoscopy may indicate the excision of LM at an early phase, before the lesion is associated with the ABCD signs of melanoma. Dermatologists should avoid the mistake of immediately excluding a diagnosis of malignancy when examining an ABCD-negative pigmented skin lesion of the face.

Summary Three children with severe atopic dermatitis were noted at routine follow-up to have developed multiple small pigmented macules during long-term therapy with topical tacrolimus 0·1% (Protopic®, Fujisawa). Representative lesions in two of the three cases were confirmed histologically as simple lentigines. The focal distribution of lentigines to sites of tacrolimus use, and the temporal association between use of tacrolimus and development of lesions, suggest that topical tacrolimus is of direct aetiological relevance to their development. Careful long-term follow-up will be required to assess the clinical implications of these findings and whether they represent an increase in risk for melanocytic neoplasia.

Summary Background Depigmented extramammary Paget's disease (EMPD) has been reported in a few cases. Depigmented macules or patches may be the only presenting sign or may coexist with the classical erythematous lesions. Objectives To investigate the occurrence rate and clinical presentation of depigmentation in EMPD. Methods All pathology-proven cases of EMPD diagnosed in our department during 1990–2003 were retrieved. The clinical photographs were reviewed for evidence of local depigmentation. The pathological diagnosis of EMPD in the whitish lesions was confirmed by positive expression of cytokeratin 7 or carcinoembryonic antigen, and/or the presence of intracytoplasmic mucin. Results Of 19 cases of EMPD, six (30%) manifested depigmented lesions which were confirmed to be EMPD pathologically. In two patients, the hypopigmentation was associated with erythematous lesions at the initial presentation. In four others, the depigmentation developed later as local recurrence after excision, cryotherapy, photodynamic therapy or radiotherapy. The progressive enlargement of the depigmentation and the appearance of separate new white lesions in these four cases suggested that the localized depigmentation was unlikely to be simple postinflammatory hypopigmentation. Conclusions Our study suggests that depigmented EMPD may not be rare. Localized depigmentation in the genital area can be an early sign of EMPD and its local recurrence. In patients with an established diagnosis of EMPD, appearance of new white lesions and continuous enlargement of depigmented patches should not be dismissed as simple treatment-induced postinflammatory hypopigmentation or another type of hypopigmented lesion without biopsy confirmation.

We report two sisters, 27 and 30 years of age, with a cutaneous pigmentary anomaly, which seems to be a new entity. At the age of 26 years the elder sister developed an asymptomatic and persistent rash consisting of discrete, grouped, round to oval, guttate and nummular, hypopigmented macules, 0.2-5 cm in diameter. The distribution of the lesions was unilateral. They were located on the right side of the thorax with a moderately sharp demarcation in the mid-line and ran in a segmental distribution over the right arm, hand and fingers. Microscopic examination of lesional skin scrapings was negative for fungi. Examination with Wood's light accentuated the lesions from the surrounding normal skin. The younger sister had experienced identical, mostly guttate, skin lesions for many years, which at examination were distributed on all extremities and buttocks, and to a lesser degree on the trunk, but here in a segmental distribution. Histological examination (Masson-Fontana staining) of lesional skin of both sisters was identical. A slightly thinned epidermis and a marked decrease in pigmentation of the epidermal basal layer was seen. Electron microscopic examination of lesional skin showed an overall linear increase of morphologically and cytologically normal melanocytes just above the epidermal basal membrane. At many places the density of melanocytes was so high that the keratinocytes were displaced from the basal layer. The melanocytic dendrites extended into the suprabasal layer. The keratinocytes of lesional skin showed a decreased number of melanosomes. It is paradoxical that a hypomelanotic macule shows a histological picture of an increase in normal functioning melanocytes. In all probability a deficient melanosome transfer is responsible for this unexpected phenomenon.

There is increasing evidence that hypomelanosis of Ito and related disorders such as linear and whorled naevoid hypermelanosis are due to mosaicism for a variety of chromosomal abnormalities. This group of disorders is better termed 'pigmentary mosaicism'. In this review we explain how disparate chromosomal abnormalities might manifest as a common pigmentary phenotype. In particular, we provide evidence supporting the hypothesis that the chromosomal abnormalities reported in these disorders specifically disrupt expression or function of pigmentary genes.

Summary Background Lentigo maligna (LM) is an in situ form of malignant melanoma, and surgical excision is often unsatisfactory. Imiquimod cream is an immune response modifier and induces a predominantly T-helper 1 type response. Objectives Assessment of histological and clinical response of surgically resectable LM after treatment with 5% imiquimod cream. Methods Six patients with LM were treated with 5% imiquimod cream daily for 6 weeks. The whole site of the original lesion was then excised. Clinical and histological and appearances were measured using clinical response and histological grading scores. Results Complete or almost complete clearance of pigmentation with minimal residual histological evidence of LM was observed in four patients, one patient showed no clinical or histological improvement, and the remaining patient had almost no residual pigmentation clinically after treatment yet histopathological changes remained as severe as before treatment. Conclusions Topical imiquimod cream merits further investigation as a new therapy for LM.

Summary Background Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant pigmentary genodermatosis characterized by hyperpigmented and hypopigmented macules on the extremities, which has recently been mapped to an 11·6-cM interval on chromosome 1q11–21. So far, most cases of DSH have been reported in Japan and dermatologists around the world might think this disorder mainly occurs in Japan. In fact, there are 17 DSH families including 136 cases reported in China since 1980, but most of them are described in Chinese. Objectives To refine the previously mapped region that facilitates the identification of the DSH gene and to delineate the clinical and genetic features of Chinese DSH cases by a literature review of 136 cases reported in China. Methods We performed genotyping and linkage analysis using polymorphic microsatellite markers at 1q11–22 in two Chinese DSH families, and reviewed all of the DSH cases reported in China since 1980. Results A cumulative maximum two-point lod score of 3·68 was produced with marker D1S506 at a recombination frequency of θ = 0·00 in these two families. Haplotype analysis refined the DSH locus to a 9·4-cM interval flanked by D1S2343 and D1S2635. The genetic and clinical features of Chinese cases with DSH were summarized. In some Chinese cases, hyperpigmented and hypopigmented macules were scattered on the neck and chest, but among Japanese patients there were no similar skin lesions to be reported on these sites. Conclusions This study confirms linkage of DSH to a previously mapped region and refines the DSH gene to a 9·4-cM interval at 1q21–22. Likewise, the literature review indicates that DSH is not an uncommon disorder in China and the differences in the distribution of skin lesions could be related to race and environment.

Summary Background Early detection of melanoma results in excision of thinner melanomas, which are associated with better prognosis. Total cutaneous photography provides a temporal comparison of lesions, which allows clinicians and patients to recognize new and subtly changing lesions. Objectives We examined the utility of total cutaneous photography in detecting melanoma, identified the reason for biopsy of suspicious lesions and determined who detected new melanomas, the physician on follow-up examination or the patient on self-examination. Patients/methods The charts of the 576 patients in the total cutaneous photography database were reviewed. Twelve patients were identified who had melanoma diagnosed with photographic assistance. Baseline and prebiopsy photographs, dermatology clinic notes (115 patient visits) and pathology reports for each biopsied lesion were reviewed. Histological diagnosis, cause for biopsy, and whether the lesion was detected by the patient or physician, was recorded for each of the biopsied lesions. Also noted were all the lesions that concerned patients, the cause for concern, and whether these lesions were biopsied. Results A total of 93 lesions were biopsied in these patients. Twenty-seven (35%) of 77 melanocytic lesions were histologically diagnosed as melanoma. The thickest melanoma found measured 1·1 mm, indicating a favourable prognosis in our patients. Seventy-four per cent of the melanomas were biopsied due to changes from baseline and 19% were biopsied because they were new lesions. The changes noted were subtle and the lesions that proved to be melanoma did not satisfy the classical clinical criteria for melanoma. Eight (30%) of the melanomas were identified by patients on skin self-examination. Twenty-six per cent of the lesions that concerned patients were not biopsied after evaluation by a physician. Conclusions We found that photographically assisted follow-up helped detect new and subtly changing melanomas, which did not satisfy the classical clinical features of melanoma. In addition, photographically assisted follow-up helped detect nonmelanoma skin cancers. Patient skin self-examination proved to be valuable, in that it complemented physician follow-up examination in detecting melanomas. Photographic follow-up was also valuable in avoiding unnecessary biopsy in suspicious, but stable lesions. Total cutaneous photography therefore may be an effective way to increase the sensitivity and specificity for detecting melanoma.

Summary We describe a 57-year-old woman with a history of nail dystrophy since the age of 11 years. Multiple nail clippings were negative and multiple empirical treatments for presumed onychomycosis were unsuccessful. The patient has a daughter with classical incontinentia pigmenti. Molecular genetic analysis was positive for the NEMO gene deletion on the X chromosome, confirming the diagnosis of incontinentia pigmenti. Nail dystrophy was the sole feature of the disease in our patient.

We report a case of three distinct adnexal neoplasms associated with a naevus sebaceous of the scalp: a nodular pigmented trichoblastoma, a smaller flat pigmented trichoblastoma and a syringocystadenoma papilliferum, and discuss the clinical and histological features of these neoplasms. The clinical manifestation was suggestive of malignant melanoma, a feature that has never been reported before. For the first time in the literature we describe the case also by means of a noninvasive analysis, i.e. epiluminescence microscopy. In our experience, epiluminescence microscopy does not appear to be more diagnostically accurate than simple clinical examination when diagnosing lesions of the scalp, contrary to other regions.

Xeroderma pigmentosum (XP) is an autosomal recessive disease in which patients have a 1000-fold increased risk of developing cutaneous neoplasms. Management of patients with XP is a difficult therapeutic challenge as they usually present with many cutaneous malignancies and continue to form skin tumours at a high rate. We describe a 19-year-old woman with XP who had been previously treated with many different therapeutic approaches. She had an excellent clinical response of her multiple small pigmented basal cell carcinomas and pigmentary changes using imiquimod 5% cream with only minor side-effects.

Summary Background Detection of CDw60 in skin is representative of ganglioside D3 expression. This ganglioside is expressed primarily by melanocytes, and is of interest as a membrane antigen targeted by immunotherapy for melanoma patients. Expression of CDw60 by keratinocytes is defined by the presence of T-helper cell (Th)1 vs. Th2 cytokines, and can serve as a sentinel molecule to characterize an ongoing skin immune response. Objectives These immunobiological characteristics have provided the incentive to study the expression of CDw60 in the context of progressive vitiligo. Methods Frozen sections were obtained from control skin and from vitiligo lesions and immunostained to show CDw60. Cells were cultured, their CDw60 expression studied and ribonuclease protection assays run to detect cytokine mRNA. Results Resistance to cytokine-mediated regulation of CDw60 expression was demonstrated in vitro by melanocytes, which appeared capable of generating autocrine and paracrine regulatory molecules supporting CDw60 expression. Induction of CDw60 expression was inhibited by antibodies to interleukin (IL)-4, suggesting that this cytokine was responsible, at least in part, for melanocyte-induced CDw60 expression. Marginal skin from patients with progressive generalized vitiligo consistently showed a reduction in epidermal CDw60 expression alongside elevated human leucocyte associated antigen (HLA)-DR expression at the margin. It thus appears that inflammatory infiltrates present in marginal skin generate type 1 rather than type 2 cytokines, supportive of a cell-mediated autoimmune response. Conclusions These results support an active role of melanocytes within the skin immune system, and associate their loss in generalized vitiligo with a cell-mediated immune response mediated by type 1 cytokines.

We describe a new method for treating livedoid vasculopathy. The typical presentation of livedoid vasculopathy includes chronic, recurrent painful ulcers, satellite scar-like atrophy and telangiectasia involving the lower extremities. Histologically, these lesions show areas of ulceration and dermal vessel occlusion without frank inflammatory cell infiltration. There is currently no satisfactory therapy available for this disease. Hyperbaric oxygen (HBO) has recently established itself as one of the most effective methods of treating ischaemic wounds, including diabetic ulcers. We used this therapy in two patients whose lesions were resistant to multiple therapeutic modalities. Not only did their ulcers respond rapidly to the HBO therapy, but the disturbing wound pain also resolved at the same time. To our knowledge, this is the first successful trial of HBO therapy in livedoid vasculopathy. We believe this to be a very promising new therapy for livedoid vasculopathy and to be worth further investigation.

Desmoplasia has been described in melanoma and Spitz naevus but not in giant congenital melanocytic naevus (GCMN). In melanoma desmoplasia is associated with a better survival. Four paediatric patients with hard, ligneous, progressively hypopigmented and alopecic GCMN were seen among 143 cases of GCMN at the Department of Dermatology of the National Institute of Paediatrics, Mexico City. Clinically, induration was progressive in three patients and regressive in one. Pigmentation was regressive in all. Histopathologically, all four patients showed intense dermal fibrosis, scarce naevus cells, and hypotrophic or absent hair follicles. Follow-up and serial biopsies in three patients documented the progressive nature of fibrosis and naevus cell depletion. No evidence of malignant transformation was found. Naevus cell depletion resulted in pigment loss and may have reduced the risk of malignant transformation. Although the cause of fibrosis is unknown, the possibility of an immune reaction to naevus cells is postulated.

SummaryBackground Lentigo maligna (LM) and lentigo maligna melanoma (LMM) are the most common melanocytic neoplasms on sun-exposed skin of elderly patients. Objectives To perform a retrospective study of 150 patients with LM and LMM treated with radiotherapy using Grenz or soft X-rays. Methods The information recorded and analysed included gender, age, diagnosis, size of the lesion, localization, X-ray treatment, recurrence rate, other skin malignancies and non-dermatological neoplasms. Results The 150 patients comprised 78 women and 72 men (mean age 70 years). Ninety-three patients had LM, 54 had LMM and three had both neoplasms. Ninety per cent of lesions were located on the face. Treatment was with Grenz rays in 96 patients with LM and 11 with LMM (70%) and with soft X-rays in 46 patients with LMM (30%). Three patients were treated using both modalities. One hundred and one patients were followed up for at least 2 years after radiotherapy (mean 8 years). The mean time to recurrence was 45·6 months, and the recurrence rate was 7% (seven of 101). Other skin malignancies were observed in 65 of 150 patients, including basal cell carcinoma in 23 (35%) and actinic keratosis in 20 (31%). Four patients developed internal cancers. Conclusions The study showed that radiotherapy of LM and LMM was curative. In particular, radiotherapy proved to be an excellent treatment for elderly patients. Owing to the high incidence of other skin cancers, LM patients need careful follow-up.

We describe a 20-year-old woman with trisomy 18 mosaicism, who presented with skeletal anomalies, epilepsy, mental retardation, and linear and whorled naevoid hypermelanosis.

We describe four patients with mycosis fungoides (MF) in whom depigmentation, and also leucotrichia in one, occurred following the resolution of the eruption during phototherapy (psoralen plus ultraviolet A treatment in three patients, climatotherapy in one). In all cases, the depigmentation was localized to the area of the pre-existing MF lesions. There was no clinically obvious phototoxicity. Biopsy study including S100 staining in all cases, and electron microscopy in one case, demonstrated the total absence of melanocytes, with no evidence of MF. It is suggested that the phototherapy may have activated a cell-mediated immunity leading to destruction of the melanocytes. We recommend that vitiligo-like leucoderma be added to the list of untoward effects of phototherapy in MF.

Dyschromatosis symmetrica hereditaria (DSH) is a hereditary skin disease characterized by the presence of pigmented and hypopigmented macules on the extremities and freckles on the face. However, if clinical features are not fully developed in infantile patients, it is difficult to differentiate DSH from xeroderma pigmentosum by clinical features alone. A 2-year-old boy (patient 1), revealed atypical features of DSH with slight susceptibility to sunburn. However, his grandfather (patient 4) who was 67 years old, revealed typical features of DSH, which helped to make an exact diagnosis in patient 1. For patient 2, a 5-year-old boy, and patient 3, a 3-year-old girl, it was more difficult to make a diagnosis because there were no family members with DSH features. DNA repair ability was tested for all four cases by means of unscheduled DNA synthesis and colony formation of skin fibroblasts after ultraviolet light irradiation, which resulted in an accurate diagnosis of DSH. We propose that these tests be performed to make a diagnosis of DSH in the case of poor or atypical clinical symptoms.

Background Vitiligo is a depigmenting disease of the skin, which may derive from programmed melanocyte death or destruction due to inherent sensitivity to oxidative stress arising from either toxic intermediates of melanin, a melanocyte-specific protein, or other sources. Tyrosinase-related protein (TRP) -1 has been shown to be involved not only in melanin biosynthesis but also in the prevention of premature melanocyte death in animals. Objectives To clarify the biological role of human TRP-1 in melanocyte survival. Methods Cultured melanocyte strains from an active advancing border of vitiligo were established and studied. Results The established ‘vitiligo melanocytes’ showed large perikaryon and stubby dendrites. They showed early cell death when exposed to oxidative stress (ultraviolet B) and increased and abnormal immunostaining and immunoprecipitation by antibodies against human and mouse TRP-1, indicating an altered synthesis and processing of TRP-1. In pulse–chase and sequential immunoprecipitation experiments, vitiligo melanocytes revealed abnormal protein–protein interaction with calnexin, a melanogenesis-associated chaperone, suggesting altered folding and maturation of nascent TRP-1 polypeptides. Northern blot analysis indicated a decreased expression of TRP-1 mRNA, but heteroduplex analysis and verification of the mutation at the carboxy terminus of TRP-1 by restriction enzyme analysis did not show any abnormality. Conclusions Our study suggests that the early cell death of vitiligo melanocytes is related to their increased sensitivity to oxidative stress, which may arise from complex processes of abnormal synthesis and processing of TRP-1 and its interaction with calnexin.

The MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) belongs to the category of mitochondrial disorders. The most common molecular aetiology of the syndrome is a mutation at base pair (bp) 3243 in the mitochondrial genome (mtDNA). The phenotype is varied and, apart from central nervous system involvement, the patients with this mutation may present with neurosensory hearing loss, diabetes mellitus and cardiomyopathy. These phenotypes suggest that organs dependent on aerobic metabolism suffer most. We investigated the possible clinical and physiological manifestations of impaired energy metabolism in the skin of 28 patients with the bp 3243 mutation in mtDNA. Non-invasive sonography and laser Doppler flowmetry were used to measure skin thickness and the blood flow of the skin. Skin collagen synthesis was assayed from suction blister fluid. Evaporimetry was used to assess the re-epithelialization rate of suction blister wounds. Histochemistry and immunohistochemistry were used to evaluate the melanocytes and pigment in the skin. Vitiligo was found in three of the 28 patients (11%), which was markedly more than in the general population. Histological findings showed an absence of pigment, but an apparently normal distribution of melanocytes in the dermoepidermal junction. Seborrhoeic eczema and atopy were also somewhat more frequent. No features of premature ageing, such as a marked decrease in skin thickness, blood flow, collagen synthesis or re-epithelialization rate, were demonstrated.

Longitudinal melanonychia displaying features of keratinized acanthoma is described in two patients. In both cases, a pigmented band consisting of a subungual keratinized epithelial ridge originated in the nail bed. We have been able to show, using the clinical and histological findings, that the origin of the pigment is linked to its synthesis within the acanthoma of the nail bed. These lesions are reminiscent of pigmented seborrhoeic keratosis. The horny cysts are replaced, because of the special physiological longitudinal arrangement of the ridges in the nail bed, by a single, prominent, longitudinal, keratinized and pigmented mass.

We investigated the occurrence of pigmentary changes after flash lamp pumped dye laser treatment in 125 Norwegian patients. Post-treatment hyperpigmentation occurred with equal frequency during summer and winter (23%), and the facial regions did not exhibit higher occurrence than lesions located elsewhere. The patients that achieved hyperpigmented skin were not exposed to any higher fluence than those without this complication. On the contrary, we found that during the summer period from April to September the patients with post-treatment hyperpigmentation had been exposed to a significantly lower dose than those without pigmentary changes. These results indicate that the epidermal melanin content is not the only criterion for obtaining post-treatment hyperpigmentation. There might also be a constitutional disposition. In predisposed individuals the threshold dose for hyperpigmentation might be reduced in summer when the skin is more pigmented.

Four Chinese patients with xeroderma pigmentosum (XP), who had different degrees of skin symptoms, were tested for their genetic complementation groups. Skin fibroblasts obtained from the patients were used for complementation analysis done by a cell-fusion technique. Three of the patients belonged to group C and one, who had the mildest cutaneous manifestations, to group E. This is the first report of a group E XP patient in China. Our present findings together with previous reports suggest that group C XP is more common in China, similar to the distribution among Caucasian XP patients but markedly different from the Japanese distribution.

Summary Human skin grafted on to athymic nude mice (BALB/C-nu/nu) spontaneously hyperpigments. We wished to identify the morphological and molecular bases for the hyperpigmentation for this phenomenon. We present data on the relationship of healing, regeneration of melanocytes and production of some melanogenic stimuli. Biopsies were taken at preset times post-graft and studied by histological and immunohistochemical methods. DOPA-positive melanocytes first became visible 120 h post-graft and melanin deposition became visible along the basal cell layer 2 weeks post-graft and increased in quantify with time. By immunochemical stains the quantity of three melanocyte specific enzymes, i.e. tyrosinase, tyrosinase-related protein-1 (TRP-1) and DOPA-chrome tautomerase (TRP-2), was markedly enhanced 1 week after grafting and persisted until 4 weeks post-graft. α-Melanocyte-stimulating hormone and adrenocorticotrophic hormone were clearly detected in the epidermis soon after grafting. They were still strongly detected in the epidermis and in the dermis 2–4 weeks post-graft. We conclude that hyperpigmentation in the grafted skin accompanies a marked increase in the quantity of melanogenic enzymes and melanogenic peptides. The neouropeptides might be one of many factors which stimulate melanogenesis.

Hyperpigmentation is a well-recognized feature of cutaneous graft-versus-host disease (GVHD), and is usually restricted to sites where lichenoid or sclerodermiform lesions have occurred. Since 1975, two of 745 patients treated by allogeneic bone marrow transplantation in our institution have developed diffuse melanoderma which differed considerably from the classic presentations. They both developed acute GVHD, then lichen planus-like chronic lesions and diffuse melanoderma. Histology of biopsies of the pigmented skin showed intense pigment deposition in the basal and suprabasal layers, and in dermal macrophages. On split-dopa, melanocyte counts were 98 and 93 per field, respectively. Electron microscopy showed melanocytes protruding into the dermis, and dark melanosomes in all epidermal layers and in macrophages. These findings were suggestive of post-inflammatory hyperpigmentation. In bone marrow recipients, de novo melanoderma is a rare event which could represent a feature of cutaneous GVHD in pigmented subjects.

Chrysiasis is a distinctive and permanent pigmentation of light-exposed skin resulting from the administration of parenteral gold salts. We report a study of 40 Caucasian patients with rheumatoid arthritis, treated with intramuscular sodium aurothiomalate, of whom 31 had chrysiasis. Visible changes develop above a threshold, equivalent to 20 mg/kg gold content, and their severity depends upon cumulative dose. Focal aggregates of particulate gold are deposited in the reticular and papillary dermis in amounts that correlate with the degree of pigmentation. Characteristically, initially the periorbital region is affected by a mauve discoloration, which intensifies and deepens into a blue/slate-grey colour, while extending to involve the face, neck and upper limbs. Although chrysiasis develops insidiously and patients may be unaware of the changes, positive identification is important in order to avoid misdiagnosis and medical mismanagement, and afford appropriate reassurance. Prevention is difficult, but measures to reduce sunlight exposure may be helpful.

We report familial acanthosis nigricans affecting a 35-year-old woman, her 7-year-old son and 5-year-old daughter. Absence of the eyebrows and eyelashes was noted in this family. The mother had no axillary hair and her pubic hair was sparse. The boy also suffered from congenital heart disease and a congenital cataract in the left eye. The combination of acanthosis nigricans and ectodermal defects in this family may represent a distinct nosological entity.

Human piebaldism is a rare autosomal dominant disorder characterized by congenital depigmented patches of skin and hair. Piebaldism results from mutations of the kit proto-oncogene, which encodes a cell-surface receptor, tyrosine kinase, whose ligand is the stem/mast cell growth factor. We report four unrelated patients with piebaldism and consider the variations in phenotype in relation to the site of the kit gene mutation.