Malignant Skin Diseases Research Articles

Photodynamic therapy using 5-aminolaevulinic acid for the treatment of dysplasia in Barrett's oesophagus

Background: 5-Aminolaevulinic acid (ALA) is the naturally occurring metabolic precursor of an endogenously formed photosensitiser, protoporphyrin IX. It is used topically to treat benign and malignant skin disorders by a process called photodynamic therapy (PDT). Recently, data are emerging on its systemic use in the treatment of dysplasia in Barrett's oesophagus. Objective: To investigate the use of ALA-PDT for the treatment of dysplasia and early cancer in Barrett's oesophagus. Methods: A systematic literature review and synopsis is given. Conclusion: ALA is an attractive alternative to the currently approved photosensitiser (porfimer sodium) due to its oral route of administration, shorter generalised skin photosensitivity period and lower rate of stricture formation. The studies presented demonstrate that ALA-PDT is both safe and effective for the treatment of dysplasia and early cancer in Barrett's oesophagus.

Langerhans cells in premalignant and malignant skin diseases

Langerhans cells in premalignant and malignant skin diseases

Premalignant and malignant skin diseases Assessment of proliferation indexes

Premalignant and malignant skin diseases Assessment of proliferation indexes

Expression of minichromosome maintenance 5 protein in proliferative and malignant skin diseases

The entire minichromosome maintenance (MCM) family (MCM2-7) play roles in the initiation and elongation of DNA replication. Many studies have demonstrated that MCM proteins may be better indicators of a wide variety of proliferative or cancer cells in malignant tissues. To characterize the pattern and frequency of MCM5 expression in proliferative and malignant skin diseases in comparison with those of proliferating cell nuclear antigen (PCNA). Twelve normal skin specimens, 12 specimens of psoriasis, 21 specimens of bowenoid papulosis (BP), 16 specimens of Bowen's disease (BD), 38 specimens of skin squamous cell carcinoma (SCC), and 11 specimens of basal cell carcinoma (BCC) were subjected to immunohistochemical staining for MCM5 and PCNA. Results MCM5 protein was expressed in the lower layers of epidermis in psoriasis, while MCM5 protein were present throughout the tumor cells in BP, BD, and moderately/poorly differentiated SCC. MCM5 protein was preferentially expressed in the periphery of well-differentiated SCC or bigger nests of BCC, although some small nests of BCC seemingly showed diffuse staining patterns. The percentages of MCM5-positive cells were 15.7% in normal skin, 21.8% in psoriasis, 75.9% in BP, 83.8% in BD, 63.5% in well-differentiated SCC, 77.5% in moderately differentiated SCC, 79.8% in poorly differentiated SCC, and 21.2% in BCC in average. Well-differentiated SCC showed a significantly lower percentage of positive cells than did moderately differentiated SCC or poorly differentiated SCC. MCM5 staining basically show a similar staining pattern to that of PCNA, but more cells tended to be stained with MCM5 than with PCNA. Our results demonstrate pattern and frequency of MCM5 expression in various skin diseases and suggest that MCM5 may be a useful marker to detect cell proliferation in skin tissue sections.

In situ depletion of CD4+ T cells in human skin by Zanolimumab

CD4(+) T cells, in activated or malignant form, are involved in a number of diseases including inflammatory skin diseases such as psoriasis, and T cell lymphomas such as the majority of cutaneous T cell lymphomas (CTCL). Targeting CD4 with an antibody that inhibits and/or eliminates disease-driving T cells in situ may therefore be a useful approach in the treatment of inflammatory and malignant skin diseases. Depletion of CD4(+) T cells in intact inflamed human skin tissue by Zanolimumab, a fully human therapeutic monoclonal antibody (IgG1, kappa) against CD4, was studied in a human psoriasis xenograft mouse model. Zanolimumab treatment was shown to induce a significant reduction in the numbers of inflammatory mononuclear cells in upper dermis. This reduction in inflammatory mononuclear cells in situ was primarily due to a significant reduction in the numbers of skin-infiltrating CD4(+), but not CD8(+) CD3(+) T cells. The capacity of Zanolimumab to deplete the CD4(+) T cells in the skin may be of importance in diseases where CD4(+) T cells play a central role. Indeed, in a phase II clinical trial Zanolimumab has shown a dose-dependent clinical response in patients with CTCL and the antibody is currently in a phase III clinical trial for CTCL, a disease for which there is no safe and effective treatment available today.

Detection of mucosal human papilloma virus DNA in bowenoid papulosis, Bowen's disease and squamous cell carcinoma of the skin

Human papilloma virus (HPV) is known to be an etiologic agent for benign warts of the skin. Recently, HPV have been detected in malignant skin and mucosal diseases suggesting that HPV infection can induce malignant skin tumors. In the present study, we examined the presence of mucosal HPV DNA in normal tissue, Bowen's disease (BD), Bowenoid papulosis (BP) and squamous cell carcinoma (SCC) of the skin. We detected the HPV DNA with polymerase chain reactions, and identified the type by DNA sequencing. In the results, we detected HPV DNA in none of the 17 normal controls, two of the three BP (66.7%), one of the 21 BD (4.8%), and six of the 26 SCC of the skin samples (23.0%). The occurrence rates of HPV in BP and SCC were significantly elevated compared to that of normal controls (P < 0.01 and P < 0.01, respectively). In addition, the occurrence rate of HPV in BP was significantly elevated compared to that of BD (P < 0.05). The reproducibility was confirmed with a polymerase chain reaction (PCR) with another primer pair. Of the two cases of BP with positive HPV DNA, one case showed HPV 31 and the other case HPV 16. The case of BD with positive HPV DNA showed HPV 31. Of the six cases of SCC with positive HPV DNA, one case showed HPV 16, another case HPV 34, and the other four cases HPV 31. These results showed that mucosal HPV, including HPV 31 and 16, could be detected in SSC of the skin. Mucosal HPV, not only the epidermodysplasia verruciformis type, appear to induce malignant skin tumors.

The Role of Apoptosis in the Pathogenesis of Dermatitis Herpetiformis

Apoptosis is a form of cell death that is claimed to be involved in a number of chronic inflammatory and malignant skin diseases. The aim of this study was to investigate whether apoptosis may contribute to the pathogenesis of epidermal changes in dermatitis herpetiformis (DH) and, in particular, whether certain apoptosis-related markers such as Bax, Bcl-2, Fas and Fas ligand (FasL) take part in this process. For the detection of apoptotic nuclei, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling technique (TUNEL) was employed on cryostat sections. Skin lesions from six and perilesional skin from four DH patients were stained with monoclonal antibodies to Bax, Bcl-2, Fas and FasL. The same evaluation was also performed on three patients affected by bullous pemphigoid (BP) and in two healthy donors. Using TUNEL technique, a remarkable increase in the apoptotic rate within the epidermal compartment was observed in DH and BP patients in comparison with normal controls. In our immunohistochemical analysis, Bax/Bcl-2 ratio was almost the same in the epidermis of perilesional/lesional DH, BP and healthy skin specimens. In DH and BP specimens both Bax and Bcl-2 proteins were increased in the dermal perivascular compartment. Fas showed a prevalently epidermal staining, both in DH and BP lesions, while FasL was distributed in perivascular and subjunctional dermis; some FasL+ cells infiltrated the DEJ and the basal layer of epidermis. This study allowed us to highlight conspicuous apoptotic phenomena in basal and suprabasal keratinocytes within lesional and perilesional skin of DH. We conclude that in DH, as well as in BP, apoptosis plays a role in the pathogenesis of cutaneous lesions in concert with other pathogenetic mechanisms.

Familiares Auftreten einer segmentalen Typ-2-Manifestation der kutanen Leiomyomatose. Familial occurrence of a type 2 segmental manifestation of cutaneous leiomyomatosis

There are several malignant or benign skin diseases which can be explained by the phenomenon of mosaicism or segmental manifestation, e. g. segmental neurofibromatosis 1 or cutaneous leiomyomatosis. Loss of heterozygosity is a crucial element for segmental manifestations. Two types of segmental manifestations can be defined in autosomal dominant skin diseases such as cutaneous leiomyomatosis. Type 1 is caused by a novel postzygotic segmental mutation; type 2 reflects an additional postzygotic loss of heterozygosity of the gene locus responsible for cutaneous leiomyomatosis in a initially heterozygous embryo. Loss of heterozygosity is a genetic process when a heterozygous cell becomes homozygous or hemizygous by loosing the corresponding wild-type allele. This phenomenon can be regarded as a precondition for tumor growth. In type-2 cases, the segmental manifestation is more distinctive with additional disseminated disease because of a germline mutation with heterozygosity of all somatic cells outside the strongly affected area.A 74-year-old female patient and her 52-year-old son presented with segmental leiomyomas following the lines of Blaschko as well as disseminated skin tumors. The woman has undergone hysterectomy at the age of 29 because of multiple uterine leiomyomas, as had her mother and grandmother.Based on their typical clinical appearance, these cases represent the rare familial occurrence of type-2 manifestation of leiomyomas which indicates a postzygotic loss of the wild-type allele.Very unusual is the familial occurrence in mother and son of this type-2 manifestation of cutaneous leiomyomatosis. Apparently the gene locus is prone to a postzygotic loss of heterozygosity.

UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review.

BackgroundBroad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare.MethodsSearching the PubMed database the current article systematically reviews established and innovative therapeutic approaches of broad-band UVA irradiation, UVA1 phototherapy and PUVA photochemotherapy in a variety of different connective tissue disorders.ResultsPotential pathways include immunomodulation of inflammation, induction of collagenases and initiation of apoptosis. Even though holding the risk of carcinogenesis, photoaging or UV-induced exacerbation, UVA phototherapy seems to exhibit a tolerable risk/benefit ratio at least in systemic sclerosis, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus and a number of sclerotic rarities.ConclusionsBased on the data retrieved from the literature, therapeutic UVA exposure seems to be effective in connective tissue diseases and related disorders. However, more controlled investigations are needed in order to establish a clear-cut catalogue of indications.

In this Issue

In this Issue

Treatment of anal intraepithelial neoplasia in patients with acquired HIV with imiquimod 5% cream*

Anal intraepithelial neoplasia (AIN) is a precursor lesion for squamous cell carcinoma of the anus. Three different grades, depending on the epithelial involvement, are distinguished: mild (AIN 1); moderate (AIN 2); and severe (AIN 3) dysplasia. Biologically, anal cancer resembles cervical cancer in several ways, including a similar histopathologic appearance.1Palefsky J.M Anal squamous intraepithelial lesions relation to HIV and human papillomavirus infection.J Acquir Immune Defic Syndr. 1999; 21: 42-48Crossref PubMed Google Scholar Both anal and cervical cancers share a strong association with high-risk human papillomavirus (HPV). In particular, HPV-16 and HPV-18 are causally associated with anogenital cancer.2Frisch M, Glimelius B, van den Brule AJ, et al. Sexually transmitted infection as a cause of anal cancer. N Engl J Med 1997;337:1350-8Google Scholar Concomitant HIV infection seems to drastically increase the risk for AIN and anal cancer. Perianal HPV infections have been detected in 93% of homosexual men and a high incidence of high-grade AIN has been reported in these patients.3Lacey HB, Wilson GE, Tilston P, et al. A study of anal intraepithelial neoplasia in HIV positive homosexual men. Sex Transm Inf 1999;75:172-7Google Scholar Highly active antiretroviral therapy, with its improvement in immune status and prolonged survival, has been proven effective in decreasing some viral infections (eg, human herpesvirus [HHV]-8-related Kaposi′s sarcoma). The effects on the incidence and progression of HPV infections and their associated malignancies remain obscure, although preliminary data suggest that high-grade lesions most likely progress to invasive cancer.4Palefsky J.M Holly E.A Ralston M.L Jay N Berry J.M Darragh T.M High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men.AIDS. 1998; 12: 495-503Crossref PubMed Scopus (325) Google Scholar There is currently still no accepted standard of treatment for AIN and the literature is very limited on this subject. Surgical excision or ablation is the primary form of treatment, although extensive anal operation may have considerable morbidity. Therefore, simple local therapies such as carbon-dioxide laser ablation, cautery fulguration, and cryotherapy have been considered for small lesions. However, HPV DNA can persist latently in surrounding tissue and may lead to recurrence of AIN. We treated 10 HIV-positive homosexual men with different grades of AIN by applying imiquimod 5% cream. All patients were positive for HPV-16 before treatment. Imiquimod was self-applied 3 times a week for a maximum of 16 weeks. There were no adverse events related to the use of the cream except a slight erythema and burning at the beginning of therapy. However, this resolved within a few days without any further action taken. Follow-up histologic studies showed regression of the disease by at least two grades. In most of the cases, nearly normal epidermis without residual dysplasia was achieved (Fig 1, Fig 2). HPV-16 DNA was no longer detectable by polymerase chain reaction after treatment.Fig 2No major pathologic changes after treatment. (Hematoxylin-eosin stain; original magnification ×20.)View Large Image Figure ViewerDownload (PPT) Imiquimod is a novel immune response modifier with indirect antiviral and antitumor activity through the stimulation of local cytokine production, up-regulation of cell-mediated responses, and enhancement of functional maturation of Langerhans cells. It has been approved for the treatment of genital warts, but has also shown to be effective in malignant skin diseases such as actinic keratosis, Bowen′s disease, basal cell carcinoma, and lentigo maligna. Diakomanolis et al5Diakomanolis E Haidopoulos D Stefanidis K Treatment of high-grade vaginal intraepithelial neoplasia with imiquimod cream.N Engl J Med. 2002; 347: 374Crossref PubMed Scopus (37) Google Scholar recently reported complete clearance of vaginal intraepithelial neoplasia and down-regulation of p53 in 3 patients after treatment with imiquimod. Our results in this preliminary study are encouraging and indicate that imiquimod appears to be effective in treating AIN, even for patients with HIV infection. Long-term follow-up and regular examinations are indicated because of the risk for recurrent or invasive disease in this growing patient population.

Acitretin treatment in (pre)malignant skin disorders of renal transplant recipients: histologic and immunohistochemical effects

Background The incidence of (pre)malignant skin lesions after renal transplantation is high. Acitretin treatment appears to decrease the number of new squamous cell carcinomas and ameliorates the aspect and reduces the number of actinic keratoses. However, no histologic and immunohistochemical studies have been performed to further substantiate these observations. Methods In 33 renal transplant recipients, biopsies were taken before and after 3 months of treatment with acitretin in doses up to 0.4 mg/kg/day. Histologic and immunohistochemical parameters for dysplasia, epidermal thickness, proliferation, differentiation, apoptosis, and dermal inflammation were analyzed. Results Following acitretin treatment, a significant reduction in epidermal thickness ( P = .002) and a significant increase in normal differentiation parameter K10 ( P = .02) was observed. Epidermal proliferation did not change, nor did apoptosis, inflammation, keratinocytic epidermal neoplasia score, or transglutaminase staining. At baseline, in 8 actinic keratoses, a single cell expression pattern of K13 and/or K19 was found. This was associated with high levels of parameters indicative of high-risk lesions ( P < .05). After acitretin treatment, an increase in K13 ( P = .006) and K19 ( P = .05) was found, together with a change in expression towards a focal or band-like staining pattern. Conclusion Acitretin improves the aspect of actinic keratoses via alteration of keratinization, resulting in peeling of the stratum corneum. No significant change in proliferation was found, which may explain the rapid recurrence of actinic keratoses seen after cessation of acitretin treatment.

P53 protein expression and cell proliferation in non-neoplastic and neoplastic proliferative skin diseases.

The p53 protein is essential for the regulation of cell proliferation and its aberrant accumulation is usually seen in malignant tumors but also occurs in squamous epithelium of inflammatory skin diseases characterized by hyperproliferation. The aim of this study is to elucidate the role of the p53 tumor suppressor protein in the pathogenesis of different hyperproliferative, non-malignant and malignant skin diseases, and to determine the association between p53 overexpression and cell proliferation. We also investigated the influence of aging on p53 and Ki-67 protein expression. One hundred and fifty skin specimens divided into 30 samples each of normal skin (NS), psoriatic skin (PS), keratoacanthomas (KA), basal cell carcinomas (BCC), and squamous cell carcinomas (SCC) were examined immunohistochemically to assess p53 and Ki-67 protein expression. p53 immunostaining of NS, PS, KA, BCC and SCC was detected in 39.0%, 46.7%, 66.7%, 80% and 86.7% of cases, respectively. Median values and ranges of p53 protein expression were as follows: 0.0% (range, 0.0-1.8%) in NS, 0.0% (range, 0.0-6.5%) in PS, 9.2% (range, 0.0-24.0%) in KA, 19.3% (range, 0.0-48.1%) in BCC and 30.1% (range, 0.0-68.1%) in SCC. p53- and Ki-67-positive cells were present in basal (NS) and suprabasal layers (PS), and not only in cancer nests of KA, BCC and SCC but also in dysplastic and even morphologically normal epidermis adjoining cancers. The positivity of p53 and Ki-67 proteins differed significantly among the groups, with no differences in p53 expression between NS and PS and in Ki-67 expression between PS and KA. Within all groups there was a significant correlation between p53 and Ki-67 expression. Lesion location and patient age, with the exception of location in PS and age in BCC, were significantly related to p53 and Ki-67 expression in all groups. Our findings suggest that p53 overexpression occurs mainly in neoplastic skin lesions, although it may also occur in squamous epithelium of inflammatory skin diseases such as PS, as well as in normal skin epithelium. It is associated with cell proliferation in normal as well as altered epithelium. p53 protein overexpression is an age-related process and significantly associated with sun exposure, especially in NS and PS but also in KA and SCC. Our findings suggest that Ki-67 rate and p53 protein expression reflect the degree of malignancy in the examined cutaneous neoplasms.

Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin

Introduction After renal transplantation, the incidence of premalignant and malignant skin lesions is high. Treatment with acitretin improves the number and aspect of actinic keratoses and appears to reduce the incidence of squamous cell carcinomas, but treatment is hampered by frequent side effects. No optimal long-term dosing advice is available. Methods A total of 26 long-term renal transplant recipients were randomized to 1-year treatment with acitretin, either 0.4 mg/kg/d throughout the whole year or 0.4 mg/kg/d during the first 3 months followed by 0.2 mg/kg/d for the remaining 9 months. At 9 different time points, the number of actinic keratoses and tumors was counted, and erythema and thickness of the lesions, and severity of side effects were scored. Patient's judgment was recorded using visual analog scores. Results In both groups, the number of actinic keratoses decreased by nearly 50%, but the number of new malignant tumors during the study year was similar to the number of tumors in the year before the study. Thickness of the keratoses decreased significantly in both groups. Acitretin dose had to be reduced in most patients because of the frequent occurrence of mucocutaneous side effects, such as cheilitis, excessive peeling of the skin, and hair disorders. In the 14 patients randomized to continuous treatment with a dose of 0.4 mg/kg/d, this dose could be maintained in 3 of 14 patients only. Temporary interruption of acitretin therapy was necessary in 7 of 26 patients. Patients' contentment about the aspect of their skin increased significantly, with no differences between groups. Conclusions Acitretin therapy decreased the number of actinic keratoses in renal transplant recipients at a low maintenance dose of 0.2 mg/kg/d and significantly decreased the degree of thickness of the lesions. However, the incidence of new skin malignancies remained unchanged. Despite the high incidence of mucocutaneous side effects, patient's contentment with the aspect of their skin increased significantly.

Cytokines: interleukin and interferon therapy in dermatology.

Cytokines are highly potent biologically active proteins that play an essential role in intercellular communication. They are vital to the mediation and regulation of inflammatory and specific immune reactions as well as to nonimmunological processes. Several cytokines are already used for the treatment of malignant, inflammatory and infectious skin diseases. This in particular includes certain interleukins (ILs) and interferons (IFNs). Whereas some cytokine therapies are already approved and well established, such as IFN-alpha and IL-2 (approved in the USA) for melanoma, others are in the early stages of development and are used in explorative trials (e.g. IL-4 and IL-10 in the treatment of psoriasis). It is likely that some of the new approaches currently under investigation will actually lead to both the registration of new drugs for dermatological treatment, and to supplementation of existing therapeutic options. The aim of this review is to give an overview on the current state of cytokine therapy in dermatology.

Cytokine therapy in dermatology.

Cytokines have been in the focus of scientific interest for some years now. Analysing their expression permitted a better understanding of the pathogenesis of various diseases, including in dermatology. Moreover, they are now far beyond the stage when they were of interest only to the pathophysiological research sector: some cytokine therapies are already being employed as part of the clinical practice. In fact, several cytokines are used for the treatment of malignant, inflammatory and infectious skin diseases. Their stage of development ranges from advanced, already approved and well established therapies (e.g. IFN-alpha and IL-2 for melanoma) to early explorative trials (e.g. IL-4 and IL-10 for psoriasis). Some of the new approaches currently under investigation will actually lead to registration of new drugs for dermatological treatment and to supplement existing therapeutic options. Beside this, the results of clinical trials with cytokines are significantly contributing to our understanding of the pathophysiology of diseases. They will give a better insight into which mechanisms play a greater or lesser part in their development and may generate momentum for still better targeted pharmacological approaches. Here we would like to give an overview about the current stage of cytokine therapy and the prospects for dermatological indications. The terminology and immunobiology of cytokines are also briefly discussed, since for a sensible interpretation of the relevant findings a basic knowledge of these biologically highly active messenger substances is essential.

IL-10 does not play a role in cutaneous Photofrin photodynamic therapy-induced suppression of the contact hypersensitivity response.

Photodynamic therapy (PDT) treatment of both malignant and benign skin diseases has proven to be effective, and its use is increasing worldwide. However, preclinical studies using murine models have shown that PDT of the skin inhibits cell-mediated immune reactions, as measured by the suppression of the contact hypersensitivity (CHS) reaction. We have previously demonstrated that PDT enhances IL-10 expression in treated skin, and that the kinetics of induction of IL-10 is similar to the kinetics of suppression of systemic CHS reactions by cutaneous PDT. In the following report we have expanded upon these studies to demonstrate that cutaneous PDT, using Photofrin, induces elevated levels of systemic IL-10 that persist for at least 28 days following treatment. The increase in systemic IL-10 correlates to a prolonged suppression of CHS of at least 28 days following cutaneous PDT. IL-10 has been implicated as the causative agent in the suppression of cell-mediated immune reactions by UVB and transdermal PDT. However, in the studies reported here we demonstrate that the suppression of CHS by cutaneous PDT occurs via an IL-10 independent mechanism, as administration of anti-IL-10 antibodies had no effect on the ability of PDT to induce CHS suppression. These results were further confirmed using IL-10 knockout (KO) mice. Cutaneous PDT of IL-10 KO mice resulted in CHS suppression that was not significantly different from suppression induced in wild-type mice. Thus, it appears as though IL-10 does not play a role in CHS suppression by cutaneous PDT. Suppression of cell-mediated immune reactions by UVB and transdermal PDT is reversible by IL-12, which is critical for the development of these reactions. We show that administration of exogenous IL-12 is also able to reverse CHS suppression induced by cutaneous PDT, suggesting that whereas suppression of cell-mediated immune reactions by UVB, transdermal PDT and cutaneous PDT occurs via different mechanisms, a common regulatory point exists.

Malignant skin disease in children

Abstract Cutaneous malignancies are rare in the pediatric patient, and their diagnosis should raise suspicion for an underlying predisposing condition. For some disorders, such as Langerhans cell histiocytosis, our understanding of etiopathogenic mechanisms and optimal therapy continues to evolve and is the focus of ongoing investigations. Major breakthroughs in genetic discoveries pertaining to some cancers, such as basal cell carcinoma and malignant melanoma, have increased awareness of the role of genes in cell growth regulation, and opened doors to continued research into the clinical applicability of such revelations, including genetic testing, prenatal diagnosis, cancer surveillance, genetic counseling and gene therapy. Increased survival of childhood cancer patients and organ transplant recipients, a 20th century phenomenon, translates into increased numbers of immunosuppressed patients at greater risk for subsequent malignancies, including those of the skin. Attention to aggressive surveillance strategies and clinical diligence in the evaluation and therapy of such patients will be necessary for dermatologists to keep up with these evolving medical trends.

Long term follow up of topical mustine treatment for cutaneous Langerhans cell histiocytosis

BACKGROUND AND OBJECTIVESSkin lesions in Langerhans cell histiocytosis (LCH) are often painful and difficult to treat. Topical application of nitrogen mustard (0.02% mechlorethamine hydrochloride, mustine), an alkylating cytostatic agent, has...

Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) in malignant and nonmalignant skin diseases.

Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) was performed in skin from patients with various malignant and nonmalignant skin diseases using anti-PCNA monoclonal antibodies. The malignant diseases included squamous cell carcinoma (SCC), adult T lymphotrophic leukemia (ATL), mycosis fungoides, malignant melanoma and malignant lymphoma, and the nonmalignant diseases included severe treatment-resistant atopic dermatitis (AD), psoriasis vulgaris, verruca vulgaris, and others. The percentage of PCNA-positive cells (the labeling index, LI) was highest for the malignant diseases (56.5+/-7.1%). The LIs for severe treatment-resistant AD, psoriasis, and verruca vulgaris were also significantly higher than those for the normal control or nonlesional skin of the patients. The PCNA LIs were, however, not significantly elevated in eczema and contact dermatitis. The high PCNA LIs in severe AD and psoriasis vulgaris were considerably lower in the skin improved by treatment. Labeling with Ki67, a nuclear protein expressed in cycling cells, was also performed in skin from subsets of each patient group. The results were very similar to those found with PCNA labeling. PCNA-positive cells were found throughout the dermis as well as the basal layer in the malignant diseases, whereas they were found only in the basal layer in the nonmalignant diseases. The results suggest that in human skin diseases, the extent of staining for PCNA, which is a cofactor of DNA polymerase-delta and is essential for cell proliferation, correlates with the extent to which the disease is treatment-resistant. In addition, our findings suggest that the PCNA LI and distribution of PCNA-positive cells in the skin may be helpful in the early diagnosis of skin malignancies.