T-cadherin loss induces an invasive phenotype in human keratinocytes and squamous cell carcinoma (SCC) cells in vitro and is associated with malignant transformation of cutaneous SCC in vivo.

BACKGROUND: Cadherins play important roles in controlling keratinocyte growth, differentiation and survival. Atypical glycosylphosphatidylinositol-anchored T-cadherin (T-cad) is highly expressed in the basal keratinocyte layer of skin. The role of T-cad in keratinocyte biology and pathology is unclear. OBJECTIVES: To define the role of T-cad in the pathogenesis of cutaneous squamous cell carcinoma (SCC) through gain-of-function and loss-of-function studies in vitro and through examination of T-cad expression patterns in human cutaneous SCC specimens in relation to histological classification of degree of tumour differentiation. METHODS: In vitro studies employed lentiviral-mediated overexpression/silencing of T-cad in normal human keratinocyte (HaCaT) and SCC (A431) cell lines, monolayer and multicellular spheroid culture models, cell morphology analyses and assays of random motility and invasion. Immunohistochemistry was performed on skin specimens from patients with actinic keratosis, Bowen disease or SCC. RESULTS: In vitro, silencing of T-cad induced a morphologically elongated and disorganized cell phenotype, increased random motility and markedly enhanced invasive potential. Overexpression of T-cad induced a morphologically spread and compact cell phenotype and blunted invasive potential. In vivo, regional loss of T-cad expression was more frequent and prominent in SCC classified as moderately-to-poorly differentiated than in SCC classified as well differentiated. However, in both categories aberrant and/or absence of T-cad expression was associated with histological features of a potentially more malignant and invasive phenotype of cutaneous SCC. CONCLUSIONS: T-cad is a controlling determinant of SCC phenotype and invasive behaviour and its loss is associated with the process of malignant transformation from noninvasive to invasive SCC.

Changes of epidermal mu-opiate receptor expression and nerve endings in chronic atopic dermatitis.

There is increasing evidence that neuropeptides such as a substance P, neurotrophins or beta-endorphin, an endogenous agonist for mu-opioid receptor, are involved in the pathogenesis of atopic dermatitis in which mental stress and scratching deteriorate the disease. mu-Opioid receptor, a G-protein-coupled receptor, can be downregulated and internalized by agonists and other factors in vitro. In this study, we investigated the regulation of mu-opioid receptor and nerve endings in atopic dermatitis patients. Skin biopsies from atopic dermatitis patients revealed a significant downregulation of mu-opiate receptor expression in epidermis of atopic dermatitis. Permeabilization of the skin showed that the receptor in keratinocytes from atopic dermatitis is internalized. The mRNA expression pattern of the mu-opiate receptor is different in epidermis taken from patients with chronic atopic dermatitis compared to normal skin. In atopic dermatitis, the mRNA is concentrated in the subcorneal layers of the epidermis and in normal skin in the suprabasal layers. Staining of the nerve endings using protein gene product 9.5 shows a different pattern of epidermal nerve endings in normal skin compared to atopic dermatitis. In normal skin, the epidermal nerve endings are rather thick. However, in atopic dermatitis, the epidermal nerve endings are thin and run straight through the epidermis. Based on these observations and combining the 'intensity' and 'pattern' hypothesis, we propose a new theory especially for histamine-unrelated, peripheral induction of chronic pruritus. We suggest that 'itch' is elicited in the epidermal unmyelinated nerve C-fibers and 'pain' in the dermal unmyelinated nerve fibers. The downregulation of the opioid receptor in the epidermis contributes to the chronic itching. We call this new hypothesis the 'layer hypothesis'.

Fas-ligand gene silencing in basal cell carcinoma tissue with small interfering RNA.

Basal cell carcinoma (BCC) is the most frequent cancer in the Caucasian population. Cells of BCC strongly express Fas-ligand (FasL), a member of the tumor necrosis family, which induces apoptosis in Fas receptor-expressing cells. It has been suggested that by expression of FasL, BCC cells may evade the attack of Fas-positive immune effector cells allowing the tumor to expand. Thus, downregulation of FasL should prime BCC to the assault of immune effector cells. Recently, it has been shown that RNA interference is a highly successful approach to specifically silence a gene of interest in single cells and some animal models. However, RNAi in human tissues has not been shown so far. Here, we provide evidence that small interfering RNAs (siRNAs) efficiently transfect tumor tissue ex vivo and silence the gene of interest. We demonstrate that a specific siRNA efficiently downregulates FasL not only in FasL-positive indicator cells but also in surgically excised BCC tissue at both the protein and the mRNA level. The successful transfection of tumor tissues with siRNAs now allows to test the function of the molecule under study and opens up the investigation of other target genes in the tumor.

Circumscribed juvenile pityriasis rubra pilaris.

We report the case of a 20-year-old woman with a 10-year history of circumscribed juvenile-onset pityriasis rubra pilaris (PRP, type IV). Our patient had well-defined keratotic follicular papules on an erythematous base located on the extensor aspects of the extremities and dorsal aspects of the feet but no involvement of the palms and soles. Although most cases of type IV PRP follow a favourable course with spontaneous resolution of the lesions, this case demonstrates that circumscribed juvenile PRP can be more persistent and lasts several years.

Pancreatic panniculitis in a patient with an acinar cell cystadenocarcinoma of the pancreas.

We describe a 60-year-old man with pancreatic panniculitis associated with arthritis and peripheral eosinophilia in whom the skin symptoms led to a diagnosis of an underlying acinar cell cystadenocarcinoma. The panniculitis involved initially the legs, but soon thereafter lesions developed on the trunk and upper extremities. In the literature, only 5 cases of pancreatic acinar cell cystadenocarcinoma have been reported, none of these in association with panniculitis.

Cutaneous myiasis due to Dermatobia hominis.

Cutaneous myiasis caused by the human botfly Dermatobia hominis involves the infestation of tissue with dipterous fly larvae and is common in the neotropical region of the New World. We report a case of D. hominis imported in Switzerland from Costa Rica. In the past, various approaches to extract the botfly larva have been reported.

Cutaneous plasmablastic lymphoma in an HIV-positive male: an unrecognized cutaneous manifestation.

Plasmablastic lymphoma (PBL) is a rare and relatively new entity originally described in HIV-infected individuals. This subset of Epstein-Barr-virus (EBV)-related non-Hodgkin lymphomas is now regarded as a distinct clinicopathological category of AIDS-associated lymphomas occurring preferentially in the oral cavity and showing a poor prognosis. We describe for the first time an EBV-associated PBL with an isolated cutaneous distribution on the lower extremities in an HIV-infected heterosexual male and point to the unique clinical, morphological and immunophenotypic characteristics of this lymphoma. The patient presented with fast growing solid and livid nodules on both legs. The large, blastic tumor cells showed the following immunophenotype: CD138+, CD45+, CD20-, CD10-, CD3-, CD30-, bcl-2-, bcl-6-, LMP-1- and EMA-. The proliferation fraction (Mib-1) was >90%. EBV association was demonstrated by in situ hybridization (EBV-encoded RNAs 1/2). Polymerase-chain-reaction-based DNA analysis demonstrated a clonal IgH rearrangement in the absence of a bcl-2/IgH translocation. PBL in HIV patients may occur not only in the oral cavity, but can probably involve any other organs including the skin.

Papular elastorrhexis. report of five cases.

Papular elastorrhexis is a rare disorder that occurs predominantly during adolescence. We report 5 patients with asymptomatic white, nonfollicular, firm papules scattered over the trunk and extremities. Histologically, the papules demonstrate focal areas of collagen homogenization with decreased and fragmented elastic fibers. The clinical differential diagnosis includes papular acne scars, dermatofibrosis lenticularis disseminata (Buschke-Ollendorff syndrome), cutaneous collagenoma and nevus anelasticus, but histology clearly separates papular elastorrhexis from the other entities.

Common skin disorders of the penis.

Diseases of the male genitalia range from infectious lesions to inflammatory and neoplastic conditions, including many genital manifestations of more general skin diseases. This review highlights the clinical features, diagnosis and treatment of the most common dermatoses of the male genitalia. Herpes genitalis and infections caused by human papillomavirus (HPV) are increasing, particularly in young sexually active people. Herpes simplex virus infection is the commonest infectious cause of genital ulceration, with evidence that many infections are asymptomatic. HPV infection may be latent, subclinical and clinical. The most common causal agents for condyloma acuminatum are low-risk HPV 6 and 11; high-risk HPV types 16 and 18 are associated with premalignant and malignant lesions. Treatment for genital warts remains unsatisfactory; recurrences are common. Imiquimod, a new topical immunotherapeutic agent, which induces interferon and other cytokines, has the potential to be a first-line therapy for genital warts. Scabies and pediculosis are transmitted by skin-to-skin contact and sexual transmission is common, with the penis and scrotum favourite locations for scabious lesions. Oral ivermectin, a highly active antiparasitic drug, is likely to be the treatment of choice, but until approval is granted it should be reserved for special forms of scabies. Common skin diseases, e.g. psoriasis and lichen planus, may have an atypical appearance in the genital area. The typical psoriatic scale is usually not apparent because of moisture and maceration. Allergic contact dermatitis of the genital area may result from condoms, lubricants, feminine hygiene deodorant spray and spermicides. More often, contact dermatitis is irritant, resulting from persistent moisture and maceration. Lichen sclerosus is a chronic inflammatory disease that occurs as atrophic white patches on the glans penis and foreskin. The penile form is a common cause of phimosis in uncircumcised men; involvement of the urethral meatus may lead to progressive meatal stenosis. Plasma cell balanitis is a benign, idiopathic condition presenting as a solitary, smooth, shiny, red-orange plaque of the glans and prepuce of a middle-aged to older man. Squamous cell carcinoma (SCC) in situ, e.g. erythroplasia of Queyrat and Bowen's disease, cannot be excluded clinically; their apparent clinical benignity may lead to lengthy periods of misdiagnosis and biopsy is required to confirm the diagnosis. SCC is the most common malignancy of the penis and the role of oncogenic HPV-types has been also established in SCC of the penis. Prevention of SCC of the penis presupposes an identification of risk factors, early detection of all pre-cancerous lesions and treatment of phimosis.

Ultraviolet light downregulates CD95 ligand and TRAIL receptor expression facilitating actinic keratosis and squamous cell carcinoma formation.

Long-term ultraviolet light exposure of human skin epidermis in Caucasians is associated with an increased risk for the development of melanoma and nonmelanoma skin cancers. Ultraviolet radiation not only induces DNA damage in epidermal cells, it also interferes with skin homeostasis, which is maintained by a unique distribution pattern of apoptosis-inducing and apoptosis-preventing molecules. We demonstrate that, beside CD95 ligand, TRAIL and TRAIL receptors also function as important sensors in the human epidermis preserving skin integrity and preventing cell transformation. Ultraviolet irradiation extensively changes the expression pattern of some of these molecules, diminishing their sensor function. In particular, CD95 ligand and to a somewhat lesser extent TRAIL receptors are downregulated upon ultraviolet light exposure. CD95 ligand downregulation is not due to protein degradation as in situ hybridization experiments strongly support a transcriptional regulation. The downregulation of these molecules with sensor function increases the risk that aberrant cells are less efficiently eliminated. This concept is supported by the fact that the expression of these molecules is also low or absent in actinic keratosis, a precancerous state that has developed as the consequence of long-term ultraviolet exposure. Progression to invasive neoplasms is then accompanied by an upregulation of CD95 ligand and a downregulation of CD95 and of the TRAIL receptors. The high expression of CD95 ligand, TRAIL, and FLIP in squamous cell carcinoma may then contribute to the immune escape of the tumor, whereas the lack of expression of CD95 and TRAIL receptors prevents autolysis of the tumor.

Segmental forms of autosomal dominant skin disorders: the puzzle of mosaicism.

Autosomal dominant inherited disorders of the skin sometimes present as a segmental phenotype. In recent years molecular studies have demonstrated that genetic mosaicism leads to such a clinical manifestation. In general the skin outside the segmental disorder is normal. This rather common variant of segmental manifestation has been termed type 1. Recently, Happle delineated a second type of segmental manifestation of autosomal dominant genodermatosis. This variant is characterized by a more diffuse clinical presentation of the disease, and a very marked linear pattern can be recognized. An explanation of this phenotype is a germline mutation of the gene manifests after a postzygotic mutation leading to double inactivation of the gene. The severe linear manifestation then reflects a doubling of the genetic burden. We present a number of clinical cases to demonstrate this phenomenon, and we present a case of the segmental Naegeli-Franceschetti-Jadassohn syndrome born to a mother with the diffuse manifestation of the disorder.

Cutaneous manifestations of Paecilomyces lilacinus infection induced by a contaminated skin lotion in patients who are severely immunosuppressed.

BACKGROUND: New opportunistic fungal infections cause significant morbidity and death in patients who are severely immunocompromised. Cutaneous lesions may be the first clinical manifestation and give the clue to early diagnosis. OBJECTIVE: The purpose of this study was to describe the clinical and histologic manifestations of Paecilomyces lilacinus infection in patients who are severely immunosuppressed. METHODS: Within a 3-month period, we observed 5 patients with allogenic bone marrow transplantation and 4 patients with aplasia after chemotherapy for hematologic malignancies who developed skin eruptions caused by invasive P lilacinus. RESULTS: The skin lesions began in 7 cases during or shortly after recovery of pancytopenia. Most of the skin lesions were located on the lower extremities. The cutaneous manifestations were highly variable including erythematous macules, nodules, pustules, vesicular lesions, and necrotic crusts. In 3 biopsy specimens, histologic examination revealed hyphae in periodic acid-Schiff-stained sections. In all patients P lilacinus was isolated from skin tissue samples. P lilacinus was identified from all lesions either by skin biopsy or needle aspiration from clinically evident lesions. In 3 additional cases, the patient's hands were colonized without skin lesions. The source of the epidemic outbreak was finally traced down to several contaminated lots of a topical moisturizing agent. Two patients died; one patient had septic lesions in the eye and kidney as the result of P lilacinus. CONCLUSION: Clinical and histologic findings of P lilacinus infection with cutaneous manifestations in patients who are severely immunosuppressed are summarized. P lilacinus is resistant to all systemic antimycotics available, and in general, recovery of immunosuppression is necessary to eradicate the mold. Contaminated topical dermatologic agents should be included in the differential diagnosis as a source for severe epidemic cutaneous manifestations of fungal infection in patients who are severely immunosuppressed. This fact implies that additional safety guidelines are necessary for topical dermatologic agents used for patients who are severely immunosuppressed.

Regression of basal cell carcinoma by intralesional interferon-alpha treatment is mediated by CD95 (Apo-1/Fas)-CD95 ligand-induced suicide.

Basal cell carcinoma (BCC) is the most common skin cancer in humans, and although metastasis rarely occurs, the tumor cells are nevertheless able to invade and destroy the surrounding tissue. Intralesional injection of IFN-alpha has been found to be highly effective in inducing BCC regression by an unknown mechanism. We show that in untreated patients, BCC cells express CD95 ligand, but not the receptor, which may allow tumor expansion by averting the attack of activated CD95 receptor-positive lymphoid effector cells. The CD95 ligand of BCC cells is functional as CD95-positive cells incubated on BCC cryosections become apoptotic and are lysed. In IFN-alpha-treated patients BCC cells express not only CD95 ligand but also CD95 receptor, whereas the peritumoral infiltrate that mainly consists of CD4+ T cells predominantly contains CD95 receptor and only few CD95 ligand-positive cells. Thus, in treated patients BCC most likely regresses by committing suicide through apoptosis induction via CD95 receptor-CD95 ligand interaction.

Lymphoproliferative responses to Borrelia burgdorferi in patients with erythema migrans, acrodermatitis chronica atrophicans, lymphadenosis benigna cutis, and morphea.

BACKGROUND AND DESIGN: Specific humoral and cell-mediated immune responses play an important role in the pathogenesis of Lyme borreliosis. Several previous studies demonstrated that a specific cellular immune response to Borrelia burgdorferi can occur independently of a diagnostic humoral response. Little is known about T-cell reactivities against B burgdorferi in early and late cutaneous manifestations of Lyme borreliosis. We studied the lymphoproliferative response of peripheral blood mononuclear cells to B burgdorferi antigen from 99 patients (25 with erythema migrans, 16 with acrodermatitis chronica atrophicans, 13 with lymphadenosis benigna cutis, and 45 with localized scleroderma) and 21 control subjects. The results are expressed as a stimulation index (SI) (mean count per minute of triplicate cultures with stimulant divided by mean count per minute without stimulant). The serum samples from all patients and control subjects were tested for antibodies to B burgdorferi by indirect immunofluorescence assay. RESULTS: The 21 healthy seronegative controls had an SI of 3.3 +/- 2.0 (mean +/- SD). Compared with that of control subjects, the SIs were significantly elevated in patients with erythema migrans (9.8 +/- 9.1), acrodermatitis chronica atrophicans (11.8 +/- 8.2), and lymphadenosis benigna cutis (7.2 +/- 6.2). The 45 patients with localized scleroderma had elevated proliferative responses, with an SI of 6.5 +/- 7.3, but these responses did not significantly differ from those of controls. Elevated titers of antibodies to B burgdorferi were present in six (24%) of 25 patients with erythema migrans, five (38%) of 13 patients with lymphadenosis benigna cutis, and 13 (29%) of 45 patients with localized scleroderma. All 16 patients with acrodermatitis chronica atrophicans had markedly elevated antibody titers. CONCLUSIONS: Our findings show that a significant lymphoproliferative response to B burgdorferi occurs in the majority of patients with cutaneous manifestations of Lyme borreliosis. The lymphocyte proliferation assay may be of diagnostic value in patients in whom Lyme borreliosis is strongly clinically suspected and who have nondiagnostic levels of antibodies against B burgdorferi.

Isolated lichen planus of the lip.

Oral lichen planus (LP) is a relatively common disorder of unknown aetiology. Oral LP occurs most often on the buccal mucosa, but the gingivae, tongue, floor of the mouth, retromalar pads and lips may also be affected. Usually, patients have multiple sites of involvement. We report a 44-year-old patient with a 3-year history of isolated swelling of the lower lip, erosions and crusting. Histology of a biopsy from the lip revealed features of LP. Oral treatment with acitretin and low-dose steroid led to complete resolution of the lesions within 10 weeks. This is the first well-documented case of isolated LP of the lip. Diagnostic difficulties and differential diagnosis are reviewed.

Zosteriform metastases in melanoma.

Zosteriform metastasis is a rare form of tumor spread to the skin that most often arises from an internal carcinoma or a hematologic malignancy. We describe a 29-year-old woman with malignant melanoma of the back in whom zosteriform metastases developed along the fifth thoracic dermatome.

Lichen planus of the eyelids.

Ocular involvement of lichen planus (Lp) is a rare event. Only 10 cases with Lp of the eyelids have been reported in the literature. Ocular Lp may also affect mucosal surfaces of the eye and lead to cicatrizing conjunctivitis. Lp of the eyelids may appear as isolated lesions and in those cases diagnosis is very difficult. Lp should be considered in the differential diagnosis of all erythematous and papular eruptions of the eyelids together with lupus erythematosus, psoriasis vulgaris or contact dermatitis.

Allergic contact dermatitis from ethyl chloride and sensitization to dichlorodifluoromethane (CFC 12).

Despite the widespread use of ethyl chloride as a local anesthetic and chlorofluorocarbons as propellants in medical and cosmetic aerosols, contact allergy to these 2 gases is rare. In a 30-year-old woman, an unusual itchy dermatitis appeared at all skin sites where a medical aerosol containing ethyl chloride had been briefly applied. Subsequent re-exposure to the spray and patch tests revealed contact sensitization to ethyl chloride and dichlorodifluoromethane (CFC 12). Histologic and immunohistochemical examinations of the test reaction were consistent with a T-cell-mediated allergic reaction. The low incidence of contact allergy to ethyl chloride and chlorofluorocarbons may be due to the rapid evaporation of these volatile gases, thus preventing intense and prolonged contact with the skin and consequently contact sensitization. A modified patch test procedure using perforated plastic chambers to allow gas evaporation is necessary to test volatile agents.