T-Cadherin Expression in Actinic Keratosis Transforming to Invasive Squamous Cell Carcinoma.

BACKGROUND/AIMS: Clinical and histological features of actinic keratosis (AK) cannot predict malignant transformation to invasive squamous cell carcinoma (iSCC) in individual lesions. We investigated whether patterns/distribution of T-cadherin in AK lesions have biomarker value in predicting transformation to iSCC. METHODS: 28 specimens of cutaneous iSCC exhibiting adjacent or overlying AK were immunostained for T-cadherin and classified according to AK histological grade (AK I-III) and basal growth pattern (PRO I-III). RESULTS: T-cadherin staining was absent/very weak in 16 and strongly positive in 12 cases. iSSCs lacking T-cadherin expression were most commonly (12/16 cases) associated with type AK I or PRO I lesions, whereas the majority (10/12 cases) of T-cadherin-positive iSCCs originated from AK II and AK III/PRO II and PRO III. In T-cadherin-negative iSCCs, T-cadherin expression was absent in overlying AK and early invasive tumour but retained in AK areas adjacent to the tumour. In contrast, T-cadherin-positive iSCCs displayed expression of T-cadherin in the adjacent AK and early invasive tumour. CONCLUSION: T-cadherin-negative iSCC arises from AK showing partial or extensive regional loss of T-cadherin in the basal layer of the epidermis. We speculate that T-cadherin loss in individual AK lesions could indicate potential transformation of AK into aggressive iSCC.

T-Cadherin Expression in the Epidermis and Adnexal Structures of Normal Skin.

BACKGROUND: T-cadherin is an atypical glycosylphosphatidylinositol-anchored member of the cadherin superfamily of adhesion molecules. The role of T-cadherin in biology of the skin is poorly understood. Expression of T-cadherin in basal keratinocytes and dermal blood vessels of the healthy epidermis has been demonstrated, but studies on expression in skin appendages are rare. METHODS: We conducted an immunohistochemical analysis of T-cadherin expression in the epidermis and adnexal structures of normal skin. RESULTS: T-cadherin expression is restricted to basal keratinocytes of the epidermis. The basal cell layer of sebaceous glands was T-cadherin positive, whereas sebocytes were negative. Within apocrine glands, only myoepithelial cells were T-cadherin positive. In contrast, both the secretory coils and excretory ducts of eccrine glands were T-cadherin positive. In terminal hair follicles, the outer root sheath layers strongly expressed T-cadherin throughout different regions of the follicle, with the strongest immunoreactivity at the bulge and suprabulbar regions. T-cadherin and CK15 stem cell marker similarly localized within the bulge and suprabulbar region. T-cadherin and CD34 stem cell marker similarly localized at the suprabulbar level. CONCLUSION: The specific patterns of T-cadherin expression in the epidermis and adnexal structures suggest an important guardian role in skin homeostasis.

Primary cutaneous marginal zone lymphoma in children: a report of 3 cases and review of the literature.

: Primary cutaneous marginal zone lymphoma (PCMZL) is one of the most common cutaneous B-cell lymphomas. It affects mostly patients in their fourth decade and manifests with multifocal nodules mostly on the arms and upper trunk in more than half of the patients. PCMZL is, however, rare in children and adolescents, with only 20 cases reported in patients aged 20 and younger. The authors present 3 cases of PCMZL in teenagers. The patients were 2 girls aged 18 and 13 and a 17-year-old boy. Two patients presented with multiple lesions involving various anatomic sites, whereas in 1 patient, 2 small closely opposed papules on the abdomen were seen. Histopathologically, the characteristic appearance of PCMZL was found in 3 of 4 specimens, with nodular infiltrates composed of small lymphocytes in the interfollicular compartment, reactive germinal centers, and plasma cells in small clusters mainly at the periphery of the infiltrates, whereas 1 specimen showed a dense lymphocytic infiltrate with small granulomas. Clonality was demonstrated by monotypic immunoglobulin light chain expression and/or monoclonal rearrangement of the immunoglobulin heavy chain genes. No Borrelia burgdorferi was identified on serology or by polymerase chain reaction in any of the cases. Treatment included excision or administration of antibiotics with complete remission in all the 3 patients indicating that PCMZL in children and young adolescents follows the same indolent course with a tendency for recurrences, but excellent prognosis as in adults. The pertinent literature on PCZL in childhood and adolescence is reviewed.

Multicenter, double-blind, parallel group study investigating the non-inferiority of efficacy and safety of a 2% miconazole nitrate shampoo in comparison with a 2% ketoconazole shampoo in the treatment of seborrhoeic dermatitis of the scalp.

OBJECTIVES: This study investigated the non-inferiority of efficacy and tolerance of 2% miconazole nitrate shampoo in comparison with 2% ketoconazole shampoo in the treatment of scalp seborrheic dermatitis. METHODS: A randomized, double-blind, comparative, parallel group, multicenter study was done. A total of 274 patients (145 miconazole, 129 ketoconazole) were enrolled. Treatment was twice-weekly for 4 weeks. Safety and efficacy assessments were made at baseline and at weeks 2 and 4. Assessments included symptoms of erythema, itching, scaling ['Symptom Scale of Seborrhoeic Dermatitis' (SSSD)], disease severity and global change [Clinical Global Impressions (CGIs) and Patient Global Impressions (PGIs)]. CONCLUSIONS: Miconazole shampoo is at least as effective and safe as ketoconazole shampoo in treating scalp seborrheic dermatitis scalp.

T-cadherin loss promotes experimental metastasis of squamous cell carcinoma.

T-cadherin is gaining recognition as a determinant for the development of incipient invasive squamous cell carcinoma (SCC). However, effects of T-cadherin expression on the metastatic potential of SCC have not been studied. Here, using a murine model of experimental metastasis following tail vein injection of A431 SCC cells we report that loss of T-cadherin increased both the incidence and rate of appearance of lung metastases. T-cadherin-silenced SCC metastases were highly disordered with evidence of single cell dissemination away from main foci whereas SCC metastases overexpressing T-cadherin developed as compact, tightly organised sheets. SCC cell adhesion to vascular endothelial cells (EC) in culture was increased for T-cadherin-silenced SCC and decreased for T-cadherin-overexpressing SCC. Confocal microscopy showed that T-cadherin-silenced SCC adherent on EC display an elongated morphology with long thin extensions and a high degree of intercalation within the EC monolayer, whereas SCC overexpressing T-cadherin formed poorly-spread multicellular aggregates that remain on the outer surface of the EC monolayer. T-cadherin-deficient SCC or human keratinocyte cells exhibited increased transendothelial migration in vitro which could be attenuated in the presence of EGFR inhibitor gefitinib. Our data suggest that loss of T-cadherin can increase metastatic potential and aggressiveness of SCC, possibly due to facilitating arrest and extravasation through the vascular wall and/or more efficient establishment of metastases in the new microenvironment.

T-Cadherin is an auxiliary negative regulator of EGFR pathway activity in cutaneous squamous cell carcinoma: impact on cell motility.

Genetic and epigenetic studies in different cancers, including cutaneous carcinomas, have implicated T-cadherin (T-cad) as a tumor suppressor. Immunohistochemical and in vitro studies have suggested that T-cad loss promotes incipient invasiveness in cutaneous squamous cell carcinoma (SCC). Molecular mechanisms are unknown. This study found that the main consequence of T-cad silencing in SCC is facilitation of ligand-dependent EGFR activation, whereas T-cad overexpression impedes EGFR activation. Gain- and loss-of-function studies in A431 SCC cells demonstrate T-cad-controlled responsiveness to EGF with respect to pharmacological inhibition of EGFR and to diverse signaling and functional events of the EGFR activation cascade (EGFR phosphorylation, internalization, nuclear translocation, cell retraction/de-adhesion, motility, invasion, integrin ß1, and Rho small GTPases such as RhoA, Rac1, and Cdc42 activation). Further, T-cad modulates the EGFR pathway activity by influencing membrane compartmentalization of EGFR; T-cad upregulation promotes retention of EGFR in lipid rafts, whereas T-cad silencing releases EGFR from this compartment, rendering EGFR more accessible to ligand stimulation. This study reveals a mechanism for fine-tuning of EGFR activity in SCC, whereby T-cad represents an auxiliary "negative" regulator of the EGFR pathway, which impacts invasion-associated behavioral responses of SCC to EGF. This action of T-cad in SCC may serve as a paradigm explaining other malignancies displaying concomitant T-cad loss and enhanced EGFR activity.

Paradoxical effects of T-cadherin on squamous cell carcinoma: up- and down-regulation increase xenograft growth by distinct mechanisms.

Mechanisms underlying cutaneous squamous cell carcinoma (SCC) tumour growth and invasion are incompletely understood. Our previous pathological and in vitro studies suggest that cell surface glycoprotein T-cadherin (T-cad) might be a controlling determinant of the behaviour of SCC. Here we used a murine xenograft model to determine whether T-cad modulates SCC tumour progression in vivo. Silencing or up-regulation of T-cad in A431 (shTcad or Tcad(+) , respectively) both resulted in increased tumour expansion in vivo. To explain this unanticipated outcome, we focused on proliferation, apoptosis and angiogenesis/lymphangiogenesis, which are important determinants of the progression of solid tumours in vivo. shTcad exhibited enhanced proliferation potential in vitro and in vivo, and their signalling response to EGF was characterized by a higher Erk1/2:p38MAPK activity ratio, which has been correlated with more aggressive tumour growth. T-cad over-expression did not affect proliferation but staining for cleaved caspase 3 revealed a minimal occurrence of extensive apoptosis in Tcad(+) tumours. Immunofluoresence staining of xenograft sections revealed increased intra-tumoural total microvessel (CD31(+)) and lymphatic vessel (LYVE-1(+)) densities in Tcad(+) tumours. shTcad tumours exhibited decreased microvessel and lymphatic densities. Tcad(+) expressed higher levels of transcripts for VEGF-A, VEGF-C and VEGF-D in vitro and in vivo. Culture supernatants collected from Tcad(+) enhanced sprout outgrowth from spheroids composed of either microvascular or lymphatic endothelial cells, and these in vitro angiogenic and lymphangiogenic responses were abrogated by inclusion of neutralizing VEGF antibodies. We conclude that T-cad can exert pleiotropic effects on SCC progression; up- or down-regulation of T-cad can promote SCC tumour expansion in vivo but through distinct mechanisms, namely enhancement of angio/lymphangiogenic potential or enhancement of proliferation capacity.

[Keratosis pilaris and keratosis pilaris atrophicans faciei]. / Keratosis pilaris und Keratosis pilaris atrophicans faciei.

Keratosis pilaris and ulerythema ophryogenes (keratosis pilaris atrophicans faciei) are hereditary disorders with altered follicular keratinization that show follicular, horny papules surrounded by an erythematous halo. Ulerythema ophryogenes is an uncommon variant of keratosis pilaris characterized by erythematous follicular papules of the eyebrows and cheeks followed by a gradual loss of hair. On the background of 15-year-old boy who presented with keratosis pilaris and ulerythema ophryogenes, we discuss the various clinical manifestations of keratosis pilaris.

Rosacea: an update.

Rosacea is a common chronic cutaneous disorder of unknown etiology which occurs most commonly in middle-aged individuals. Cutaneous manifestations include transient or persistent facial erythema, telangiectasia, edema, papules and pustules that are usually confined to the central portion of the face. The National Rosacea Society's Expert Committee on the Classification and Staging of Rosacea identified four subtypes of rosacea: erythematotelangiectatic, papulopustular, phymatous and ocular. Recently, a standard grading system for assessing gradations of the severity of rosacea has been reported. Little is known about the cause of rosacea. Genetic, environmental, vascular, inflammatory factors and microorganisms such as Demodex folliculorum and Helicobacter pylori have been considered. Topical metronidazole and azelaic acid have been demonstrated to be effective treatments for rosacea. Severer or persistent cases may be treated with oral metronidazole, tetracyclines or isotretinoin.

Unilateral aplasia cutis congenita on the leg.

We present the case of a newborn male with aplasia cutis congenita on the extensor side of the right leg, with unilateral absence of skin on the lower limb. There was no abnormality in pregnancy or birth and there was no associated malformation or skin disease such as blistering or nail pathology. The management of this large ulcer was conservative, using silver sulfadiazine ointment, and healing occurred within 3 months. The follow-up after 21 months showed little scar formation and no handicap regarding function and appearance. The psychomotor development was normal. According to the classification outlined by Frieden, we classified this condition as type VII aplasia cutis congenita.

Fas ligand downregulation with antisense oligonucleotides in cells and in cultured tissues of normal skin epidermis and basal cell carcinoma.

Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis upon interaction with Fas-receptor-expressing cells. FasL normally plays an important immune regulatory role, but it can also cause severe skin diseases if overexpressed and it may serve some tumors for immune evasion. Thus, in situ inhibition of FasL expression with antisense oligonucleotides in patients may be a novel approach to overcome its pathogenic role. We designed and evaluated 15 phosphorothioate antisense oligonucleotides directed against different regions of the human FasL mRNA. They exhibited different inhibitory activities on FasL expression in HEK293 cells. The most potent antisense oligonucleotide, ASO8, specifically downregulated 90% FasL expression at the protein level and 80% at the mRNA level. FasL downregulation reduced the effector function of HEK293 cells toward Fas receptor positive target cells. Further studies demonstrated that ASO8 efficiently inhibited FasL synthesis in split skin and basal cell carcinoma tissue. Our results show that the modulation of FasL expression by antisense oligonucleotides is possible in cells as well as tissue and indicate that antisense oligonucleotides may provide a promising strategy for the therapy of FasL-mediated disorders.

Cutaneous larva migrans associated with Löffler's syndrome.

We describe a patient who was admitted to hospital after returning from a holiday in Thailand with coronary artery disease and ventricular tachycardia. As an incidental finding, the routine chest radiography showed migratory pulmonary infiltrates. A peripheral blood smear showed eosinophilia. Physical examination revealed multiple, slightly raised, erythematous, serpentine tracks on the buttocks. A clinical diagnosis of larva migrans was made, and the patient was treated with oral albendazole 400 mg on 5 consecutive days and a single dose of oral praziquantel 3600 mg. By the end of treatment, most of the cutaneous lesions, the pulmonary infiltrates and the peripheral eosinophilia had resolved. The final diagnosis was larva migrans associated with Löffler's syndrome.

Intralesional interferon in basal cell carcinoma: how does it work?

Basal cell carcinoma (BCC) is the most common skin cancer among Caucasians, and its incidence is increasing. Intralesional injection of interferon alpha (IFN alpha) has been shown to provide a safe and effective treatment for BCCs. The predominant mechanism for the effect of IFN alpha on BCC has been partially identified. We have shown that in untreated patients, BCC cells constitutively express CD95 ligand (CD95L), but not the receptor. BCC cells make use of the CD95 ligand to escape from a local immune response by averting the attack from activated CD95 receptor-positive CD4+ T cells. The CD95L of BCC cells is functional as CD95+ target cells incubated on BCC cryosections become apoptotic and are lysed. In IFN alpha-treated patients BCC cells express not only CD95L but also CD95 receptor, and regress by committing suicide or fratricide through apoptosis induction via CD95 receptor-CD95L interaction. Peritumoral infiltrating cells, predominantly CD4+ T cells, may support regression of BCC by the secretion of cytokines such as IFN gamma or interleukin-2 which may also be responsible for the up-regulation of CD95 on BCC cells.