Therapeutic Effects of Focused Ultrasound on Expression of Notch1, C-Fos and Transforming Growth Factor-ß3 in Vulvar Skin of SD Rats with Vulvar Lichen Simplex Chronicus.

The purpose of this study was to investigate the therapeutic effects of focused ultrasound on the expression of notch1, c-fos and transforming growth factor-ß3 (TGF-ß3) in genital skin of SD rats with vulvar lichen simplex chronicus (LSC). Fifty-six female SD rats with LSC were randomly divided into therapy and sham groups. The therapy group was exposed to focused ultrasound. The sham group received the same therapy with an instrument that had no power output. Four wk after a singly focused ultrasound therapy, histologic analyses revealed that recovered SD rats accounted for 75% of SD rats in the therapy group and 10.7% in the sham group. Total collagen fiber density in the superficial layer of dermis in the therapy group was significantly lower than that in the sham group. Notch1 and c-fos protein expression in the therapy group was significantly lower than that in the sham group, with the opposite effect present for TGF-ß3. Focused ultrasound therapy may inhibit superficial collagen fibrosis in the dermis by affecting expression of notch1, c-fos and TGF-ß3 in vulvar skin tissue and consequently reduce the recurrence rate of LSC.

Abnormal expression of the co-stimulatory molecule B7-H3 in lichen simplex chronicus is associated with expansion of Langerhans cells.

BACKGROUND: The co-stimulatory molecule B7-H3, a cell surface transmembrane glycoprotein, was assessed for its functional and prognostic role in lichen simplex chronicus (LSC). AIM: To investigate if abnormal expression of the co-stimulatory molecule B7-H3 in LSC is associated with Langerhans cell (LC) expansion. METHODS: We used immunohistochemistry to stain LSC skin tissue, and evaluated if the immunostaining of B7-H3 and interleukin (IL)-6 was significantly different. RESULTS: Our results indicated that B7-H3 is abnormally expressed in LSC skin tissue and positively regulates LC expansion. We also found that IL-6 might modulate B7-H3 expression. Moreover, LC expansion in LSC leads to the proliferation of T cells. CONCLUSIONS: Our study indicates the potential value of immunotherapy as a treatment for LSC.

Classic Vulvar Intraepithelial Neoplasia With Superimposed Lichen Simplex Chronicus: A Unique Variant Mimicking Differentiated Vulvar Intraepithelial Neoplasia.

High-grade vulvar intraepithelial neoplasia, a precursor lesion to vulvar squamous cell carcinoma, is subdivided into 2 types, classic or usual vulvar intraepithelial neoplasia (CVIN) and differentiated vulvar intraepithelial neoplasia (DVIN). CVIN, which is a human papilloma virus (HPV)-dependent lesion, is typically distinguished from DVIN, a p53 mutation-dependent process, by its distinct histomorphologic and immunohistochemical characteristics. However, distinguishing between the 2 entities becomes challenging in cases of CVIN with superimposed inflammatory changes, especially lichen simplex chronicus (LSC). Twelve cases of DVIN, 9 cases of LSC, and 9 cases of CVIN with superimposed LSC were assessed for a number of morphologic features, including hyperkeratosis, hypergranulosis, acanthosis, hypercellularity, abnormal maturation (i.e. abnormal keratinization close to the base and/or dyskeratosis), hyperchromasia, and basal atypia. Immunohistochemistry for p53, p16, and MIB-1 was performed for all cases. When sufficient tissue was available, HPV genotyping was performed for cases of CVIN with superimposed LSC. DVIN uniformly demonstrated abnormal maturation, and atypia involving the basal cell layer; they were all p16 negative and demonstrated p53 positivity of moderate to strong intensity in a basal and parabasal distribution. CVIN with superimposed LSC frequently displayed hyperchromasia involving the basal 3 to 4 cell layers, basal to full-thickness atypia, and apoptosis. CVIN with superimposed LSC demonstrated intense p16 positivity extending from the basal cells to the mid-epithelium and a reduction or loss of staining in maturing keratinocytes. P53 staining revealed a unique pattern of parabasal and mid-epithelial weak to moderate staining with sparing of the basal layer. Cases of LSC demonstrated heterogenous p53 positivity and were negative for p16. MIB-1 staining showed a similar range of positivity for all diagnoses. HPV genotyping revealed HPV 16 in all 5 cases of CVIN with LSC that underwent testing. We conclude that, although CVIN with superimposed LSC can closely resemble DVIN, morphologic features such as nuclear hyperchromasia uniformly involving the basal 3 to 4 cell layers, apoptosis, and absent or less pronounced cytoplasmic maturation are more suggestive of CVIN with superimposed LSC. In cases where the morphology remains ambiguous, immunohistochemistry for both p16 and p53 can be helpful. In particular, p53 parabasal and mid-epithelial staining without involvement of the basal layer appears to be a characteristic finding in CVIN with superimposed LSC. MIB-1 staining is of little utility in distinguishing between these entities and should not be routinely performed.

[Establishment of a SD rat model of vulvar lichen simplex chronicus and detection of the expression of protease activated receptor 2].

OBJECTIVE: To establish a SD rat model of vulvar lichen simplex chronicus (LSC) and investigate the expression of protease activated receptor 2 (PAR2) in the genital skin. METHODS: Seventy female SD rats were randomly divided into group A (blank control group, n=10), group B (with application of acetone solution 3 times per week for 10 weeks, n=10), group C (with chronic mechanical irritation 3 times per week for 10 weeks, n=10), and group D (with topical treatment with 0.5= 7,12-Dimethylbenzanthracene [DMBA] in acetone solution and chronic mechanical irritation 3 times per week for 10 weeks, n=40). The changes of the genital skin changes were observed regularly and the expression of PAR2 in groups A and D was detected with immunohistochemistry, Western blotting and qRT-PCR. RESULTS: In group D, LSC occurred in 23 rats (57.5=) at 8 weeks and in 38 rats (95=) at 10 weeks; 8 rats (20=) showed papilloma at 12 weeks. Acetone treatment or chronic mechanical irritation did not cause LSC in the rats. Immunohistochemistry, Western blotting and qRT-PCR showed significantly increased expressions of PAR2 in group D at both the protein and mRNA levels as compared with those in group A (P<0.05). CONCLUSION: 0.5= DMBA in acetone solution along with chronic mechanical irritation can induce LSC in female SD rats, and PAR2 is closely related with the occurrence and progression of LSC.

To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease.

Despite similar components, the heterogeneity of skin characteristics across the human body is enormous. It is classically believed that site-specific fibroblasts in the dermis control postnatal skin identity by modulating the behavior of the surface-overlying keratinocytes in the epidermis. To begin testing this hypothesis, we characterized the gene expression differences between volar (ventral; palmoplantar) and nonvolar (dorsal) human skin. We show that KERATIN 9 (KRT9) is the most uniquely enriched transcript in volar skin, consistent with its etiology in genetic diseases of the palms and soles. In addition, ectopic KRT9 expression is selectively activated by volar fibroblasts. However, KRT9 expression occurs in the absence of all fibroblasts, although not to the maximal levels induced by fibroblasts. Through gain-of-function and loss-of-function experiments, we demonstrate that the mechanism is through overlapping paracrine or autocrine canonical WNT-ß-catenin signaling in each respective context. Finally, as an in vivo example of ectopic expression of KRT9 independent of volar fibroblasts, we demonstrate that in the human skin disease lichen simplex chronicus, WNT5a and KRT9 are robustly activated outside of volar sites. These results highlight the complexities of site-specific gene expression and its disruption in skin disease.

Glucocorticoid receptors GRα and GRß are expressed in inflammatory dermatoses.

BACKGROUND: Glucocorticoids (GC) are the most commonly used anti-inflammatory drugs in dermatology. The actions of GCs are mediated by the glucocorticoid receptor (GR). Alternative splicing of GR mRNA gives rise to different isoforms, GRα and GRß being the most important. GRß antagonizes the activity of GRα and its up-regulation has been associated with glucocorticoid insensitivity in several non-cutaneous inflammatory diseases. METHODS: Using immunohistochemical stainings, we analyzed the expression of GRα and GRß in lesional skin samples of patients with atopic dermatitis, lichen ruber planus, eczema nummulare and lichen simplex chronicus. We also conducted a study of 13 severe atopic patients to investigate the effect of prednisolone treatment on the expression of GR isoforms using quantitative PCR, western blot and immunohistochemical analysis. RESULTS: GRα and GRß were expressed in atopic dermatitis, lichen ruber planus, eczema nummulare and lichen simplex chronicus. Our novel finding was that GRß is abundant in keratinocytes and cutaneous neutrophils. Nuclear staining of both GRα and GRß was strongest in keratinocytes of patients with lichen ruber planus, whereas the least nuclear positivity was detected in keratinocytes of patients with atopic dermatitis. In severe atopic dermatitis GRα and GRß were expressed in both peripheral blood mononuclear cells and the skin. The expression of GRα and GRß varied during prednisolone therapy but the changes were not related to treatment response or GC insensitivity. CONCLUSION: GRα and GRß are expressed in inflammatory dermatoses. In severe atopic dermatitis the increased expression of GRß mRNA is not connected to insensitivity against prednisolone treatment.

An update on vulvar intraepithelial neoplasia: terminology and a practical approach to diagnosis.

There are two distinct types of vulvar intraepithelial neoplasia (VIN), which differ in their clinical presentation, aetiology, pathogenesis and histological/immunophenotypical features. One form driven by high-risk human papilloma virus infection usually occurs in young women and has been termed classic or usual VIN (uVIN). The other, not related to viral infection, occurs in postmenopausal women with chronic skin conditions such as lichen sclerosus and lichen simplex chronicus and is termed differentiated or simplex-type VIN. The latter is the precursor lesion of the most common type of squamous cell carcinoma (SCC) in the vulva, namely keratinizing SCC (representing 60% of cases). In contrast, uVIN usually gives rise to basaloid or warty SCC (40% of cases). The histological features of uVIN are similar to those of high grade lesions encountered in other lower anogenital tract sites (hyperchomatic nuclei with high nuclear to cytoplasmic ratios and increased mitotic activity). However, differentiated VIN has very subtle histopathological changes and often escapes diagnosis. Since uVIN is driven by high-risk human papilloma virus infections, p16 immunohistochemistry is diffusely positive in these lesions and is characterized with a high Ki-67 proliferation index. In contrast, differentiated or simplex-type VIN is consistently negative for p16 and the majority of the cases harbour TP53 mutations, correlating with p53 positivity by immunohistochemistry.

Unexpected diminished innervation of epidermis and dermoepidermal junction in lichen amyloidosus.

BACKGROUND: Lichen amyloidosus is a localized, chronic, pruritic skin disease characterized by deposition of amyloid in the papillary dermis. The pathogenesis of the pruritus of lichen amyloidosus is largely unknown. OBJECTIVES: To determine any change in the nerve fibre density in lichen amyloidosus lesions as an explanation for itch. METHODS: Using an antibody to protein gene product (PGP) 9.5, the immunohistochemical analysis of the skin biopsies of 30 Hispanic patients with clinicopathologically proven lichen amyloidosus and of 11 healthy Hispanic controls matched for age, sex and site was performed. RESULTS: Unexpectedly, the mean amount of PGP9.5 stain, a measure for nerve fibre amount, for the healthy controls was higher than the lichen amyloidosus group both in the epidermis (P < 0.0019) and dermoepidermal junction (P < 0.0064). No change was observed in the papillary dermis. Furthermore, the proportion of area covered by PGP9.5 showed a significant decrease in the epidermis (P < 0.0024) and dermoepidermal junction (P < 0.0075) in lichen amyloidosus compared with healthy controls. Age, gender and body site were found not to be influencing factors in nerve fibre amounts in lichen amyloidosus samples. CONCLUSIONS: We speculate that the severe pruritus observed in lichen amyloidosus might be the result of the hypersensitivity of the remaining nerve fibres as a response to an unexplained neurodegeneration of the absent nerve fibres.

Benign alveolar ridge keratosis (oral lichen simplex chronicus): A distinct clinicopathologic entity.

Benign alveolar ridge keratosis is a common benign white papule or plaque that occurs on the keratinized gingiva of the maxillary or mandibular alveolar ridge that is probably traumatic/frictional in origin, with characteristic histologic features, similar to those of lichen simplex chronicus of the skin. This is a retrospective study of 108 consecutive specimens displaying characteristic histopathologic features of benign alveolar ridge keratosis accessioned during a 36-month period. There was a male:female ratio of 3.7:1. It occurred on the attached gingiva, with the retromolar area and the edentulous alveolar ridge involved in 51% and 49% of cases, respectively; 19% were bilateral and all bilateral cases were on the retromolar pad. Detailed clinical information was available on 27 cases by a mail-in questionnaire. Histologically, the lesions were characterized by moderate to marked hyperorthokeratosis and wedge-shaped hypergranulosis. The epithelium exhibited slight surface papillomatosis and acanthosis in the form of long, tapered rete ridges that frequently anastomosed at the base. There was generally insignificant inflammation. These features are similar if not identical to lichen simplex chronicus of the skin, a benign condition caused by chronic irritation. Ten randomly selected cases were immunostained for p16INK4A(p16), a tumor suppressor protein expressed in dysplastic epithelium. All lesions were negative for p16. Benign alveolar ridge keratosis is a specific clinicopathologic entity that should be removed from the category of leukoplakia as is currently the practice for clinical white lesions with a specific, consistently recognizable histologic appearance.

Lichen amyloidosus: a consequence of scratching.

BACKGROUND: Lichen amyloidosus (LA) is generally said to be a pruritic type of amyloidosis of unknown cause. Histopathologically, it is characterized by epidermal changes of lichen simplex chronicus and by deposits of amyloid in the papillary dermis that are derived from keratin peptides of necrotic keratinocytes. Chronic scratching is responsible for the development of lichen simplex chronicus and may lead to necrosis of individual keratinocytes. OBJECTIVE: Our purpose was to evaluate whether chronic scratching may also be responsible for the formation of amyloid in LA. METHODS: We studied patients with LA in regard to histopathologic findings, onset of pruritus, associated diseases, and response to treatment. RESULTS: In most cases, pruritus had preceded the skin lesions. Eight of nine patients suffered from diseases other than LA that may be associated with pruritus. Histopathologically, amyloid was confined to areas that also showed signs of lichen simplex chronicus. Systemic treatment with sedating antihistamines and intense local treatment with corticosteroids were found to be effective. CONCLUSION: LA is considered to be a variant of lichen simplex chronicus in which scratching leads to necrosis of keratinocytes and eventually to the formation of amyloid in the papillary dermis. Because chronic scratching seems to be the cause and not the result of the deposits of amyloid, treatment should be directed at the amelioration of pruritus.

Lichen simplex chronicus.

A review of the literature for the last 20 years shows no monumental advances in the diagnosis or treatment of the disease; however, there have been some very intriguing insights into the causes. The physical and emotional aspect of the skin condition is well known but the genetic, vascular, and neurogenic implications are of interest.

[Glycation of proteins and methods of its assessment]. / Glikirovanie belkov i sposoby ego otsenki.

Glycation of purified preparations of amino acids, hemoglobin and albumin has been studied. The content of glycated blood proteins in children with different diseases (diabetes mellitus, thyroid gland function disturbances, obesity, neurodermititis) has been determined. Application of the protein glycation for diagnosis and prediction of diseases is proved to be expedient.

[Cytophotometric and electron microscopic study of chronic human skin lymphomas. I. A study of skin manifestations]. / Tsitofotometricheskoe i élektronno-mikroskopicheskoe issledovanie khronicheski protekaiushchikh limfom kozhi cheloveka. I. Issledovanie kozhnykh proiavlenii.

Electron microscopic and cytophotometric studies of low-grade malignant cutaneous lymphomas and non-malignant skin diseases revealed substantial differences between these groups of diseases. In the latter case, the DNA content per nucleus is diploid but in the former an atypical distribution of DNA content per nucleus (more than 5% aneuploid and polyploid nuclei) is observed in addition to a significant excess of the mean DNA content per nucleus above the diploid standard level. In lymphomas electron microscopy reveals clusters of atypical lymphoid cells with irregularly shaped nuclei, nuclear pockets, nuclear extrusions, network of cytoplasmic microfilaments. These features never occur with skin diseases. The data obtained can be helpful in the diagnostics of the low-grade malignant cutaneous lymphomas.