Sallie Neill

Autoantibodies to extracellular matrix protein 1 in lichen sclerosus

BACKGROUND Lichen sclerosus is a common acquired inflammatory disorder of skin and mucous membranes. The aetiology is unknown, although HLA-subtype susceptibility and high rates of other autoimmune disorders suggest that autoantibodies to specific mucocutaneous antigens are involved. The clinicopathological similarities between lichen sclerosus and lipoid proteinosis, which results from mutations in extracellular matrix protein 1 (ECM1), suggest this protein as an autoantigen. METHODS We analysed serum autoantibody profiles in 171 individuals (86 with lichen sclerosus, 85 healthy controls) by immunoblotting of extracts from normal human skin and lipoid proteinosis skin (lacking ECM1). We generated a full-length glutathione-S-transferase fusion protein for ECM1 to confirm specific immunoreactivity. We affinity-purified serum from patients with lichen sclerosus and did indirect immunofluorescence microscopy on normal skin with or without preabsorption with recombinant ECM1. FINDINGS By immunoblotting, IgG autoantibodies were found in 20 (67% [95% CI 45-84]) of 30 lichen sclerosus serum samples. The highest titre was 1 in 20. The bands were not detected in ECM1-deficient substrate. These samples, and those from 56 other patients with lichen sclerosus, showed immunoreactivity to the recombinant ECM1 protein (64 of 86 positive; 74% [65-84]). Only six (7% [2-13]) of 85 control serum samples were positive. Affinity-purified IgG from serum of patients with lichen sclerosus labelled skin similarly to a polyclonal antibody to ECM1. The positive staining was blocked by preabsorption with excess recombinant ECM1 protein. INTERPRETATION These findings provide evidence for a specific humoral immune response to ECM1 in lichen sclerosus and offer insight into disease diagnosis, monitoring, and approaches to treatment.

Physiological Changes Associated with the Menstrual Cycle: A Review

The cyclic hormonal changes that regulate the menstrual cycle are a significant biological influence on the female body, one with both physical and emotional ramifications. Menstruation is governed by tightly orchestrated changes in the levels of ovarian estrogen and progesterone, which produce varying responses in diverse tissues and organs. The skin, the largest organ in the body, is replete with estrogen receptors (in both dermis and epidermis) and to a lesser extent, progesterone receptors. Cyclically fluctuating levels of estrogen and progesterone influence numerous characteristics of the epidermis, including skin surface lipid secretion and sebum production, skin thickness, fat deposition, skin hydration, and barrier function. Dermal collagen content, which contributes to skin elasticity and resistance to wrinkling, is also influenced. Interestingly, estrogen levels also influence skin pigmentation and UV susceptibility, as well as resident microflora. In addition, changing hormone levels across the menstrual cycle produce measurable variations in immune function and disease susceptibility. An understanding of the profound influence that fluctuating estrogen and progesterone levels have on the biological responses of the premenopausal adult woman is critical to optimizing the efficacy of medical therapies in this population. Target Audience: Obstetricians & Gynecologists, Family Physicians Leaning Objectives: After completion of this article, the reader should be able to produce anticipatory guidance to patients regarding skin changes in pregnancy, predict clinical skin changes common in post menopausal women, and recall the physiology of the menstrual cycle.

Altered p53 expression and epidermal cell proliferation is seen in vulval lichen sclerosus

Aberrant p53 immunoreactivity has been found in skin premalignancies and dysplasias such as Bowens disease and actinic keratoses. Vulval lichen sclerosus (LS) has been reported to be pre‐malignant, with an association of vulval carcinoma in 3% to 6% of patients. In contrast, non‐genital LS appears to have no malignant potential. In this immunocytochemical study, we investigated p53 expression in 10 cases of histologically proven vulval LS and 9 cases of non‐genital LS using the murine monoclonal antibody Do‐1 raised against recombinant human p53 which reacts with both wild‐type and mutant p53. None of the vulval specimens had epithelial dysplasia or malignancy. Normal vulval (7 cases) and non‐genital skin (5 cases) were used as tissue controls, respectively. The cell proliferation index was also studied using the MIB 1 monoclonal antibody which detects the cell‐cycle associated Ki‐67 antigen. The technique of microwave irradiation for antigen unmasking was employed on Formalin‐fixed and paraffin‐embedded tissues. There was a significant increase in p53 immunoreactivity in vulval LS (32.13 ± 15.11 epidermal cells per 100 basal cells) compared to normal vulval skin (7.52 ± 5.04 epidermal cells per 100 basal cells) (p < 0.001), whereas the MIB 1 labelling index was lower in vulval LS (39.45 ± 15.88 epidermal cells per 100 basal cells) than in normal controls (86.26 ± 32.31 epidermal cells per 100 basal cells) (0.001 < p < 0.01). In contrast, there was no significant difference in p53 immunoreactivity or MIB 1 labelling index between non‐genital LS and normal controls. Vulval LS, when compared to non‐genital LS (8.76 ± 6.61 epidermal cells per 100 basal cells), also demonstrated a significant increase in P53 immunoreactivity (p < 0.001). The reduced proliferative index in vulval LS may be directly related to its increase in p53 expression and is in keeping with the role ol p53 in the negative regulation of cell proliferation. We propose that the difference in p53 expression may represent a difference in biological behavior between vulval LS and non‐genital LS. What role it plays in the evolution of vulval carcinoma in a setting of long standing LS is uncertain.

Mucous membrane pemphigoid

Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease frequently associated with scarring of involved clinical sites. At present, therapeutic intervention in the form of immunomodulating or immunosuppressive agents is often reserved until the onset of significant inflammation and/or early cicatrization. We have therefore studied the clinical and immunopathological findings in 67 patients with MMP in order to try to establish a reliable prognostic indicator by which patients at high risk may be identified early in the disease. Inclusion criteria were a predominantly mucosal disease and the detection of IgG and/or C3 anti‐basement membrane zone (BMZ) immunoreactants using immunofluorescence techniques. Patients were allocated to three disease subgroups on the basis of the modality and duration of therapeutic intervention required to achieve effective control of disease. In addition, at presentation and at each follow‐up visit, a clinical score for severity of involved clinical sites was awarded and serum collected for indirect immunofluorescence (IIF). A dual circulating anti‐basement membrane zone (anti‐BMZ) antibody response with IgG and IgA was significantly associated with a more severe and persistent disease profile (P < 0.001). The odds ratios for requiring systemic therapy were: 11.6 among patients in whom there was a clinical score ≥ 5 compared with a score < 5, and 31.3 and 66.9 among patients with IgG alone and both IgG and IgA, respectively, compared with negative IIF. The findings suggest that an assessment based upon a combination of site severity score and the presence of circulating IgG and IgA by IIF using 1 mol/L salt‐split human skin substrate may be considered a useful prognostic indicator.

Lacrimal canalicular duct scarring in patients with lichen planus.

BACKGROUND Lichen planus (LP) is a mucocutaneous inflammatory disease that affects multiple sites, including the skin, oral cavity, vulva, and vagina and can result in scarring and stricture formation. It has also been shown to cause lacrimal canalicular blockage in a series of patients attending an ophthalmology clinic. We describe a cohort of women with vulvovaginal LP who also had signs of lacrimal canalicular scarring on examination. OBSERVATIONS We report 9 cases of LP with scarring of the conjunctiva around the lacrimal ducts. Seven of 9 women had symptoms of epiphora, and in 2 women lacrimal canalicular scarring was an incidental finding. Seven of 9 cases were diagnosed by an ophthalmologist. All women had biopsy-proven LP at 1 mucocutaneous site each. Seven of 9 women had vulvovaginalgingival syndrome, which is a subgroup of severe erosive LP. CONCLUSIONS Given the strong association between erosive mucocutaneous LP and multisite scarring sequelae, it is not unexpected that ocular inflammation may lead to lacrimal duct stenosis. We believe that this complication has been underreported among patients with LP and that an ophthalmological history and examination of the punctum of the lacrimal duct should be sought, especially in patients with the erosive subtype of LP.

Vulvar Cancer and the Need for Awareness of Precursor Lesions

Vulvar cancer continues to rise in incidence. In the absence of screening, attempts to reduce this cancer must focus on recognizing precursor lesions, namely, lichen sclerosus and vulvar intraepithelial neoplasia (VIN). The steep rise in human papillomavirus-repeated VIN will fall after the introduction of vaccination against human papillomavirus; in the meantime, those patients with VIN must be treated and then reviewed carefully and frequently. Lichen sclerosus has a 3% to 5% risk of progressing to vulvar cancer. Recommendations about which patients require referral to and follow-up by specialists/specialist clinics are given.

The spectrum of histopathologic patterns secondary to the topical application of EMLA® on vulvar epithelium: clinicopathological correlation in three cases

EMLA® (eutectic mixture of local anesthetics, 2.5% each of lidocaine and prilocaine in an oil and water emulsion) is used as a topical anesthetic. We report three cases of EMLA®‐induced histopathologic changes on the vulvar epithelium. While there are some similar histopathologic features to those reported in extragenital skin, we describe additional findings on vulvar epithelium, which, to our knowledge, have not been reported previously. The patients presented with clinical signs suggestive of lichen sclerosus or erosive lichen planus (LP), but were all confirmed histopathologically as LP. The biopsy was taken after 15 min of EMLA® application and intradermal injection of 1% lidocaine. Blistering prior to intradermal lidocaine and the biopsy procedure was observed in two patients. The histopathologic changes observed in the epithelium included pallor of the upper epidermis, mild spongiosis, intraepidermal subcorneal and suprabasal acantholysis, congestion of the papillary dermal capillaries and extravasated erythrocytes. Basophilic granules were present, but rare, while the necrosis with multifocal clefting was more marked than in extragenital skin. It is important to be aware of these changes occurring on genital mucosa; these may occur in the absence of clinical signs and may obscure the primary underlying pathology, thus representing a diagnostic pitfall.

Unusual vulval papules

A 27-year-old woman was referred with a 4-year history of asymptomatic vulval lesions that had been increasing in number. She had a history of genital warts and cervical intraepithelial neoplasia that had been treated by laser ablation. On physical examination, multiple skin-coloured dermal papules and small nodules were seen on the outer labia majora (Fig. 1). The labia minora and perineum were normal, and there were no similar lesions at any other site.

Cáncer vulvar y necesidad de identificación de las lesiones precursoras

▪ Resumen El cáncer vulvar continúa aumentando de incidencia. En ausencia de métodos de cribaje para su detección, los intentos de reducir este cáncer deben centrarse en la identificación de las lesiones precursoras, es decir, el liquen escleroso y la neoplasia intraepitelial vulvar (VIN). El notable aumento de la VIN asociada al virus del papiloma humano disminuirá tras la introducción de la vacunación contra este virus; mientras tanto, las pacientes con VIN deben ser tratadas y luego debe aplicarse una revisión cuidadosa y frecuente. El liquen escleroso tiene un riesgo de progresión a cáncer vulvar de un 3% a 5%. Se presentan recomendaciones acerca de qué pacientes deben ser remitidas a especialistas/clínicas especializadas para su seguimiento. ▪