Analysis of hedgehog signaling in periocular sebaceous carcinoma

PURPOSE: Sebaceous carcinoma (SC) is a clinical masquerader of benign conditions resulting in significant eye morbidity, sometimes leading to extensive surgical treatment including exenteration, and even mortality. Little is known about the genetic or molecular basis of SC. This study identifies the involvement of Hedgehog (Hh) signaling in periocular SC. METHODS: Fifteen patients with periocular SC patients were compared to 15 patients with eyelid nodular basal cell carcinoma (nBCC; a known Hh tumor), alongside four normal individuals as a control for physiological Hh expression. Expression of Patched 1 (PTCH1), Smoothened (SMO), and glioma-associated zinc transcription factors (Gli1 and Gli2) were assessed in histological sections using immunohistochemistry and immunofluorescence (IF) techniques. Antibody specificity was verified using Western-blot analysis of a Gli1 over-expressed cancer cell line, LNCaP-Gli1. Semi-quantification compared tumors and control tissue using IF analysis by ImageJ software. RESULTS: Expression of the Hh pathway was observed in SC for all four major components of the pathway. PTCH1, SMO, and Gli2 were more significantly upregulated in SC (P < 0.01) compared to nBCC. Stromal expression of PTCH1 and Gli2 was observed in SC (P < 0.01). In contrast, stromal expression of these proteins in nBCC was similar or down-regulated compared to physiological Hh controls. CONCLUSIONS: The Hh signaling pathway is significantly more upregulated in periocular SC compared to nBCC, a known aberrant Hh pathway tumor. Furthermore, the stroma of the SC demonstrated Hh upregulation, in particular Gli2, compared to nBCC. Targeting of this pathway may be a potential treatment strategy for SC

The associations of floppy eyelid syndrome:a case control study

Objective: To describe the demographic features of a large series of patients with floppy eyelid syndrome (FES) and to investigate the associations of the condition with keratoconus, obstructive sleep apnea-hypopnea syndrome (OSAHS), and a variety of upper and lower eyelid features.Design: Case control study.Participants: The test group comprised 102 patients with FES. A control group of 102 patients were recruited from a diabetic retinopathy clinic and matched on a 1: 1 basis on age, gender, and body mass index (BMI).Methods: A full medical and ophthalmic history was taken. Patients also underwent a full ocular examination, including an assessment of upper and lower lid laxity and upper lid levator function. Keratoconus grading was made using the Oculus Instruments Pentacam imaging system (Oculus Optikgerate GmbH, Wetzlar, Germany). Patients were screened for OSAHS using the Epworth daytime somnolence score. Matched statistical analysis of dichotomous data was made using Mantel-Haenszel methods for odds ratios and McNemar's test. Analysis of continuous data was performed using a matched t test and tests for symmetry of larger tables were made using the McNemar-Bowker test.Main Outcome Measures: The significance of association of FES with keratoconus, OSAHS, smoking history, medial and lateral canthal laxity of the upper and lower lids, levator function, lash ptosis, and dermatochalasis.Results: Significant associations were found between FES and OSAHS (P = 0.0008), keratoconus (P < 0.0001), lash ptosis (P < 0.0001), dermatochalasis (P = 0.02), upper lid medial canthal laxity (P = 0.02), upper lid distraction (P = 0.001), palpebral aperture (P = 0.004), and levator function (P = 0.005).Conclusions: Floppy eyelid syndrome seems to be a condition strongly associated with OSAHS and keratoconus. As well as providing a platform for an etiologic hypothesis for the condition, these findings should also encourage clinicians to be aware of these associations and to direct further treatment

Changes in tarsal plate fibrillar collagens and elastic fibre phenotype in floppy eyelid syndrome

Background: The aims of this study are to investigate the expression of the main structural components of the tarsal extracellular matrix (ECM) in floppy eyelid syndrome (FES) focusing on elastic fibres and collagen types I and 111, and also to identify possible cell-mediated inflammatory mechanisms in the pathogenesis of this condition.Methods: A histopathological case control study was conducted using 30 upper lid specimens from patients with FES and 15 undiseased upper lid control specimens. Structural ECM components were assessed using a combination of immunctorial ataining ohistochemical and techniques including antibodies to collagens I and III, Verhoeff's iron haematoxylin, Gomori's aldehyde fuchsin and Lillie's oxidised aldehyde fuchsin. The contribution of different cellular components of the inflammatory response was investigated by immunohistochemical techniques using antibodies to CD3, CD20, CD68. Slide scoring was performed using a semiquantitative technique on an ordinal scale. Statistical analysis was performed using matched ordinal regression analysis.Results: FES tarsal plate tissue demonstrated a decreased abundance of mature elastic fibres (P <= 0.001) and an increased abundance of oxytalan fibres (P = 0.006). Intensity of staining for collagens (P = 0.012) and III (P < 0.001) was increased. No significant difference in the abundance of CD3, CD20 and CD68 expressing cells was identified.Conclusions: The findings of altered elastic fibre phenotype and collagen accumulation are consistent with an adaptive response to cyclic mechanical loading of the tarsal plate, rather than an aetiological feature. These findings are important in understanding how the tarsal ECM responds to mechanical loading