HMG-CoA reductase expression in human eyelid tissue and in a human meibomian gland epithelial cell line.

PURPOSE: 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme of cholesterol production, has been found to contribute to lipid secretion from skin sebaceous glands and hair follicles. We assessed for HMGCR expression in human eyelid tissue and in immortalized human meibomian gland epithelial cells (HMGECs) using immunohistochemistry. METHODS: Full thickness human eyelid specimens in archival paraffin blocks were obtained. A section from each block was stained with hematoxylin and eosin and examined by an ocular pathologist for validation of tissue pathology. Immunohistochemistry was performed using rabbit anti-human HMGCR antibody on serial sections using the Ventana automated staining system. HMGCR expression was examined for in HMEGCs with fluorescence immunocytochemistry and confocal microscopy. RESULTS: Thirteen full thickness eyelid specimens met the inclusion criteria. All specimens contained meibomian glands, and 2 (15%) contained glands of Zeis, 3 (23%) pilosebaceous glands, 2 (15%), accessory lacrimal glands, and 2 (15%), glands of Moll, respectively. Immunohistochemistry showed HMGCR expression in meibocytes of meibomian glands and sebocytes of Zeis and pilosebaceous glands in all specimens. HMGCR expression was also evident in vascular endothelium. Immunofluorescence was positive for HMGCR expression on HMGEC cells. No labeling was seen for the negative Ig control. CONCLUSION: HMGCR was expressed in all eyelid sebaceous-type glands and in HMGECs, consistent with a role for cholesterol production in the genesis of tear film lipids. The observed expression also provides a rationale for using topical statins, inhibitors of HMGCR, as novel tear film lipid stabilizers in conditions such as blepharitis, where meibum production is aberrant.

Expression of matrix metalloproteinase-1, -9, -13, and tissue inhibitor of metalloproteinases-1 in basal cell carcinomas of the eyelid.

BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) function in the remodelling of the extracellular matrix in morphogenesis, angiogenesis, tissue repair, and tumor invasion. Elevated levels of distinct MMPs in tumor tissue are related to worse prognosis. However, no overall consistent pattern of expression in human cancer has been identified. The aim of the present study was to evaluate the expression of MMP-1, -9, -13 and TIMP-1 in tumor epithelial cells and surrounding connective tissue in primary basal cell carcinomas (BCC) of the eyelid, and to assess their role as prognostic markers for tumor recurrence. METHODS: Surgical specimens of 49 histologically proven primary BBCs of the eyelid of different histological subtypes were included. Immunohistological studies were performed using antibodies against MMP-1, MMP-9, MMP-13 and TIMP-1, and staining intensity was analyzed semi-quantitatively. RESULTS: MMP-1, -9, -13, and TIMP-1 were expressed at various intensities in epithelial tumor cells and surrounding stromal cells including fibroblasts, inflammatory cells, and vascular endothelial cells in all tumor subtypes. Staining was especially prominent at the invading edge of the BCC. A statistically significant correlation was seen between increased TIMP-1 expression in tumor and/or stromal cells with the presence of MMP-13 (p = 0.007 and p < 0.0001 respectively). Moreover, TIMP-1 expression in tumor and/or stroma was significantly associated with relapse (p = 0.012 and p = 0.042 respectively). CONCLUSION: MMP-9, MMP-13 and TIMP-1 expression may serve as a prognostic marker for early tumor invasiveness. Moreover, up-regulation of TIMP-1 in tumor and/or surrounding stromal cells may indicate an increased risk for BCC recurrence.

Pathogenesis of involutional ectropion and entropion: the involvement of matrix metalloproteinases in elastic fiber degradation.

PURPOSE: To determine the elastic fiber content and ultrastructure as well as the expression of elastin-degrading enzymes in biopsy specimens from patients with involutional ectropion and entropion. MATERIALS AND METHODS: Twenty consecutive patients with involutional ectropion (group 1) and twenty consecutive patients with entropion (group 2) were matched with twenty control patients (basal cell carcinoma) regarding age and gender. Full-thickness eyelid resections performed in study and control patients were examined by light and transmission electron microscopy, computer-assisted measurements, and immunohistochemistry using antibodies against matrix metalloproteinase (MMP)-2, MMP- 7, and MMP-9. The Kruskal-Wallis test and the Pearson chi-square test were performed. RESULTS: Histopathologic analysis of the surgical specimens from patients with involutional ectropion and entropion showed a significant loss of elastic fibers in the eyelid skin, the pretarsal orbicularis oculi muscle, the perimeibomian tarsal stroma, and the intermeibomian tarsal stroma (P < 0.001). Residual elastic fibers revealed an abnormal ultrastructure. Immunohistochemistry demonstrated a significant overexpression of MMP- 2, MMP-7, and MMP-9 in the eyelid skin, the pretarsal orbicularis oculi muscle, the perimeibomian tarsal stroma, the intermeibomian tarsal stroma, and the conjunctiva in groups 1 and 2 compared to controls (P < 0.001). CONCLUSIONS: The present findings indicate that upregulation of elastolytic enzymes contributes to elastic fibre degradation in patients with involutional ectropion and entropion.

Cutaneous presentation on the eyelid of primary, systemic, CD30+, anaplastic lymphoma kinase (ALK)-negative, anaplastic large-cell lymphoma (ALCL).

AIM: To report an unusual case of cutaneous presentation on the eyelid of systemic (or nodal), CD30+, anaplastic large-cell lymphoma (ALCL). METHODS: A 39-year-old man presented with a rapidly growing exophytic mass on the left upper eyelid, with a protuberant, ulcerated aspect and with discharge. The patient showed lymph node involvement 3 months after the appearance of the lesion on the eyelid (the lesion itself appeared 1 week before examination). RESULTS: The histopathologic and immunohistochemical diagnosis was ALCL, T-cell phenotype, strongly positive for CD43 and CD30, and negative for CD3, anaplastic lymphoma kinase (ALK), and B-cell antigens. Treatment was by radiotherapy and, later, chemotherapy (cyclophosphamide, adriamycin, vincristine, and prednisolone, CHOP) for skin recurrences and lymphadenopathies over 5 years. There has been no recurrence for more than 6 years. CONCLUSIONS: Primary, systemic, CD30+, ALK-negative, ALCL presentations generally have a poor prognosis and tend to occur in older individuals, although the clinical outcome is highly variable and difficult to predict in individual cases. Only three cases of ALCL have been described in the ocular adnexae and none was ALK-negative.

[Collagenase-3 (MMP-13) expression in epithelial cancers of the eyelids]. / Expresión de colagenasa-3 (MMP-13) en carcinomas epiteliales de los párpados.

PURPOSE: To determine, by means of immunohistochemistry, tumoral expression of collagenase-3, a matrix metalloproteinase linked to cancer and to basal cell and squamous cell carcinomas of the eyelid. MATERIAL AND METHOD: Retrospective review of 23 basal cell carcinomas and 25 squamous cell carcinomas of the eyelid treated at different hospitals during the last five years. We evaluated collagenase-3 expression and the possible relationship to patient and tumour characteristics which included age, sex, histological type, tumour location and surgical margins status. RESULTS: 65% of the basal cell carcinomas and 88% of the squamous cell carcinomas of the eyelids stained positively for collagenase-3. In both cases, the immunostaining was localized in the cytoplasm of the malignant cells and, occasionally in the surrounding stromal cells. CONCLUSIONS: Statistical analysis showed no significant association between collagenase-3 immunostaining and patients or tumour characteristics but the expression of this protein was more intense in the epithelial tumoral cells located at the invading front which could explain the aggressive behaviour of this kind of tumours.

Telomerase expression in sebaceous carcinoma of the eyelid.

BACKGROUND: In humans telomerase is expressed in most cancers and immortal cell lines, and activation of telomerase may play important roles in tumorigenesis and immortalization. This study was to investigate the roles of telomerase activity (TA) and human telomerase RNA (hTR) in sebaceous carcinoma of the eyelid. METHODS: The telomerase repeated amplification protocol (TRAP) was used to demonstrate telomerase activity in 12 cases of sebaceous carcinoma of the eyelid. In situ hybridization (ISH) was used to demonstrate the expression of hTR in 55 cases of paraffin-embedded sebaceous carcinoma of the eyelid, and the results were compared with the proliferative index determined by Mib-1 immuno-labeling, histological patterns and recurrence of the tumor. RESULTS: Different telomerase activity was shown in the 12 cases of sebaceous carcinoma of the eyelid. The positive expression of hTR was 85.5% (47/55) in tumor cells, but not in the adjacent tissues. The positive expression of hTR was correlated with the proliferative activity (as assessed by Mib-1 immunolabelling, r = 0.942, P < 0.001) and the differentiation of sebaceous carcinoma of the eyelid (chi(2) = 17.621, P < 0.001), but not significantly related to tumor recurrence. The level of hTR expression increased with the decrease of differentiation of sebaceous carcinoma of the eyelid. CONCLUSIONS: The results suggest that the up-regulation of telomerase expression plays some roles in tarsal gland carcinogenesis, and the expression of hTR is a useful marker for malignant degree of sebaceous carcinoma of the eyelid.

[Telomerase expression in tarsal gland carcinoma].

OBJECTIVE: To investigate the roles of telomerase activity (TA) and human telomerase RNA (hTR) in tarsal gland carcinoma. METHODS: The telomerase repeated amplification protocol (TRAP) was used to demonstrate telomerase activity in 12 tarsal gland carcinomas. In situ hybridization (ISH) was used to demonstrate the expression of hTR in 55 cases of paraffin-embedded tarsal gland carcinoma, and the results were compared with the proliferative index determined by Mib-1 immunolabeling, histological patterns and recurrence of the tumor. RESULTS: The telomerase activity was revealed in 12 tarsal gland carcinomas with different degrees. The positive expression of hTR was 85.5% (47/55) and observed in tumor cells, but not in the adjacent tissues. The expression of hTR was correlated with the proliferative activity (as assessed by Mib-1 immunolabelling, r = 0.942, P < 0.001) and the differentiation of tarsal gland carcinoma (chi(2) = 17.621, P < 0.001), but no significant relationship with tumor recurrence. The level of hTR expression had a gradually raised tendency along with the decrease of differentiation of tarsal gland carcinoma. CONCLUSION: The results suggest that up-regulation of telomerase expression play some roles in tarsal gland carcinogenesis, and the expression of hTR be a useful marker for malignant degree of tarsal gland carcinoma.

15-Lipoxygenase-2 expression in benign and neoplastic sebaceous glands and other cutaneous adnexa.

15-Lipoxygenase-2 has a limited tissue distribution in epithelial tissues, with mRNA detected in skin, cornea, lung, and prostate. It was originally cloned from human hair rootlets. In this study the distribution of 15-lipoxygenase-2 was characterized in human skin using immunohistochemistry and in situ hybridization. Strong uniform 15-lipoxygenase-2 in situ hybridization (n = 6) and immunostaining (n = 16) were observed in benign cutaneous sebaceous glands, with expression in differentiated secretory cells. Strong 15-lipoxygenase-2 immunostaining was also observed in secretory cells of apocrine and eccrine glands. Variable reduced immunostaining was observed in skin-derived sebaceous neoplasms (n = 8). In the eyelid, Meibomian glands were uniformly negative for 15-lipoxygenase-2 in all cases examined (n = 9), and sebaceous carcinomas apparently derived from Meibomian glands were also negative (n = 12). The mechanisms responsible for differential expression in cutaneous sebaceous vs eyelid Meibomian glands remain to be established. In epidermis, positive immunostaining was observed in the basal cell layer in normal skin, whereas five examined basal cell carcinomas were negative. Thus, the strongest 15-lipoxygenase-2 expression is in the androgen regulated secretory cells of sebaceous, apocrine, and eccrine glands. This compares with the prostate, in which 15-lipoxygenase-2 is expressed in differentiated prostate secretory cells (and reduced in the majority of prostate adenocarcinomas). The product of 15-lipoxygenase-2, 15-hydroxyeicosatetraenoic acid, may be a ligand for the nuclear receptor peroxisome proliferator activated receptor-gamma, which is expressed in sebocytes, and contribute to secretory differentiation in androgen regulated tissues such as prostate and sebaceous glands.

Merkel cell carcinoma of the eyelid.

PURPOSE: To demonstrate the clinical variability and histologic characteristics of Merkel cell carcinoma of the eyelid. METHODS: We investigated two cases of Merkel cell carcinoma of the eyelid in a 67-year-old man and an 83-year-old woman, respectively. Both lesions were initially misdiagnosed as benign tumors on clinical examination. RESULTS: After the correct diagnosis was made, both lesions were treated with wide resection aided by frozen sections, and reconstructive surgery. CONCLUSIONS: Merkel cell carcinoma is an aggressive tumor with variable clinical manifestation. Radical surgical therapy and close follow-up are indicated.