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Eyelid sebaceous gland carcinoma (SGC) is an aggressive skin cancer characterized by a heightened risk of recurrence and metastasis. While surgical excision is the primary treatment, unraveling the molecular intricacies of SGC is imperative for advancing targeted therapeutic interventions and enhancing patient outcomes. This comprehensive review delves into the molecular landscape of eyelid SGC, emphasizing key genetic alterations, signaling pathways, epigenetic modifications, and potential therapeutic targets. Significant findings include aberrations in critical signaling pathways (β-catenin, lymphoid enhancer binding factor, hedgehog, epidermal growth factor receptor, P53, and P21WAF1) associated with SGC progression and poor prognosis. Notably, eyelid SGC manifests a distinctive mutational profile, lacking ultraviolet signature mutations in tumor protein 53 (TP53), indicating alternative mutagenic mechanisms. Next-generation sequencing identifies actionable mutations in genes such as phosphatase and tensin homolog (PTEN) and Erb-B2 receptor tyrosine kinase 2 (ERBB2), facilitating the emergence of personalized medicine approaches. Molecular chaperones, specifically X-linked inhibitor of apoptosis protein (XIAP) and BAG3, emerge as pivotal players in promoting tumor survival and proliferation. The review underscores the role of epithelial-mesenchymal transition, where regulators like E-cadherin, vimentin, and ZEB2 contribute to SGC aggressiveness. Epigenetic modifications, encompassing DNA methylation and microRNA dysregulation, further elucidate the molecular landscape. This review consolidates a comprehensive understanding of the molecular drivers of eyelid SGC, shedding light on potential therapeutic targets and providing a foundation for future investigations in diagnostic, prognostic, and personalized treatment strategies for this formidable malignancy., (Copyright © 2024 Copyright: © 2024 Indian Journal of Ophthalmology.)

Purpose: Eyelid sebaceous carcinoma (SeC) is the third most frequent eyelid malignancy worldwide and is relatively prevalent in Asian patients. An eyelid SeC cell line model is necessary for experimental research to explore the etiology and pathogenesis of eyelid SeC. This study established and characterized an eyelid SeC cell line with a TP53 mutation that might be useful for analyzing potential treatment options for eyelid SeC., Methods: The eyelid SeC cell line SHNPH-SeC was obtained from a patient with eyelid SeC at Shanghai Ninth People's Hospital (SHNPH), Shanghai JiaoTong University School of Medicine. Immunofluorescence staining was employed to detect the origination and proliferation activity. Short tandem repeat (STR) profiling was performed for verification. Chromosome analysis was implemented to investigate chromosome aberrations. Whole exome sequencing (WES) was used to discover genomic mutations. Cell proliferation assays were performed to identify sensitivity to mitomycin-C (MMC) and 5-fluorouracil (5-FU)., Results: SHNPH-SeC cells were successively subcultured for more than 100 passages and demonstrated rapid proliferation and migration. Karyotype analysis revealed abundant chromosome aberrations, and WES revealed SeC-related mutations in TP53, KMT2C, and ERBB2. An in vivo tumor model was successfully established in NOD/SCID mice. Biomarkers of eyelid SeC, including cytokeratin 5 (CK5), epithelial membrane antigen (EMA), adipophilin, p53, and Ki-67, were detected in SHNPH-SeC cells, original tumors, and xenografts. MMC and 5-FU inhibited the proliferation and migration of SHNPH-SeC cells, and SHNPH-SeC cells presented a greater drug response than non-TP53-mutated SeC cells., Conclusions: The newly established eyelid SeC cell line SHNPH-SeC demonstrates mutation in TP53, the most commonly mutated gene in SeC. It presents SeC properties and malignant characteristics that may facilitate the investigation of cellular behaviors and molecular mechanisms of SeC to explore promising therapeutic strategies.

Purpose: To identify the molecular background of eyelid sebaceous gland carcinomas (SCs), we conducted the integrated whole-exome sequencing and transcriptome sequencing for eyelid SCs in this study., Methods: The genetic alterations were studied by whole-exome sequencing, and the messenger RNA expression was studied using Oxford Nanopore Technologies (ONT) in five paired fresh eyelid SC tissues and adjacent normal tissues. Integrated analysis of exome and transcriptomic information was conducted for filtering candidate driver genes. Protein-protein interaction (PPI) network of filtered candidate genes was analyzed by STRING. The protein expression was verified by immunohistochemistry in 29 eyelid SCs and 17 compared normal sebaceous gland tissues., Results: The average numbers of pathogenic somatic single-nucleotide variants (SNVs) and indels in eyelid SCs were 75 and 28, respectively. Tumor protein p53 (TP53), zinc finger protein 750 (ZNF750), filaggrin 2 (FLG2), valosin-containing protein (VCP), and zinc finger protein 717 (ZNF717) were recurrent mutated genes. A mean of 844 differentially expressed genes (DEGs) were upregulated, and 1401 DEGs were downregulated in SC samples. The intersection of DEG-based pathways and mutation-based pathways was mainly involved in microbial infection and inflammation, immunodeficiency, cancer, lipid metabolism, and the other pathways. The intersection of DEGs and mutated genes consisted of 55 genes, of which 15 genes formed a PPI network with 4 clusters. The PPI cluster composed of scavenger receptor class B member 1 (SCARB1), peroxisome proliferator-activated receptor γ (PPARG), peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A) was involved in cholesterol metabolism. The expression of SCARB1 protein was found to be increased, whereas that of PPARG protein was decreased in eyelid SCs compared to that in the normal sebaceous glands., Conclusions: Increased SCARB1 and decreased PPARG indicated that dysregulation of cholesterol metabolism might be involved in carcinogenesis of eyelid SCs., Translational Relevance: The malfunction in cholesterol metabolism might advance our knowledge of the carcinogenesis of eyelid SCs.

Purpose: To investigate the effect on meibomian gland function of super pulse carbon dioxide (CO 2 ) laser excision in the treatment of eyelid tumors at palpebral margin., Methods: 36 patients with 36 eyelid tumor size ≤ 1 cm and within 1 mm to palpebral margin were recruited in this study. Of which, 16 cases with tumors in the upper eyelid and 20 cases in the lower eyelid were involved. The eyelid tumors of all the patients were treated by super pulse CO 2 laser with its power density varied between 0.6 and 21.1 W/mm 2 and in repeat mode. The laser spot size ranged from 120 to 200  μ m. Ocular surface parameters including tear film break-up time (BUT) and meibograde, meibum expressibility, and meibum quality were evaluated at pretherapy, 1 week, 1 month, and 3 months posttherapy in all 36 patients., Result: All the patients were satisfied with the therapy. No infective complications and recurrence occurred in any of the 36 patients at the following period. The eyelid wound recovered well with nearly normal appearing after 2 to 3 weeks. The morphology of limbi palpebralis, BUT, meibograde, meibum expressibility, and meibum quality of all the 36 patients showed no significant difference before and after the therapy., Conclusions: Super pulse CO 2 laser had no effect on meibomian gland function and morphology in the excision of tumors at palpebral margins, which was an efficacy and well-tolerated therapy with lower complications and recurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Songjiao Zhao et al.)

Background: Immune checkpoint blockade strategies have gained attention in the treatment/prognosis of cancers by targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway alone or in combination with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade and are currently in clinical trials. The present study investigated the expression of the PD-1, PD-L1, CTLA-4, CD4 and CD8 proteins and their prognostic value in the tumour microenvironment of sebaceous gland carcinoma (SGC)., Methods: The expression levels of PD-1, PD-L1, CTLA-4, CD4 and CD8 proteins were assessed in 52 cases of SGC by immunohistochemistry and validated by western blotting. mRNA expression was measured by quantitative real-time PCR. Kaplan-Meier curves and Cox proportional hazard models were used to analyse the correlation of protein expression with clinicopathological parameters and disease-free survival., Results: The expression of PD-L1 was found to be higher in tumour cells than in stromal cells. In univariate analysis, the expression of PD-1 in tumour-infiltrating lymphocytes (tPD-1) and PD-L1 in tumour cells was associated with reduced disease-free survival, whereas PD-L1 expression in stromal lymphocyte infiltration (sPD-L1) was associated with the increased survival of patients (p<0.05). However, by multivariate analysis, the expression of tPD-1 was found to be an independent prognostic factor for poor survival., Conclusion: Our study highlights the prognostic outcome of PD-1 and PD-L1 protein expression in cells of tumour-stromal compartments. These results indicate that the PD-1/PD-L1 pathway mediates important interactions within the tumour microenvironment in SGC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Squamous cell carcinoma (SCC) occurs frequently in the human Xeroderma Pigmentosum (XP) syndrome and is characterized by deficient UV-damage repair. SCC is the most common equine ocular cancer and the only associated genetic risk factor is a UV-damage repair protein. Specifically, a missense mutation in horse DDB2 (T338M) was strongly associated with both limbal SCC and third eyelid SCC in three breeds of horses (Halflinger, Belgian, and Rocky Mountain Horses) and was hypothesized to impair binding to UV-damaged DNA. Here, we investigate DDB2-T338M mutant's capacity to recognize UV lesions in vitro and in vivo, together with human XP mutants DDB2-R273H and -K244E. We show that the recombinant DDB2-T338M assembles with DDB1, but fails to show any detectable binding to DNA substrates with or without UV lesions, due to a potential structural disruption of the rigid DNA recognition β-loop. Consistently, we demonstrate that the cellular DDB2-T338M is defective in its recruitment to focally radiated DNA damages, and in its access to chromatin. Thus, we provide direct functional evidence indicating the DDB2-T338M recapitulates molecular defects of human XP mutants, and is the causal loss-of-function allele that gives rise to equine ocular SCCs. Our findings shed new light on the mechanism of DNA recognition by UV-DDB and on the initiation of ocular malignancy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Eyelid basal cell carcinoma (BCC) is the most common eyelid malignancy. Metabolic reprogramming is critical in tumorigenesis, but the metabolic feature of eyelid BCC remains elusive. In this study, we aim to reveal the metabolic profile in eyelid BCC using targeted metabolomics. Eyelid samples were collected from patients who had removal of BCC and from control patients who underwent blepharoplasty. Multivariate analysis of metabolomics data distinguished the two groups, indicating that eyelid BCC has significantly different metabolome than the healthy tissue. We found 16 increased and 11 decreased metabolites in the BCC tissues. These metabolites were highly enriched in the metabolism of nicotinamide adenine dinucleotide (NAD), glutathione metabolism, polyamine metabolism, and the metabolism of glycine, serine, threonine, arginine and proline. amino acid metabolism. Metabolites from NAD metabolism (Nicotinamide; Nicotinamide riboside; N1-Methylnicotinamide) had the highest sensitivity, specificity, and prediction accuracy in a prediction model for eyelid BCC. In conclusion, eyelid BCC has a signature change of cell metabolome. Metabolites in NAD metabolic pathways could potentially be biomarkers or therapeutic targets for eyelid BCC., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Vimentin is an intermediate-sized filament which is highly expressed in mesenchymal cells and is associated with epithelial-mesenchymal transition (EMT). EMT markers ZEB2 and Slug lead to Vimentin overexpression and E-cadherin loss, resulting in invasion and metastasis. However, the status of Vimentin remains unexplored in eyelid sebaceous gland carcinoma (SGC). The study aims to determine status of Vimentin in SGC and its association with EMT markers E-cadherin, ZEB2 and Slug., Methods: Vimentin protein expression was undertaken in 66 cases with SGC by immunohistochemistry (IHC). Messenger RNA (mRNA) expression was determined in 42 fresh tissues by quantitative real-time PCR. Association of Vimentin with E-cadherin, ZEB2 and Slug was also analysed. Patients were followed up for 17-69 months (mean 34.02 ± 14.73 months)., Results: IHC revealed Vimentin overexpression in 37/66 (56%) cases. This overexpression showed significant association with lymph node metastasis (p=0.004) and pagetoid spread (p=0.05). Patients with high Vimentin expression also had poor disease-free survival (p=0.033). Univariate Cox regression model indicated that high Vimentin expression (p=0.043) and advanced tumour stage (p=0.002) were independent adverse prognostic factors. High Vimentin mRNA expression was seen in 16/42 (38%) cases and correlated significantly with lymph node metastasis (p=0.027), advanced tumour stage (p=0.002) and large tumour size (p=0.023). Vimentin expression overall showed a significant inverse association with E-cadherin and direct association with ZEB2 expression., Conclusions: Vimentin overexpression in SGC is associated with EMT and leads to poor clinical outcome. It also emerged as a novel predictor for lymph node metastasis and poor survival., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To investigate the overexpression of genes in sebaceous gland carcinoma (SGC) of the eyelid compared to sebaceous adenoma of the eyelid in order to elucidate the molecular mechanism underlying pathogenesis., Methods: We performed histopathological examination of eyelid tissues surgically removed from four patients diagnosed with SGC (cases 1-3) and sebaceous adenoma (case 4) of the eyelid. Next, we performed global gene expression analysis of surgical tissue samples using a GeneChip ® system and the Ingenuity Pathways Knowledge Base. The results of the GeneChip ® analysis were explored with quantitative real-time polymerase chain reaction (qRT-PCR) analysis., Results: In the SGC samples, we found that 211, 199, and 199 genes, respectively, showed ≥ 2.0-fold higher expression than those in the sebaceous adenoma sample (case 4); 194 genes were common to all three SGC samples. For the 194 genes with upregulated expression, functional category analysis showed that SGC of the eyelid employed a unique gene network, including cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase 1 (CDK1), and cyclin E1 (CCNE1), which are related to cell cycle progression, incidence of tumor, and cell viability. Furthermore, qRT-PCR analysis showed that the expression levels of CDKN2A, CDK1, and CCNE1 were significantly upregulated in all SGC cases compared to those in the sebaceous adenoma case. These data were similar to the results of microarray analysis., Conclusion: Overexpression of cell cycle-related genes CDKN2A, CDK1, CCNE1, and their gene network may help elucidate the pathogenic pathway of SGC of the eyelid at the molecular level.

Purpose: Eyelid sebaceous gland carcinoma (SGC) is an aggressive but rare malignancy of ocular region. Over-expression of PD-L1 and PD-1 has been demonstrated in a variety of solid tumors including conjunctival melanoma. PD-L1 is an immunoinhibitory molecule that suppresses the effective T cells response against tumor antigen leading to the progression of tumors. Inhibitors of the interaction of PD-L1 and PD-1 are associated with good clinical response various carcinomas. The prognostic value of the PD-1/PD-L1 axis in SGC remains unexplored. The purpose of this study was to evaluate expressions of PD-1 and its ligand PD-L1 in SGC and correlate its expression with clinicopathological features and patients survival., Methods: The immunohistochemical expression of PD-L1 and PD-1 was evaluated in 30 SGC cases., Results: PD-L1 immunopositivity was detected in 41.9% of the SGC cases. PD-1 expression in tumor infiltrative lymphocytes (TILs) was observed in 53.3% samples. Tumor PD-L1 positivity, PD-1 expression in TILs and tumor size (>10 mm) was associated with reduced disease-free survival. On multivariate analysis only tumor size (>10 mm) and a combined positivity of PD-L1 in tumor cells and PD-1 in TILs with an odds ratio of 5.212 (95% confidence interval 1.449-18.737) continued to be significantly associated with SGC recurrence., Conclusion: PD-L1 is overexpressed in 50% of SGC cases. The combined tumor PD-L1 positivity and TILs showing PD-1 expression within the same SGC patient's samples predict high-risk SGC, suggesting that the up-regulation of PD-L1 in tumor cells and PD-1 positivity within the same SGC patient may aggravate tumor recurrence., Competing Interests: None

Competing Interests: There are no conflicts of interest.

Merkel cell carcinoma (MCC) is one of the rarest eyelid tumors, with high mortality rate due to lymphatic and metastatic spread. We hereby report six cases of patients with histological diagnosis of MCC referred to our Orbit Unit between 2012 and 2018, focusing on diagnosis, treatment, and subsequent follow up. All patients underwent surgical excision and systemic work-up. Both MCC TNM and eyelid MCC TNM were used to stage lesions. MCC of the eyelid is usually misdiagnosed as benign or other malignant lesions. A prompt examination and a wide local excision are mandatory. A close follow-up of these patients is advised due to high recurrence rate and lymphatic spread.

Adenoid cystic carcinoma (ACC) is a rarely seen malignant epithelial tumor of the eyelids. We present a rare case of primary ACC arising from the tarsal plate of the lower lid that clinically resembled a chalazion. A 66-year-old female presented with a recurring nodule in her left lower lid. She gave history of surgery for chalazion removal from the same site twice earlier. An initial diagnosis of a recurrent chalazion was made, and incision and curettage was done. Light microscopy showed a solid tumor composed predominantly of sheet-like and nested pattern of basaloid to low-columnar cells with intervening fibrovascular septa and lacking an obvious cribriform or tubular architecture. The tumor cells were positive for pan-cytokeratin and CD117 and negative for adipophilin, HMB45, and BerEP4. A diagnosis of solid variant of ACC of the eyelid was made. Wide excision was performed and eyelid defect was reconstructed., Competing Interests: There are no conflicts of interest

Purpose: This study aimed to evaluate the relationships between androgen receptor (AR) expression and clinicopathologic features of sebaceous gland carcinoma (SGC) of the eyelid., Methods: AR expression was evaluated via immunohistochemistry analysis of surgically derived samples from 11 patients with SGC of the eyelid., Results: The expression of AR was evident in 9 of 11 patients (82%). We divided patients into high AR (7 patients) and low AR (4 patients: 2 patients with low expression and 2 patients with no expression) groups. The low AR group showed significantly greater progression than the high AR group with regard to T category and exhibited a lower grade of differentiation., Conclusion: In patients with SGC of the eyelid, a marked decrease in AR expression may be associated with a poor prognosis. AR may be a prognostic factor and a potential therapeutic target in cases of SGC of the eyelid.

Sweat gland neoplasms are rare adnexal tumors that pose a diagnostic challenge for both, ophthalmologists and pathologists. Endocrine, mucin producing sweat gland carcinoma (EMPSGC), considered to be analogous to the solid papillary mammary carcinoma is one such tumor. It usually affects elderly, is more frequent in women and has a predilection for skin of the eyelid. Although it has an indolent clinical course, EMPSGC is believed to be a precursor of the invasive mucinous carcinoma and has a potential for local recurrence. We report a series of 10 biopsy-proven EMPSGCs with their immunohistochemical features and review the literature., Competing Interests: There are no conflicts of interest

Purpose : Dermatofibromas are common cutaneous lesions, but rarely occur in the eyelid skin. The reason for the low incidence in the palpebral skin has not been elucidated. In this study, we analyze the histopathologic features of an illustrative case of dermatofibroma and review previously published cases to determine whether eyelid dermatofibroma develops differently from the prototypical dermatofibroma. Methods : Histopathologic analysis of a new illustrative case of eyelid dermatofibroma and retrospective review of published cases. Results : The distinguishing features of the illustrative lesion included a rounder gross appearance, nonacanthotic epithelium, basophilic staining, cellular character, and a paucity of "collagen trapping." These features deviated from the typical features associated with classic dermatofibroma. Review of the 11 previously published cases of eyelid dermatofibroma revealed that they were more similar in appearance to the illustrative lesion than to classic dermatofibroma. Discussion : The rarity and histological deviations of the eyelid dermatofibroma suggest that the dermal substrate from which the lesion develops differs from that of the classic dermatofibroma. This difference may be explained microanatomically based on the fact that the dermis of the eyelid is predominantly papillary, whereas the dermis of extrapalpebral skin where dermatofibromas are more common is predominantly reticular. Conclusions : Although related, eyelid dermatofibromas appear to be histologically distinct from classic dermatofibromas, owing to the unique dermal composition of the site of origin.

Purpose: A limited number of therapies are available for patients with metastatic eyelid sebaceous carcinoma (SC). Programmed death receptor Ligand 1 (PD-L1) expression and its clinical significance in sebaceous cell carcinoma are presently unknown. This study aimed to evaluate the expression level of PD-L1 in SC., Methods: This single centre, retrospective, and comparative study was conducted at the Ninth People's Hospital between August 1, 2013 and September 1, 2016. Twenty primary, 11 recurrent, and 10 lymph node metastatic eyelid SCs of 41 consecutive patients and paired control eyelid samples were enrolled in the study. Immunohistochemical staining of PD-L1 was performed on slides containing SC embedded in paraffin wax. Patient clinical characteristics and PD-L1 expression related to SC prognostic values were evaluated., Results: Of the 41 patients with eyelid SCs, 58.5% (24/41) were female, and 41.5% (17/41) were male. A total of 43.9% (18/41) were left-sided, and 56.1% (23/41) were right-sided. A total of 2.4% (1/41) of the SCs were located at the canthus, 51.2% (21/41) were located at the upper eyelid, 41.5% (17/41) were located at the lower eyelids, and 2.4% (1/41) invaded the lacrimal sac. A total of 24.4% of the SCs were metastatic (10/41), 48.8% (20/41) were primary tumours, and 26.8% (11/41) resulted from recurrence. A total of 48.8% (20/41) were moderately graded and 51.2% (21/41) were poorly graded. Programmed death receptor Ligand 1 (PD-L1) positive expression was found in 20 (48.8%) cases. Programmed death receptor Ligand 1 (PD-L1) expression was observed on the tumour cell membrane. Higher expression of PD-L1 was correlated with metastatic cases when compared with primary cases (F = 6.69, p = 0.001). There was a higher expression of PD-L1 in the poorly differentiated group compared with the moderately graded group (57.1% poorly graded versus 45.0% moderately graded)., Conclusion and Relevance: Inhibition of PD-L1 expression may be a therapeutic option for metastatic eyelid SCs, although this hypothesis needs to be tested in future clinical trials., (© 2018 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To report the clinical and histopathologic features of two cases of eyelids metastases from uveal melanoma diagnosed in a metachronous and synchronous fashion., Methods: Monocentric retrospective case series of histopathologically proven eyelids metastases from uveal melanoma at our institution., Results: Two patients were presented to our hospital for upper eyelids pigmented and firm lesions. Patient 1 had an history of left uveal melanoma treated conservatively with proton beam therapy 5 years earlier. Examination revealed bilateral upper eyelids lesions. Patient 2 had no malignancy history but was incidentally diagnosed with a cerebral nodule few months earlier. Examination revealed a right upper eyelid nodule and a previously unknown right uveal melanoma. Excisional biopsy was performed for both patients. Pathological assessment allowed the presence of melanoma cells. The lack of BAP1 nuclear expression on immunohistochemistry as well as the absence of cutaneous or mucosal melanoma were consistent with an uveal origin. Diffuse metastatic spread was noted for both patients. Systemic therapies were prescribed. Patient 1 died from metastatic spread (62 months and 4 months after uveal melanoma diagnosis and eyelids metastases removal, respectively) whereas patient 2 was still alive (14 months follow up)., Conclusions: Eyelids metastases from uveal melanoma is an exceptional finding. Excisional biopsy and pathological assessment are of main importance to confirm the diagnosis and to identify genetic mutations for further targeted therapies. Currently, prognosis remains poor.

Introduction: Primary Apocrine adenocarcinomas (PAA) are very infrequent tumors that are often confused initially with benign lesions. Little is known about this disease and there is still much to be clarified. We present a case of PAA on the eyelid successfully treated with surgery alone and a literature review regarding what is currently described about this disease., Methods: Noncomparative, retrospective case report of a patient with PAA on the eyelid succesfully treated with surgery alone and a literautre review., Results: A 91-year-old man with a 2 months lesion on the upper left eyelid was treated with surgery alone with oncological margins of 5mm. The Hystopathology diagnosis was a PAA of the eyelid and free margins were obtained. After 12 months of follow-up, the patient does not show any signs of local recurrence or distant metastasis. A review of the literature suggests these tumors are located more frequently in the axilla (50%) and secondly in the head and neck (35%), with similar distribution in the upper (41%) and lower eyelid (45%). The most commonly used treatment is surgical excision, but radiotherapy and chemotherapy have also been used with variable results., Conclusions: PAA is a very rare and aggressive tumor. Because it is so infrequent, treatments are based on the sporadic cases encountered in the literature. As more cases are reported, more can be elucidated about the characteristics of this tumor, its behavior and best treatment choice and this may allow progress in the understanding and management of this disease.

Purpose: Basal cell carcinoma (BCC) is a locally invasive skin tumor which can be subdivided into a circumscribed nodular and an invasive fibrosing subtype. There is increasing evidence that macrophages play an important role in interacting between tumor cells and their microenvironment, thereby affecting not only the invasive potential but also the patients' prognosis. Thus, we wanted to compare these two BCC variants with regard to tumor-related inflammation, COX-2 expression, distribution, and polarization of tumor-associated macrophages., Material and Methods: 30 BCCs (nodular: n = 15; fibrosing: n = 15) of the ocular adnexae were investigated by histopathology and immunohistochemistry. The grade of inflammation was evaluated on hematoxylin and eosin stains (score: 0-3). Immunohistochemical stains for CD68 (macrophages), Ki67 (proliferative activity), and COX-2 as well as immunofluorescence stains for CD68 and CD163 (to distinguish M1 and M2 macrophage subtypes) were performed. SPSS was used for statistical analysis., Results: Fibrosing BCCs were predominantly located on the lower lid, while nodular BCCs showed a broader distribution (p = 0.013). The fibrosing BCC subtype was associated with a higher degree of inflammation (p < 0.001) and revealed a higher COX-2 immunoreactivity than nodular BCC (p = 0.012). COX-2-positive cells were predominantly located on the infiltrating edge of the tumor. Macrophage polarization was balanced regarding M1 and M2 macrophage subtypes. There was no difference in macrophage number (p = 0.389) or polarization (p = 0.161) between nodular and fibrosing BCC., Conclusions: The findings indicate that COX-2 represents a factor for invasion of BCC. Macrophage polarization did not play a major role for aggressive behavior. However, other inflammatory components than tumor-associated macrophages seem to be involved in tissue destruction and thereby an invading growth pattern since fibrosing BCC revealed a significantly more intense inflammatory reaction in the surrounding tissue.

Primary mucinous adenocarcinoma (PMA) of the eyelid is an exceptionally rare clinical entity. Often, it mimics with benign lesions on clinical examination and with metastatic mucinous adenocarcinoma on histological examinations. We report a case of PMA in a 60-year- old male patient who came with a slow-growing, painless swelling near the lower lid of the left eye. Excisional biopsy from the mass revealed a mucinous adenocarcinoma. To differentiate it from a metastatic mucinous adenocarcinoma, a wide range of immunohistochemistry panel was run. The tumor cells showed strong positivity for cytokeratin7, cytokeratin5/6, P63, estrogen receptor, progesterone receptor and negativity for cytokeratin20. Moreover, extensive metastatic work-up did not show any primary malignancy elsewhere, hence a final diagnosis of PMA was made. We believe that, this is the second reported case from the Middle East and the first in the Madinah region of Saudi Arabia.

Background: p53 is a stress-activated tumour suppressor gene, and its mutation has been associated with solid tumours including non-melanoma skin cancers. Sestrin2 expression is associated with DNA damage and oxidative stress and has been described as a downstream target of p53 network. However, its role in sebaceous gland carcinoma (SGC) remains unexplored., Objectives: To determine the role of p53 and its downstream target gene sestrin2 expression and p53 gene mutation status in SGC., Methods: Twenty cases of eyelid SGC tumour and circulating cell-free DNA (ccfDNA) were subjected to mutational analysis of p53 gene. p53 and sesrin2 expression was evaluated by immunohistochemistry. Results were correlated with the clinicopathological features of eyelid SGC., Results: p53 gene mutations was detected in 25% of the SGC cases. A C>T transition was identified in exon 6 in a single patient in both tumour and ccfDNA. A G>T transversion leading to amino acid change D259Y was seen in four patients. A splice site mutation affected a single case in exon 6. p53 expression was observed in 55% SGC. Loss of sestrin2 in 55% SGC cases correlated with poor tumour differentiation (P=0.0001), upper eyelid involvement (P=0.004), p53 mutation (P=0.039) and with mutant p53 expression (P=0.0001)., Conclusion: Sestrin2 expression was found to be significantly reduced in p53 mutated SGC cases and in cases with strong p53 nuclear immunopositivity, suggesting that loss of sestrin2 may be of biological significance in the development of SGC and as a key downstream component of p53 tumour suppression network in eyelid SGC., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

A healthy 31-year-old female presented with an elevated vascular lesion on the right lower eyelid margin. Histology results from excisional biopsy demonstrated a range of intradermally nested atypical melanocytes with negative staining for BRCA1-associated protein 1, confirming the diagnosis of Wiesner nevus. Wiesner nevi may be a cutaneous hallmark of the BRCA1-associated protein 1-associated cancer susceptibility syndrome, and to our knowledge, this is the first report of such a lesion presenting anywhere on the ocular adnexa.

Purpose: The purpose of the study was to evaluate the characteristics of sebaceous gland carcinoma (SGC) of the ocular adnexae, which is due to a high variability in clinical, histological and immunohistochemical characteristics often challenging to diagnose., Methods: Records of six patients with SGC were reviewed, who underwent surgical excision and who were histologically diagnosed with SGC. For comparison, there were specimens from four patients with basal cell carcinoma (BCC) and four patients with squamous cell carcinoma (SCC). Histological and immunohistochemical analysis included stains for HE, cytokeratins (CKpan, Cam5.2), epithelial membrane antigen (EMA), androgen receptor (AR441), perforin and adipophilin., Results: SGC's were located in the upper (n = 2) or lower (n = 4) eyelid and were associated with various presenting clinical signs including chalazion-like lesions with pyogenic granuloma (n = 1), papillomatous conjunctival tumors (n = 3), a hyperkeratotic exophytic neoplasm (n = 1) and an ulcerating crusted lesion resembling chronic blepharitis (n = 1). The treatment was tumor resection, followed (if necessary) by adjuvant therapy with topical Mitomycin C (n = 2). Histologic characteristics included basophilic pleomorphic cells with vacuolated cytoplasm, prominent nucleoli, mitotic figures and in some cases pagetoid spread (n = 2). CKpan, EMA and Cam5.2 showed strong positive immunoreactivity in all specimens (SGC, BCC, SCC). Perforin immunostaining showed a varying, but overall weak, non-specific cytoplasmatic staining reaction in all lesions. AR441 positivity was noted with variable intensity in almost all lesions and in particular in pagetoid spread in contrast to non-tumor cells. Adipophilin showed an annular staining of lipid granules in immature sebaceous cells in SGC in contrast to a more granular staining pattern in BCC and SCC., Conclusion: SGCs display a variety of clinical signs and may mimic many other lesions. Tumor resection, followed by histological and immunohistochemical analysis, leads to the diagnosis and initiation of the proper treatment regimen. Herein, immunohistochemistry showed an unequivocal profile in SGC and did not allow for an exact differentiation from BCC and SCC by immunohistochemical means only. An extended evaluation of HE stains remains essential. However, immunohistochemistry can make relevant contributions to the diagnosis of SGC, especially in cases of inconclusive histology, by positive staining for adipophilin in immature sebaceous cells or by AR441 labeling in cases of pagetoid spread.

A 66-year-old man developed a painless 2 mm to 3 mm recurrent nodule at the left upper eyelid margin. Excision disclosed a spindle cell lesion without frank atypia or mitotic activity growing in a twisted fascicular pattern often referred to as storiform. All the surgical margins were involved with tumor. Immunohistochemistry demonstrated that many of the constituent spindle and dendritic tumor cells were CD34, factor XIIIa, and CD 163, the latter 2 being biomarkers for monocytic lineage. The lesion was diagnosed as a dermatofibroma rather than a fibrous histiocytoma, a term that should be reserved for more aggressive lesions of deeper fascial planes. Facial dermatofibromas are rarer and more likely than those of the extremities to recur and therefore deserve wider local excision at first surgery with careful and frequent clinical follow ups. Eyelid dermatofibroma has probably often been misdiagnosed as another tumor in the past. Immunohistochemistry can supply valuable biomarker criteria for diagnosis.

There are very few published cases of periocular keratin horns that have been reported in children. This study reports 2 pediatric cases of periocular keratin horns. The authors describe a 7-year-old male child who developed a keratin horn on the right lower eyelid and a 16-year-old female who developed a caruncular keratin horn. Both cases underwent excision biopsy, and subsequent histology confirmed that there was no evidence of malignancy. However, on the basis of the current evidence in adults and the difficulty in drawing firm conclusions from the small number of reported pediatric cases, the authors suggest that these lesions should be carefully managed due to the possibility of premalignant or malignant change at the base of the lesion.

Background: Bcl-2-associated athanogene 3 (BAG3), a co-chaperone of heat shock protein 70 (HSP70), has been shown to play a role in anti-apoptosis of various malignant tumors. In this study, the expression of BAG3 was examined in human sebaceous gland carcinoma of the eyelid., Materials and Methods: The expression of BAG3 was evaluated by immunohistochemistry of surgical samples from 5 patients with sebaceous gland carcinoma in the eyelid., Results: BAG3 was positive diffusely in the cytoplasm in all patients. The average positive rate of BAG3 was 73.0±26.0% in tumor cells of all patients., Conclusion: BAG3 was highly expressed in sebaceous gland carcinoma of the eyelid. BAG3 may play an important role in the pathogenesis and progression of sebaceous gland carcinoma of the eyelid., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Merkel cell carcinoma of the eyelid is an aggressive, highly malignant tumor of the skin. Totaling approximately 0.5 % of all tumors of the eyelid, it constitutes a relatively small group of lid tumors. Nevertheless Merkel cell carcinoma is of significance to the ophthalmologist. Because of its clinical presentation it can be easily confused as a chalazion, a hordeolum or the lesser aggressive basal cell carcinoma. This often leads to delayed treatment. In this article we describe clinical aspects, which aim to help the ophthalmologist suspect Merkel cell carcinoma earlier. Additionally we outline a diagnostic and therapeutic workup taking into consideration the special anatomy of the eyelid.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare, often underrecognized, low-grade sweat gland carcinoma of the skin of the eyelid. To date, only 20 cases of this carcinoma have been reported, most frequently in Caucasian females with an average age of 70 years. Although the diagnosis is primarily made with immunohistochemical stain, compared to endocrine ductal carcinoma in situ, clinical detection serves as a potentially curative treatment. Further, its benign appearance clinically makes this tumor often misdiagnosed and undertreated. This disease commonly presents in Caucasian women of advanced age, aiding in the diagnosis of this tumor, which presents an even more critical diagnosis in a patient with a rare presentation. In the available literature, we could find no case of EMPSGC in younger African American women. The following case is the first case presented in the literature. Here, we present a case of an atypical presentation of the tumor in a young African American female, as well as a review of literature on the pathophysiology, clinical presentation, and treatment of EMPSGC.

Purpose: To report a very rare eyelid mass confirmed to be a metastasis from lung adenocarcinoma., Methods: A 68-year-old man had a two-month history of a large nodule in the right upper eyelid. He was a known case of lung adenocarcinoma since 2 years without a history of systemic metastasis. He underwent further investigations including orbital imaging and biopsy of the lesion., Results: Biopsy and immunohistochemical evaluations of the eyelid lesion revealed a moderate to poorly differentiated adenocarcinoma, a similar histology to the lung lesion., Conclusions: Metastatic involvement of the eyelids is rarely seen; specifically, those associated with lung adenocarcinoma as the source have been reported extremely rare. Eyelid metastases present with various and non-specific clinical features, and therefore biopsy of suspicious or recurrent lesions is highly recommended to rule out such malignant processes.

Aims: Sebaceous gland carcinoma (SGC) is a malignancy associated with the pilosebaceous unit, and occurs at ocular or non-ocular sites. Cyclooxygenases (COXs) are enzymes that are crucial for lipid metabolism. COX-2 is overexpressed in various cancers, and its inhibition by non-steroidal anti-inflammatory drugs is known to reduce the risk of many cancers. Peroxisome proliferator-activated receptor (PPAR)-γ is a transcription factor involved in adipogenesis. PPAR-γ is a potential therapeutic target for the treatment of malignant tumours, including colon carcinoma. The aim of this study was to explore the status of COX-2 and PPAR-γ as prognostic markers in human eyelid SGC., Methods and Results: The immunohistochemical expression of COX-2 and PPAR-γ was evaluated in 31 SGC cases. Cytoplasmic expression of COX-2 was detected in 80% of the SGC cases, and nuclear expression of PPAR-γ in 87%. There were significant correlations of PPAR-γ expression with well-differentiated SGC [19/21 (90%)] and of COX-2 overexpression with reduced disease-free survival (P = 0.0441, log rank analysis). COX-2 expression [odds ratio (OR) 3.82, 95% confidence interval (CI) 1.02-14.33, P = 0.046] and lymph node metastasis (OR 0.17, 95% CI 0.04-0.65, P = 0.009) emerged as significant risk factors in the univariate analysis. However, COX-2 expression did not emerge as a significant independent prognostic factor in multivariate analysis., Conclusions: COX-2 is a potential marker for identifying high-risk SGC patients. Expression of PPAR-γ in eyelid SGC cases reflects terminal sebaceous differentiation. Inhibitors of COX-2 signalling and PPAR-γ agonists are both prospective novel therapeutic targets in the management of eyelid SGC patients., (© 2016 John Wiley & Sons Ltd.)

Purpose: Eyelid sebaceous carcinoma (SC) remains a common diagnostic pitfall for both the clinician and histopathologist. The aim of this study was to describe perforin as a new marker in the immunohistochemistry panel for SC., Methods: A total of 29 cases were retrieved from the Pathology archives, including 11 sebaceous neoplasms (nine SC; two sebaceomas), 10 squamous cell carcinomas (SCC) and eight basal cell carcinomas (BCC). These were stained using the monoclonal antibody for perforin, epithelial membrane antigen (EMA), Ber-EP4 and adipophilin (ADP). Sensitivity and specificity of perforin as an immunohistologic marker for sebaceous tumours were compared to EMA, ADP and Ber-EP4., Results: Perforin stained strongly 9/11 (81%) of the sebaceous neoplasms (SN), 7/9 SC and 2/2 of sebaceomas (2/2), similar to ADP. Epithelial membrane antigen (EMA) stained 8/9 SC and was negative (1/2) or only very weakly expressed (1/2) in sebaceomas. The specificity of perforin in identifying SN versus SCC and BCC was 100% (95% CI 69-100), while EMA specificity in identifying SN varied according the comparison group (SCC: 50%, 95% CI 18-81, 100% (95% CI 63-100). Perforin better highlighted the intraepithelial spread of SC than EMA. Ber-EP4 was strongly expressed in six of nine SC, but was consistently negative in sebaceomas., Conclusions: The expression pattern of perforin in sebaceous neoplasms enables us to recommend the use of perforin as a new immunohistochemical marker for sebaceous neoplasms., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

A 60-year-old man developed a rubbery thickening and erythema of his left lateral upper and lower eyelids and lateral canthus over several months. He was treated for an extended period of time for blepharitis and chalazia. Incisional biopsy eventually disclosed microscopically a hypercellular lymphoid population sparing the epidermis that surrounded adnexal structures and infiltrated between orbicularis muscle fibers. Immunohistochemically, the lesion was found to be composed of neoplastic, kappa-restricted B cells with an equal number of reactive T cells and small reactive follicles. The diagnosis was a primary cutaneous extranodal marginal zone B-cell lymphoma of the eyelid skin (EMZL). We review the distinguishing clinical, histopathologic, and immunohistochemical features of cutaneous EMZL and contrast those with EMZL of other ocular adnexal sites. Also offered is a differential diagnosis of cutaneous lymphomas of the eyelid skin, which are predominately T-cell lesions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Meibomian gland carcinoma (MGC) and basal cell carcinoma (BCC) are common eyelid carcinomas that exhibit highly dissimilar degrees of proliferation and prognoses. We address here the question of the differential mechanisms between these two eyelid cancers that explain their different outcome. A total of 102 confirmed MGC and 175 diagnosed BCC cases were analyzed. Twenty confirmed MGC and twenty diagnosed BCC cases were collected to determine the telomere length, the presence of senescent cells, and the expression levels of the telomere capping shelterin complex, P53, and the E3 ubiquitin ligase Siah1. Decreased protein levels of the shelterin subunits, shortened telomere length, over-expressed Ki-67, and Bcl2 as well as mutations in P53 were detected both in MGC and BCC. It suggests that the decreased protein levels of the shelterin complex and the shortened telomere length contribute to the tumorigenesis of MGC and BCC. However, several parameters distinguish MGC from BCC samples: (i) the mRNA level of the shelterin subunits decreased in MGC but it increased in BCC; (ii) P53 was more highly mutated in MGC; (iii) Siah1 mRNA was over-expressed in BCC; (iv) BCC samples contain a higher level of senescent cells; (v) Ki-67 and Bcl2 expression were lower in BCC. These results support a model where a preserved P53 checkpoint in BCC leads to cellular senescence and reduced tumor proliferation as compared to MGC., (© 2015 UICC.)

A 16-year-old boy developed over a 2-month interval a lightly pigmented left upper eyelid lesion measuring 1.5 mm in greatest diameter that, when excised, microscopically was hypercellular and composed almost exclusively of nonpigmented epithelioid cells that created florid, large intraepidermal junctional nests and sheets and nests of subepidermal cells. The diagnosis was a Spitz nevus. HMB-45, MART-1, and microphthalmia-associated transcription factor were all positive and established the melanocytic nature of the benign tumor. The Ki-67 proliferation index (5%) and 2 mitoses/mm(2) were both low; p16 protein was immunohistochemically identified in the nevoid cells. We review the clinical, histopathologic, and other immunohistochemical features of this entity and provide a brief differential diagnosis (including separation from a Spitzoid melanoma). This is only the third eyelid Spitz nevus reported in the literature and is the most fully characterized immunohistochemically. At their present stage of development, contemporary immunohistochemical biomarkers, while providing supplemental information, nonetheless remain less than definitive in terms of reliably distinguishing benign from malignant Spitz lesions., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Infantile myofibromatosis is a rare mesenchymal neoplasm that commonly involves the head and neck but rarely the eyelid. We report the case of a newborn boy referred for evaluation of a left eyelid lesion that occluded the visual axis. Urgent biopsy was performed to evaluate for malignancy. Histopathologic analysis demonstrated myofibroma. Although these lesions have been reported to regress spontaneously, debulking surgery was performed to prevent sensory or anisometropic amblyopia. Follow-up systemic evaluation revealed numerous subcutaneous and deep soft tissue lesions. There was no visceral involvement., (Published by Elsevier Inc.)

A 16-year-old African American male, the youngest patient to date, presented with a well-circumscribed upper eyelid lesion. On excision, the dermal nodule was contiguous with the epidermis, displayed trichohyalin-like bodies in an expanded outer root sheath, and was composed chiefly of small cellular clusters separated by a prominent network of periodic acid Schiff -positive hyaline bands of basement membrane material. The tumor cells were positive for high molecular weight cytokeratins (CK) 5/6, CK14, and CK34βE12 and were negative for CK7, carcinoembryonic antigen and epithelial membrane antigen. Negative S100, glial fibrillary acidic protein, and smooth muscle actin immunoreactions ruled out a myoepithelial lesion. The Ki-67 proliferation index was <10%. The diagnosis was a hyalinized trichilemmoma, contrasting with the more common lobular type. As an isolated lesion, trichilemmoma does not portend Cowden syndrome.

Purpose: To determine the incidences, clinical features, and detailed histopathologic and immunohistochemical findings of 10 peripheral nerve tumors (isolated neurofibromas, solitary circumscribed neuromas [SCNs], and schwannomas) localized to the eyelid dermis., Methods: In this retrospective clinicopathologic study, clinical records and paraffin sections subjected to hematoxylin and eosin, Masson trichrome, periodic acid-Schiff, reticulin, and Alcian blue staining were critically reviewed from each case. Additional paraffin sections were immunoreacted for S100, neurofilament, CD34, epithelial membrane antigen (EMA), glucose transporter-1 (glut-1), and calretinin., Results: Ten patients with a median age of 57 years had solitary, small, flesh-colored papules, 70% at the eyelid margin. Microscopically, they were diagnosed either as a SCN or an isolated neurofibroma. SCN was diffusely S100-positive (and sometimes diffusely calretinin-positive) with myriad neurofilaments. Fascicles of cells were separated by CD34-positive septa, and the lesions were surrounded by a glut-1/EMA-positive capsule. Neurofibromas were calretinin-negative and had a moderate number of S100-positive cells, with widely scattered neurofilaments, many CD34-postive intermixed cells, and no capsule. No schwannomas were diagnosed., Conclusions: Peripheral nerve tumors of the eyelid have a distinct clinical presentation at the eyelid margin. Careful histopathologic and immunohistochemical studies can reliably separate the entities in the categories of isolated neurofibroma, SCN, and schwannoma when the last occurs. These distinctions can have important systemic implications.

A tumor represents an abnormal tissue growth that can arise from any ocular structure, such as eyelids, muscles or the optic nerve. At the eyelids, there are two main tumor types: basal cell carcinoma and squamous cell carcinoma. Angiogenesis plays a crucial role in growth, invasion and metastasis processes of any tumor. It is well known the fact that without new vessels formation tumors cannot exceed 1-2 mm diameter. Immunohistochemical analysis has been performed on 43 cases of primary carcinomas of the eyelid, diagnosed between 2010 and 2014 in the Laboratory of Pathological Anatomy of the University Emergency County Hospital of Craiova, Romania. Biological material was represented by surgical resection samples, coming from the Clinic of Ophthalmology the anteriorly named Hospital. Within the immunohistochemical study, we have evaluated epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) expression in a group of 43 cutaneous carcinomas of the eyelid, depending on the type and differentiation grade of the tumor. Of the 43 samples, 23 came from patients with eyelid basal cell carcinoma and 20 came from patients with eyelid squamous cell carcinoma. In our study, EGFR and VEGF immunoexpression was superior for squamous cell carcinomas, compared to basal cell carcinomas, fact that was statistically significant. Regarding squamous cell carcinomas, the immunoexpression of these two markers was superior in moderate÷poor differentiated forms, compared to well differentiated forms, fact that was statistically significant. The markers used in this study were found to be associated with the acquisition of aggression and angiogenic phenotypes by analyzed carcinomas.