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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.)

Ocular adnexal sebaceous carcinoma (SebCA) represents one of the most clinically problematic periocular tumors, often requiring aggressive surgical resection. The pathobiology of this tumor remains poorly understood, and few models exist that are suitable for preclinical testing. The aim of this study was to establish new cell lines to serve as models for pathobiological and drug testing. With patient consent, freshly resected tumor tissue was cultured using conditional reprogramming cell conditions. Standard techniques were used to characterize the cell lines in terms of overall growth, clonogenicity, apoptosis, and differentiation in vitro. Additional analyses including Western blotting, short tandem repeat (STR) profiling, and next-generation sequencing (NGS) were performed. Drug screening using mitomycin-C (MMC), 5-fluorouricil (5-FU), and 6-Diazo-5-oxo-L-norleucine (DON) were performed. JHH-SebCA01, JHH-SebCA02, and JHH-SebCA03 cell lines were established from two women and one man undergoing surgical resection of eyelid tumors. At passage 15, they each showed a doubling time of two to three days, and all could form colonies in anchorage-dependent conditions, but not in soft agar. The cells contained cytoplasmic vacuoles consistent with sebaceous differentiation, and adipophilin protein was present in all three lines. STR profiling confirmed that all lines were derived from their respective patients. NGS of the primary tumors and their matched cell lines identified numerous shared mutations, including alterations similar to those previously described in SebCA. Treatment with MMC or 5-FU resulted in dose-dependent growth inhibition and the induction of both apoptosis and differentiation. MYC protein was abundant in all three lines, and the glutamine metabolism inhibitor DON, previously shown to target high MYC tumors, slowed the growth of all our SebCA models. Ocular adnexal SebCA cell lines can be established using conditional reprogramming cell conditions, and our three new models are useful for testing therapies and interrogating the functional role of MYC and other possible molecular drivers. Current topical chemotherapies promote both apoptosis and differentiation in SebCA cells, and these tumors appear sensitive to inhibition or MYC-associated metabolic changes.

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.

Sebaceous carcinoma (SC) is a malignant neoplasm demonstrating sebocytic differentiation, commonly in the periocular area. Sebocytic differentiation is recognized by multivesicular cytoplasmic clearing with frequent nuclear scalloping. The vesicles can be highlighted by immunohistochemical stains against the perilipin family proteins including adipophilin. Extraocular SC is uncommon but well reported, often in the setting of Muir-Torre syndrome; however, vulvar SC is exceptionally rare. The literature review yielded only 12 prior cases of vulvar SC, all of which showed invasion. Here we report 2 additional similar cases from 2 different institutions of an intraepithelial carcinoma with sebaceous differentiation. Histologic examination of multiple specimens from both patients showed similar features: a multifocal intraepithelial basaloid nodular neoplasm sparing the basal layer with occasional pagetoid spread. The tumor cells demonstrated a high nuclear to cytoplasmic ratio, mitoses, variably foamy vacuolated cytoplasm, and nuclear indentation. Multiple specimens from both patients showed evidence of sebaceous differentiation (substantiated by adipophilin positivity in a membranous vesicular pattern in case 1 and by androgen receptor and epithelial membrane antigen positivity in case 2), and squamous differentiation (substantiated by p63/p40 and weak CK 5/6 expression), as well as human papillomavirus (HPV) association (substantiated by p16 block positivity and detection of high-risk HPV by in situ hybridization). One case was a true in situ lesion without evidence of invasion, and the other case was predominantly an in situ carcinoma with prominent adnexal extension and focal superficial invasion of <1 mm seen in one of multiple specimens. To our knowledge, these 2 cases are the first to show a vulvar SC/carcinoma with sebaceous differentiation that is predominantly limited to the epidermis, and the first documentation of HPV infection in vulvar sebaceous neoplasms. Vulvar intraepithelial carcinoma with sebaceous differentiation is the umbrella term we chose for this entity. Whether this is a true SC in situ that is HPV positive/driven, or a vulvar intraepithelial neoplasia with sebaceous differentiation, is not entirely clear. We emphasize the importance of looking for this morphology to avoid misclassification. Due to the rarity of cases, optimal treatment at this site has not been established., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Aims: Clear cells formed due to depositions of glycogen or lipids in the cytoplasm commonly occur in various tissues. Adipophilin (ADP), a lipid regulatory protein, is closely related to lipid droplets. This study aims to examine adipophilin expression in clear cells of various skin lesions., Methods: ADP expression was examined using immunohistochemistry in 108 sections from 15 skin lesion types with clear cell histology, namely, sebaceoma (n=16), sebaceous adenoma (n=3), sebaceous carcinoma (n=12), xanthomata cutis (n=10), xanthogranuloma (n=8), Paget's disease (n=10), Bowen disease (n=10), hidradenoma (n=9), atypical lipoma (n=5), superficial lipomatous nevus (n=5), metastatic renal cell carcinoma (n=5), squamous cell carcinoma (n=4), seborrheic keratosis (n=4), dermatofibroma (n=4) and clear cell sarcoma (n=3)., Results: ADP was not expressed in Bowen disease, hidradenoma or seborrheic keratosis. Four expression patterns, foamy, reticular, granular and punctate, were summarised based on their expression in clear cells. Different expression patterns were related to tissue origin and differentiation degree. Foamy expression was commonly observed in lesions with mature sebaceous glands and xanthomas; reticular expression in adipocytes; granular expression in xanthoma, xanthogranuloma and metastatic renal carcinoma and punctate expression in sebaceoma, sebaceous carcinoma, Paget's disease, squamous cell carcinoma and clear cell sarcoma. Furthermore, stronger staining with focal vesicular labelling was noted in sebaceoma than in sebaceous carcinoma. Characteristic labelling was noted, including the circular distribution in Touton giant cells of xanthogranulomas and focal distribution in the clear cells along the edge of necrotic tissue in clear cell sarcoma., Conclusions: ADP is useful in identifying intracytoplasmic lipids and can be used to diagnose skin lesions with clear cell histology, especially in some lesions with characteristic labelling., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Sebaceous carcinoma (SC) is a rare malignant neoplasm with sebaceous differentiation. SC is classified into eyelid and extraocular SC clinically. Most studies have focused on the eyelid SC in terms of pathogenesis, treatment, and prognosis. In skin, Wnt/beta-catenin and hedgehog signaling are two major pathways in sebaceous differentiation. We aimed to characterize the clinical and histopathological features of extraocular SC and to measure the expression of beta-catenin, lymphoid enhancer-binding factor 1 (LEF1), sonic hedgehog (Shh), and protein patched homolog 1 (PTCH) in extraocular SC. Ten cases of extraocular SC were identified from 2007 to 2020. The clinical features, microscopic findings, and prognosis were analyzed. Immunohistochemical stain for beta-catenin, LEF1, Shh, and PTCH were performed in extraocular SC and other benign sebaceous tumors including sebaceous hyperplasia, sebaceous adenoma, and sebaceoma. The male:female ratio was 4:6. The median onset age was 73.5 years (range, 43-88). Seven patients out of 10 were diagnosed after 60 years. Most extraocular SC were located on the head and neck with indurated plaque. Two patients had concurrent internal cancers and three patients showed lymph node metastasis at time of presentation. Five-year overall-survival was 40%. Beta-catenin was expressed membranously in all sebaceous hyperplasia, but was expressed variably in extraocular SC (1/5). While LEF1 was unequivocally expressed in normal hair follicles, LEF1 expression was absent in all extraocular SC and benign sebaceous tumors. Regarding the sonic hedgehog signaling, Shh and PTCH were all expressed in the cytoplasm of sebaceous hyperplasia, sebaceous adenoma, and sebaceoma. In contrast, PTCH was absent in all cases of extraocular SC and only 50% of the extraocular SC expressed cytoplasmic Shh. To conclude, extraocular SC commonly affects facial skin in the elderly. Inactivated Wnt/beta-catenin and aberrant hedgehog pathway may contribute to the carcinogenesis of extraocular SC. Further studies may be required to elucidate the causative mechanism of these pathways in extraocular SC., (© 2022 Japanese Dermatological Association.)

Background: Immunohistochemistry for preferentially expressed antigen in melanoma (PRAME) has been studied in melanocytic lesions but not nonmelanoma skin cancers (NMSCs). This study evaluated PRAME expression in NMSCs and dermoepidermal junction (DEJ) melanocytes in the surrounding skin., Methods: Ninety-nine NMSCs were studied: 23 Merkel cell carcinomas (MCCs), 25 well to poorly differentiated squamous cell carcinomas (SCCs), 14 basal cell carcinomas (BCCs), five basosquamous carcinomas, four sebaceous carcinomas, ten atypical fibroxanthomas, 11 dermatofibrosarcoma protuberans, and seven leiomyosarcomas. Staining quality was considered low or high intensity. Staining quantity was reported as negative 0%, 1% to 24%, 25% to 50%, and >50%. DEJ melanocyte PRAME expression was recorded., Results: Forty-eight percent of NMSCs showed PRAME expression, mostly low intensity in fewer than 25% of cells. High-intensity expression was noted in one poorly differentiated SCC, six BCCs, and seven MCCs. Only MCCs showed expression in greater than 25% of tumor cells. Focal DEJ melanocytes expressed high-intensity PRAME in 18% of cases, most commonly SCCs (11/23)., Conclusions: PRAME is negative or expressed with low intensity in a small percentage of NMSCs, with the exception of some MCC showing high-intensity and diffuse staining. Focal DEJ melanocytes showed high-intensity PRAME reactivity in the skin surrounding some NMSCs., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Traditional systemic treatments for unresectable, recurrent, and/or advanced sebaceous carcinoma (SC) are ineffective. Tumoral immune microenvironment characterization is essential for considering immune checkpoint inhibitors as a treatment option., Methods: A total of 173 resected SCs were reviewed. Clinical information, lesion size, and location were collected. Microscopic examination documented histopathologic features and expression of immunohistochemical markers PD-L1 and CD8. PD-L1 percentage was assessed amongst tumor (PD-L1 + Tu) and immune infiltrating cells (PD-L1 + Inf). Each case was attributed a combined positive score (CPS) following Head and Neck squamous cell carcinoma recommendations. PD-L1 expression was evaluated according to clinicopathologic parameters. Human Papilloma Virus presence (HPV) was analyzed using PCR microarray scanning., Results: A therapeutically relevant CPS was seen in 51.4% of cases. Higher PD-L1 + Tu, PD-L1 + Inf, and CPSs were positively associated with greater lesion size and an extraocular location. No association was seen with patient age or gender. 9.2% of SCs showed PD-L1 + Tu ≥ 1, while 52.0% showed PD-L1 + Inf ≥ 1. A higher CD8 + T-lymphocyte density was significantly associated with a higher CPS, PD-L1 + Tu, and PD-L1 + Inf. Tumor-associated T-cell infiltrate's density was higher along tumor periphery. HPV-16, HPV-43, HPV-52, and HPV-66 were detected in 8.4% of SCs. There was no significant association between HPV status, PD-L1 expression, and CPS. A significant number of SCs express PD-L1 at therapeutic levels. Nevertheless, PD-L1 expression shows a higher intertumoral heterogeneity, in extraocular than in biologically distinct periocular cases., Conclusion: Our data support the need for large-scale prospective studies evaluating anti-PD-L1 immunotherapy mainly in extraocular SC treatment.

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.)

Purpose: To evaluate the expression of programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) in ocular adnexal sebaceous carcinoma (OASC), and to appraise these findings within the context of recent comparable studies., Designs: Retrospective case series., Methods: Twenty cases of primary OASC were immunostained for PD-L1, PD-L2 and CD8. PD-L1 and PD-L2 expression were graded with both the combined positive score (CPS) and the tumor proportion score (TPS). Both raw CPS and TPS were reported, as well as positivity with TPS and CPS ≥1. CD8 expression was graded on a 0-3 scale. Charts were reviewed for clinical correlations. The results of the current study were compared with results of similar recent investigations., Results: For the 20 cases, mean expression of PD-L1 with CPS was 29.7 (range 0-101.5) and with TPS was 12.2 (range 0-95.8); mean expression of PD-L2 with CPS was 7.9 (range 0-37.3) and with TPS was 1.9 (range 0-12.9). PD-L1 CPS ≥1 was detected in 95% of OASC, while PD-L1 TPS ≥1 was found in 75%. PD-L2 CPS ≥1 was present in 60%, while only 20% had PD-L2 TPS ≥1. Immune cells appeared to contribute to a substantial proportion of PD-L1 and PD-L2 positivity, and a conspicuous CD8-positive T-lymphocytic infiltrate was present in most tumors. Significant correlations were identified between tissue expression of PD-L1, PD-L2, and CD8. Tissues with greater levels of PD-L1 tended to express higher levels of PD-L2 and CD8. The degree of PD-L1 and PD-L2 expression was also associated with the area in millimeters squared of the immunostained tumor, suggesting that tumor sampling may influence interpretation of PD-L1 and PD-L2 expression in ocular adnexal tumors., Conclusions: The current and preceding studies confirm that PD-L1 and PD-L2 are expressed in a high percentage of OASCs. These results support the premise that checkpoint inhibitor drugs hold considerable therapeutic promise for patients with OASC and stimulate the institution of clinical trials., (Copyright © 2020 Elsevier Inc. 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.

Our aim was to investigate sebaceous differentiation in thymus tumours and to identify new actionable genomic alterations. To this end we screened 35 normal and 23 hyperplastic thymuses, 127 thymomas and 41 thymic carcinomas for the presence of sebaceous differentiation as defined by morphology and expression of adipophilin and androgen receptor (AR). One primary thymic carcinoma showed morphology of sebaceous carcinomas (keratinizing and foam cells, calcifications, giant cells), a strong expression of adipophilin and AR together with squamous markers. NGS revealed high-level amplification of fibroblast growth factor receptor 2 (FGFR2). In thymuses and thymomas, no cells with sebaceous morphology were present. Occasionally, macrophages or epithelial cells showed adipophilin-positivity, however, without co-expression of AR. Thymic sebaceous carcinoma should be considered if a thymic carcinoma shows clear or foamy features. Testing for FGFR2 amplification might be warranted when searching for actionable genomic alterations in sebaceous carcinomas in the mediastinum and in other locations.

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

To shed more light on the pathogenesis of sebaceous carcinoma, we analysed the expression of proteins related to angiogenesis in 18 ocular and 22 extraocular sebaceous carcinomas using a broad panel of immunohistochemical markers. To quantify the expression of D2-40, vascular endothelial growth factor, vascular endothelial growth factor receptor-2 and -3, we calculated a quantification score by considering the percentage of positive tumour cells (0=0%, 1=up to 1%, 2=2-10%, 3=11-50%, and 4=>50%) in relation to the staining intensity (0=negative, 1=low, 2=medium, and 3=strong). Additionally, lymphatic microvessel density in the D2-40 stained sections was counted. Vascular endothelial growth factor receptor-3 (quantification score 9.42 ± 2.94) was significantly more strongly expressed than vascular endothelial growth factor receptor-2 (quantification score 2.15 ± 2.42, p < 0.001). Furthermore, epidermal vascular endothelial growth factor expression was negatively correlated with the intratumoural lymphatic vessel density, and the ratio of small lymphatics to large lymphatics was much higher in intratumoural tissue than in paratumoural tissue and in intraindividual control tissue, suggesting a lymphangiogenetic potential of sebaceous carcinoma.

Background: Sebaceous carcinoma (SeC) is an uncommon malignancy arising from sebaceous glands of the conjunctiva and skin. Recurrent mutations in the ZNF750 were recently identified in ocular SeC. We assessed whether ZNF750 loss is a specific feature of ocular SeC or a general feature of sebaceous tumors., Methods: Immunostaining for ZNF750 expression was performed in 54 benign and malignant sebocytic proliferations. Staining for ZNF750 was scored on a three-tier scale: positive (>75%), partially positive (5%-74%), and negative (<5%)., Results: ZNF750 expression was negative in 4/11 ocular SeC, and partially positive in 4/11 ocular SeC and 6/13 cutaneous SeC. No extraocular tumors were negative. No loss was found in sebaceous adenoma or sebaceous hyperplasia. In nine previously sequenced ocular SeCs, two lacked detectable somatic mutations in ZNF750, but showed complete loss of staining, indicating non-mutational inactivation of ZNF750., Conclusion: We show complete loss of the ZNF750 epidermal differentiation regulator in about half of ocular SeC, highlighting the most common genetic defect in this cancer type. Loss of ZNF750 expression is seen even in tumors without truncating mutations and reduced in many of the remaining ocular and cutaneous SeC. In contrast, no ZNF750 loss was detected in benign sebaceous proliferations., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.

Microcystic adnexal carcinoma (MAC) is a rare malignancy of sweat glands that has been reported most often on the face in the form of a cutaneous lesion, with the potential for deeper invasion. The synonyms of MAC include sclerosing sweat duct carcinoma, syringomatous carcinoma, and malignant syringoma. Clinically, MAC in the periocular area has been misdiagnosed as basal cell carcinoma, squamous cell carcinoma, or even chalazia. We report a case of MAC presenting clinically as sebaceous gland carcinoma with pagetoid spread for the first time in literature.

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.

Context: - Basal cell carcinoma (BCC) is the most common human malignant neoplasm and is a frequently encountered diagnosis in dermatopathology. Although BCC may be locally destructive, it rarely metastasizes. Many diagnostic entities display morphologic and immunophenotypic overlap with BCC, including nonneoplastic processes, such as follicular induction over dermatofibroma; benign follicular tumors, such as trichoblastoma, trichoepithelioma, or basaloid follicular hamartoma; and malignant tumors, such as sebaceous carcinoma or Merkel cell carcinoma. Thus, misdiagnosis has significant potential to result in overtreatment or undertreatment., Objective: - To review key features distinguishing BCC from histologic mimics, including current evidence regarding immunohistochemical markers useful for that distinction., Data Sources: - Review of pertinent literature on BCC immunohistochemistry and differential diagnosis., Conclusions: - In most cases, BCC can be reliably diagnosed by histopathologic features. Immunohistochemistry may provide useful ancillary data in certain cases. Awareness of potential mimics is critical to avoid misdiagnosis and resulting inappropriate management.

Purpose: Overexpression of the inhibitors of apoptosis proteins have been demonstrated in a variety and of solid tumors including melanomas and nonmelanomas skin cancers. X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of apoptosis which prevents apoptosis by inhibiting caspases 9, 7, and 3. The prognostic value of XIAP in sebaceous gland carcinoma (SGC) remains unexplored., Methods: The immunohistochemical expression of XIAP was evaluated in 29 SGC cases., Results: The cytoplasmic overexpression of XIAP was detected in 62% SGC cases. XIAP expression was found to be significantly associated with advanced age, large tumor size, and with reduced disease-free survival (P = 0.0174). XIAP expression and advance tumor Grade III emerged as significant risk factors on univariate analysis. On stepwise multivariate analysis, both increased cytoplasmic XIAP expression and high tumor grade were found to be significantly associated with recurrence. Patients with low XIAP immunoexpression had a longer disease-specific survival than those with high expression in the 5-year follow-up., Conclusion: The present study demonstrates at the immunohistochemical level that XIAP is overexpressed in SGC and that high expression could be of biological significance in the development of eyelid SGC. Our finding suggests that up-regulation of XIAP may aggravate tumor metastasis in SGC.

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.

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.)

Although the histogenesis of sebaceous carcinomas remains unclear, the occurrence of intraepidermal or intraepithelial sebaceous carcinoma in the epidermis or conjunctiva may suggest de novo histogenesis. This report describes a case of sebaceous carcinoma within preexisting rippled/carcinoid pattern sebaceoma. This lesion was composed of two (benign and malignant) components, and the benign component of the lesion showed the typical features of a rippled/carcinoid pattern sebaceoma. Although evidence of trauma as well as a vertical orientation was seen in this lesion, the malignant component of the lesion showed histopathological evidence of malignancy (sebaceous carcinoma), such as the aggregations with irregular and infiltrated borders, a sheet-like growth pattern, and the cytopathological findings of the neoplastic cells, showing a high-grade of malignancy (a high mitotic index and abnormal mitotic figures). The immunohistochemical staining for p53, Ki-67 and D2-40 also favored this diagnosis. This sebaceous carcinoma component was considered to be the incipient stage of carcinoma within preexisting sebaceoma, therefore, it was still considered to be a vertically oriented lesion. This case shows the possibility that abnormal (malignant) sebaceous germinative cells may originate within a sebaceoma, thereby suggesting that some sebaceous carcinomas may develop from preexisting sebaceomas., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To identify crucial molecular alterations of receptor tyrosine kinases that can be used as potential therapeutic targets for eyelid sebaceous gland carcinoma (SbGC)., Methods: The expression levels of HER2, EGFR, C-MET, and FGFR1 were determined by immunohistochemistry (IHC). The copy numbers of the HER2, EGFR, C-MET, and FGFR1 genes were assessed by fluorescence in situ hybridization. The IHC and molecular results were correlated with the clinical parameters., Results: A total of 49 patients with eyelid SbGC were included in this study. HER2, EGFR, C-MET, and FGFR1 protein expression was detected in 8 of 44 (16.3 %), 8 of 45 (17.8 %), 3 of 35 (8.6 %), and 0 of 45 patient samples, respectively. Increased copy numbers of the HER2 gene were found in 5 of 42 patient samples (11.9 %), including two with amplification (4.7 %) and three with polysomy (7.2 %). EGFR amplification was found in 2 of 33 (6.1 %) and FGFR1 amplification in 4 of 33 patient samples (12.1 %; high-level amplification in one and low-level amplification in three). None of the samples examined exhibited C-MET amplification. Gene copy number of the HER2 gene was correlated with its protein expression (p < 0.0001), whereas copy number of EGFR, C-MET, or FGFR1 was not correlated with protein expression. However, samples with EGFR amplification also exhibited a high level of expression of this protein., Conclusions: Extra copies of the HER2, EGFR, and FGFR1 genes were identified in a 6-12 % of eyelid SbGCs. A high level of concordant HER2 expression detected by immunohistochemistry can be predictive of a copy number gain of the HER2 gene. Our data suggest that the therapeutic targeting of HER2 might benefit for a subset of patients with periocular SbGCs.

Background: Sebaceous cell carcinoma of the eyelid is a malignant tumor. However, the pathoetiology of sebaceous cell carcinoma is not clear. Retinoic acid (RA) signaling is essential for skin epidermal differentiation including the eyelids. In this study, we investigate the expression of β-catenin, RA-binding proteins and RA receptors in sebaceous cell carcinoma of the eyelid and try to estimate their influence on its pathoetiology., Methods: Retrospective, noncomparative, consecutive interventional case series. Sixteen cases of eyelid sebaceous gland carcinoma who received tumor excision at our hospital between 2001 and 2011 were included. Immunohistochemical staining for β-catenin, cellular retinoic acid binding protein 1 (CRABP1), cellular retinoic acid binding protein 2 (CRABP2), fatty acid-binding protein 5 (FABP5), retinoic acid receptors (RAR-α, -β, -γ), and retinoid X receptors (RXR-α, -β, -γ) was performed on tissue samples obtained from tumor excision., Results: Of the 16 sebaceous cell carcinoma cases reviewed, six were male and 10 female. The mean follow-up period was 6.7 ± 3.66 years (range, 0.3-13 years). Of these 16 cases, the expression of β-catenin was significantly increased in sebaceous cell carcinoma cases. CRABP1 was similarly expressed in the sebaceous cell carcinoma and control groups. CRABP2 and FABP5 were expressed in hair follicles of lid skin in both groups, whereas the CRABP2 and FABP5 were aberrantly expressed in the tumor cells of the sebaceous glands. Notably, the expression of retinoic acid receptor (RAR-β) and retinoid X receptors (RXR-β, -γ) was significantly upregulated in sebaceous cell carcinoma of the eyelids., Conclusions: Our findings indicate that retinoic acid signaling is related to the pathogenesis of sebaceous cell carcinoma of the eyelids.

Epithelial-mesenchymal transition (EMT) plays a pivotal role in tumor invasion and metastasis in various malignancies. ZEB2/SIP1 is an important EMT regulator and down-regulates E-cadherin expression. The present study was planned to explore status of EMT-associated markers ZEB2/SIP1 and E-cadherin in eyelid sebaceous gland carcinoma (SGC) and to correlate with clinicopathological high-risk features. Expressions of ZEB2 and E-cadherin were evaluated by immunohistochemistry in 65 cases of histopathologically proven eyelid SGC. The results were correlated with clinicopathological high-risk features and survival of the patients to determine the prognostic significance of ZEB2, E-cadherin, and various high-risk features. Cytoplasmic overexpression of ZEB2 and membranous loss of E-cadherin were seen in 68% and 66% of cases of eyelid SGC, respectively. ZEB2 overexpression was significantly associated with E-cadherin loss (P = .002). Overexpression of ZEB2 also showed significant association with lymph node metastasis (P = .046), orbital invasion (P = .049), large tumor size (P = .018), and advanced tumor stages (P = .036). Survival analysis revealed that patients with ZEB2 overexpression had poor survival. ZEB2 overexpression and orbital invasion were found to be independent prognostic indicators (univariate analysis). However, multivariate analysis showed that ZEB2 (hazard ratio, 0.094; 95% confidence interval, 00.012-0.709; P = .022) was the best poor prognostic indicator of eyelid SGC. Our study demonstrates the role of both ZEB2 and E-cadherin in the promotion of EMT in eyelid SGC. The outcome of this study also points toward ZEB2 as an independent prognostic marker as well as a potential therapeutic target in eyelid SGC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background/aims: Sebaceous adenomas (SAs) are rare, benign sebaceous gland tumours of the eyelid. SAs may be associated with primary internal malignancies. This association is known as Muir-Torre Syndrome (MTS). The purpose of this study was to approximate the prevalence of SAs, to determine the reliability of the clinical diagnosis of SAs and to demonstrate immunohistochemical staining of DNA mismatch repair proteins mutL homologue 1 (MLH1) and mutS homologue 2 (MSH2) for a case of MTS., Methods: We reviewed the histopathology reports from all eyelid specimens collected between 1993 and 2013 at the Henry C Witelson Ocular Pathology Laboratory to determine the proportion of SAs. For the SAs identified on histopathology, we looked at patient charts to see what diagnosis was originally suspected on clinical examination. Immunohistochemical staining for MLH1 and MSH2 was performed on all SAs to screen for MTS., Results: Of the 5884 eyelid specimens collected, 9 were SAs (6 women, 3 men; 42-72 years old). The diagnosis of SA was suspected clinically in only one of the nine cases based on the gross appearance of the eyelid lesion. Immunohistochemistry revealed one SA case with positive MLH1 expression and negative MSH2 expression. These findings prompted systemic work-up and this patient was diagnosed with MTS after discovery of a colon adenocarcinoma T2M0N0., Conclusions: The diagnosis of eyelid SA is rare. The importance of this benign eyelid tumour stems from its association with internal malignancies in MTS. Immunohistochemical staining of mismatch repair proteins MLH1 and MSH2 is a valid and accessible strategy for investigating MTS in patients with SAs., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Sebaceous carcinomas (SBCs) are aggressive tumors with the potential to cause great morbidity and mortality. Poorly-differentiated tumors may at times pose challenges for the correct diagnosis. p40, a new antibody that targets a short isoform of p63 has been shown as a promising squamous cell marker. In this study, we sought to evaluate cytomorphological features of SBC and p40 expression analysis., Methods: A total of 29 previously diagnosed cases of SBCs including fine-needle aspirates and histopathology specimens from various sites were reviewed and studied for p40 expression. p40 nuclear expression was semi-quantitatively assessed. Adequate positive and negative controls of non-small cell lung carcinoma were taken for comparison. Expression pattern of normal sebaceous glands was also analyzed., Results: Of the 29 cases, 13 (44.8%) were from the periocular region. The most common extraocular site was parotid gland. Morphologically tumors were categorized into well- and poorly-differentiated varieties based on extent of sebaceous differentiation. p40 positivity was seen in all cases of cytology aspirates and histology sections with similar intensity. No difference in percentage positivity of cells was recorded in well- and poorly-differentiated tumors., Conclusion: p40 can be a valuable marker when evaluating tumors with possible sebaceous differentiation. Although p40 expression in SBCs is not as useful for the differential diagnosis that includes poorly-differentiated squamous cell carcinoma, this study, for the first time in the literature, highlights an important observation that p40 can be utilized as a marker for sebaceous lineage., (© 2015 Wiley Periodicals, Inc.)

Purpose: To investigate the expression of cancer stem cell (CSC) marker proteins in eyelid sebaceous gland carcinoma and evaluate the clinical significance., Methods: Archival tissue blocks from 50 cases of eyelid sebaceous gland carcinoma were tested via immunohistochemistry for 16 putative CSC markers. Levels of protein expression were analyzed alongside various clinicopathologic parameters such as metastasis-free survival time., Results: Ten patients (20%) showed nodal or distant metastasis during the follow-up period (median, 35.2 months; range, 1-128 months) without any mortality in our series. Among the 16 markers, ALDH1, CD44, CD133, ABCG2, Sox4, Sox9, and slug were selected for candidates of CSC markers because they were frequently and predominantly found in the tumor cells compared with control tarsus cells, which showed negative or very low expression. Univariate analysis revealed that ALDH1, CD133, and ABCG2 were significantly associated with metastasis; patients with ALDH1- or CD133-positive tumors developed metastasis more frequently than patients with tumors that were negative for these markers (log-rank test, P = 0.014, P = 0.013, respectively), and diffuse expression of ABCG2 was associated with significantly shorter metastasis-free survival (log-rank test, P = 0.010). Multivariate Cox proportional hazard model revealed that ALDH1 (hazard ratio [HR] = 5.682, P = 0.038) was significantly associated with metastasis., Conclusions: Development of metastasis in eyelid sebaceous gland carcinoma might be attributed to increased number of CSCs or acquisition of dedifferentiated phenotype. Our findings suggest that CSCs are involved in the disease progression of eyelid sebaceous gland carcinoma, and in particular, expression of ALDH1 is a predictor of a poor outcome., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: The study aimed at evaluating the expression of androgen receptor (AR) and nuclear survivin (NS) in periocular sebaceous gland carcinoma (SGC) and to determine whether this expression is associated with histopathological features, markers of apoptosis and proliferation and with clinical outcomes., Methods: This was a retrospective, comparative case series which included 56 patients with a biopsy-proven periocular SGC. Immunohistochemical staining for AR, survivin, p53 and Ki-67 was analysed in all cases., Results: All patients expressed AR, p53 and Ki-67 in the nucleus of tumour cells. Twenty-four patients (42.8%) had a high AR score, and 32 patients (57.2%) had a low AR score. Twenty-four (42.8%) patients expressed survivin in the nucleus of tumour cells. Nine (37.5%) had a high NS score, and 15 (62.5%) had a low NS score. Patients with a high AR score had a greater recurrence (p < 0.005), higher expression of Ki-67 (p < 0.0001) and a lower p53 expression (p < 0.005). Nuclear expression of survivin correlated with a high Ki-67 labelling index (0.0001) and low p53 expression (<0.005). Neither nuclear expression of survivin nor the NS score correlated with any clinicopathological features., Conclusion: Expression of AR significantly impacts prognosis and is thus promising prognostic marker in periocular SGC., (© 2014 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To assess the role of androgen receptor detection in diagnosing eyelid sebaceous carcinomas and to compare it with that of adipophilin., Design: Retrospective, clinicopathologic study., Methods: Ten sebaceous carcinomas (8 invasive, 2 intraepithelial only) were stained immunohistochemically for androgen receptors and were compared with adipophilin staining. Receptor staining also was performed on benign sebaceous tumors (a sebaceoma and an adenoma) and as controls on eyelid basal cell carcinomas, eyelid squamous cell carcinomas, conjunctival squamous dysplasias, and conjunctival melanomas., Results: All 8 patients with an invasive component of sebaceous carcinoma underwent a biopsy in which the tumor cells showed diffusely positive results for androgen receptors (>20% of cells and usually >40%) and positive results for adipophilin. Eight cases displaying an intraepithelial (or pagetoid) component of spread also showed diffusely positive results for androgen receptors and adipophilin in at least 1 of multiple biopsy samples from each patient. However, in 8 of 21 separate conjunctival biopsy specimens with intraepithelial cytologic atypia, adipophilin results were negative. A sebaceoma and a sebaceous adenoma also showed positive results for both of these biomarkers. Among the controls, squamous carcinomas and melanomas showed negative results for androgen receptors and adipophilin. Basal cell carcinomas displayed focal receptor positivity in fewer than 5% of cells and showed negative results for adipophilin., Conclusions: Androgen receptors and adipophilin can separate sebaceous tumors immunohistochemically from squamous carcinomas and melanomas, which showed negative results for both, and from basal cell carcinomas, which showed positive receptor results in a distant minority of cells. Regarding intraepithelial (or pagetoid) spread, androgen receptor detection was more sensitive and reliable than adipophilin in highlighting this component of the disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To characterize mismatch repair protein expression and the role of DNA repair abnormalities in sebaceous carcinomas of the ocular adnexa., Design: Retrospective case-series study., Methods: We reviewed 10 cases of sporadic sebaceous carcinoma and 1 case involving a patient with a family history consistent with Muir-Torre syndrome. Immunohistochemistry was used to analyze the presence of 4 mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) in these tumors. DNA was extracted from 7 of the larger tumors as well as from adjacent normal control tissue and microsatellite instability (MSI) analysis using 5 highly sensitive mononucleotides and 2 pentanucleotides was performed., Results: All 10 sporadic periocular sebaceous carcinomas maintained strong staining of the 4 mismatch repair genes, while tumor from the patient with Muir-Torre syndrome showed loss of staining for the mismatch repair genes MSH2 and MSH6. MSI testing of 7 tumors identified no changes in sporadic cases and yielded results supporting presence of repeat sequence instability in the Muir-Torre-associated case., Conclusions: Sporadic sebaceous carcinoma of the ocular adnexa is not commonly associated with a loss of mismatch repair genes or microsatellite instability., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the fine cytopathologic features and immunohistochemistry of eyelid sebaceous carcinoma., Design: Retrospective clinicopathologic study., Methods: Clinical records and microscopic glass slides of 12 patients diagnosed with sebaceous carcinoma were reviewed. Paraffin-embedded tissue recuts were immunoreacted for epithelial membrane antigen (EMA), Ber-EP4, p53, Ki-67, and adipophilin for cytoplasmic lipid. Invasive growth and intraepithelial spread were analyzed separately. Cytoplasmic and nuclear characteristics were correlated with the results of the immunohistochemical profiling., Results: Five patients experienced recurrences, but no metastases or tumor-related deaths were discovered. The nuclei in 11 invasive tumor cells were typically round with finely divided, granular, or smudgy chromatin without prominent margination at the nuclear membrane; they exhibited small punctate nucleoli. Positivity for EMA (both diffuse and focal), p53 (72% of nuclei), and Ki-67 (45% proliferation index) was demonstrated. Adipophilin positivity in vesicular and granular forms was detected in paraffin sections in all invasive tumors, most prominently in moderately differentiated and well-differentiated lesions. Among 9 cases exhibiting intraepithelial extensions, 6 showed mostly granular positivity and 3 vesicular positivity. p53 identified residual atypical intraepithelial cells when conjunctival epithelial sloughing occurred., Conclusions: Immunohistochemistry can make significant contributions to the diagnosis of sebaceous carcinoma. p53 and vesicular granular adipophilin positivity were highly reliable in supplementing the routine microscopic diagnosis of infiltrative tumors and both can be used in paraffin sections, thereby obviating cumbersome oil red O staining of frozen sections. The cells found in intraepithelial spread were strongly EMA and p53 positive, with more granular than vesicular adipophilin positivity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Although adipophilin has been reported to be a sensitive marker for sebaceous carcinoma, others have noted its expression in squamous cell carcinoma and a variety of noncutaneous tumors, suggesting that lipid droplet accumulation is a frequent feature of neoplastic cells. We investigated the expression of adipophilin and perilipin in 101 cutaneous carcinomas. They included 30 cases of sebaceous carcinoma, 28 squamous cell carcinoma with clear cell change (18 invasive and 10 in situ tumors), 8 hidradenocarcinomas, 1 spiradenocarcinoma, 10 porocarcinomas, 4 malignant chondroid syringomas, 1 malignant cylindroma, 7 apocrine carcinomas, 6 eccrine carcinomas, 5 aggressive digital papillary adenocarcinomas, and 1 pilomatrical carcinoma. Adipophilin stained the rim of cytoplasmic lipid droplets in various tumor types, including sebaceous carcinomas (30/30, 100%), squamous cell carcinoma with clear cell change (21/28, 75%), and eccrine-apocrine carcinomas (25/43, 58%). On the other hand, perilipin expression was seen in 13 (43%) of 30 sebaceous carcinoma and only 1 hidradenocarcinoma. The remaining 28 squamous cell carcinomas with clear cell change and 42 eccrine-apocrine carcinomas were negative. Although specific for invasive sebaceous carcinoma, perilipin expression was not helpful in distinguishing sebaceous carcinoma in situ from squamous cell carcinoma in situ with clear cell change. The expression of adipophilin seen in variety of cutaneous tumors suggests that the biosynthesis of lipid is altered in these neoplasms., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Sebaceous carcinoma represents a rare and potentially fatal adnexal malignancy. Poorly-differentiated sebaceous carcinoma consisting of infiltrative basaloid tumor cells with inapparent lipid vesicles can mimic basal cell carcinoma (BCC). Conversely, other epithelial tumors can exhibit clear cell histopathology and mimic sebaceous carcinoma. At the present time, immunohistochemical markers unique for sebaceous carcinoma are limited., Methods: We evaluated the expression of three lipid synthesis/processing protein markers alpha/beta hydrolase domain-containing protein 5 (ABHD5), progesterone receptor membrane component-1 (PGRMC1) and squalene synthase (SQS) in sebaceous carcinoma and investigated their utility in differentiating sebaceous tumors from BCC with clear cell features. Immunohistochemistry was performed on 23 sebaceous carcinomas, 14 sebaceomas and 14 BCCs with clear cell features., Results: In sebaceous carcinomas, ABHD5 showed dispersed, cytoplasmic punctate and/or vesicular staining (n = 19/23, 83%), while PGRMC1 and SQS each showed vesicular and membranous staining in tumor cells (n = 22/23, 96%). In all sebaceomas, these markers highlighted tightly clustered lipid vesicles in sebocytes. All BCCs with clear cell features were negative for these three markers., Conclusion: ABHD5, PGRMC1 and SQS are novel markers for sebaceous carcinoma and can reliably distinguish sebaceous neoplasms from non-sebaceous tumors, specifically BCC with clear cell features., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Activation or dysregulation of the Sonic hedgehog (Shh) and Wnt signaling pathways is suggested to lead to the development of many human malignancies. In this study, we investigated Shh and Wnt signaling protein expression in eyelid sebaceous gland carcinoma, and analyzed their correlation with clinical characteristics of the tumor., Methods: Patients who underwent surgical resection of eyelid sebaceous gland carcinoma from 1999 to 2011 were recruited for the study. Immunohistochemical stainings of Shh signaling proteins (Shh, Gli-1, Gli-2, Gli-3, and ABCG2) and Wnt signaling proteins (Wnt, glycogen synthase kinase 3β, β-catenin, lipoprotein receptor-related protein [LRP], and c-Myc) were conducted., Results: Thirty-seven cases of eyelid sebaceous gland carcinoma were included in this study. Twenty-nine patients showed no metastasis, and eight patients showed lymph node or distant metastasis. Shh, ABCG2, and Wnt proteins were more highly expressed in the group with metastasis than in the group without metastasis (P = 0.031, P = 0.015, and P = 0.001, respectively; χ(2) test). Patients showing high ABCG2 expression, Wnt, or LRP expression developed metastasis more commonly than those with low ABCG2, or without Wnt or LRP expression (log rank test, P = 0.019, 0.001, and 0.000, respectively)., Conclusions: The group with metastasis showed higher expression levels of Shh, ABCG2, and Wnt than did the group without metastasis, and patients with strong ABCG2 expression, Wnt, or LRP expression showed higher cumulative incidence of lymph node or distant metastasis, implying that activation of the Shh and Wnt signaling pathway is associated with aggressive behavior of the tumor.

Sebaceous neoplasms are commonly considered in their relationship to the Muir-Torre syndrome and the now well-documented loss of DNA mismatch repair proteins leading to microsatellite instability. However, sebaceous neoplasms showing microsatellite instability comprise only a subset of this group of tumors, and thus, alternative tumorigenic mechanisms must exist. This article explores the relationship of p53, a tumor suppressor implicated in other cutaneous malignancies, and sebaceous neoplasia. We examined 94 sebaceous tumors from 92 patients. Tumors with strong nuclear p53 staining were significantly associated with the diagnosis of sebaceous carcinoma compared with benign sebaceous lesions, most notably for periocular carcinomas. Importantly, nuclear mismatch repair protein expression was intact in all lesions showing p53 alterations, suggesting that p53 dysfunction may represent a divergent pathway in the molecular pathogenesis of these tumors.

Background: Since the E-cadherin-catenin complex is of importance in the cancerogenesis of epithelial tumors, we examined the expression of E-cadherin and β-catenin in sebaceous adenocarcinomas of the eyelid and correlated the results with clinicopathological parameters., Methods: The study included histological specimen of 32 patients with sebaceous adenocarcinomas of the eyelid. The expression of E-cadherin, β-catenin, and Ki-67 nuclear antigen was analyzed by immunohistochemistry., Results: The membranous expression of E-cadherin and of β-catenin was reduced in 17 (53%) patients and 18 (56%) patients, respectively, while elevated cytoplasmic levels and a nuclear accumulation of β-catenin were found in 27 (84%) and six (19%) patients, respectively. The low expression of membranous β-catenin was associated with a high degree of tumor infiltration (p = 0.02), high amount of inflammation (p = 0.01), and high degree of poor tumor differentiation (p < 0.001). In a similar manner, a low membranous E-cadherin expression in tumors was significantly associated with poor tumor differentiation (p = 0.001) and high tumor cell proliferation rate (p = 0.004). The Ki-67 proliferation index was significantly higher in the group with low membranous E-cadherin expression than in the group with high membranous E-cadherin expression (62.3 ± 20.8 versus 42.1 ± 15.3; p = 0.004). The membranous E-cadherin expression and the membranous β-catenin expression were significantly associated with each other (Fisher's exact probability test, p = 0.03)., Conclusions: Sebaceous eyelid adenocarcinomas showed a decrease in the membranous expression of E-cadherin and of β-catenin. These changes were associated with poor tumor differentiation and an increase in the tumor infiltration and inflammation, pointing at a potential role of a low E-cadherin and low β-catenin expression for poor prognosis of sebaceous eyelid adenocarcinomas. Correspondingly, the cell proliferation index and the expression of E-cadherin were inversely correlated with each other. The findings suggest that the immunohistochemical detection of a low E-cadherin and low β-catenin expression may help in the examination and staging of sebaceous eyelid adenocarcinomas.

Background: No previous reports on the variation in the histopathological patterns of well-differentiated sebaceous carcinoma are yet to be published., Methods: We reviewed the histopathology of six examples of well-differentiated extraocular sebaceous carcinoma., Results: Two distinct histopathological patterns of sebaceous carcinoma, namely a secretory pattern (N = 2) and a non-secretory pattern (N = 4), were defined. The secretory pattern is typified by sebaceous lobular architecture with focal holocrine secretion, whereas the non-secretory pattern lacks this organoid quality. Both carcinomas with the secretory pattern showed low-grade cytological atypia, whereas the four carcinomas with the non-secretory pattern included three lesions with high-grade cytological atypia. A sebaceous adenoma-like area was seen in both secretory pattern carcinomas, whereas a focus of intraepithelial sebaceous carcinoma (sebaceous carcinoma in situ) was seen in two of the non-secretory pattern carcinomas., Conclusions: The clinicopathological significance of the two histopathological patterns remains unclear, because the number of reported cases is limited. It is possible that these two histopathological patterns of carcinoma have different histogenetic and prognostic implications, but no definitive conclusions can be made until further studies of a larger number of cases can be completed., (Copyright © 2011 John Wiley & Sons A/S.)

This study examined immunohistochemical findings of sebaceous carcinoma and sebaceoma. An immunohistochemical study using 13 anti-cytokeratin (CK) antibodies (anti-CK1, 5-8, 10 and 14-20) and 35 cases of sebaceous carcinoma (16 cases on ocular and 19 cases on extraocular regions) and 10 cases of sebaceoma (no cases arose on the eyelids) was performed. Overall, those in ocular lesions were almost the same as those for extraocular lesions in sebaceous carcinoma other than CK8. The findings in sebaceous carcinoma were almost equal to those of sebaceoma. Over 75% of cases with sebaceous carcinoma were positive with anti-CK5 and anti-CK14 antibodies and negative with anti-CK1, CK10, CK15, CK17, CK18 and CK20 antibodies. Most cases (50-75%) of those were positive with CK7 and negative with CK6, CK16, CK19 and CK8. The sensitivity and specificity of immunohistochemical detection of sebaceous carcinoma using the panel of anti-cytokeratin antibodies were lower than those of other antibodies. Immunohistochemical detection of cytokeratins in diagnosing sebaceous carcinoma should be considered to be ancillary to conventional microscopic findings and those of other antibodies., (© 2011 Japanese Dermatological Association.)

The rates of distant metastases and tumor death in sebaceous carcinoma (SC) have been reported to be higher than those of other cutaneous carcinomas, such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), regardless of whether they occur in ocular or extraocular regions. Therefore, strict differentiation of SC from SCC and BCC is required. In this article, we report immunohistochemical findings of SC and compare these data to those of SCC, BCC, and sebaceoma. An immunohistochemical study was performed using 7 antibodies [anti-carcinoembryonic antigen (CEA), anti-epithelial membrane antigen (EMA), anti-CA15-3, anti-CA19-9, anti-androgen receptor (AR), anti-epithelial antigen (Ber-EP4), and anti-adipophilin (ADP)] on 35 cases of SC (16 cases in ocular and 19 cases in extraocular regions) and 10 cases of each SCC (5 cases in ocular and 5 cases in extraocular regions), BCC (5 cases in ocular and 5 cases in extraocular regions), and sebaceoma (no cases arose on the eyelids). In summary, the typical immunophenotypes of SC were EMA+, CA15-3+, AR+, Ber-EP4-, and ADP+; those of sebaceoma were CEA-, EMA+, Ber-EP4-, and ADP+; those of SCC were CEA-, EMA+, CA19-9-, AR-, Ber-EP4-, and ADP-; and those of BCC were CEA-, EMA-, CA15-3-, Ber-EP4+, and ADP-. Other antibody tests for each neoplasm were positive in about half of the cases. The detection of AR and ADP was useful for differentiating SC from SCC, whereas the determination of EMA, CA15-3, Ber-EP4, and ADP was valuable in differentiating SC from BCC.

Mismatch repair protein immunohistochemistry is a widely used method for detecting patients at risk for Lynch syndrome. Recent data suggest that a two-antibody panel approach using PMS2 and MSH6 is an effective screening protocol for colorectal carcinoma, but there are limited data concerning this approach for extraintestinal tumors. The purpose of this study was to review the utility of a two-antibody panel approach in colorectal carcinoma and extraintestinal tumors. We evaluated mismatch repair protein expression in two cohorts: (1) a retrospective analysis of intestinal and extraintestinal tumors (n=334) tested for mismatch repair protein immunohistochemistry and (2) a prospectively accrued series of intestinal, gynecologic tract, and skin sebaceous neoplasms (n=98). A total of 432 cases were analyzed, including 323 colorectal, 50 gynecologic tract, 49 skin sebaceous, and 10 other neoplasms. Overall, 102/432 tumors (24%) demonstrated loss of at least one mismatch repair protein. Concurrent loss of MLH1 and PMS2 was the most common pattern of abnormal expression (50/432, 12%) followed by concurrent loss of MSH2 and MSH6 (33/432, 8%). Of 55 cases with abnormal PMS2 expression, 5 (9%) demonstrated isolated loss of PMS2 expression. Of 47 cases with abnormal MSH6 expression, 14 (30%) demonstrated isolated loss of MSH6 expression. Isolated loss of MLH1 or MSH2 was not observed. Colorectal carcinomas more frequently demonstrated abnormal expression of PMS2 (39/59, 66%). Skin sebaceous neoplasms more frequently demonstrated abnormal expression of MSH6 (18/24, 75%, respectively). A total of 65 tumors with abnormal mismatch repair protein expression were tested for microsatellite instability (MSI): 47 (72%) MSI high, 9 (14%) MSI low, and 9 (14%) microsatellite stable (MSS). Abnormal MSH6 expression accounted for 14/18 (78%) cases that were MSS or MSI low. Our findings confirm the utility of a two-antibody approach using PMS2 and MSH6 in colorectal carcinoma and indicate that this approach is effective in extraintestinal neoplasms associated with Lynch syndrome.

Sebaceous carcinoma is the rarest type of oral malignancies. We report a case of primary sebaceous carcinoma of the tongue. Systemic imaging studies revealed that the patient had a T2N2cM0 (International Union Against Cancer guidelines) primary lingual tumor. Histopathological examination revealed neoplastic sebocytic and basaloid cells, and Sudan III staining and electron microscopy revealed intracytoplasmic lipid droplets. The neoplastic cells stained positive for adipophilin; epithelial membrane antigen; epithelial antigen; and cytokeratins 7, 8, and 15, but negative for cytokeratins 5/6, 18, 19, and 20; the androgen receptor; and carcinoembryonic antigen. Superselective intraarterial chemotherapy was administered via the superficial temporal artery concurrent with daily radiotherapy. Multiple biopsies confirmed a complete response of the primary lesion. The patient then underwent neck dissection followed by pathological examination, which revealed lymph nodes metastases. After postoperative radiotherapy to the neck, distant metastases were identified in the mediastinal lymph nodes and the lung. The patient died 17 months after completing the initial course of chemoradiotherapy. Our case demonstrates that superselective intraarterial chemotherapy combined with concurrent radiotherapy can be effective in treating the primary lesion of patients with a sebaceous carcinoma of the tongue. However, an effective strategy to eradicate metastases has yet to be established.