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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.)

Ocular sebaceous carcinoma is an uncommon, aggressive tumor arising from the Meibomian gland, Zeis gland, or sebaceous glands in the caruncle or eyelashes. We described a rare case of sebaceous carcinoma in situ in a 51-year-old female that was characterized by intraepithelial growth of sebaceous carcinoma cells with no invasive carcinoma in the underlying sebaceous glands. Early stromal invasion was identified that featured 2 distinctive but focally intermixed populations of sebaceous carcinoma cells and squamous carcinoma cells. The 2 populations of cells exhibited their respective distinct immunophenotype but both showed strong overexpression of p53. This case provides evidence to support the hypothesis that some ocular sebaceous carcinoma may arise from intraepithelial pluripotent stem cells.

Sebaceous carcinoma is a rare cutaneous malignancy that frequently mimics other dermatologic conditions. Extraocular subtypes are uncommon, but when present are frequently located in the head and neck region. Herein, we present a patient with a rapidly growing upper back mass eventually diagnosed as sebaceous carcinoma and managed with wide surgical excision. Currently, sparse literature exists to guide management of such patients. This case highlights not only the diagnostic challenges of sebaceous carcinoma, but also the need for further studies to investigate therapeutic interventions and long-term outcomes.

Muir-Torre syndrome (MTS) is a rare autosomal dominant condition characterized by the presence of at least one cutaneous sebaceous tumor and one visceral malignancy, arising mostly from the gastrointestinal tract. We present the case of a 63-year-old man with several cutaneous and visceral neoplasias in the context of MTS, and a pelvic lymph node lesion diagnosed initially as metastatic sebaceous carcinoma, but later identified as metastasis from a newly diagnosed prostatic adenocarcinoma. Histological similarities between these 2 lesions are discussed. A systematic literature review was conducted evaluating all published cases of patients with MTS in which metastases were reported. Eighteen articles were included in the final synthesis, representing 20 patients with a total of 26 metastases. Seventeen patients (85%) exhibited metastases originating from MTS-related neoplasms, whereas only 2 patients (11%) exhibited metastases from concomitant malignancies. Of the 85% of patients with metastases from MTS-related malignancies, most originated from noncutaneous sources (78% from visceral neoplasms and 22% from sebaceous carcinomas). When stratifying according to metastases, 23 cases (88%) originated from MTS-related lesions, whereas only 3 (12%) originated from unrelated malignancies. Our findings thus demonstrate that most metastases found in MTS patients (88%) do indeed originate from MTS-related neoplasms. Nevertheless, it remains imperative that a broad differential diagnosis is maintained when assessing a novel lesion, to avoid misdiagnoses, as in the present case, with significant therapeutic and prognostic implications.

BACKGROUND Sebaceous gland carcinoma (SGC) is a rare malignant lesion that occurs on the eyelids. It is known to mimic other benign or malignant lesions in clinical presentation, such as a chalazion, basal cell carcinoma, and squamous cell carcinoma. The histopathological diagnosis is the mainstay for diagnosis and is often challenging. CASE REPORT We describe a case of SGC in a 53-year-old woman who presented with a cauliflower-appearing lesion with pearly telangiectatic vessels and raised margins at the lower eyelid margin. Clinically, we suspected a diagnosis of basal cell carcinoma. Upon complete resection of the lesion, the final diagnosis was SGC based on the histopathological features and immunohistochemical staining characteristics of the tissue. CONCLUSIONS Due to the possibility of SGC presenting similarly to other lesions, it is essential for ophthalmologists to have a high index of suspicion in its diagnosis. The early and accurate diagnosis of such lesions is important for appropriate management to prevent metastasis or recurrence related to advanced tumors.

Cutaneous sebaceous carcinoma occurs almost exclusively on the head and neck and has a significant propensity for recurrence and metastasis. It is easily mistaken for benign conditions, resulting in inappropriate management. Thus, it is important to maintain a high index of suspicion. Despite previous reports, sebaceous carcinoma may occur with similar frequency in Asians and whites. Recent genetic data suggest there are multiple mutational groups of sebaceous carcinoma, paving the way for targeted treatment. After a diagnosis, investigations for staging and for Muir-Torre syndrome should be considered. The available evidence on the treatment options for sebaceous carcinoma is discussed, and specific recommendations for management are made., (© 2020 The Australasian College of Dermatologists.)

Importance: Appropriate use criteria for Muir-Torre syndrome (MTS) screening suggest that mismatch repair protein (MMRP) immunohistochemical (IHC) testing is usually appropriate in patients with 2 or more sebaceous neoplasms (SNs). While MTS is known to be caused by a germline mutation in mismatch repair genes, data are limited as to whether individual sebaceous tumors in these patients with multiple lesions show identical MMRP IHC staining patterns., Objective: To determine concordance of MMRP IHC staining patterns in lesions of patients with MTS who have multiple SNs., Design, Setting, and Participants: This retrospective single-center case series evaluated 38 SNs in 11 patients with MTS confirmed by genetic testing for MMRP IHC staining patterns. Tumor sites were classified as either facial or extrafacial. Data were collected between January 1, 2007, and January 1, 2018., Main Outcomes and Measures: In each patient, MMRP IHC staining patterns for SNs were compared with one another to evaluate intrapatient concordance between lesions, and to the patient's known germline mutation., Results: A total of 11 patients (7 women and 4 men) with MTS, with a mean (SD) age of 59.3 (10.6) years at time of SN biopsy, were identified. There was high concordance between MMRP IHC staining results (2-4 lesions per patient) and the patient's mutation status, with 36 of 38 total lesions (95%) matching (sensitivity, 94.7%; 95% CI, 82.3%-99.4%). Extrafacial site tumors represented 16 of 38 total lesions (42%) and demonstrated 100% concordance of IHC results to germline mutation. Only 1 of 11 patients (9%) demonstrated discordant results, with both lesions in this patient occurring on a facial site., Conclusions and Relevance: In patients with known MTS, SNs present with highly concordant MMRP IHC staining profiles across multiple lesions. There is also a strong association with underlying germline mutations. A diagnosis of MTS might be supported by MMRP IHC when the pretest probability is high.

Cutaneous sebaceous neoplasms show a predilection for the head and neck area of adults and include tumours with benign behaviour, sebaceous adenoma and sebaceoma, and sebaceous carcinoma with potential for an aggressive disease course at the malignant end of the spectrum. The majority of tumours are solitary and sporadic, but a subset of tumours may be associated with Lynch syndrome, also known as hereditary non-polyposis colon cancer (HNPCC) and previously referred to as Muir-Torre syndrome (now known to be part of Lynch syndrome). This review provides an overview of the clinical and histological features of cutaneous sebaceous neoplasia with an emphasis on differentiating features and differential diagnosis. It also offers insights into the recently described molecular pathways involved in the development of sebaceous tumours and their association with Lynch syndrome., (© 2020 John Wiley & Sons Ltd.)

Background: Extraocular sebaceous carcinoma (EOSC) is an aggressive malignancy of the sebaceous gland. Surgery is considered the cornerstone of treatment, but there is lack of clarity about extent and adjuvant treatment., Methods: We conducted a systematic review and analysis of individual patient data of all published cases of EOSC to look into demography, pattern of care, importance of type of surgery, and other adjuvant treatment and survival outcome. A search of PubMed and Google Scholar was done with the key words sebaceous carcinoma, extraocular sebaceous carcinoma, and Muir-Torre syndrome till December 2017. The data were compiled in an Excel chart and analyzed using SPSS IBM software., Results: Data of 206 patients were retrieved. Median age at presentation was 65 years (range: 11-96 years). Surgery was performed in all except 13 patients. Of these 13, eight were deemed inoperable for extensive disease, and five had metastatic disease. Median PFS and OS for the entire cohort were 84 months (95% CI: 10-158 months) and 92 months (95% CI: 59-126 months). Univariate analysis revealed significantly poor survival for patients with a metastatic disease, regional nodal metastasis, and those with Mohs micrographic or incomplete surgery., Conclusion: EOSC is a disease of elderly patients with good prognosis. Complete surgery with regional lymph node dissection is standard treatment. The role of adjuvant radiotherapy is debatable but can be considered in patients with incomplete surgery or high-risk factors., (© 2019 The International Society of Dermatology.)

Background: The purpose was to describe the Nordic treatment practices and to reach a Nordic consensus for the treatment of sebaceous eyelid carcinoma., Methods: The treatment practices data was collected by a questionnaire with 37 questions to the Nordic oculoplastic surgeons and analyzed. A PubMed MEDLINE database search was done to gather data on the published treatment practices and recommendations. A working group that consisted of in minimum one senior consultant from each leading Nordic University Eye Hospital was assigned. A structured interactive method was used to establish the consensus., Results: Twenty-four doctors responded to the questionnaire. 23/24 (96%) of the respondents took a biopsy before surgery. Regional lymph node scanning was routinely done by 14/23 (61%) and a systemic screening of a metastatic disease by 13/23 (57%). 6/22 (27%) never took conjunctival mapping biopsies and 12/23 (52%) never screened for Muir- Torre. Respondents used Mohs surgery, frozen section or multi-stage excision with delayed closure, and 5-6 mm was the mostly preferred margin. Sentinel lymph node biopsy was a possible option for 9/22 (41%) and cryotherapy and Mitomycin C for 6/22 (27%) respondents. 50% of respondents considered radiation as a treatment option. 15/16 (94%) respondents always followed-up their patients, most for 5 years. Two thirds scanned regional lymph nodes during the follow-up. Consensus was reached for 18 statements representing three domains: preoperative work-up, treatment and follow-up., Conclusion: Treatment practices differ in between the five Nordic countries which have similar public health care systems. In the article the authors present a Nordic consensus for the treatment of eyelid sebaceous carcinoma.

Intraepithelial sebaceous neoplasia in the forms (or subclassification) of pagetoid spread and carcinoma in situ is a common feature of periocular sebaceous carcinoma and is associated with less favourable outcomes. Seminal studies of periocular sebaceous carcinoma in the 1980s indicated that the two patterns of intraepithelial spread had differing influences on prognosis with pagetoid invasion being worse. Later studies reported conflicting results, but careful inspection of those studies revealed considerable variation in what was meant by pagetoid invasion. Different interpretations of pagetoid spread continue, leading to ambiguous results in clinical studies and miscommunication with potential unintended decisions affecting clinical management. This paper reviews the background leading to the frequent interchangeable use of pagetoid spread with in situ sebaceous carcinoma and how this problem confounds interpretation of clinical studies. The author recommends that for effective communication, all morphological patterns of in situ spread of sebaceous carcinoma fall under the term intraepithelial sebaceous neoplasia , which can be accompanied by subclassification whenever desired., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Nevus sebaceus is a benign skin hamartoma of congenital onset that grows during puberty, and in adulthood can develop secondary benign and malignant neoplasms. The most common benign neoplasms occurring in nevus sebaceus are believed to be syringocystadenoma papilliferum, trichilemmoma, and trichoblastoma. A patient with nevus sebaceus developed not only syringocystadenoma papilliferum but also prurigo nodularis within her hamartomatous lesion; multiple biopsies were necessary to establish the diagnoses. Excision of the residual nevus sebaceus also revealed an apocrine cystadenoma, basaloid follicular proliferation, and sebaceoma. Also, it is important to select the appropriate biopsy site and size when evaluating a patient for secondary neoplasms within their nevus sebaceous. Indeed, more than one biopsy may be required if additional diagnoses are suspected.

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.

The purpose of this study is to codify the microscopic diagnostic criteria for ocular adnexal brow and caruncular sebaceous gland hyperplasias (pseudoadenomatoid) that distinguish it from an adenoma. Clinical records and photographs were critically reviewed and microscopic slides were stained with hematoxylin and eosin and immunochemically stained for adipophilin, androgen receptor, p16, p53, a spectrum of cytokeratins, Ki-67 and mismatch repair nuclear protein expression for MLH1, MSH2, PMS2, and MSH6. The patients and their close relatives had no history of cancer. Cytokeratin 7 and especially cytokeratin 17 highlighted the presence of ducts in the hyperplastic lesion, which are not present in adenomas. p16 and p53 were negative and Ki-67 immunostaining demonstrated similar low proliferation indices for normal and hyperplastic glands. The mismatch repair nuclear protein expressions were preserved in both lesions. Histopathologic misdiagnosis of adenomatoid sebaceous gland hyperplasia as an adenoma can lead to the impression of an association with the Muir-Torre syndrome. Cytokeratins 7 and 17 immunostaining can be helpful in highlighting compressed ducts that in exuberant sebaceous gland hyperplasias may lead to a diagnosis of an adenoma (in which ducts are absent). Negative immunostaining for p16 rules out a possible etiologic role of human papillomavirus in hyperplasias and the negative p53 staining indicates the lesions are not truly neoplastic. The preservation of mismatch repair nuclear protein expression rules out the likelihood of the Muir-Torre syndrome. The current cases convincingly establish that sebaceous hyperplasia is not associated with the Muir-Torre syndrome by both clinical findings and immunohistochemical testing.Two yellow lesions, from the brow and caruncle, were examined microscopically and immunohistochemically to establish the diagnosis of sebaceous gland hyperplasia and to rule out the Muir-Torre syndrome.

Objective: The present study aims to detect the presence of human papillomavirus (HPV) in ocular malignant tumours, including retinoblastoma, eyelid squamous cell carcinoma (SCC), and sebaceous gland carcinoma (SGC), in the North Indian population., Design: Prospective observational non randomized study., Participants: In this study, 142 prospective cases of ocular malignant tumours (retinoblastoma, SGC, and SCC) were included., Methods: HPV was detected by multiplex PCR using PGMY09/11 primers in 142 patients with ocular malignancies. This was followed by genotyping using linear array (reverse hybridization)., Results: Of the 142 tumours studied, 72 were retinoblastoma, 30 SGC, and 40 SCC. The HPV genome was detected in 2.8% (4 of 142) of cases by multiplex PCR; all positive cases (4 of 40) were SCC. Genotyping revealed that all positives belonged to the high-risk HPV16 genotype. HPV-positive SCC patients had better disease-free survival. Retinoblastoma and SGC cases were negative for HPV., Conclusions: Low prevalence of HPV in ocular malignancies was observed in this study. The HPV genome was detected only in ocular squamous cell carcinoma cases and these patients were associated with better prognosis. HPV may not have a role in retinoblastoma and SGC in the North Indian population., (Copyright © 2019 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

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.

Myeloid sarcoma (MS) is a rarely encountered extramedullary localized tumor that is composed of immature myeloid cells. We reported an extremely rare case of MS with concurrent bone marrow (BM) involvement that invaded into a preexisting sebaceous lymphadenoma in the parotid gland and neck lymph nodes. Prompted by this case, we also present a literature review of MS invasion into salivary glands. A 62-year-old man was initially diagnosed with carcinoma that arose in a sebaceous lymphadenoma in the parotid gland, through a total parotidectomy with neck dissection. After an extensive histopathological review that included immunohistochemistry, a pathologic diagnosis of MS with infiltration into the sebaceous lymphadenoma with concurrent BM involvement was confirmed. MS is difficult to diagnose accurately; herein, we analyzed the clinical presentations and effectiveness of the various diagnostic methods with a review of the literature. There are 17 cases, including our case, reported in 13 studies. Of the cases in which the salivary glands were affected, 10 involved the parotid gland, six involved the submandibular gland, and one involved both. Isolated invasion of the salivary gland was found in one case of parotid gland invasion and three cases of submandibular gland invasion. In 13 cases, the salivary glands were affected by various other lesions. Although there were no incidences of isolated MS, six patients were diagnosed with secondary MS and eight patients with MS with BM involvement, including this case. The diagnosis of MS is difficult given its rarity, and a high index of suspicion and integrated radiologic and careful histopathologic evaluation are required. Most cases of MS infiltrating the salivary gland might be indicated by the possibility of BM involvement. MS with BM involvement predicts poor prognosis and the need for intensive systemic treatment., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this study., (Copyright © 2019 Sunmi Jo et al.)

A 52-year-old woman was referred to a dermatologist with a changed yellowish lesion on her scalp. Histological features were those of a sebaceous naevus with secondary malignant differentiation into superficial and solid basal cell carcinoma. A sebaceous naevus is a benign, congenital, hamartomatous lesion. In adulthood, secondary neoplasms may develop within them.

Both architectural and cytologic characteristics are used to distinguish benign from malignant sebaceous neoplasms; however, specific cytopathologic features of sebocytes have not been well defined. The authors assessed architectural and cytological features of 63 sebaceous neoplasms [15 sebaceous hyperplasias, 12 sebaceomas, 16 sebaceous adenomas (SA), 14 sebaceous carcinomas (SC), and 6 ocular sebaceous carcinoma (OSC)] to investigate whether cytological grading may facilitate classification of lesions. Among other criteria, nuclear pleomorphism (size, nucleolar appearance, membrane irregularity, crowding, mitoses, and chromatin pattern) was assessed and 3 theoretical nuclear grades established. Immunohistochemistry for CK10, p16, adipophilin and ki67 was performed on 7 cases of each type of tumor. Most sebaceous neoplasms, except OSC, showed a bland architectural silhouette. However, SA, SC, and OSC revealed larger nuclei (≥14 μm in ≥50% of cases), evident to multiple nucleoli, membrane irregularity, coarse to clumped chromatin, and nuclear grade ≥2 (latter in ≥56% of cases); by contrast, sebaceous hyperplasia and sebaceomas showed smaller nuclei (≤10 μm in ≥50% of cases), smooth borders, inconspicuous nucleoli, fine chromatin, and grade 1 nuclei (latter in 100% of cases). In the setting of a well-circumscribed architecture, cytologic features gain importance in the classification of sebaceous neoplasms. Interestingly, cytologic similarities found in SA and SC may indicate a close relationship of both neoplasms.

Muir-Torre syndrome (MTS) is clinically characterized by the occurrence of skin, usually sebaceous, and visceral tumors in the same individual. The most common underlying mechanism is a constitutional defect of the mismatch repair (MMR) genes that cause Lynch syndrome (LS). Herewithin we report on a 76 years-old male patient heterozygous for a pathogenic MSH2 missense substitution who presented with a striking cutaneous phenotype in the absence of typical LS visceral tumors. The patient developed 20 skin tumors, including sebaceous adenomas/carcinomas and keratoacanthomas. Two skin tumors showed immunohistochemical loss of MSH2 and MSH6 expression. There was no apparent family history of neoplasia. Based on the variable involvement of the skin and internal organs, we suggest that the definition of tumor associations that are often observed as variants of inherited tumor syndromes, such as MTS, should be guided by the underlying molecular bases. In addition, the presence of multiple sebaceous tumors, especially if showing MMR deficiency, appears to be a very strong indicator of a constitutional MMR gene defect. The reasons underlying the high phenotypic variability of cutaneous phenotypes associated with constitutional MMR defects are yet to be determined.

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: To determine the practice patterns of ophthalmic plastic surgeons regarding the management of eyelid sebaceous carcinoma (SC)., Methods: An electronic survey was distributed to oculoplastic surgical colleagues in the Asia Pacific region requesting clinical information and treatment approaches to SC., Results: The responses from 192 respondents from the Asia Pacific region was included and analyzed in this study. For initial diagnosis, most surgeons selected incisional biopsy (55%), followed by complete excision (35%). Initial workup was mainly by palpation of lymph nodes, chest X-ray, and computerized tomography scan (CT-scan) of the orbit. Conjunctival map biopsy was done in selected cases. Sentinel lymph node biopsy (SLNB) was done mainly for tumors larger than 10 mm. Management was mainly by surgical excision (5 mm margin) combined with adjuvant therapy in some cases, with radiotherapy being the most common. Margin status was determined most frequently by frozen section as evaluated by the pathologist (57%) followed by Mohs micrographic surgery (18%). Surveillance was based mainly on physical examination alone., Conclusion: The Asia Pacific oculoplastic surgeons prefer incisional biopsy for lesions suspicious of SC prior to definitive surgery. This is in contrast to survey results previously reported in other populations. Frozen section control (done by an oculoplastic surgeon with pathology support) is most commonly used for margin control and conjunctival map biopsies are done only in selected cases. Despite the potential benefits of SLNB, access and expertise in this area is currently lacking in the Asia Pacific region.

Background: It remains controversial if Mohs surgery is superior to surgical excision in treating localized sebaceous carcinoma., Objective: To compare Mohs surgery and surgical excision for treating patients with localized sebaceous carcinoma., Materials and Methods: The US National Cancer Database was used to identify patients with histologically confirmed Stage 0 to 2 sebaceous carcinoma from 2004 to 2014. Clinicopathologic and socioeconomic factors were compared between treatment groups using the chi-square test. Overall survival (OS) was evaluated by log-rank test, multivariable Cox proportional hazard regression, and propensity score-matched analysis. Relative survival analyses compared with age- and sex-matched US population were performed., Results: Of 1,265 patients, 234 received Mohs surgery and 1,031 received surgical excision. Mohs surgery had a higher rate of negative margin (p = .004). On multivariate Cox regression analysis, Mohs surgery was associated with longer OS than surgical excision (HR: 0.703, 95% CI: 0.496-0.995, p = .047). The survival benefit of Mohs surgery persisted on relative survival analysis and propensity score-matched analysis (p = .0385), after matching the 2 groups on patient and disease characteristics., Conclusion: Patients who received Mohs surgery had significantly longer OS when compared with those who received surgical excision. Prospective clinical trials comparing these treatment paradigms are warranted.

The correct identification of pigmented nodular lesions of the scalp is often challenging. Despite the importance of clinical patterns and dermoscopy, important adjuvant tools that are usually helpful, their interpretation sometimes is not clear-cut. Here, the authors discuss a case of sebaceoma mimicking a malignant pigmented neoplasia, with conclusive histopathology., (Copyright © 2019. Published by Elsevier España, S.L.U.)

Purpose: To evaluate prognostic factors and survival of patients with sebaceous carcinoma of the eyelid through a population-based analysis. Methods: A total of 940 patients with primary sebaceous carcinoma of the eyelid were derived from the Surveillance, Epidemiology, and End Results (SEER) database in the United States from 1973 to 2013. Kaplan-Meier univariate analysis and Cox Regression multivariate analysis were performed to examine prognostic factors in overall survival (OS). 5- and 10-year survival rates, median survival, and prognostic variables with statistical significance were measured. Results: Kaplan-Meier analysis showed that OS is 66% and 44% at 5 years and 10 years respectively. Median OS is 9.4 years. Multivariate Cox regression analysis demonstrated that independent prognostic factors for OS are age at diagnosis (HR = 4.61 [95% CI 1.93-11.0], P = 0.001), surgical treatment (HR = 0.196 [95% CI 0.07-0.55], P = 0.002), combined surgical and radiation treatment (HR = 0.227 [95% CI 0.06-0.81], P = 0.023), and greater tumor size at diagnosis (HR = 3.381, [95% CI 1.77-6.45], P < 0.001). Conclusion: We report the largest population study to date to evaluate prognostic factors of patients with sebaceous carcinoma of the eyelid. Multivariate analysis shows that older age, and greater tumor size correlate with decreased overall survival, whereas surgical treatment or combined surgical and radiation treatment correlate with increased overall survival. Interestingly, tumor grade, lymph node involvement, and distant extent of tumor have not demonstrated to be independent prognostic factors for overall survival.

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.

Muir Torre syndrome is an autosomal dominant disorder characterised by germline mutations in mismatch repair genes involved in DNA repair, leading to microsatellite instability and a propensity to tumour formation. We report a case of a 67-year-old gentleman who underwent biopsy of a smooth nodular lesion on the nasal tip, histopathologically consistent with sebaceous adenoma. Immunohistochemistry suggested a loss of MSH6. Subsequent colonoscopy identified a poorly differentiated adenocarcinoma, with loss of staining for MSH6 and a germline mutation identified on genetic analysis. These findings were consistent with a diagnosis of Muir Torre syndrome. Whilst there is controversy in the literature regarding universal screening for Muir Torre syndrome, the early detection of visceral neoplasms is crucial. The authors strongly support screening for Muir Torre syndrome (with patient consent) upon discovery of a cutaneous sebaceous neoplasm, even in the absence of a personal or family history of visceral malignancy., (© 2019 The Australasian College of Dermatologists.)

Background: Sebaceous neoplasms (SN) may appear sporadically in the general population but may also be part of the Muir-Torre variant of Lynch syndrome (MT-LS). There are few studies in southern Europe on the incidence of MT-LS in the population of patients with SN., Aim: To retrospectively review patients with SN and to analyse their clinical features and the incidence of MT-LS., Methods: Patients with SN diagnosed between 1995 and 2015 were enrolled in the study. The diagnosis of MT-LS was made according to established clinical criteria and, whenever possible, was confirmed by germline mutation analysis., Results: In 60 patients (32 men, 28 women, mean age 69.22 years), 96 SN were diagnosed: 65 adenomas (67.7%), 16 sebaceomas (16.7%) and 15 carcinomas (15.6%). Of the 60 patients, 50 (83.3%) had a single SN and 10 (16.7%) had multiple lesions. Patients diagnosed with MT-LS (12 patients, 20%) were younger (63.25 years vs. 70.71 years), and had a higher incidence of extrafacial SN (4/12 patients, 33.3%), and were significantly (P < 0.001) more likely to have multiple SNs (8/12, 75%) and keratoacanthomas (KAs) (6/12, 50%)., Conclusion: Our study confirms that all patients with SN should be investigated, as 20% of our patients were diagnosed with MT-LS. The most specific features of SN associated with MT-LS in our study were the presence of multiple lesions and association with KAs., (© 2018 British Association of Dermatologists.)

The aim of this study was to determine the clinicopathologic characteristics and evaluate the prognostic factors in eyelid malignancies. This was a retrospective, comparative, case series of 70 patients with eyelid malignancies. The mean age at diagnosis was 72.0 years (range 30.5-93.0 years) with 64.3% female. The 2 most common histologic types were basal cell carcinoma (BCC) followed by sebaceous gland carcinoma (SGC). In total, 47.1% of the malignancies were located in the lower eyelid and the majority of tumor (T) category was T1. The authors assessed the disease-specific survival rates of 64 surgical patients using Kaplan Meier curves. Univariate and multivariate analyses identified the predictors associated with disease-specific survival. Of the 64 surgical patients, 4 had regional nodal metastasis (2 SGC, 1 squamous cell carcinoma [SCC], and 1 adenocarcinoma) and distant metastasis at diagnosis was in 3 patients (2 SGC and 1 malignant melanoma [MM]). Six patients died of disease during follow-up. The 5-year disease-specific survival in BCC, SCC, and SGC were 100%, 100%, and 64.8%, respectively. The predictive factors affecting worse disease-specific survival on multivariate models were T4 category (adjusted hazard ratio [aHR] 14.15, P = 0.022) and tumor recurrence (aHR 6.84, P = 0.045). In conclusion, BCC was the most common eyelid malignancy in southern Thailand followed by SGC. In this study, T4 category and tumor recurrence were the most important prognostic factors in eyelid malignancies.

Skin adnexal cancers (SAC) are a heterogeneous group of rare malignancies with histological differentiation towards epithelial adnexa, which lack effective systemic treatments. The aim of this work is to identify any potentially druggable genomic alterations for possible targeted therapies. Cases of primary or recurrent/metastatic (RM) SAC between 2002 and 2014 were identified by searching the institutional cancer registration database. Histological sections of all referral cases were reviewed by a dedicated pathologist to confirm diagnosis. Immunohistochemistry was performed to assess the expression of androgen receptors (AR) and human epidermal growth factor receptor type 2 (HER2). Targeted next-generation sequencing (T-NGS) was performed to identify targetable mutations (panel of 50 genes analyzed by Cancer Hotspot Panel, Ion-Torrent Personal Genome Machine). Mutational analysis of the PTCH1 gene not present in the T-NGS panel was assessed by Sanger sequencing. A total of 45 cases with available histological samples were identified (35 primary, 10 RM). The most frequent histological type was porocarcinoma (n = 12). Globally, 14 cases (31%) were AR+ (6/10 RM, 60%; 8/35 primary, 23%). HER2 was shown as 2+ in eight of 42 (19%) cases (2/9 RM, 22%; 6/33 primary, 18%). DNA was adequate for T-NGS analysis in 25 cases. In the majority of cases (17 cases, 68%) at least one mutation in oncogenes or tumor suppressor genes was found: the most frequent ones involved TP.53 (13 cases, 76% of mutated SAC) and PIK3CA (three cases, 18%). The rate of PTCH1 mutation was 30%. These findings support the use of molecular screening in patients with advanced SAC., (© 2019 Japanese Dermatological Association.)

Background: Sebaceous adenocarcinomas are rare and potentially aggressive tumors, which typically arise in the periocular region. Surgical treatments for eyelid sebaceous adenocarcinomas include Mohs micrographic surgery (MMS) and wide local excision (WLE). The objective of this study was to compare long-term survival outcomes of MMS versus WLE techniques for eyelid sebaceous adenocarcinomas., Methods: A retrospective analysis was performed using data obtained from the Surveillance, Epidemiology, and End Results (SEER) cancer registry database. We analyzed cases diagnosed from 1998 to 2015 within the database. Patients diagnosed with sebaceous adenocarcinoma were identified using ICD codes. Cases were limited to primary sebaceous adenocarcinomas involving specifically the eyelid region. The main outcomes were assessed by Kaplan-Meier (KM) survival and Cox proportional hazards model., Results: Sixty-seven cases of MMS were compared with 114 cases of WLE for eyelid sebaceous carcinoma. Overall KM survival rates for MMS compared to WLE at 5-year (75.6% vs. 70.3%) and 10-year follow-up (69.2% vs. 46.9%) did not show significant difference by logrank (P = 0.062). Similarly, after adjusting for demographic, tumor, and treatment characteristics, there was no significant difference in cancer-specific survival (HR 0.45, 95% CI 0.03-6.92, P = 0.57) and overall survival (HR 0.94, 95% CI 0.50-1.74, P = 0.83) when MMS surgical technique was compared with WLE techniques., Conclusions: Our adjusted analyses demonstrated no differences in overall survival or cancer-adjusted survival for patients with eyelid sebaceous adenocarcinomas treated with MMS compared with WLE. In areas requiring preservation of tissue because of cosmetic or functional purposes, MMS is a reasonable surgical approach., (Copyright © 2019 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a β-catenin-independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9-positive Lef1-negative hair follicle progenitors that give rise to the upper SG Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)

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.)

Introduction: Mature sebaceous glands do not contain Merkel cells. Neither do sebaceous tumors in the vast majority of cases. Recently, however, it was showed that rare sebaceous adenomas with a carcinoid-like or labyrinthine pattern can contain intratumoral Merkel cells. Our purpose in this study is to examine for the presence of Merkel cells in extraocular sebaceous carcinomas., Methods: Nineteen cases of extraocular sebaceous carcinoma were retrospectively studied with cytokeratin 20., Results: One out of 19 cases (5.3%) contained Merkel cells in the basal layers of the tumoral nests of a sebaceous carcinoma from the cheek of a 76-year-old woman., Conclusions: Merkel cells are rarely evident in extraocular sebaceous carcinoma, and therefore, their evidence does not exclude this diagnosis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The histogenesis of extraocular sebaceous carcinomas is - in contrast to ocular sebaceous carcinomas - unclear, and information about the exact cellular architecture of these lesions and even of the normal sebaceous gland is still scarce. This study attempts to elucidate the histogenesis of sebaceous tumors, using multicolor immunofluorescence stainings to analyze 21 cases of sebaceous tumors (six each of extraocular sebaceous carcinoma, sebaceous adenoma and sebaceoma, and three cases of steatocystomas) and eight cases of normal sebaceous glands for p63, several keratins, androgen receptor, adipophilin, epithelial membrane antigen (EMA) and Ki-67. The data of this observational study provide evidence for the existence of two subpopulations of progenitors in normal sebaceous glands: (i) p63 + K5 + progenitors which generate the K10 + luminal cells of sebaceous ducts; and (ii) p63 + K5 + K7 + progenitors which finally generate K7 + adipophilin + EMA + sebocytes. Without exception, all types of sebaceous tumors contained p63 + K5 + cells. Furthermore, these tumors showed a cellular hierarchy and differentiation to adipophilin + and/or EMA + mature sebocytes and to K10 + ductal cells through intermediary cells. Notably, a considerable number of sebaceous tumors lack the K7 pathway of cell maintenance in the normal sebaceous lobule. Based on our data, we propose a cellular algorithmic model of the hierarchy of normal sebaceous glands and of sebocytic tumors in which p63 + K5 + cells play a major role., (© 2019 Japanese Dermatological Association.)

TLE1 immunohistochemistry is widely used as a biomarker for synovial sarcoma. Recently, we identified TLE1 expression in a subset of melanomas and noted staining in sebaceous glands and follicular epithelium. TLE1 immunohistochemistry has not been well studied in cutaneous tumors. The aim was to investigate TLE1 expression in sebaceous neoplasms, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) to determine whether the staining patterns may aid in the diagnosis or classification of these neoplasms. TLE1 immunohistochemistry was performed on sebaceous adenoma (n = 26), sebaceoma (n = 10), sebaceous carcinoma (n = 19), BCC (n = 20), and SCC (n = 19). Positivity was defined as dark-brown nuclear staining and graded as 3+ (strong staining of >50% of cells at 4×), 2+ (moderate staining of 10-50% of cells at 4× or >50% of cells staining at 10×), and 1+ (weak staining of <50% of cells at 10×). No staining was scored as 0. A score of 2-3+ was considered positive and 0-1+ negative. Nuclear TLE1 expression was identified in 25/26 (96%) sebaceous adenomas, 8/10 (80%) sebaceomas, and 17/19 (90%) sebaceous carcinomas. TLE1 also labeled 19/20 (95%) BCCs and 12/19 (63%) SCCs. TLE1 immunohistochemistry frequently highlights sebaceous neoplasms, BCC, and SCC with a fairly high sensitivity (63%-96%). Therefore, TLE1 is not a specific biomarker for synovial sarcoma and should be evaluated with caution, particularly in cases in which the differential diagnosis may include other cutaneous tumors. In addition, TLE1 does not seem to be useful in the diagnosis or classification of these neoplasms.

Aims: Sebaceous gland carcinoma (SGC) of the eyelid is a rare but potentially deadly cancer. The purpose of this study was to determine whether the American Joint Committee on Cancer (AJCC) 7th Edition T category for SGC correlated with metastasis and survival in the Chinese population., Methods: This was a retrospective, single-centre cohort study. Patients with surgically resected eyelid SGC between January 2001 and May 2015 at the Hong Kong Eye Hospital were reviewed. Tumours were staged using the AJCC criteria. The main outcome measures included local recurrence, metastasis and death. Disease-free survival (DFS) was measured from the completion of treatment; overall survival was measured from the date of initial diagnosis., Results: The study included 22 Chinese patients with a mean age of 65.4 years. The majority presented as a nodular lesion (91%) with 12 eyes (54.5%) initially misdiagnosed and a mean presentation time of 1 year. It was found that those with AJCC stage T2b or higher were significantly associated with lymph node metastasis (P=0.002) when compared with those with stage T2a. Older age at diagnosis (P=0.035) and no misdiagnosis (P=0.025) were associated with shorter DFS. Those with stage 3a or higher were associated with shorter DFS (P=0.007) and overall survival (P=0.024)., Conclusion: Similar to previous reports, in this Chinese cohort, AJCC staging for SGC correlated with lymph node metastasis, DFS and overall survival. Those with stage 2b or higher on presentation will need closer surveillance for lymph node metastasis and may benefit from sentinel lymph node biopsy., 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.)

Background: To report "Lamellar Rotation Surgery",a new technique for repairing large and moderate full-thickness upper eyelid defects., Methods: A two-stage technique is described in which a vertical incision is made in the tarsus of the lower eyelid with elevation of the lateral posterior lamella while sparing the lower eyelid orbicularis and skin to be rotated superiorly to form the reconstructed posterior lamella of the upper eyelid. Additionally, a lateral periosteal flap is used to reconstruct the lateral canthal tendon, and a McGregor procedure is used to reconstruct the anterior lamella of the upper eyelid. The flap is divided during a second-stage surgery at 3 months. Three cases are described to showcase this technique., Results: Good functional and aesthetic results were achieved for the eyelids., Conclusions: This new procedure may help to address the challenge of repairing full-thickness defects of the upper eyelid., Trial Registration: Registration number: ChiCTR1800018990 , 20 Oct 2018, retrospectively registered.