Sebaceous Neoplasms Research Articles

Multiomics Profiling Distinguishes Sebaceous Carcinoma from Benign Sebaceous Neoplasms and Provides Insight into the Genetic Evolution of Sebaceous Carcinogenesis.

Sebaceous carcinoma is the third most common nonkeratinocyte skin cancer in the United States with 1,000 cases per year. The clinicopathologic features of sebaceous carcinoma and benign sebaceous neoplasms (adenomas, sebaceomas) can overlap, highlighting the need for molecular biomarkers to improve classification. This study describes the genomic and transcriptomic landscape of sebaceous neoplasms in order to understand tumor etiology and biomarkers relevant for diagnosis and treatment. We performed whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS) of sebaceous neoplasms from six academic and two federal healthcare facilities in the United States diagnosed between January 1, 1999, and December 31, 2021. We evaluated 98 sebaceous neoplasms: 64 tumors (32 adenomas, 2 sebaceomas, 5 atypical sebaceous neoplasms, 25 carcinomas) had sufficient material for WGS, 96 tumors (42 adenomas, 11 sebaceomas, 8 atypical sebaceous neoplasms, 35 carcinomas) had sufficient material for WTS, and 62 tumors (31 adenomas, 2 sebaceomas, 5 atypical sebaceous neoplasms, 24 carcinomas) had sufficient material for combined WGS and WTS. Overall, we found decreased cholesterol biosynthesis and increased TP53 mutations, copy number gains (chromosome 6, 8q, and/or 18), and tumor mutation burden-high (>10 mutations/MB) in carcinomas compared to adenomas. Although diminished compared to adenomas, most carcinomas still had higher cholesterol biosynthesis than nonmalignant skin. Multiomics profiling also supported a precancerous model of tumor evolution with sebaceomas and atypical sebaceous neoplasms being likely intermediate lesions. The study findings highlight key diagnostic biomarkers for sebaceous carcinoma and suggest that immunotherapy and modulation of cholesterol biosynthesis could be effective treatment strategies.

FREQUENCY OF LOSS OF MISMATCH REPAIR PROTEINS’ IMMUNOHISTOCHEMICAL EXPRESSION IN SEBACEOUS NEOPLASMS, POTENTIAL MARKERS/TOOLS INDICATING THE POSSIBILITY OF MUIR-TORRE SYNDROME

Screening for Muir-Torre Syndrome (MTS) using Mismatch Repair (MMR) gene immunohistochemistry (IHC) on sebaceous neoplasms (SNs) is technically feasible. Research for this indication is limited, especially in Asia. To address this knowledge gap, we examined the frequency of loss of IHC staining of MMR proteins in SNs. Methods: We conducted a cross-sectional study including 98 patients (120 SNs). Eleven out of 98 patients had concurrent or subsequent SNs. Results: The size and type of tumor showed a significant association with MMR loss. Fifteen (12.5%) sebaceous adenomas, 12 (10.0%) sebaceous, and 93 (77.5%) sebaceous carcinomas were included in the study—sixty-one (50.83 %) SNs presented with loss of one or more MMR proteins. Isolated loss of MSH2 was the most common IHC pattern (27.8%). Fifty cases (29.58%) showed a combined loss of MSH2 and MSH6, and 40 (23.66%) showed a combined loss of MLH1 and PMS2. Most SAs showed isolated loss of MLH1 and PMS2 (7, 26.9% each). Sebaceomas showed isolated loss of MSH2 and MSH6 as the most common (4, 33.3%) pattern. Isolated loss of MSH2 only (37, 28.2%) was the predominant pattern of IHC loss in SCs. Weak to fragile associations between MMR protein status and histopathological findings were observed, with the most notable association being between MLH1 and ulceration on the surface. The models have an accuracy of around 50%, indicating moderate prediction capability. In our cohort, personal and family history was available in 33 cases (25 out of 98 patients). Conclusion: We recommend that MMR IHC be performed routinely on all SNs, considering clinicopathological factors of the lesions, mainly the anatomic site and tumor type. The panel should include antibodies against all four MMR proteins.

Sebaceous gland epithelioma with potential malignancy in a dog

Sebaceous gland tumors consist of neoplastic proliferations of sebaceous gland cells located around hair follicles in the dermis. These tumors are subclassified as sebaceous epithelioma, sebaceous adenoma, sebaceous adenocarcinoma and nodular hyperplasia. In this case report, a nodular growth in the sacral region of an eight-year-old male Belgian Malinois dog was presented. Macroscopically, the nodular mass had a slightly soft consistency, grayish-white, and dark red-black appearance. The mass was measured in the dimension of 2x1x1 cm. Histopathologically, the tumor was observed to have a multilobular structure shaped by neoplastic cell islands. The tumor consisted mainly of eosinophilic cells with small cytoplasm resembling epithelial basaloid cells and to a lesser extent differentiated sebocytes. The parenchyma of the tumor consisted of irregular islets containing a small number of mature sebocytes. Their nuclei are oval with one to three small nucleoli. Immunohistochemically, tumor cells for Ki67 antibody showed strongly positive immunoreactivity. Based on the histopathological and immunohistochemical features, the tumor was diagnosed as sebaceous epithelioma having, a potential malignancy. Since no case of sebaceous epithelioma with malignant potential has been reported in our country, we aimed to present the case with histopathological and immunohistochemical features.

Head and neck tumors detected in dogs and cats between 2011 and 2021: A retrospective study

The aim of this study is to determine and compare the distribution, localization, breed, age and gender incidences of head and neck region tumors by years, by evaluating the results of dog-cat biopsies and/or operation material brought to Ankara University, Faculty of Veterinary Medicine, Department of Pathology between the years 2011 and 2021. In the study, 244 (15.9%) of 1533 tumors diagnosed in dogs and cats between 2011 and 2021 belonged to the head and neck region, of which 159 were in dogs and 85 in cats. Dogs with tumors were generally more than 6 years old (n=108) and cats were mostly 1 year old and older (n=75). In the head and neck region tumors observed in dogs, malignant and benign tumors of epithelial origin were most common (n=81; 50.9%), with sebaceous tumors (n=22) being the most common, and mostly observed around the eyes (n=26), while malignant and benign tumors of mesenchymal origin were most commonly found in the mouth region. Among the tumors of this region, epithelial tumors were mostly encountered in cats (n=39, 45.8%), and 51.2% of the epithelial tumors were squamous cell cancer (n=20), with epithelial tumors being the most common in the mouth (n=12) and nose (n=9). As a result, epithelial malignant and benign tumors were mostly seen in the eyes, and mesenchymal malignant and benign tumors were detected in the mouth. Among tumor types, papilloma in benign tumors and squamous cell carcinoma in malignant tumors were noted.

O09 Microsatellite-unstable sporadic sebaceous and duodenal tumours are associated with loss of mismatch protein expression

Abstract Introduction and aims Lynch syndrome (LS) is a common heritable cancer predisposition syndrome. Tumours from patients with LS demonstrate microsatellite instability (MSI-high), a genetic signature detectable by low-cost DNA sequencing assays that is currently utilized in colorectal cancer screening. The utility of MSI assays for LS detection has not been extensively studied in unselected sebaceous skin tumours or duodenal tumours, where currently immunohistochemical (IHC) expression of mismatch repair (MMR) proteins is used. In addition, it has recently been suggested that cutaneous squamous cell carcinoma (cSCC) could be linked to LS; however MSI status has not been studied in patients with early-onset cSCC. Methods We investigated MSI status in archival formalin-fixed paraffin-embedded cases with ethical approval. We examined 110 sebaceous tumours (STs) (45 female patients, 65 male patients; median age 77 years), 50 duodenal tumours (DTs) (28 female patients, 22 male patients; median age 64 years), and 148 cSCCs selected from patients under 50 years of age (69 female patients, 79 male patients; median age 49 years). Immunohistochemistry (IHC) was performed on each MSI-high sample to determine the expression of MMR proteins MLH1, MSH2, MSH6 and PMS2. Samples that passed quality control were included in the analysis. Results A total of 42 of 106 STs (39.6%) were MSI-high. All STs had loss of at least one MMR protein. Overall, 10 of 41 (24%) DTs were MSI-high. All DTs had loss of at least one MMR protein. We found that 12 of 148 (8.1%) cSCCs were MSI-high and 5 of 12 SCCs exhibited loss of at least one MMR protein expression (41%). Conclusions MSI-high status correlated well with loss of MMR protein expression in STs and DTs samples. Future studies will help establish MSI status in tumours initially selected by MMR loss on IHC, informing its use as an adjunct to MMR IHC in LS detection in patients with STs and DTs.

Histopathological and Immunohistochemical Characterization of Sebaceous Adenoma and Epithelioma in Dogs.

Sebaceous gland tumors are neoplasms originating from the sebaceous gland and are the third most common type of skin tumor, accounting for 21-35% of all cutaneous neoplasms in dogs. According to their histopathological characteristics, sebaceous gland tumors can be classified into adenoma as a benign tumor and epithelioma as a malignant tumor. Sebaceous epithelioma is distinguished from sebaceous adenoma by containing 90% or more reserve cells. However, this simple numerical criterion is insufficient to histologically distinguish between epitheliomas and adenomas. In addition, sebaceoma in humans, a similar tumor to sebaceous epithelioma, is a term used for tumors with more than 50% of reserve cells, unlike epithelioma. Therefore, we aimed to compare and characterize the histological and immunohistochemical profiles of comprehensive sebaceous adenoma, epithelioma, and borderline tumors that have more than 50% but less than 90% of reserve cells. A total of 14 canine sebaceous tumors were diagnosed as seven adenomas, four borderline tumors, and three epitheliomas. Histologically, the sebaceous adenomas showed nodules consisting of mature sebocytes surrounded by monolayer basaloid cells. In contrast, the portion of the reserve cells was increased, the portion of lipidized cells was decreased, and the majority of lipidized cells were found to be immature in sebaceous epithelioma. In the sebaceous adenomas, necrosis was not observed and mitotic figures were rarely seen. However, necrosis and mitotic figures were highly frequent in both borderline tumor and sebaceous epithelioma. Immunohistochemistry revealed that borderline tumor and sebaceous epithelioma showed significantly higher expression against Ki-67 than sebaceous adenoma. We conclude that it is more accurate to employ the cut-off value of 50% reserve cells in humans rather than the current 90% reserve cells for classifying sebaceous gland tumors in dogs, thereby providing new insight into the characterization of the sebaceous gland tumors.

Incidence and molecular characteristics of deficient mismatch repair conditions across nine different tumors and identification of germline variants involved in Lynch-like syndrome

BackgroundBased on molecular characteristics, deficient DNA mismatch repair (dMMR) solid tumors are largely divided into three categories: somatically MLH1-hypermethylated tumors, Lynch syndrome (LS)-associated tumors, and Lynch-like syndrome (LLS)-associated tumors. The incidence of each of these conditions and the corresponding pathogenic genes related to LLS remain elusive.MethodsWe identified dMMR tumors in 3609 tumors from 9 different solid organs, including colorectal cancer, gastric cancer, small-bowel cancer, endometrial cancer, ovarian cancer, upper urinary tract cancer, urinary bladder cancer, prostate cancer, and sebaceous tumor, and comprehensively summarized the characterization of dMMR tumors. Characterization of dMMR tumors were performed as loss of at least one of MMR proteins (MLH1, MSH2, MSH6, and PMS2), by immunohistochemistry, followed by MLH1 promotor methylation analysis and genetic testing for MMR genes where appropriate. Somatic variant analysis of MMR genes and whole exome sequencing (WES) were performed in patients with LLS.ResultsIn total, the incidence of dMMR tumors was 5.9% (24/3609). The incidence of dMMR tumors and the proportion of the three categorized dMMR tumors varied considerably with different tumor types. One to three likely pathogenic/pathogenic somatic MMR gene variants were detected in 15 out of the 16 available LLS tumors. One patient each from 12 patients who gave consent to WES demonstrated non-MMR germline variants affect function (POLQ or BRCA1).ConclusionsOur data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.

Clinicopathological Analysis of Skin Adnexal Tumours: Four Year Retrospective Study

Background: Cutaneous adnexal tumours are rare, heterogeneous, benign, or malignant tumours that differentiate into one or more types of skin appendages. Methods: This is a retrospective study of 68 cases of cutaneous adnexal tumours diagnosed in our anatomical pathology department over 4 years period from September 2019 to September 2023. Results: Benign adnexal tumours are the most common, accounting for an estimated 97% of cases. These tumours are more frequent in male patients aged between 51 and 70 years. The head and neck region is the most affected area (51% of cases). Tumours originating from the sweat glands were the most frequent. Follicular and sebaceous tumours came second and third. Conclusion: Adnexal tumours are a very diverse group of rare neoplasms. Accurate diagnosis is a challenge for the dermatologist and usually requires the histological study.

Expanding the Spectrum of Skin Neoplasms in Muir-Torre Syndrome: Beyond Sebaceous Tumours.

Expanding the Spectrum of Skin Neoplasms in Muir-Torre Syndrome: Beyond Sebaceous Tumours.

Efficient Topical Treatment of Canine Nodular Sebaceous Hyperplasia with a Nitric Acid and Zinc Complex Solution.

Nodular sebaceous gland hyperplasia in the often middle-aged to old dog is a common, benign proliferation that results in exophytic, pink to yellow, alopecic, and often multilobulated nodules. Removal is usually carried out by surgical excision. As many old dogs have comorbidities that increase the risk of anesthesia, a topical treatment is warranted. We hypothesized that the application of a solution containing nitric acid, zinc, copper, and organic acids (Verrutop®), would be a safe and efficient way to treat these nodules. Eleven dogs with a total of 29 nodules, grossly compatible with nodular sebaceous gland hyperplasia, were included in the study. Eighteen of the nodules were treated; 11 were left untreated. No anesthesia or sedation was needed. Four weeks after one application, 17/18 treated nodules had decreased by 100% in volume. There was a statistically significant difference in percentual volume change between the treated and untreated nodules from day 0 to day 28 (p < 0.0001). No serious side effects were noted. Sebaceous hyperplasia cannot always be distinguished grossly from sebaceous tumors. Cytological evaluation can be helpful, and in cases of deviant macroscopic features, local recurrence, or more aggressive behavior, the appropriate intervention would be to biopsy or excise the nodule for histopathology. Topical application of Verrutop® is an easy, low-cost, and efficient way to remove canine sebaceous gland hyperplasia with minimal side effects in cases where surgery and anesthesia are not desired.

Mosaic Muir Torre Syndrome: Keratoacanthoma as a Piece of the Puzzle.

Lynch syndrome is an inherited condition, which increases the risk of numerous visceral malignancies and cutaneous tumors such as keratoacanthomas and sebaceous tumors. It is typically identified by immunohistochemistry of tissue taken from tumors or through genetic testing with next-generation sequencing. Diagnosing Lynch syndrome becomes more complex when the individual is mosaic for the relevant pathogenic variant. There are very few cases of this reported in the medical literature. It is even more unusual for the diagnosis to be made based on testing of a keratoacanthoma lesion. We report a case where immunohistochemistry of a keratoacanthoma helped make a diagnosis of mosaic Lynch syndrome. We will explore how mosaicism should be considered when a phenotype is strong, even if next-generation sequencing reports no pathogenic or likely pathogenic variant and how lesions such as keratoacanthomas can have a role in the early detection and treatment of future malignancies.

Aquaporin 3 is expressed in the basaloid cells of canine sebaceous glands.

The role of aquaporin proteins (AQPs) in tumor biology has attracted attention over the past 20 years. However, the expression profiles of AQPs in canine sebaceous gland tumors remain obscure. This study was performed to clarify the expression of AQP1, 3, 5, the most studied AQPs in tumor biology, in sebaceous adenoma and sebaceous epithelioma. Among these AQPs, only AQP3 was expressed in normal tissue and both tumor types and located to only undifferentiated sebocytes (basaloid cells). A cellular proliferation marker, Ki-67, was detected only in the area including basaloid cells in both tumor types. These findings suggest that AQP3 is useful for clarifying the origin of sebaceous gland tumors, and that AQP3 may be related to sebaceous gland development.

Androgen Receptor Immunohistochemistry is Superior to PRAME for the Differentiation of Sebaceous Carcinoma From Primary Cutaneous Basaloid Mimics.

Cutaneous sebaceous neoplasia comprises a spectrum of disease ranging from benign adenomas to malignant carcinomas. The hallmark of these lesions is sebaceous differentiation. However, poorly-differentiated sebaceous carcinoma (SC), which lacks significant overt sebaceous differentiation, can show morphologic overlap with a variety of other basaloid cutaneous neoplasms. The accurate classification of SC is essential not only for diagnosis, but also because of the potential association with Muir-Torre syndrome. Androgen receptor (AR) is a sensitive, but not entirely specific immunohistochemical marker that has been used for the diagnosis of SC. PReferentially expressed Antigen in MElanoma (PRAME) demonstrates strong cytoplasmic labeling of mature sebocytes and has been reported to be expressed in a variety of sebaceous neoplasms, including in the basaloid cell component. Therefore, we sought to compare the diagnostic use of cytoplasmic PRAME expression with that of AR for the distinction of SC from a cohort of basaloid cutaneous mimics; namely basal cell carcinoma, basaloid squamous cell carcinoma, pilomatricoma, cutaneous lymphadenoma, and extra-mammary Paget disease. We report that cytoplasmic PRAME expression is uncommon in poorly differentiated SC, and although specific, it shows very low sensitivity (22%). In contrast, AR was moderately sensitive (66%) and highly specific (92%) for the distinction of SC from basaloid mimics. These attributes, in addition to the nuclear expression of AR in the sebocytic and basaloid components of SC, suggest that AR is superior to PRAME for the diagnosis of SC.

The prevalence of lynch syndrome (DNA mismatch repair protein deficiency) in patients with primary localized prostate cancer using immunohistochemistry screening

BackgroundProstate cancer is one of the most heritable human cancers. Lynch syndrome is an autosomal dominant inheritance caused by germline mutations in DNA mismatch repair (MMR) genes, which are also associated with an increased incidence of prostate cancer. However, prostate cancer has not been defined as a Lynch syndrome-associated cancer. The proportion of Lynch syndrome patients in primary prostate cancers is unclear. In this study, we investigated MMR protein loss using universal immunohistochemical screening to determine the prevalence of Lynch syndrome in patients with localized prostate cancer who underwent radical prostatectomy.MethodsOne hundred twenty-nine surgical specimens from radical prostatectomy performed at Toranomon Hospital between 2012 and 2015 were retrospectively tested using universal screening with immunohistochemistry staining for expression of the MMR proteins MLH1, PMS2, MSH2, and MSH6. For all suspected MMR-deficient patients, germline genetic tests focusing on MMR genes were performed.ResultsMMR protein loss was found in only one patient (0.8%) who showed dual MSH2/MSH6 loss. This patient showed a single nucleotide pathogenic germline mutation from c.1129 C to T (p.Gln377*) at exon 7 in the MSH2 gene. He was diagnosed with a primary prostate cancer at 66 years of age. He had a documented history of Lynch syndrome (Muir–Torre syndrome) with previous colon cancer, sebaceous tumor, and keratoacanthoma as well as subsequent bladder cancer, all of which also showed dual MSH2/MSH6 loss. He also had a strong family history of colorectal and other Lynch syndrome-associated cancers. The pathological stage was pT3aN0M0, and the pathological grade was Gleason 7(4 + 3) with tertiary pattern 5.ConclusionsIn this study, immunohistochemical screening of MMR proteins for Lynch syndrome was performed in a series of prostate cancer cases. The prevalence of Lynch syndrome in localized prostate cancer was 0.8%, which is low compared with other Lynch syndrome-associated cancers.

Immunohistochemistry, Molecular Biology, and Clinical Scoring for the Detection of Muir-Torre Syndrome in Cutaneous Sebaceous Tumors: Which Strategy?

Background: Sebaceous neoplasms (SNs) always raise the possibility of an association with Muir-Torre syndrome (MTS) and permit to screen internal malignancies, colorectal and endometrial carcinomas, before they become symptomatic. Immunohistochemistry (IHC), molecular biology, and clinical examination are different approaches for detection of MTS. We conducted a retrospective analysis of non-selected SNs in order to determine the optimal tools to implement for MTS screening. Methods: Deficient MMR phenotype (dMMR) was determined by either IHC using antibodies directed to four mismatch repair (MMR) antigens on tissue microarray or molecular biology using pentaplex PCR. The Mayo Clinic risk score of MTS was calculated from medical records. Sensibility and specificity of each test for the detection of MTS were determined. Results: We included 107 patients, 8 with multiple SNs, for a total of 123 SNs (43 sebaceous adenomas, 19 sebaceomas, and 61 sebaceous carcinomas (SC)). Loss of at least one MMR protein was observed in 70.7% of tumors, while 48% had a microsatellite instable phenotype. Concordance between both techniques was 92.9%, with a 0.85 Cohen’s kappa coefficient. Nineteen patients (20.2%) had a ≥2 points Mayo Clinic risk score, one having a pMMR SC. Among the 13 patients with confirmed MTS, 2 had a low Mayo Clinic risk score (1 point). IHC had the highest sensitivity for MTS screening (100%) with a specificity of 34.1%, while a >2-point Mayo Clinic risk score had a lower sensitivity (92%) but a higher specificity (89%). Conclusion: To detect MTS in SN patients, the first-line Mayo Clinic risk score followed by IHC appears to be the most accurate strategy with lower cost for society. This strategy should be adapted to the medico-economic resources of each country.

Machine learning for classification of cutaneous sebaceous neoplasms: implementing decision tree model using cytological and architectural features

BackgroundThis observational study aims to describe and compare histopathological, architectural, and nuclear characteristics of sebaceous lesions and utilized these characteristics to develop a predictive classification approach using machine learning algorithms.MethodsThis cross-sectional study was conducted on Iranian patients with sebaceous tumors from two hospitals between March 2015 and March 2019. Pathology slides were reviewed by two pathologists and the architectural and cytological attributes were recorded. Multiple decision tree models were trained using 5-fold cross validation to determine the most important predictor variables and to develop a simple prediction model.ResultsThis study assessed the characteristics of 123 sebaceous tumors. Histopathological findings, including pagetoid appearance, neurovascular invasion, atypical mitosis, extensive necrotic area, poor cell differentiation, and non-lobular tumor growth pattern, as well as nuclear features, including highly irregular nuclear contour, and large nuclear size were exclusively observed in carcinomatous tumors. Among non-carcinomatous lesions, some sebaceoma and sebaceous adenoma cases had features like high mitotic activity, which can be misleading and complicate diagnosis. Based on multiple decision tree models, the five most critical variables for lesion categorization were identified as: basaloid cell count, peripheral basaloid cell layers, tumor margin, nuclear size, and chromatin.ConclusionsThis study implemented a machine learning modeling approach to help optimally categorize sebaceous lesions based on architectural and nuclear features. However, studies of larger sample sizes are needed to ensure the accuracy of our suggested predictive model.

Cytopathology of benign sebaceous salivary gland neoplasia: Comparison of two analogous yet dissimilar entities.

Benign sebaceous salivary gland (SG) neoplasms represent approximately 0.2% of all salivary gland neoplasms. Not only are fine needle aspiration (FNA) biopsy findings of sebaceous adenoma (SA) and sebaceous lymphadenoma (SLA) limited, but their findings are also rarely compared with one another. Our cytopathology files were searched for examples of benign sebaceous SG neoplasms with concomitant histopathological verification. FNA biopsy and cell collection were performed using standard technique. One case each of parotid SA and parotid SLA showed markedly dissimilar cytomorphology. The SA case was composed of a repetitive population of profusely multivacuolated polygonal cells with single and multiple nuclei, and was specifically recognised cytologically as a sebaceous neoplasm due to its characteristic cytoplasmic vacuolisation. The SLA case, however, was characterised by smears filled primarily with lymphocytes and only scant widely scattered basaloid cell clusters. A non-specific diagnosis of basaloid neoplasm was rendered. In retrospect, recognition of sebaceous differentiation was limited to rare cell groups. Though nominally, epidemiologically, and to a degree histopathologically analogous, the cytopathology of SA and SLA are markedly dissimilar, reflecting the dominant cell component in each. With FNA biopsy, a specific interpretation is more likely for SA than SLA due to the overwhelming obscuring lymphoid population in the latter.

Utility of GLI1 RNA Chromogenic in Situ Hybridization in Distinguishing Basal Cell Carcinoma From Histopathologic Mimics

Basal cell carcinoma (BCC) is the most common human malignancy and is a leading cause of nonmelanoma skin cancer-related morbidity. BCC has several histologic mimics which may have treatment and prognostic implications. Furthermore, BCC may show alternative differentiation toward a variety of cutaneous structures. The vast majority of BCCs harbor mutations in the hedgehog signaling pathway, resulting in increased expression of the GLI family of transcription factors. GLI1 immunohistochemistry has been shown to discriminate between several tumor types but demonstrates high background signal and lack of specificity. In this study, we evaluated the utility of GLI1 RNA chromogenic in situ hybridization (CISH) as a novel method of distinguishing between BCC and other epithelial neoplasms. Expression of GLI1 by RNA CISH was retrospectively evaluated in a total of 220 cases, including 60 BCCs, 37 squamous cell carcinomas (SCCs) including conventional, basaloid, and human papillomavirus infection (HPV)-associated tumors, 16 sebaceous neoplasms, 10 Merkel cell carcinomas, 58 benign follicular tumors, and 39 ductal tumors. The threshold for positivity was determined to be greater than or equal to 3 GLI1 signals in at least 50% of tumor cells. Positive GLI1 expression was identified in 57/60 BCCs, including metastatic BCC, collision lesions with SCC, and BCCs with squamous, ductal, or clear cell differentiation or with other unusual features compared to 1/37 SCCs, 0/11 sebaceous carcinomas, 0/5 sebaceomas, 1/10 Merkel cell carcinomas, 0/39 ductal tumors, and 28/58 follicular tumors. With careful evaluation, GLI1 RNA CISH is highly sensitive (95%) and specific (98%) in distinguishing between BCC and nonfollicular epithelial neoplasms. However, GLI1 CISH is not specific for distinguishing BCC from most benign follicular tumors. Overall, detection of GLI1 RNA by CISH may be a useful tool for precise classification of histologically challenging basaloid tumors, particularly in the setting of small biopsy specimens, metaplastic differentiation, or metastatic disease.

BI09 Microsatellite instability and loss of mismatch repair proteins in nonmelanoma skin cancer and treatment-resistant phenotypically distinct precancerous lesions in Muir–Torre/Lynch syndrome: a multicentre retrospective study

Abstract DNA mismatch repair (MMR) gene mutations resulting in microsatellite instability (MSI) are associated in the pathogenesis of Muir–Torre syndrome (MTS), a variant of Lynch syndrome (LS). It is characteristically defined by the association of at least one sebaceous skin neoplasm and/or keratoacanthoma and a visceral malignancy. The presence of cutaneous lesions plays a vital role in the early detection and preventive cancer screening of the disease; however, nonmelanoma skin cancers (NMSCs) and their precursors are seldom reported. We conducted a retrospective multicentre study between 2011 and 2022 of adults with a confirmed genetic diagnosis of MTS/LS across two specialist institutions presenting with phenotypically distinct treatment-resistant precancerous skin lesions and/or NMSC with the associated loss of MMR expressions consistent with their germline mutations which are currently not recognized diagnostic features. Median age at the onset of precancerous/NMSC in eight individuals was 57.5 years, with an equal sex distribution. Lesions occurred mostly on the face (n = 14), followed by the forearms (n = 8), dorsum of the hands (n = 9), the legs (n = 4) and the chest (n = 1). Our study histologically and immunohistochemically examined MMR expressions and MSI in 20 precancerous and/or NMSCs. Loss of expression and MSI were found in actinic keratoses (AK) (n = 6/7), disseminated superficial actinic porokeratosis (DSAP; n = 1/2), squamous cell carcinoma (n = 4/5) and basal cell carcinoma (n = 4/4). Additionally, we found sebaceomas with atypia (n = 2/2). In 17 lesions, the loss of MMR expression and MSI were consistent with their germline mutations. We also discovered that all lesions identified with MSI had normal adjacent skin with no loss of MMR expression. Our observations suggest the detection of MSI, and MMR gene abnormality, play a critical role in the development of precancerous and NMSC other than sebaceous neoplasms in this disease. To date, the diagnostic criteria for MTS/LS do not include NMSC and their precursors, and these have rarely been reported. We note a clinically distinct presentation of widespread erythematous scaly lesions resembling AK/DSAP, resistant to multiple treatments, which is an additional recognizable clinical feature in this patient subgroup. This is an important association in cancer-prone individuals and immunohistochemistry testing for MMR genes should be encouraged. This can be a powerful investigative tool as AK/DSAP are easily identifiable, numerous and readily accessible for DNA analysis; therefore, detecting the presence of MSI in the skin may aid in screening individuals promptly. MTS/LS is best managed by a multidisciplinary team with close surveillance for visceral malignancies, highlighting the importance of routine monitoring for precancerous and nonsebaceous skin cancers.

DP18 Extraocular sebaceous carcinoma in situ

Abstract Extraocular sebaceous carcinoma in situ (SCIS) is exceedingly rare with &amp;lt; 10 cases reported in the literature (Jeong KM, Seo JY, Kim A et al. Extraocular sebaceous carcinoma in situ concurrent with actinic keratosis: a case report and review of the literature. Korean J Dermatol 2021; 59:307–9). An 80-year-old man reported a 3-month history of a right forehead lesion that had been bleeding. This was a subtle 5 × 5 mm papule on clinical examination, and dermoscopy showed arborizing telangiectasia. Past medical history was significant for 20 basal cell carcinomas, one squamous cell carcinoma, Bowen disease and actinic keratoses. Histology showed sun-damaged skin with a partially eroded neoplasm of lobular architecture, with surface and infundibular epithelium containing atypical sebocytes and squamous cells with no infiltrative growth pattern, which was consistent with SCIS and was fully excised. Immunohistochemistry revealed patchy adipophilin and androgen receptor staining and stronger epithelial membrane antigen staining. Furthermore, there was preserved expression of MSH2, MSH6, MLH1 and PMS2. Sebaceous carcinoma in situ is a debated entity not formally recognized in the classification of sebaceous neoplasms. Kazakov et al. reported five cases of dermal sebaceous tumours with ‘benign’ architectural features (well-circumscribed and no evidence of invasion) but with cytological atypia (abnormal mitoses and pleomorphism) (Kazakov D, Kutzner H, Spagnolo DV et al. What is extraocular cutaneous sebaceous carcinoma in situ? Am J Dermatopathol 2010; 32:857–8). The authors questioned whether these cases represented sebaceous adenomas with atypia or sebaceous carcinomas (Kazakov et al.). In response, it has been argued that such architectural–cytological discordant tumours can be regarded as SCIS owing to the fact that, by definition, carcinoma in situ is a cancer that remains wholly at the site of origin. However, it is argued that these lesions have an unclear origin and may not arise from sebaceous glands in the skin, unlike the more common aggressive periorbital sebaceous carcinomas that arise from meibomian glands and glands of Zeis (Kazakov et al.). It has been postulated that a SCIS diagnosis should be reserved for intraepidermal tumours not extending beyond the epidermal basement membrane, which is a vanishing minority of sebaceous neoplasms (Kazakov et al.). Similar to our case, a 2021 case report identified SCIS without any connection to an adnexal component but concurrent with actinic keratosis. These authors proposed that the tumour cells of intraepidermal squamous neoplasia can differentiate towards malignant sebocytes (Jeong et al.). Although controversial, SCIS appears to have reasonable, clear histological criteria for diagnosis and an excellent prognosis, with no reports of recurrence following surgical excision. We feel it is important to increase identification to avoid the overtreatment of such lesions.