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Dessinioti C, Stratigos AJ. Mapping the potential for anti-PD-1 therapy in advanced rare skin carcinomas. Eur J Cancer 2025; 222:115403. [PMID: 40294476 DOI: 10.1016/j.ejca.2025.115403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/20/2025] [Accepted: 03/28/2025] [Indexed: 04/30/2025]
Abstract
This review, focusing on cutaneous adnexal carcinomas, extramammary Paget disease (EMPD), cutaneous angiosarcomas (cAS) and Kaposi sarcoma (KS), summarizes their local recurrence and metastasis rates, tumor mutation burden (TMB), PD-L1 expression, and off-label treatment with systemic anti-PD-1 agents. PD-L1 expression and tumor mutation burden (TMB) were highly variable in adnexal carcinomas (also depending on the histological subtype), cAS and KS tumors, and some responses were noted even in lack of PD-L1 expression or in low-TMB tumors. There were encouraging best overall responses in patients with advanced rare skin carcinomas treated with anti-PD-1 agents in the literature, mostly after failure of other systemic treatments. We identified a total of 3 patients with sebaceous carcinoma (2 with complete response [CR], 1 with partial response [PR]), 5 with porocarcinoma (3 CR, 1 PR, 1 progression of disease [PD]), 2 with spiradenocarcinoma (1 PR, 1 PD), 1 with trichilemmal carcinoma with PR, 9 with EMPD (1 CR, 5 PR, 3 PD), 32 with cAS (5 CR, 18 PR, 9 PD), and 92 with KS (5 CR, 53 PR, 23 SD, 11 PD). However, a large variety of anti-PD-1 agents were used, in monotherapy or in combination with other systemic therapy, in a relatively small number of patients, limiting interpretations on their individual efficacy. The development of clinical guidelines on rare skin carcinomas may provide standardized guidance to physicians towards best care.
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Affiliation(s)
- Clio Dessinioti
- Skin Cancer and Melanoma Unit, 1st Department of Dermatology, Andreas Sygros Hospital, University of Athens, Greece.
| | - Alexander J Stratigos
- Skin Cancer and Melanoma Unit, 1st Department of Dermatology, Andreas Sygros Hospital, University of Athens, Greece
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Legrand M, Louveau B, Macagno N, Mancini M, Kazakov DV, Pissaloux D, Tirode F, Tallet A, Mourah S, Lepiller Q, de la Fouchardière A, Sohier P, Frouin E, von Deimling A, Goto K, Cribier B, Calonje E, Taibjee S, Battistella M, Kervarrec T. Recurrent GRHL fusions in a subset of sebaceoma: microscopic and molecular characterisation of eight cases. Histopathology 2025; 86:571-584. [PMID: 39564735 PMCID: PMC11791738 DOI: 10.1111/his.15361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 09/16/2024] [Accepted: 10/16/2024] [Indexed: 11/21/2024]
Abstract
AIMS Sebaceous neoplasms constitute a group of adnexal tumours, including sebaceous adenoma, sebaceoma and sebaceous carcinoma. Although mismatch repair deficiency may be observed, the nature of the genetic alterations contributing to the development of most of these tumours is still unknown. In the present study, we describe the clinical, microscopic, and molecular features of eight sebaceomas with GRHL gene rearrangement. METHODS AND RESULTS Among these sebaceomas, four occurred in women and four in men; the median age was 63 years (range = 29-89). The tumours were located in the head and neck area in all cases. Microscopic examination revealed a well-demarcated lesion located in the dermis with focal extension into the subcutaneous tissue (three cases). The neoplasms displayed macronodular (eight cases), cribriform (seven cases) and organoid (six cases) growth patterns, occurring in combination. The tumours were mainly composed of immature basophilic cells associated with scattered mature sebocytes. Numerous small infundibular cysts were present in seven cases. Mitotic activity was low (none/one to four mitoses/mm2). Immunohistochemistry showed positivity for androgen receptor and p63. Preserved expression of MLH1, PMS2, MSH2 and MSH6 was observed in all cases. RNA-sequencing revealed RCOR1::GRHL2 (three cases), BCL6::GRHL1 (two cases), a BCOR::GRHL2 (one case), RCOR1::GRHL1 (one case) and TLE1::GRHL1 (one case) fusion transcript. Methylation analysis demonstrated that GRHL-fused sebaceomas form an independent cluster and highlight the proximity of such tumours with poromas with folliculo-sebaceous differentiation. CONCLUSIONS In conclusion, we report recurrent fusions of the GRHL genes in a distinctive subset of sebaceomas harbouring infundibulocystic differentiation, a frequent organoid growth pattern and lack of mismatch repair deficiency.
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Affiliation(s)
- Mélanie Legrand
- Department of PathologyUniversité de Tours, Centre Hospitalier Universitaire de ToursToursFrance
| | - Baptiste Louveau
- Department of Tumour Genomics and PharmacologyHôpital Saint Louis, Université Paris Cité, Human Immunology Pathophysiology and Immunotherapy (HIPI)ParisFrance
| | - Nicolas Macagno
- CARADERM Network, Fédération de Recherche CliniqueLilleFrance
- Department of Pathology, Aix Marseille UniversityLa Timone HospitalMarseilleFrance
| | - Maxence Mancini
- Department of Tumour Genomics and PharmacologyHôpital Saint Louis, Université Paris Cité, Human Immunology Pathophysiology and Immunotherapy (HIPI)ParisFrance
| | - Dmitry V Kazakov
- IDP Dermatohistopathologie InstitutPathologie Institut EngeZurichSwitzerland
| | | | - Franck Tirode
- Department of BiopathologyCenter Léon BérardLyonFrance
- Université de Lyon, Université Claude Bernard Lyon 1, Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le CancerLyonFrance
| | - Anne Tallet
- Platform of Somatic Tumour Molecular GeneticsUniversité de Tours, Centre Hospitalier Universitaire de ToursToursFrance
| | - Samia Mourah
- Department of Tumour Genomics and PharmacologyHôpital Saint Louis, Université Paris Cité, Human Immunology Pathophysiology and Immunotherapy (HIPI)ParisFrance
| | - Quentin Lepiller
- French National Papillomavirus Reference Center, CHU de BesançonUniversité de Franche‐ComtéBesançonFrance
| | - Arnaud de la Fouchardière
- Department of BiopathologyCenter Léon BérardLyonFrance
- Université de Lyon, Université Claude Bernard Lyon 1, Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le CancerLyonFrance
| | - Pierre Sohier
- CARADERM Network, Fédération de Recherche CliniqueLilleFrance
- Department of Pathology, Hôpital CochinAssistance Publique‐Hôpitaux de Paris, AP‐HP Centre‐Université Paris CitéParisFrance
| | - Eric Frouin
- CARADERM Network, Fédération de Recherche CliniqueLilleFrance
- Department of Pathologyuniversity Hospital of Nîmes, University of NîmesNîmesFrance
| | - Andreas von Deimling
- Department of NeuropathologyInstitute of Pathology, Ruprecht‐Karls‐UniversityHeidelbergGermany
- Clinical Cooperation Unit NeuropathologyGerman Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK)HeidelbergGermany
| | - Keisuke Goto
- Department of PathologyTokyo Metropolitan Cancer and Infectious Disease Center, Komagome HospitalTokyoJapan
- Department of Diagnostic PathologyShizuoka Cancer Center HospitalSuntoJapan
- Department of Diagnostic Pathology and CytologyOsaka International Cancer InstituteOsakaJapan
- Department of DermatologyHyogo Cancer CenterAkashiJapan
| | - Bernard Cribier
- CARADERM Network, Fédération de Recherche CliniqueLilleFrance
- Dermatology ClinicHôpitaux Universitaires and Université de Strasbourg, Hôpital CivilStrasbourgFrance
| | - Eduardo Calonje
- Department of Dermatopathology, St John's Institute of DermatologySt Thomas’ HospitalLondonUK
| | - Saleem Taibjee
- Dermatology DepartmentDorset County Hospital NHS Foundation TrustDorchesterUK
| | - Maxime Battistella
- CARADERM Network, Fédération de Recherche CliniqueLilleFrance
- Department of PathologySaint‐Louis University HospitalParisFrance
| | - Thibault Kervarrec
- Department of PathologyUniversité de Tours, Centre Hospitalier Universitaire de ToursToursFrance
- CARADERM Network, Fédération de Recherche CliniqueLilleFrance
- Biologie des infections à polyomavirus teamUniversité de ToursToursFrance
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Fujii C, Mochizuki A, Dreike S, Jeter JM. Genetic Drivers in Sebaceous Neoplasms: A Review of Germline and Somatic Mutations and Their Role in Treatment and Management Strategies. Cancers (Basel) 2025; 17:659. [PMID: 40002254 PMCID: PMC11852771 DOI: 10.3390/cancers17040659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 02/09/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Background: The efficacy of germline testing in colorectal cancer has been proven; however, germline testing in individuals with sebaceous neoplasms is less well defined. This review aims to summarize the literature on sebaceous neoplasms to date, describing the somatic tumor profiles, tumor screening methods, and personal and family history that are suspicious of a germline mutation. Sebaceous neoplasms can be attributed to a variety of etiologies, including UV exposure, immunodeficiency, germline mutations, or multifactorial influences associated with aging. Sebaceous tumors with abnormal microsatellite instability and mismatch repair deficiency are indicative of a germline mutation in 20-50% of cases, which is similar to rates found in colorectal tumors. Personal and familial history can also be suggestive of a germline etiology in these patients and should be assessed routinely, as approximately 30% of individuals with sebaceous neoplasms carry a germline mutation. We outline a strategy for the identification of individuals at risk for germline mutations, recommendations for the management of mutation carriers, and treatment options for individuals with sebaceous neoplasms. Conclusions: Sebaceous tumors are most often sporadic; however, evaluations of a germline etiology are prudent to effectively identify those at risk of additional malignancies as well as at-risk family members. Referral to genetic counseling and germline genetic testing for individuals at risk can significantly impact cancer treatment and screening in patients and their families.
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Affiliation(s)
| | | | | | - Joanne M. Jeter
- City of Hope, Clinical Cancer Genomics, Center for Precision Medicine, Duarte, CA 91010, USA; (C.F.); (A.M.); (S.D.)
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Zhang MG, Gallo RA, Tan CH, Camacho M, Fasih-Ahmad S, Moeyersoms AHM, Sayegh Y, Dubovy SR, Pelaez D, Rong AJ. Single-Cell RNA Profiling of Ocular Adnexal Sebaceous Carcinoma Reveals a Complex Tumor Microenvironment and Identifies New Biomarkers. Am J Ophthalmol 2025; 270:8-18. [PMID: 39393421 PMCID: PMC11735305 DOI: 10.1016/j.ajo.2024.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/23/2024] [Accepted: 10/03/2024] [Indexed: 10/13/2024]
Abstract
PURPOSE Ocular adnexal sebaceous carcinoma (OaSC) is an aggressive malignancy that often necessitates orbital exenteration. Its tumor composition and transcriptional profile remain largely unknown, which poses a significant barrier to medical advances. Here, we report the first in-depth transcriptomic analysis of OaSC at the single-cell resolution and discern mechanisms underlying cancer progression for the discovery of potential globe-sparing immunotherapies, targeted therapies, and biomarkers to guide clinical management. DESIGN Laboratory investigation with a retrospective observational case series. METHODS Single-cell RNA sequencing was performed on six patient specimens: three primary tumors, two tumors with pagetoid spread, and a normal tarsus sample. Cellular components were identified via gene signatures. Molecular pathways underlying tumorigenesis and pagetoid spread were discerned via gene ontology analysis of the differentially expressed genes between specimens. CALML5 immunohistochemistry was performed on an archival cohort of OaSC, squamous cell carcinoma, ocular surface squamous neoplasia (OSSN), and basal cell carcinoma cases. RESULTS Analysis of 29,219 cells from OaSC specimens revealed tumor, immune, and stromal cells. Tumor-infiltrating immune cells include a diversity of cell types, including exhausted T-cell populations. In primary OaSC tumors, mitotic nuclear division and oxidative phosphorylation pathways are upregulated, while lipid biosynthesis and metabolism pathways are downregulated. Epithelial tissue migration pathways are upregulated in tumor cells undergoing pagetoid spread. Single-cell RNA sequencing analyses also revealed that CALML5 is upregulated in OaSC tumor cells. Diffuse nuclear and cytoplasmic CALML5 staining was present in 28 of 28 (100%) OaSC cases. Diffuse nuclear and membranous CALML5 staining was present in 5 of 25 (20%) squamous cell carcinoma and OSSN cases, while diffuse nuclear staining was present in 1 of 12 (8%) basal cell carcinoma cases. CONCLUSIONS This study reveals a complex OaSC tumor microenvironment and confirms that the CALML5 immunohistochemical stain is a sensitive diagnostic marker.
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Affiliation(s)
- Michelle G Zhang
- From the Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center (M.G.Z., R.A.G., A.H.M., D.P., and A.J.R.), Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA; Sylvester Comprehensive Cancer Center (M.G.Z., R.A.G., D.P., and A.J.R.), University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Ryan A Gallo
- From the Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center (M.G.Z., R.A.G., A.H.M., D.P., and A.J.R.), Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA; Sylvester Comprehensive Cancer Center (M.G.Z., R.A.G., D.P., and A.J.R.), University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Charissa H Tan
- Department of Ophthalmology (C.H.T., M.C., S.F.A., Y.S., and S.R.D.), Florida Lions Ocular Pathology Laboratory, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Matthew Camacho
- Department of Ophthalmology (C.H.T., M.C., S.F.A., Y.S., and S.R.D.), Florida Lions Ocular Pathology Laboratory, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Sohaib Fasih-Ahmad
- Department of Ophthalmology (C.H.T., M.C., S.F.A., Y.S., and S.R.D.), Florida Lions Ocular Pathology Laboratory, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Acadia H M Moeyersoms
- From the Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center (M.G.Z., R.A.G., A.H.M., D.P., and A.J.R.), Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA; Sylvester Comprehensive Cancer Center (M.G.Z., R.A.G., D.P., and A.J.R.), University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Yoseph Sayegh
- Department of Ophthalmology (C.H.T., M.C., S.F.A., Y.S., and S.R.D.), Florida Lions Ocular Pathology Laboratory, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Sander R Dubovy
- Department of Ophthalmology (C.H.T., M.C., S.F.A., Y.S., and S.R.D.), Florida Lions Ocular Pathology Laboratory, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Daniel Pelaez
- From the Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center (M.G.Z., R.A.G., A.H.M., D.P., and A.J.R.), Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA; Sylvester Comprehensive Cancer Center (M.G.Z., R.A.G., D.P., and A.J.R.), University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Andrew J Rong
- From the Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center (M.G.Z., R.A.G., A.H.M., D.P., and A.J.R.), Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA; Sylvester Comprehensive Cancer Center (M.G.Z., R.A.G., D.P., and A.J.R.), University of Miami Miller School of Medicine, Miami, Florida, USA; Division of Oculofacial Plastic, Reconstructive, and Orbital Surgery (A.J.R.), Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
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Starrett GJ, Baikie BC, Stoff BK, Grossniklaus HE, Van Buren I, Berry EG, Novoa RA, Rieger KE, Sarin KY, Lynch CF, Royer MC, Piaskowski ML, Brownell I, Chu EY, Godse R, Chen SC, Yu KJ, Goldstein AM, Engels EA, Sargen MR. Multiomics Profiling Distinguishes Sebaceous Carcinoma from Benign Sebaceous Neoplasms and Provides Insight into the Genetic Evolution of Sebaceous Carcinogenesis. Clin Cancer Res 2024; 30:4887-4899. [PMID: 39287419 PMCID: PMC11530307 DOI: 10.1158/1078-0432.ccr-24-1327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/07/2024] [Accepted: 08/16/2024] [Indexed: 09/19/2024]
Abstract
PURPOSE 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. EXPERIMENTAL DESIGN 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. RESULTS 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. CONCLUSIONS The study findings highlight key diagnostic biomarkers for sebaceous carcinoma and suggest that immunotherapy and modulation of cholesterol biosynthesis could be effective treatment strategies.
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Affiliation(s)
- Gabriel J. Starrett
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Brittany C. Baikie
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Benjamin K. Stoff
- Department of Dermatology, Emory University School of Medicine, Atlanta, GA
| | - Hans E. Grossniklaus
- Department of Ophthalmology, Emory University School of Medicine, Emory University, Atlanta, GA
| | - Inga Van Buren
- Dignity Health St. Joseph’s Medical Center, Stockton, CA
| | - Elizabeth G. Berry
- Department of Dermatology and Knight Cancer Institute, Oregon Health & Science University, Portland, OR
| | - Roberto A. Novoa
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA
- Department of Pathology, Stanford University School of Medicine, Stanford, CA
| | - Kerri E. Rieger
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA
- Department of Pathology, Stanford University School of Medicine, Stanford, CA
| | - Kavita Y. Sarin
- Department of Dermatology, Stanford University School of Medicine, Stanford, CA
| | - Charles F. Lynch
- Iowa Cancer Registry, Department of Epidemiology, The University of Iowa, Iowa City, IA
| | - Michael C. Royer
- Division of Dermatopathology, The Joint Pathology Center, Silver Spring, MD
| | - Mary L. Piaskowski
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Isaac Brownell
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
| | - Emily Y. Chu
- Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Rama Godse
- Department of Internal Medicine, Pennsylvania Hospital, Philadelphia, PA
| | - Suephy C. Chen
- Duke Dermatology, Duke University School of Medicine, Durham, NC
| | - Kelly J. Yu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD
| | - Alisa M. Goldstein
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD
| | - Eric A. Engels
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD
| | - Michael R. Sargen
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD
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Jayaraj P, Ray D, Goel K, Singh A, Kant N, Sen S. Molecular landscape of eyelid sebaceous gland carcinoma: A comprehensive review. Indian J Ophthalmol 2024; 72:1393-1403. [PMID: 39331429 PMCID: PMC11573021 DOI: 10.4103/ijo.ijo_167_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 05/05/2024] [Accepted: 05/25/2024] [Indexed: 09/28/2024] Open
Abstract
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.
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Affiliation(s)
- Perumal Jayaraj
- Department of Zoology, Sri Venkateswara College, University of Delhi, Delhi, India
| | - Debjeet Ray
- Department of Zoology, Sri Venkateswara College, University of Delhi, Delhi, India
| | - Kevika Goel
- Department of Zoology, Sri Venkateswara College, University of Delhi, Delhi, India
| | - Ananya Singh
- Department of Zoology, Sri Venkateswara College, University of Delhi, Delhi, India
| | - Nimita Kant
- Department of Zoology, Shivaji College, University of Delhi, Delhi, India
| | - Seema Sen
- Department of Ocular Pathology, Dr. Rajendra Prasad Centre for Ophthalmic Science, All India Institute of Medical Science, New Delhi, India
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Lee SC, Peterson C, Wang K, Alaali L, Eshleman J, Mahoney NR, Li E, Eberhart CG, Campbell AA. Establishment and Characterization of Three Human Ocular Adnexal Sebaceous Carcinoma Cell Lines. Int J Mol Sci 2024; 25:10183. [PMID: 39337668 PMCID: PMC11432008 DOI: 10.3390/ijms251810183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 09/14/2024] [Accepted: 09/21/2024] [Indexed: 09/30/2024] Open
Abstract
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.
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Affiliation(s)
- Su-Chan Lee
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (S.-C.L.)
| | - Cornelia Peterson
- Department of Comparative Pathobiology, Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA;
| | - Kaixuan Wang
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Lujain Alaali
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (S.-C.L.)
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - James Eshleman
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (S.-C.L.)
| | - Nicholas R. Mahoney
- Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Emily Li
- Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Charles G. Eberhart
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (S.-C.L.)
- Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ashley A. Campbell
- Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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8
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Utikal J, Nagel P, Müller V, Becker JC, Dippel E, Frisman A, Gschnell M, Griewank K, Hadaschik E, Helbig D, Hillen U, Leiter U, Pföhler C, Krönig L, Ziemer M, Ugurel S. S1-Guideline Sebaceous Carcinoma. J Dtsch Dermatol Ges 2024; 22:730-747. [PMID: 38679790 DOI: 10.1111/ddg.15405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/19/2024] [Indexed: 05/01/2024]
Abstract
Sebaceous gland carcinomas are rare malignant cutaneous adnexal tumors with sebocytic differentiation. The typical predilection area is the head and neck region, where sebaceous gland carcinomas are the most common malignant adnexal tumors of the skin. According to their localization a distinction is made between periocular and extraocular sebaceous gland carcinomas. Muir-Torre syndrome (MTS) should always be ruled out if it is suspected. In terms of prognosis, sebaceous gland carcinomas are potentially aggressive tumors with a clear tendency to recur and metastasize. Only small extraocular sebaceous gland carcinomas that have been completely resected have a very good prognosis. Sebaceous gland carcinomas most frequently metastasize lymphogenously to regional or distant lymph nodes; organ metastasis occurs less frequently. Periocular sebaceous gland carcinomas have a higher metastasis rate (up to 15%) than extraocular sebaceous gland carcinomas (up to 2%). Complete micrographically controlled surgery (MCS) of the primary tumor is the therapy of first choice, regardless of periocular or extraocular localization. Adjuvant or therapeutic radiotherapy may be considered. There is currently no established standard therapy for advanced, inoperable, or metastatic sebaceous gland carcinomas. Local procedures and systemic therapies such as chemotherapy or immunotherapy can be considered. The procedure should be determined individually by an interdisciplinary tumor board. Close follow-up care is recommended for these potentially aggressive carcinomas.
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Affiliation(s)
- Jochen Utikal
- Clinical Cooperation Unit Dermato-Oncology of the German Cancer Research Center (DKFZ) Heidelberg and the Department of Dermatology, Venereology and Allergology, Medical Faculty Mannheim, Ruprecht Karl University Heidelberg, Mannheim, Germany
- DKFZ Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Germany
| | - Pia Nagel
- Clinical Cooperation Unit Dermato-Oncology of the German Cancer Research Center (DKFZ) Heidelberg and the Department of Dermatology, Venereology and Allergology, Medical Faculty Mannheim, Ruprecht Karl University Heidelberg, Mannheim, Germany
- DKFZ Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Germany
| | - Verena Müller
- Clinical Cooperation Unit Dermato-Oncology of the German Cancer Research Center (DKFZ) Heidelberg and the Department of Dermatology, Venereology and Allergology, Medical Faculty Mannheim, Ruprecht Karl University Heidelberg, Mannheim, Germany
- DKFZ Hector Cancer Institute, University Medical Center Mannheim, Mannheim, Germany
| | - Jürgen C Becker
- Translational Skin Cancer Research, Department of Dermatology, University Medical Center Essen, and German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany
| | - Edgar Dippel
- Department of Dermatology and Venereology, Ludwigshafen Medical Center, Ludwigshafen, Germany
| | - Alexander Frisman
- Department of Radiation Therapy, University Hospital Leipzig, Leipzig, Germany
| | - Martin Gschnell
- Department of Dermatology and Allergology, University Hospital Marburg, Marburg, Germany
| | - Klaus Griewank
- Department of Dermatology, Venereology and Allergology, University Medical Center Essen, Essen, Germany
| | - Eva Hadaschik
- Department of Dermatology, Venereology and Allergology, University Medical Center Essen, Essen, Germany
| | - Doris Helbig
- Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany
| | - Uwe Hillen
- Department of Dermatology and Venereology, Vivantes Hospital Neukölln, Berlin, Germany
| | - Ulrike Leiter
- Center for Dermato-Oncology, Department of Dermatology, University Medical Center Tübingen, Tübingen, Germany
| | - Claudia Pföhler
- Department of Dermatology, Venereology and Allergology and Skin Tumor Center, Saarland University Medical School, Homburg, Homburg/Saar, Germany
| | - Lisa Krönig
- Department of Dermatology and Allergology, University Hospital Marburg, Marburg, Germany
| | - Mirjana Ziemer
- Department of Dermatology, Venereology and Allergology, University Hospital Leipzig, Leipzig, Germany
| | - Selma Ugurel
- Department of Dermatology, Venereology and Allergology, University Medical Center Essen, Essen, Germany
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9
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Utikal J, Nagel P, Müller V, Becker JC, Dippel E, Frisman A, Gschnell M, Griewank K, Hadaschik E, Helbig D, Hillen U, Leiter U, Pföhler C, Krönig L, Ziemer M, Ugurel S. S1‐Leitlinie Talgdrüsenkarzinom. J Dtsch Dermatol Ges 2024; 22:730-749. [PMID: 38730519 DOI: 10.1111/ddg.15405_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 02/19/2024] [Indexed: 05/13/2024]
Abstract
Sebaceous gland carcinomas are rare malignant cutaneous adnexal tumors with sebocytic differentiation. The typical predilection area is the head and neck region, where sebaceous gland carcinomas are the most common malignant adnexal tumors of the skin. According to their localization a distinction is made between periocular and extraocular sebaceous gland carcinomas. Muir-Torre syndrome (MTS) should always be ruled out if it is suspected. In terms of prognosis, sebaceous gland carcinomas are potentially aggressive tumors with a clear tendency to recur and metastasize. Only small extraocular sebaceous gland carcinomas that have been completely resected have a very good prognosis. Sebaceous gland carcinomas most frequently metastasize lymphogenously to regional or distant lymph nodes; organ metastasis occurs less frequently. Periocular sebaceous gland carcinomas have a higher metastasis rate (up to 15%) than extraocular sebaceous gland carcinomas (up to 2%). Complete micrographically controlled surgery (MCS) of the primary tumor is the therapy of first choice, regardless of periocular or extraocular localization. Adjuvant or therapeutic radiotherapy may be considered. There is currently no established standard therapy for advanced, inoperable or metastatic sebaceous gland carcinomas. Local procedures and system therapies such as chemotherapy or immunotherapy can be considered. The procedure should be determined individually in an interdisciplinary tumor board. Close follow-up care is recommended for these potentially aggressive carcinomas.
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Affiliation(s)
- Jochen Utikal
- Klinische Kooperationseinheit Dermatoonkologie des Deutschen Krebsforschungszentrums (DKFZ) Heidelberg und der Klinik für Dermatologie, Venerologie und Allergologie, Medizinische Fakultät Mannheim, Ruprecht-Karls-Universität Heidelberg, Mannheim, Deutschland
- DKFZ Hector Krebsinstitut an der Universitätsmedizin Mannheim
| | - Pia Nagel
- Klinische Kooperationseinheit Dermatoonkologie des Deutschen Krebsforschungszentrums (DKFZ) Heidelberg und der Klinik für Dermatologie, Venerologie und Allergologie, Medizinische Fakultät Mannheim, Ruprecht-Karls-Universität Heidelberg, Mannheim, Deutschland
- DKFZ Hector Krebsinstitut an der Universitätsmedizin Mannheim
| | - Verena Müller
- Klinische Kooperationseinheit Dermatoonkologie des Deutschen Krebsforschungszentrums (DKFZ) Heidelberg und der Klinik für Dermatologie, Venerologie und Allergologie, Medizinische Fakultät Mannheim, Ruprecht-Karls-Universität Heidelberg, Mannheim, Deutschland
- DKFZ Hector Krebsinstitut an der Universitätsmedizin Mannheim
| | - Jürgen C Becker
- Translationale Hautkrebsforschung, Klinik für Dermatologie, Universitätsmedizin Essen, und Deutsches Krebsforschungszentrum (DKFZ), Heidelberg
| | - Edgar Dippel
- Klinik für Dermatologie und Venerologie, Klinikum der Stadt Ludwigshafen
| | - Alexander Frisman
- Klinik und Poliklinik für Strahlentherapie, Universitätsklinikum Leipzig
| | - Martin Gschnell
- Klinik für Dermatologie und Allergologie, Universitätsklinikum Marburg
| | - Klaus Griewank
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Essen
| | - Eva Hadaschik
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Essen
| | - Doris Helbig
- Klinik und Poliklinik für Dermatologie und Venerologie, Uniklinikum Köln
| | - Uwe Hillen
- Klinik für Dermatologie und Venerologie, Vivantes Klinikum Neukölln, Berlin
| | - Ulrike Leiter
- Zentrum für Dermatoonkologie, Universitäts-Hautklinik Tübingen, Universitätsklinikum Tübingen
| | - Claudia Pföhler
- Universitätsklinikum des Saarlandes, Klinik für Dermatologie, Venerologie und Allergologie und Hauttumorzentrum am UKS, Homburg/Saar
| | - Lisa Krönig
- Klinik für Dermatologie und Allergologie, Universitätsklinikum Marburg
| | - Mirjana Ziemer
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Leipzig AöR, Leipzig
| | - Selma Ugurel
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Essen
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10
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Jeong SU, Song JS, Lee HJ, Sa HS, Cho KJ. Prognostic Significance of Tumor-Infiltrating Lymphocytes and High-Risk Human Papillomavirus in Ocular Sebaceous Carcinoma: A Comprehensive Analysis. Mod Pathol 2024; 37:100449. [PMID: 38369185 DOI: 10.1016/j.modpat.2024.100449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 02/01/2024] [Accepted: 02/06/2024] [Indexed: 02/20/2024]
Abstract
High-risk human papillomavirus (hrHPV) and tumor-infiltrating lymphocytes (TILs) are known to have prognostic significance in oropharyngeal squamous cell carcinoma. However, their significance in ocular sebaceous carcinoma (OSC) remains unverified because of the rarity of the condition. This study aimed to investigate the association between clinicopathologic features, biomarkers, and hrHPV infection and their potential to predict prognosis in OSC patients. We analyzed the clinicopathologic features of 81 OSC patients from Asan Medical Center between 2000 and 2022. Seventeen biomarkers and hrHPV were examined using immunohistochemistry and DNA in situ hybridization on tissue microarray cores. hrHPV was identified in 31 cases (38.3%). Univariate analysis revealed that hrHPV infection was associated with comedonecrosis (P = .032), high Ki-67 labeling index (≥30%, P = .042), lower expression of E-cadherin (P = .033), and loss of expression of zinc finger protein 750 (P = .023). Multivariate analysis revealed that loss of expression of zinc finger protein 750 (P = .026) remained an independently associated factor for hrHPV. Progression-free survival analysis was performed on 28 patients who were continuously observed for more than 5 years. During a median follow-up duration of 86 months, recurrence or metastasis developed in 14 patients (50%) within the survival cohort, occurring at a median time of 48 months after excision. Univariate analysis indicated that recurrence or metastasis was associated with tumor size (P = .010), high TILs (≥10%; P = .025), lymphovascular invasion (P = 0.043), site of origin (P = .025), and high expression of bcl-2-associated athanogene 3 (P = .039). Multivariate analysis demonstrated that high TILs (P = .017) and site of origin (P = .025) were independent prognostic factors. The prognosis of OSC was hrHPV-independent, and a better prognosis was associated with the site of origin in the order of the gland of Zeis, meibomian gland, and multicentric site, as well as with high TILs.
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Affiliation(s)
- Se Un Jeong
- Department of Pathology, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea
| | - Joon Seon Song
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hee Jin Lee
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ho-Seok Sa
- Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyung-Ja Cho
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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11
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Sangiorgi E, Giannuzzi F, Molinario C, Rapari G, Riccio M, Cuffaro G, Castri F, Benvenuto R, Genuardi M, Massi D, Savino G. Base-Excision Repair Mutational Signature in Two Sebaceous Carcinomas of the Eyelid. Genes (Basel) 2023; 14:2055. [PMID: 38002998 PMCID: PMC10671510 DOI: 10.3390/genes14112055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/03/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
Personalized medicine aims to develop tailored treatments for individual patients based on specific mutations present in the affected organ. This approach has proven paramount in cancer treatment, as each tumor carries distinct driver mutations that respond to targeted drugs and, in some cases, may confer resistance to other therapies. Particularly for rare conditions, personalized medicine has the potential to revolutionize treatment strategies. Rare cancers often lack extensive datasets of molecular and pathological information, large-scale trials for novel therapies, and established treatment guidelines. Consequently, surgery is frequently the only viable option for many rare tumors, when feasible, as traditional multimodal approaches employed for more common cancers often play a limited role. Sebaceous carcinoma of the eyelid is an exceptionally rare cancer affecting the eye's adnexal tissues, most frequently reported in Asia, but whose prevalence is significantly increasing even in Europe and the US. The sole established curative treatment is surgical excision, which can lead to significant disfigurement. In cases of metastatic sebaceous carcinoma, validated drug options are currently lacking. In this project, we set out to characterize the mutational landscape of two sebaceous carcinomas of the eyelid following surgical excision. Utilizing available bioinformatics tools, we demonstrated our ability to identify common features promptly and accurately in both tumors. These features included a Base-Excision Repair mutational signature, a notably high tumor mutational burden, and key driver mutations in somatic tissues. These findings had not been previously reported in similar studies. This report underscores how, in the case of rare tumors, it is possible to comprehensively characterize the mutational landscape of each individual case, potentially opening doors to targeted therapeutic options.
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Affiliation(s)
- Eugenio Sangiorgi
- Sezione di Medicina Genomica, Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.R.); (M.R.); (M.G.)
| | - Federico Giannuzzi
- Ocular Oncology Unit, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (F.G.); (G.C.); (G.S.)
| | - Clelia Molinario
- Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (C.M.); (F.C.); (R.B.)
| | - Giulia Rapari
- Sezione di Medicina Genomica, Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.R.); (M.R.); (M.G.)
| | - Melania Riccio
- Sezione di Medicina Genomica, Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.R.); (M.R.); (M.G.)
| | - Giovanni Cuffaro
- Ocular Oncology Unit, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (F.G.); (G.C.); (G.S.)
| | - Federica Castri
- Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (C.M.); (F.C.); (R.B.)
| | - Roberta Benvenuto
- Division of Anatomic Pathology and Histology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (C.M.); (F.C.); (R.B.)
| | - Maurizio Genuardi
- Sezione di Medicina Genomica, Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.R.); (M.R.); (M.G.)
- UOC Genetica Medica, Fondazione Policlinico Universitario A. Gemelli-IRCCS, 00168 Roma, Italy
| | - Daniela Massi
- Section of Pathology, Department of Health Sciences, University of Florence, 50121 Florence, Italy;
| | - Gustavo Savino
- Ocular Oncology Unit, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (F.G.); (G.C.); (G.S.)
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12
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Kervarrec T, Sohier P, Pissaloux D, de la Fouchardiere A, Cribier B, Battistella M, Macagno N. Genetics of adnexal tumors: An update. Ann Dermatol Venereol 2023; 150:202-207. [PMID: 37270318 DOI: 10.1016/j.annder.2023.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 03/07/2023] [Indexed: 06/05/2023]
Abstract
Cutaneous adnexal tumors form a vast heterogeneous group that include frequent entities that are mostly benign, as well as rare tumors that are occasionally malignant. In contrast to cutaneous tumors arising from the interfollicular epidermis that develop as a result of accumulation of UV-induced DNA damage (basal cell carcinoma, squamous cell carcinoma), the oncogenesis of adnexal tumors is related to a broad spectrum of genetic mechanisms (e.g., point mutation, fusion genes, viral integration, etc.). In this setting, specific and recurrent genetic alterations have been progressively reported, and these allow better classification of these entities. For certain of them, immunohistochemical tools are now available, enabling precise integrated histological and molecular diagnosis since certain entities are linked to well-defined alterations. In this context, we aim in this review to summarize the main molecular tools currently available for the classification of adnexal tumors.
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Affiliation(s)
- T Kervarrec
- CARADERM Network, Lille, France; Department of Pathology, University Hospital Center of Tours, Tours, France.
| | - P Sohier
- CARADERM Network, Lille, France; Department of Pathology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, AP-HP Centre - University of Paris Cité, Paris, France; Faculty of Medicine, University of Paris Cité, Paris, France
| | - D Pissaloux
- Department of Pathology, Centre Léon Bérard, Lyon, France
| | | | - B Cribier
- CARADERM Network, Lille, France; Dermatology Clinic, University Hospital of Strasbourg, Hôpital Civil, Strasbourg, France
| | - M Battistella
- CARADERM Network, Lille, France; Department of Pathology, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, AP-HP Centre - Paris 7, Paris, France
| | - N Macagno
- CARADERM Network, Lille, France; Department of Pathology, AP-HM, University Hospital of la Timone, Marseille, France; University of Aix-Marseille, INSERM U1251, MMG, Marseille, France
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13
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Milman T, Grossniklaus HE, Goldman-Levy G, Kivelä TT, Coupland SE, White VA, Mudhar HS, Eberhart CG, Verdijk RM, Heegaard S, Gill AJ, Jager MJ, Rodríguez-Reyes AA, Esmaeli B, Hodge JC, Cree IA. The 5th Edition of the World Health Organization Classification of Tumours of the Eye and Orbit. Ocul Oncol Pathol 2023; 9:71-95. [PMID: 37900189 PMCID: PMC10601864 DOI: 10.1159/000530730] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 03/22/2023] [Indexed: 10/31/2023] Open
Affiliation(s)
- Tatyana Milman
- Departments of Ophthalmology and Pathology, Wills Eye Hospital, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA
| | - Hans E. Grossniklaus
- Departments of Ophthalmology and Pathology, Emory University School of Medicine, Atlanta, GA, USA
| | - Gabrielle Goldman-Levy
- World Health Organization, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Tero T. Kivelä
- Ophthalmic Pathology Laboratory, Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Sarah E. Coupland
- George Holt Chair of Pathology/Consultant Histopathologist, Liverpool Clinical Laboratories, Liverpool University Hospitals Foundation Trust, Liverpool, UK
| | - Valerie A. White
- World Health Organization, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Hardeep Singh Mudhar
- National Specialist Ophthalmic Pathology Service (NSOPS), Department of Histopathology, Royal Hallamshire Hospital, Sheffield, UK
| | - Charles G. Eberhart
- Departments of Pathology and Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Robert M. Verdijk
- Section Ophthalmic Pathology, Department of Pathology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Steffen Heegaard
- Department of Pathology, Eye Pathology Section and Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Anthony J. Gill
- Department of Pathology, University of Sydney, Sydney, NSW, Australia
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSW, St Leonards, NSW, Australia
- NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, St Leonards, NSW, Australia
| | - Martine J. Jager
- Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
| | - Abelardo A. Rodríguez-Reyes
- Ophthalmic Pathology Service, Asociación para Evitar la Ceguera en México, I.A.P. Faculty of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Bita Esmaeli
- Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, MDAnderson Cancer Center, Houston, TX, USA
| | | | - Ian A. Cree
- World Health Organization, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - on behalf of the WHO Classification of Tumours Editorial Board
- Departments of Ophthalmology and Pathology, Wills Eye Hospital, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA
- Departments of Ophthalmology and Pathology, Emory University School of Medicine, Atlanta, GA, USA
- World Health Organization, International Agency for Research on Cancer, World Health Organization, Lyon, France
- Ophthalmic Pathology Laboratory, Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- George Holt Chair of Pathology/Consultant Histopathologist, Liverpool Clinical Laboratories, Liverpool University Hospitals Foundation Trust, Liverpool, UK
- National Specialist Ophthalmic Pathology Service (NSOPS), Department of Histopathology, Royal Hallamshire Hospital, Sheffield, UK
- Departments of Pathology and Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Section Ophthalmic Pathology, Department of Pathology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Pathology, Eye Pathology Section and Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Pathology, University of Sydney, Sydney, NSW, Australia
- Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital St Leonards NSW, St Leonards, NSW, Australia
- NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards NSW, St Leonards, NSW, Australia
- Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
- Ophthalmic Pathology Service, Asociación para Evitar la Ceguera en México, I.A.P. Faculty of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
- Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, MDAnderson Cancer Center, Houston, TX, USA
- Indiana University School of Medicine, Indianapolis, IN, USA
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14
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Papadimitriou I, Vakirlis E, Sotiriou E, Bakirtzi K, Lallas A, Ioannides D. Sebaceous Neoplasms. Diagnostics (Basel) 2023; 13:diagnostics13101676. [PMID: 37238164 DOI: 10.3390/diagnostics13101676] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/01/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Sebaceous neoplasms describe a group of tumors with sebaceous differentiation commonly seen in lesions located primarily in the face and neck. The majority of these lesions are benign, while malignant neoplasms with sebaceous differentiation are uncommon. Sebaceous tumors present a strong association with the Muir-Torre Syndrome. Patients suspected with this syndrome should undergo neoplasm excision, followed by histopathologic and additional immunohistochemistry and genetics examinations. Clinical and dermoscopic features of the sebaceous neoplasms, as well as management procedures collected from the literature analysis regarding sebaceous carcinoma, sebaceoma/sebaceous adenoma, and sebaceous hyperplasia are described in the current review. A special note is made for describing the Muir-Torre Syndrome in patients presenting multiple sebaceous tumors.
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Affiliation(s)
- Ilias Papadimitriou
- First Department of Dermatology and Venereology, School of Health Science, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece
| | - Efstratios Vakirlis
- First Department of Dermatology and Venereology, School of Health Science, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece
| | - Elena Sotiriou
- First Department of Dermatology and Venereology, School of Health Science, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece
| | - Katerina Bakirtzi
- First Department of Dermatology and Venereology, School of Health Science, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece
| | - Aimilios Lallas
- First Department of Dermatology and Venereology, School of Health Science, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece
| | - Demetrios Ioannides
- First Department of Dermatology and Venereology, School of Health Science, Aristotle University of Thessaloniki, 54643 Thessaloniki, Greece
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15
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Frouin E, Alleyrat C, Godet J, Karayan-Tapon L, Sinson H, Morel F, Lecron JC, Favot L. The M2 macrophages infiltration of sebaceous tumors is linked to the aggressiveness of tumors but not to the mismatch repair pathway. J Cancer Res Clin Oncol 2023:10.1007/s00432-023-04629-x. [PMID: 36763173 DOI: 10.1007/s00432-023-04629-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 02/01/2023] [Indexed: 02/11/2023]
Abstract
PURPOSE The immune microenvironment of sebaceous neoplasms (SNs) has been poorly explored, especially in benign lesions, and never correlated to the mismatch repair (MMR) status. METHODS We conducted an immuno-histological study to analyze the immune microenvironment of SNs. A tissue microarray was constructed including sebaceous adenomas (SAs), sebaceomas (Ss) and sebaceous carcinomas (SCs) to performed immuno-histological analysis of T cells, B cells, macrophages, dendritic cells, and expression of Programmed Death-1 (PD-1) and Programmed Death Ligand 1 (PD-L1). An automatized count was performed using the QuPath® software. Composition of the cellular microenvironment was compared to the aggressiveness, the MMR status, and to Muir-Torre syndrome (MTS). RESULTS We included 123 SNs (43 SAs, 19 Ss and 61 SCs) for which 71.5% had a dMMR phenotype. A higher infiltration of macrophages (CD68 +) of M2 phenotype (CD163 +) and dendritic cells (CD11c +) was noticed in SCs compared to benign SNs (SAs and Ss). Programmed cell death ligand-1 but not PD-1 was expressed by more immune cells in SCs compared to benign SNs. No difference in the immune cell composition regarding the MMR status, or to MTS was observed. CONCLUSION In SNs, M2 macrophages and dendritic cells infiltrates are associated with the progression and the malignant transformation of tumors. High PD-L1 expression in immune cells in SCs is an argument for the use of immunotherapy by anti-PD1 or PD-L1 in metastatic patients. The lack of correlation between the composition of immune cells in SNs and the MMR status emphasizes the singularity of SNs among MMR-associated malignancies.
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Affiliation(s)
- Eric Frouin
- Pathology Department, University Hospital of Poitiers, Poitiers, France. .,LITEC, Université de Poitiers, Poitiers, France.
| | - Camille Alleyrat
- Plateforme Méthodologie Biostatistiques, Data-Management, University Hospital of Poitiers, 86073, Poitiers, France
| | - Julie Godet
- Pathology Department, University Hospital of Poitiers, Poitiers, France
| | - Lucie Karayan-Tapon
- ProDiCeT, Université de Poitiers, Poitiers, France.,Department of Cancer Biology, CHU de Poitiers, University Hospital of Poitiers, Poitiers, France
| | - Hélinie Sinson
- Pathology Department, University Hospital of Poitiers, Poitiers, France
| | | | - Jean-Claude Lecron
- LITEC, Université de Poitiers, Poitiers, France.,Department of Immunology and Inflammation, University Hospital of Poitiers, Poitiers, France
| | - Laure Favot
- LITEC, Université de Poitiers, Poitiers, France
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16
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Ju W, Luo GF, Shi YY, Zhou FJ, Li MQ, Xu JH, Yan ZX, Yang XH. Sebaceous Carcinoma of the Submandibular Gland a Case Report and Review of the Literature. Cancer Manag Res 2023; 15:123-130. [PMID: 36776729 PMCID: PMC9910202 DOI: 10.2147/cmar.s392573] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/17/2023] [Indexed: 02/05/2023] Open
Abstract
Objective Sebaceous carcinoma (SC) of the submandibular gland is extremely rare. Owing to the low morbidity and nonspecific clinical manifestations, diagnosis is commonly delayed, which increases metastasis and mortality. To date, there have been five reported cases of SC of the submandibular gland. Here, we present a new case and review the relevant literature. Methods and Results A 36-year-old woman presented with an enlarged left submandibular gland. Clinical features included a non-tender solitary nodular mass with normal overlying skin. There were no special findings on computed tomography or ultrasound examination except for a swollen mass in the left submandibular gland. The patient underwent surgical resection. Pathological examination confirmed the diagnosis of SC with nerve infiltration. Immunohistochemical examination of this case showed positive staining for P63, P40, CK7, CK8/18, MLH1, MSH2, MSH6, and PMS2. The specimen was negative for androgen receptor, CEA, S-100, CK5/6, SOX-10, SOX-11, SMA, and GCDFP-15. The KI-67 labeling index was determined to be 15%. PAS and anti-epithelial membrane antigen were positive in partial area. The patient is still undergoing follow-up, and no metastasis or recurrence has been observed for 2 months. Conclusion This case highlighted the fact that despite its rarity, SC should be considered as a differential diagnosis for masses located in the head and face. Early and accurate diagnosis, followed by wide surgical excision, has a favorable prognosis. Therefore, clinicians should be familiar with the clinical and pathological features of this disease.
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Affiliation(s)
- Wei Ju
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China,Department of Burn and Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China
| | - Guan-fa Luo
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China
| | - Yuan-yuan Shi
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China
| | - Fei-jun Zhou
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China
| | - Meng-qi Li
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China
| | - Jian-hui Xu
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China
| | - Zhi-xin Yan
- Department of Burn and Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China
| | - Xi-hu Yang
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, 212001, People’s Republic of China,Correspondence: Xi-hu Yang, Email
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17
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Wang Y, Li J, Hao P, Li J, Han R, Lin J, Li X. Integrated Whole-Exome and Transcriptome Sequencing Indicated Dysregulation of Cholesterol Metabolism in Eyelid Sebaceous Gland Carcinoma. Transl Vis Sci Technol 2023; 12:4. [PMID: 36735267 PMCID: PMC9907373 DOI: 10.1167/tvst.12.2.4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Purpose To identify the molecular background of eyelid sebaceous gland carcinomas (SCs), we conducted the integrated whole-exome sequencing and transcriptome sequencing for eyelid SCs in this study. Methods The genetic alterations were studied by whole-exome sequencing, and the messenger RNA expression was studied using Oxford Nanopore Technologies (ONT) in five paired fresh eyelid SC tissues and adjacent normal tissues. Integrated analysis of exome and transcriptomic information was conducted for filtering candidate driver genes. Protein-protein interaction (PPI) network of filtered candidate genes was analyzed by STRING. The protein expression was verified by immunohistochemistry in 29 eyelid SCs and 17 compared normal sebaceous gland tissues. Results The average numbers of pathogenic somatic single-nucleotide variants (SNVs) and indels in eyelid SCs were 75 and 28, respectively. Tumor protein p53 (TP53), zinc finger protein 750 (ZNF750), filaggrin 2 (FLG2), valosin-containing protein (VCP), and zinc finger protein 717 (ZNF717) were recurrent mutated genes. A mean of 844 differentially expressed genes (DEGs) were upregulated, and 1401 DEGs were downregulated in SC samples. The intersection of DEG-based pathways and mutation-based pathways was mainly involved in microbial infection and inflammation, immunodeficiency, cancer, lipid metabolism, and the other pathways. The intersection of DEGs and mutated genes consisted of 55 genes, of which 15 genes formed a PPI network with 4 clusters. The PPI cluster composed of scavenger receptor class B member 1 (SCARB1), peroxisome proliferator-activated receptor γ (PPARG), peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A) was involved in cholesterol metabolism. The expression of SCARB1 protein was found to be increased, whereas that of PPARG protein was decreased in eyelid SCs compared to that in the normal sebaceous glands. Conclusions Increased SCARB1 and decreased PPARG indicated that dysregulation of cholesterol metabolism might be involved in carcinogenesis of eyelid SCs. Translational Relevance The malfunction in cholesterol metabolism might advance our knowledge of the carcinogenesis of eyelid SCs.
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Affiliation(s)
- Yuchuan Wang
- Tianjin Eye Hospital, Tianjin Key lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin, China,Nankai University Affiliated Eye Hospital, Tianjin, China,Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China
| | - Jun Li
- Tianjin Eye Hospital, Tianjin Key lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin, China,Nankai University Affiliated Eye Hospital, Tianjin, China,Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China
| | - Peng Hao
- Tianjin Eye Hospital, Tianjin Key lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin, China,Nankai University Affiliated Eye Hospital, Tianjin, China,Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China
| | - Jing Li
- Tianjin Eye Hospital, Tianjin Key lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin, China,Nankai University Affiliated Eye Hospital, Tianjin, China,Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China
| | - Ruifang Han
- Tianjin Eye Hospital, Tianjin Key lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin, China,Nankai University Affiliated Eye Hospital, Tianjin, China,Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China
| | - Jinyong Lin
- Tianjin Eye Hospital, Tianjin Key lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin, China,Nankai University Affiliated Eye Hospital, Tianjin, China,Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China
| | - Xuan Li
- Tianjin Eye Hospital, Tianjin Key lab of Ophthalmology and Visual Science, Tianjin Eye Institute, Tianjin, China,Nankai University Affiliated Eye Hospital, Tianjin, China,Clinical College of Ophthalmology, Tianjin Medical University, Tianjin, China
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18
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Muacevic A, Adler JR. Germline Testing of Mismatch Repair Genes Is Needed in the Initial Evaluation of Patients With Muir-Torre Syndrome-Associated Cutaneous Sebaceous Neoplasms: A Case Series. Cureus 2023; 15:e33975. [PMID: 36824550 PMCID: PMC9941027 DOI: 10.7759/cureus.33975] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
Muir-Torre syndrome, a subtype of Lynch syndrome, is characterized by a germline mutation of one or more mismatch repair genes such as MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2, mismatch repair system component (PMS2) resulting in microsatellite instability and at least one malignancy and a minimum of one syndrome-associated sebaceous neoplasm such as a sebaceous adenoma, epithelioma, or carcinoma. The syndrome has an autosomal dominant mode of inheritance detectable with germline sequencing of normal body elements such as blood, saliva, or normal skin for a mismatch repair gene mutation. Sebaceous neoplasms can occur before, concurrent with, or following Muir-Torre syndrome-related cancer. Immunohistochemistry, microsatellite instability testing, and next-generation sequencing of tumor tissue can evaluate malignancies such as colorectal and endometrial cancer and sebaceous neoplasms for somatic mismatch repair gene defects. However, these tests cannot differentiate somatic (acquired) versus germline alterations, and immunohistochemistry and microsatellite stability assessment can produce false negatives. Finally, the Mayo Muir-Torre syndrome risk score algorithm cannot always reliably determine which patient with a new sebaceous neoplasm should have germline testing. We report three men who presented with a Muir-Torre syndrome-associated sebaceous neoplasm: a 67-year-old male with no personal or family history of cancer who presented with a chest sebaceous carcinoma with MSH2 and MSH6 gene expression loss on immunohistochemistry and a Mayo Muir-Torre syndrome risk score of 0 who declined germline testing; a 74-year-old male with Janus kinase 2 (JAK2)-related myelodysplastic syndrome, yet no history of a Lynch syndrome-associated cancer, who developed a sebaceous epithelioma on his leg with PMS2 gene expression loss by immunohistochemistry and, although Mayo Muir-Torre syndrome risk score was only 1 (suggests no likelihood of a Lynch syndrome germline mismatch repair gene mutation), germline testing demonstrated a PMS2 alteration; and a 59-year-old male with a germline-confirmed MLH1-associated Lynch syndrome and a prior colon carcinoma, who developed a sebaceous adenoma on his nostril that unexpectedly demonstrated preservation of normal MLH1 staining (reflecting a false negative) by immunohistochemistry. In summary, these cases are consistent with the literature suggesting that tumor immunohistochemistry and microsatellite stability testing can miss germline alterations. Hence, we recommend that the initial evaluation of a patient with even a single new Muir-Torre syndrome-associated sebaceous neoplasm should include germline mismatch repair gene mutation testing. Finding a mismatch repair gene germline mutation should prompt genetic counseling, initial and future cancer screening recommendations, and germline testing of family members.
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19
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Makaranka S, Frixou M, Mustafa A, Husain E. Cutaneous Sebaceous Carcinoma Presenting as a Large Fungating Breast Tumour in Synchronicity With Primary Carcinomata of the Breasts. Cureus 2022; 14:e28896. [PMID: 36237742 PMCID: PMC9544537 DOI: 10.7759/cureus.28896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2022] [Indexed: 11/21/2022] Open
Abstract
Sebaceous carcinomas are rare malignant tumours which arise from sebaceous glands. They are subclassified into ocular and extraocular subtypes and most commonly occur in the head and neck region. Tumours below the neck occur infrequently, and most commonly resemble benign skin lesions such as pyogenic granulomata and molluscum contagiosum, or malignant skin tumours like basal and squamous cell carcinomas (SCCs). We report a case of an 86-year-old lady presenting with a fungating breast tumour which began as a “mole” and exhibited insidious growth over five years to reach a maximum size of 10 cm. An excision biopsy was performed by the breast surgery team and histopathological analysis revealed a sebaceous carcinoma arising from the skin adnexa. On subsequent follow up, the patient was found to have a 19 mm mass in the left breast and a 20 mm mass in the right breast, which was P5 and P3 on clinical palpation, respectively. Core biopsies of left and right breast lesions showed invasive lobular carcinoma and invasive ductal carcinoma with lobular features respectively; the patient was started on primary letrozole treatment. The patient also went on to have a 2 cm wide local excision of the sebaceous carcinoma scar which was excised down to the pectoralis fascia. This is a unique presentation of a sebaceous gland carcinoma presenting as a fungating breast tumour. These tumours have a high metastatic potential and local recurrence rate, and can co-exist with primary carcinoma of the breast.
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20
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Sebaceous Carcinoma of the Eyelid in a Patient with Muir-Torre Syndrome Treated with Pembrolizumab: A Case Report. CURRENT PROBLEMS IN CANCER: CASE REPORTS 2022. [DOI: 10.1016/j.cpccr.2022.100156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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21
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Cheng AY, Lan J, Lee CH. Impaired Wnt/beta-catenin and protein patched homolog 1 signaling in extraocular sebaceous carcinoma: A clinical and histopathological study. J Dermatol 2022; 49:600-606. [PMID: 35318716 DOI: 10.1111/1346-8138.16351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/07/2022] [Accepted: 02/22/2022] [Indexed: 11/29/2022]
Abstract
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.
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Affiliation(s)
- An-Yu Cheng
- Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jui Lan
- Department of Anatomic Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chih-Hung Lee
- Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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22
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Treatment of Malignant Adnexal Tumors of the Skin: A 12-Year Perspective. Cancers (Basel) 2022; 14:cancers14040998. [PMID: 35205753 PMCID: PMC8870474 DOI: 10.3390/cancers14040998] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 01/25/2023] Open
Abstract
Malignant adnexal cancers of the skin—extremely rare neoplasms—are mostly reported as non-symptomatic, slow-growing nodules. These carcinomas occur mainly in the middle-aged (50–60 years of age); they are mostly localized on the upper part of the body and are locally aggressive, infiltrate surrounding tissue, and metastasize to regional lymph nodes. The patients’ outcomes depend on multiple prognostic factors, including the size of the primary tumor and its mitotic count. Surgical resection of the primary tumor with or without regional lymph nodes is the treatment method of choice; however, due to aggressive tumor behavior, perioperative treatment may be considered. The role and efficacy of radiotherapy in the treatment of skin adnexal malignancies are not yet fully defined. Some authors suggest that adjuvant radiotherapy may be considered in locally advanced and regional disease. The aim of this study was to evaluate treatment outcomes and assess the efficacy of combined therapy in patients with adnexal malignancies. Our analysis covered all cases of cutaneous adnexal tumor patients diagnosed and provided with multidisciplinary treatment with surgery and radiotherapy since the beginning of 2009.
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23
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Yang Y, Su X, Shen K, Zhang C, Dai H, Ma H, Jiang Y, Shuai L, Liu Z, You J, Min K, Chen Z. PUM1 is upregulated by DNA methylation to suppress antitumor immunity and results in poor prognosis in pancreatic cancer. Transl Cancer Res 2022; 10:2153-2168. [PMID: 35116535 PMCID: PMC8798770 DOI: 10.21037/tcr-20-3295] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 02/26/2021] [Indexed: 12/24/2022]
Abstract
Background Pancreatic carcinoma (PAAD) is a highly malignant cancer with a poor prognosis and high mortality rate. Pumilio homologous protein 1 (PUM1) promotes cell growth, invasion, and metastasis and suppresses apoptosis in many different kinds of cancers, such as non-small-cell lung carcinoma (NSCLC), ovarian cancer and lymphocyte leukemia. However, the underlying mechanism and potential role of PUM1 in PAAD have not been investigated. Methods Bioinformatics analysis was performed using multiple databases [The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), BBCancer, Human Protein Atlas (HPA), MethSurv, cBioPortal, The Cancer Imaging Archive (TCIA), xCell, Gene Expression Omnibus (GEO)] to explore the diagnostic and prognostic role of PUM1, and the relationship between expression of PUM1 and prognosis of patients with PAAD. The analysis was further validated using the Kaplan-Meier plotter. Results PUM1 plays a role in both diagnostic and prognostic prediction. The PUM1 mRNA expression level correlates with both the prognosis and incidence of pancreatic cancer. PUM1 can serve as a potential diagnostic indicator for pancreatic cancer. Furthermore, the DNA methylation levels of PUM1 affects its oncogene function in pancreatic cancer. PUM1 can also inhibit the immune microenvironment by altering immune cell infiltration, which affects immunotherapy response in pancreatic cancer. Conclusions PUM1 takes a crucial part in the immune microenvironment and immunotherapy response of PAAD and is potentially useful for the development of novel diagnostic and treatment strategies.
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Affiliation(s)
- Yishi Yang
- Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Xingxing Su
- Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Kaicheng Shen
- Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Chengcheng Zhang
- Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Haisu Dai
- Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Hongbo Ma
- Department of Oncology, The Fuling Central Hospital of Chongqing City, Chongqing, China
| | - Yan Jiang
- Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Ling Shuai
- Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Zhipeng Liu
- Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Jinshan You
- Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Ke Min
- Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
| | - Zhiyu Chen
- Department of Hepatobiliary Surgery, Southwest Hospital, First Affiliated Hospital of the Army Medical University, Chongqing, China
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24
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Zhang C, Zhu L, Liu X, Jiang M, Tang Q, Xu F, Lin T, He Y. Establishment of a human meibomian gland carcinoma cell model and analysis of differently expressed genes. Exp Eye Res 2022; 219:108983. [DOI: 10.1016/j.exer.2022.108983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 11/24/2022]
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25
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Plotzke JM, Adams DJ, Harms PW. Molecular pathology of skin adnexal tumours. Histopathology 2022; 80:166-183. [PMID: 34197659 DOI: 10.1111/his.14441] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 06/30/2021] [Indexed: 11/28/2022]
Abstract
AIMS Tumours of the cutaneous adnexa arise from, or differentiate towards, structures in normal skin such as hair follicles, sweat ducts/glands, sebaceous glands or a combination of these elements. This class of neoplasms includes benign tumours and highly aggressive carcinomas. Adnexal tumours often present as solitary sporadic lesions, but can herald the presence of an inherited tumour syndrome such as Muir-Torre syndrome, Cowden syndrome or CYLD cutaneous syndrome. In contrast to squamous cell carcinoma and basal cell carcinoma, molecular changes in adnexal neoplasia have been poorly characterised and there are few published reviews on the current state of knowledge. METHODS AND RESULTS We reviewed findings in peer-reviewed literature on molecular investigations of cutaneous adnexal tumours published to June 2021. CONCLUSIONS Recent discoveries have revealed diverse oncogenic drivers and tumour suppressor alterations in this class of tumours, implicating pathways including Ras/MAPK, PI3K, YAP/TAZ, beta-catenin and nuclear factor kappa B (NF-κB). These observations have identified novel markers, such as NUT for poroma and porocarcinoma and PLAG1 for mixed tumours. Here, we provide a comprehensive overview and update of the molecular findings associated with adnexal tumours of the skin.
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Affiliation(s)
- Jaclyn M Plotzke
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | | | - Paul W Harms
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
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Krishnamurthy K, Urioste SN, Cusnir M, Schwartz M, Alghamdi S, Sriganeshan V, Poppiti R. Analysis of Genetic Alterations in Cutaneous Malignant Melanomas Unveils Unique Loco-Regional Variations and Novel Predictors of Metastatic Potential. Am J Dermatopathol 2021; 43:e185-e189. [PMID: 33859081 DOI: 10.1097/dad.0000000000001953] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
ABSTRACT Cutaneous malignant melanoma is an aggressive cancer that contributes significantly to cancer-related mortality. Over the years, a deeper scrutiny of melanoma biology has led to identification of diverse evolutionary patterns involving various genetic pathways. This study attempts to further understand the genetic landscape of cutaneous malignant melanoma in terms of loco-regional variations and malignant potential. Thirty-five cases of cutaneous malignant melanoma were retrieved from the archives and were classified based on location of the primary tumor and presence or absence of metastatic disease. Next-generation sequencing data consisting of base substitutions, copy number variations, indels, and rearrangements in a total of 324 genes were analyzed for recurrent genetic alterations. Statistical analysis was performed using IBM SPSS26 software. Mutations in KDM gene family were found in 62.5% of the melanomas in the head and neck as compared with 10% in melanomas of the extremity and trunk (P = 0.03). Mutations in the RAS gene family were found in 70% of melanomas in the extremities as compared to 12.5% in melanomas of the head and neck (P = 0.003). BTK gene mutations were found exclusively in melanomas of the head and neck (P = 0.032). CREBBP mutations were seen in 50% of the nonmetastatic melanomas as compared with 3.57% of metastatic melanomas (P = 0.005). This study highlights the loco-regional variations in cutaneous malignant melanoma for genetic alterations involving the KDM, RAS, and BTK gene family. In addition, the CREBBP mutational status is identified as a potential prognostic marker for predicting metastatic potential in cutaneous malignant melanomas.
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Affiliation(s)
- Kritika Krishnamurthy
- A.M. Rywlin, MD Department of Pathology, Mount Sinai Medical Center, Miami Beach, FL
| | - Sophia N Urioste
- Department of Pathology, Florida International University, Herbert Wertheim College of Medicine, Miami, FL; and
| | - Mike Cusnir
- Department of Medical Oncology, Mount Sinai Medical Center, Miami Beach, FL
| | - Michael Schwartz
- Department of Medical Oncology, Mount Sinai Medical Center, Miami Beach, FL
| | - Sarah Alghamdi
- A.M. Rywlin, MD Department of Pathology, Mount Sinai Medical Center, Miami Beach, FL
- Department of Pathology, Florida International University, Herbert Wertheim College of Medicine, Miami, FL; and
| | - Vathany Sriganeshan
- A.M. Rywlin, MD Department of Pathology, Mount Sinai Medical Center, Miami Beach, FL
- Department of Pathology, Florida International University, Herbert Wertheim College of Medicine, Miami, FL; and
| | - Robert Poppiti
- A.M. Rywlin, MD Department of Pathology, Mount Sinai Medical Center, Miami Beach, FL
- Department of Pathology, Florida International University, Herbert Wertheim College of Medicine, Miami, FL; and
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Zhang C, Zhu L, Liu X, Jiang M, Tang Q, Xu F, Lin T, Dong L, He Y. MicroRNA-3907 promotes the proliferation and migration of sebaceous gland carcinoma of the eyelid by targeting thrombospondin 1. Oncol Lett 2021; 22:833. [PMID: 34691259 PMCID: PMC8527560 DOI: 10.3892/ol.2021.13094] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 09/16/2021] [Indexed: 12/18/2022] Open
Abstract
MicroRNAs (miRNAs/miRs) play an important role in various types of carcinoma, including sebaceous gland carcinoma (SGC) of the eyelid. miR-3907 was found to be highly expressed in lung cancer; however, to the best of our knowledge, the biological role of miR-3907 in SGC has not previously been evaluated. The aim of the present study was to determine the role and mechanism of miR-3907 in the occurrence and development of SGC. miR-3907 was screened and identified as a novel upregulated miRNA in SGC tissues and cells, as determined using miRNA microarrays and reverse transcription-quantitative (RT-q) PCR analyses. Compared with the control group, cellular proliferation and migration were enhanced in the miR-3907 mimics group, and decreased in the miR-3907 inhibitor group. Moreover, miR-3907 negatively regulated thrombospondin 1 (THBS1) expression, as shown by bioinformatics prediction, RT-qPCR, western blotting and dual-luciferase reporter assays. In addition, compared with the control group, the small interfering (si) siRNA-THBS1 group exhibited enhanced proliferation and migration abilities, which were decreased in the THBS1 overexpression group. Furthermore, THBS1 overexpression was found to attenuate the stimulative effect of miR-3907 mimics, and THBS1-knockdown reversed the inhibitory effect of the miR-3907 inhibitor in SGC cells. Collectively, the results of the present study indicated that miR-3907 promoted the proliferation and migration of SGC by downregulating THBS1, and that this axis may be a potential target for the prognostic assessment and treatment of SGC.
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Affiliation(s)
- Chuanli Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Limin Zhu
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Xun Liu
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Meixia Jiang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Qin Tang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Fei Xu
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Tingting Lin
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Lijie Dong
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
| | - Yanjin He
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, P.R. China
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Na HY, Park JH, Shin SA, Lee S, Lee H, Chae H, Choung H, Kim N, Chung JH, Kim JE. Targeted Sequencing Revealed Distinct Mutational Profiles of Ocular and Extraocular Sebaceous Carcinomas. Cancers (Basel) 2021; 13:4810. [PMID: 34638295 PMCID: PMC8508046 DOI: 10.3390/cancers13194810] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/10/2021] [Accepted: 09/22/2021] [Indexed: 11/16/2022] Open
Abstract
The biological behavior of sebaceous carcinoma (SeC) is relatively indolent; however, local invasion or distant metastasis is sometimes reported. Nevertheless, a lack of understanding of the genetic background of SeC makes it difficult to apply effective systemic therapy. This study was designed to investigate major genetic alterations in SeCs in Korean patients. A total of 29 samples, including 20 ocular SeCs (SeC-Os) and 9 extraocular SeCs (SeC-EOs), were examined. Targeted next-generation sequencing tests including 171 cancer-related genes were performed. TP53 and PIK3CA genes were frequently mutated in both SeC-Os and SeC-EOs with slight predominance in SeC-Os, whereas the NOTCH1 gene was more commonly mutated in SeC-EOs. In clinical correlation, mutations in RUNX1 and ATM were associated with development of distant metastases, and alterations in MSH6 and BRCA1 were associated with inferior progression-free survival (all p < 0.05). In conclusion, our study revealed distinct genetic alterations between SeC-Os and SeC-EOs and some important prognostic molecular markers. Mutations in potentially actionable genes, including EGFR, ERBB2, and mismatch repair genes, were noted, suggesting consideration of a clinical trial in intractable cases.
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Affiliation(s)
- Hee Young Na
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.Y.N.); (J.H.P.); (S.A.S.)
- Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Korea
| | - Jeong Hwan Park
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.Y.N.); (J.H.P.); (S.A.S.)
- Department of Pathology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul 07067, Korea
| | - Sun Ah Shin
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.Y.N.); (J.H.P.); (S.A.S.)
- Department of Pathology, National Cancer Center, Goyang 10408, Korea
| | - Sejoon Lee
- Precision Medicine Center, Seoul National University Bundang Hospital, Seongnam 13620, Korea;
| | - Heonyi Lee
- Bioinformatics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Heejoon Chae
- Division of Computer Science, Sookmyung Women’s University, Seoul 04312, Korea;
| | - HoKyung Choung
- Department of Ophthalmology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul 07067, Korea;
| | - Namju Kim
- Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam 13620, Korea;
| | - Jin-Haeng Chung
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.Y.N.); (J.H.P.); (S.A.S.)
- Department of Pathology and Translational Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Korea
| | - Ji Eun Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea; (H.Y.N.); (J.H.P.); (S.A.S.)
- Department of Pathology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul 07067, Korea
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29
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Peterson C, Moore R, Hicks JL, Morsberger LA, De Marzo AM, Zou Y, Eberhart CG, Campbell AA. NGS Analysis Confirms Common TP53 and RB1 Mutations, and Suggests MYC Amplification in Ocular Adnexal Sebaceous Carcinomas. Int J Mol Sci 2021; 22:8454. [PMID: 34445161 PMCID: PMC8395148 DOI: 10.3390/ijms22168454] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/01/2021] [Accepted: 08/04/2021] [Indexed: 01/31/2023] Open
Abstract
Ocular adnexal (OA) sebaceous carcinomas generally demonstrate more aggressive clinical and histopathological phenotypes than extraocular cases, but the molecular drivers implicated in their oncogenesis remain poorly defined. A retrospective review of surgical and ocular pathology archives identified eleven primary resection specimens of OA sebaceous carcinomas with adequate tissue for molecular analysis; two extraocular cases were also examined. Next-generation sequencing was used to evaluate mutations and copy number changes in a large panel of cancer-associated genes. Fluorescence in situ hybridization (FISH) confirmed MYC copy number gain in select cases, and immunohistochemistry to evaluate MYC protein expression. The commonest mutations occurred in TP53 (10/13) and RB1 (7/13). Additional mutations in clinically actionable genes, or mutations with a frequency of at least 25%, included the NF1 (3/12), PMS2 (4/12), ROS1 (3/12), KMT2C (4/12), MNX1 (6/12), NOTCH1 (4/12), PCLO (3/12), and PTPRT (3/12) loci. Low level copy number gain suggestive of amplification of the MYC locus was seen in two cases, and confirmed using FISH. MYC protein expression, as assessed by immunohistochemistry, was present in almost all sebaceous carcinoma cases. Our findings support the concept that alterations in TP53 and RB1 are the commonest alterations in sebaceous carcinoma, and suggest that MYC may contribute to the oncogenesis of these tumors.
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Affiliation(s)
- Cornelia Peterson
- Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
| | - Robert Moore
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (R.M.); (J.L.H.); (L.A.M.); (A.M.D.M.); (Y.Z.)
| | - Jessica L. Hicks
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (R.M.); (J.L.H.); (L.A.M.); (A.M.D.M.); (Y.Z.)
| | - Laura A. Morsberger
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (R.M.); (J.L.H.); (L.A.M.); (A.M.D.M.); (Y.Z.)
- Clinical Cytogenetics Laboratory, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Johns Hopkins Genomics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Angelo M. De Marzo
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (R.M.); (J.L.H.); (L.A.M.); (A.M.D.M.); (Y.Z.)
- Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- The Brady Urological Research Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ying Zou
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (R.M.); (J.L.H.); (L.A.M.); (A.M.D.M.); (Y.Z.)
- Clinical Cytogenetics Laboratory, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Johns Hopkins Genomics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Charles G. Eberhart
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; (R.M.); (J.L.H.); (L.A.M.); (A.M.D.M.); (Y.Z.)
- Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Ashley A. Campbell
- Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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30
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Rong AJ, Gallo RA, Zhang MG, Doddapaneni R, Griswold AJ, Lee JY, Kurtenbach S, Dubovy SR, Tse DT, Pelaez D. Establishment and Characterization of a Novel Human Ocular Adnexal Sebaceous Carcinoma Cell Line. Transl Vis Sci Technol 2021; 10:34. [PMID: 34043754 PMCID: PMC8161695 DOI: 10.1167/tvst.10.6.34] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Purpose Sebaceous carcinoma (SC) is a malignant eyelid tumor of the ocular adnexa that is primarily treated via surgical excision. Few therapies exist in advanced cases, and medical therapy is limited because of our incomplete understanding of SC biology. Herein, we describe a technique to culture human ocular adnexal SC for use as an in vitro model. Methods Human ocular adnexal SC tumor cells were isolated from a patient undergoing orbital exenteration surgery and named Bascom Palmer 50 (BP50). They were cultured in Dulbecco's modified Eagle medium/nutrient mixture F-12 supplemented with 10% fetal bovine serum and antibiotics and were maintained at 37°C in humidified 5% CO2. The cells were characterized by immunohistochemistry, exome sequencing, and short tandem repeats analysis. In vitro drug screening against mitomycin-C (MMC) was performed using a cell viability assay. Results BP50 grew past 40 passages with a doubling time of 52.3 hours. Immunocytochemical staining revealed expression of SC-associated markers adipophilin, epithelial membrane antigen, p53, and androgen receptor. Whole exome sequencing showed a significant carryover in somatic mutations between the tumor tissue and corresponding cell line, revealing genetic markers consistent with SC. MMC affected cell viability in a dose-dependent manner. Conclusions BP50 displays characteristics of ocular adnexal SC and therefore may facilitate improved understanding of SC biology and the high throughput assessment of novel therapeutic compounds and new drug combinatorial approaches targeted for this disease. Translational Relevance Drug screening with MMC against these cells shows in vitro evidence to support its continued clinical use in SC.
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Affiliation(s)
- Andrew J Rong
- Department of Oculoplastic Surgery, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ryan A Gallo
- Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Michelle G Zhang
- Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.,Ocular Oncology Laboratory, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ravi Doddapaneni
- McColl-Lockwood Muscular Dystrophy Laboratory, James G. Cannon Research Center, Atrium Health, Charlotte, NC, USA
| | - Anthony J Griswold
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - John Y Lee
- Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Stefan Kurtenbach
- Ocular Oncology Laboratory, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sander R Dubovy
- Department of Pathology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - David T Tse
- Department of Oculoplastic Surgery, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Daniel Pelaez
- Dr. Nasser Ibrahim Al-Rashid Orbital Vision Research Center, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
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31
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Martel A, Lassalle S, Picard-Gauci A, Gastaud L, Montaudie H, Bertolotto C, Nahon-Esteve S, Poissonnet G, Hofman P, Baillif S. New Targeted Therapies and Immunotherapies for Locally Advanced Periocular Malignant Tumours: Towards a New 'Eye-Sparing' Paradigm? Cancers (Basel) 2021; 13:2822. [PMID: 34198863 PMCID: PMC8201354 DOI: 10.3390/cancers13112822] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/24/2021] [Accepted: 06/02/2021] [Indexed: 12/26/2022] Open
Abstract
The management of periocular skin malignant tumours is challenging. Surgery remains the mainstay of treatment for localised eyelid cancers. For more locally advanced cancers, especially those invading the orbit, orbital exenteration has long been considered the gold standard; however, it is a highly disfiguring and traumatic surgery. The last two decades have been marked by the emergence of a new paradigm shift towards the use of 'eye-sparing' strategies. In the early 2000s, the first step consisted of performing wide conservative eyelid and orbital excisions. Multiple flaps and grafts were needed, as well as adjuvant radiotherapy in selected cases. Although being incredibly attractive, several limitations such as the inability to treat the more posteriorly located orbital lesions, as well as unbearable diplopia, eye pain and even secondary eye loss were identified. Therefore, surgeons should distinguish 'eye-sparing' from 'sight-sparing' strategies. The second step emerged over the last decade and was based on the development of targeted therapies and immunotherapies. Their advantages include their potential ability to treat almost all tumours, regardless of their locations, without performing complex surgeries. However, several limitations have been reported, including their side effects, the appearance of primary or secondary resistances, their price and the lack of consensus on treatment regimen and exact duration. The aim of this article was to review the evolution of the management of locally advanced periocular malignant tumours over the last three decades and highlight the new paradigm shift towards the use of 'eye-sparing' strategies.
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Affiliation(s)
- Arnaud Martel
- Department of Ophthalmology, University Hospital of Nice, Cote d’Azur University, 06000 Nice, France; (S.N.-E.); (S.B.)
- FHU OncoAge, Institute for Research on Cancer and Aging, Nice (IRCAN), Cote d’Azur University, 06000 Nice, France; (S.L.); (P.H.)
| | - Sandra Lassalle
- FHU OncoAge, Institute for Research on Cancer and Aging, Nice (IRCAN), Cote d’Azur University, 06000 Nice, France; (S.L.); (P.H.)
- Biobank BB-0033-00025, FHU OncoAge, IRCAN, Laboratory of Clinical and Experimental Pathology, University Hospital of Nice, 06000 Nice, France
| | - Alexandra Picard-Gauci
- Department of Dermatology, Archet 2 Hospital, 151 Route de Saint-Antoine, 06200 Nice, France; (A.P.-G.); (H.M.)
| | - Lauris Gastaud
- Department of Oncology, Antoine Lacassagne Cancer Centre, 06000 Nice, France;
| | - Henri Montaudie
- Department of Dermatology, Archet 2 Hospital, 151 Route de Saint-Antoine, 06200 Nice, France; (A.P.-G.); (H.M.)
| | - Corine Bertolotto
- Department of Biology and Pathologies of Melanocytes, Team1, Equipe Labellisée Ligue 2020 and Equipe Labellisée ARC 2019, Centre Méditerranéen de Médecine Moléculaire, Inserm, 06200 Nice, France;
| | - Sacha Nahon-Esteve
- Department of Ophthalmology, University Hospital of Nice, Cote d’Azur University, 06000 Nice, France; (S.N.-E.); (S.B.)
| | - Gilles Poissonnet
- Cervicofacial Surgery Department, Antoine Lacassagne Cancer Centre, 06000 Nice, France;
| | - Paul Hofman
- FHU OncoAge, Institute for Research on Cancer and Aging, Nice (IRCAN), Cote d’Azur University, 06000 Nice, France; (S.L.); (P.H.)
- Biobank BB-0033-00025, FHU OncoAge, IRCAN, Laboratory of Clinical and Experimental Pathology, University Hospital of Nice, 06000 Nice, France
| | - Stephanie Baillif
- Department of Ophthalmology, University Hospital of Nice, Cote d’Azur University, 06000 Nice, France; (S.N.-E.); (S.B.)
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Abstract
Sebaceous neoplasia primarily includes sebaceous adenoma, sebaceoma, and sebaceous carcinoma (SC). Sebaceous adenoma, sebaceoma, and a subset of cutaneous SC are frequently associated with defective DNA mismatch repair resulting from mutations in MLH1, MSH2, or MSH6. These tumors can be sporadic or associated with Muir-Torre syndrome. SCs without defective DNA mismatch repair have ultraviolet signature mutation or paucimutational patterns. Ocular SCs have low mutation burdens and frequent mutations in ZNF750. Some ocular sebaceous carcinomas have TP53 and RB1 mutations similar to cutaneous SC, whereas others lack such mutations and are associated with human papilloma virus infection.
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Affiliation(s)
- Jeffrey P North
- Dermatopathology, Department of Dermatology, University of California San Francisco, School of Medicine, 1701 Divisadero Street, Room 280, San Francisco, CA 94115, USA; Department of Pathology, University of California San Francisco, School of Medicine, 1701 Divisadero Street, Room 280, San Francisco, CA 94115, USA.
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33
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Simic D, Dummer R, Freiberger SN, Ramelyte E, Barysch MJ. Clinical and Molecular Features of Skin Malignancies in Muir-Torre Syndrome. Genes (Basel) 2021; 12:genes12050781. [PMID: 34065301 PMCID: PMC8160778 DOI: 10.3390/genes12050781] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND We investigated the mutational landscape of skin tumors in patients with Muir-Torre Syndrome (MTS) a hereditary autosomal dominant mismatch repair disorder of increased cancer susceptibility, and examined mutations other than in the DNA mismatch repair (MMR) genes. METHODS This retrospective single-center case series included seven patients with the diagnosis of Muir-Torre Syndrome with precise medical history and family history. Mutational analysis of tumor samples Formalin-fixed paraffin-embedded tissue blocks of skin lesions associated with Muir-Torre Syndrome were used for further analysis. All skin tumors were analyzed with the Oncomine Comprehensive Assay v3 (Life Technologies), which includes 161 of the most relevant cancer driver genes. RESULTS Eleven skin neoplasms (nine sebaceous tumors, one melanoma, one cutaneous squamous cell carcinoma) were diagnosed in seven patients. In two patients, visceral malignancies preceded the diagnosis of the skin tumors and one patient was diagnosed with a visceral malignancy after a sebaceous tumor. History of familial cancer of Lynch Syndrome (LS) was reported in three patients. The most frequently detected mutation was in the MSH2 gene, followed by mutations in the NOTCH1/2 and TP53 gene. Conclusion, this study provides a molecular analysis of Muir-Torre Syndrome associated and non-associated skin tumors in patients with Muir-Torre Syndrome. Patients with sebaceous lesions should undergo microsatellite instability analysis and accurate evaluation of personal and family history to detect a possible Muir-Torre syndrome. As secondary malignancies may appear years after the first occurrence of sebaceous tumors, lifelong screening is mandatory.
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Affiliation(s)
- Dario Simic
- Department of Dermatology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland; (D.S.); (E.R.); (M.-J.B.)
- Faculty of Medicine, University of Zurich, Raemistrasse 71, 8006 Zurich, Switzerland;
| | - Reinhard Dummer
- Faculty of Medicine, University of Zurich, Raemistrasse 71, 8006 Zurich, Switzerland;
- Correspondence:
| | - Sandra N. Freiberger
- Faculty of Medicine, University of Zurich, Raemistrasse 71, 8006 Zurich, Switzerland;
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland
| | - Egle Ramelyte
- Department of Dermatology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland; (D.S.); (E.R.); (M.-J.B.)
- Faculty of Medicine, University of Zurich, Raemistrasse 71, 8006 Zurich, Switzerland;
| | - Marjam-Jeanette Barysch
- Department of Dermatology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland; (D.S.); (E.R.); (M.-J.B.)
- Faculty of Medicine, University of Zurich, Raemistrasse 71, 8006 Zurich, Switzerland;
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34
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TERT promoter mutation in sebaceous neoplasms. Virchows Arch 2021; 479:551-558. [PMID: 33768319 DOI: 10.1007/s00428-021-03083-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 12/25/2022]
Abstract
TERT promoter (TERTp) mutations widely occur in multiple human neoplasms, and they have been related to different clinicopathological features. To date, this mutation has not been identified in sebaceous tumors. Here, we analyzed TERTp mutations in 91 sebaceous neoplasms (17 adenomas, 45 sebaceomas, and 29 carcinomas). We detected mutations in 26.7% (8 of 29) of sebaceous carcinomas by pyrosequencing and Sanger sequencing. No mutation was detected in adenomas or sebaceomas. The difference was significant between sebaceoma and carcinoma. The most frequent TERTp mutations were C228T and C250T in 37.5% (3 of 8) of mutated cases each one. The mutation was not associated with poor clinical evolution. Using NGS, 20 of 29 (68.5%) sebaceous carcinomas harbored mutations in 8 of the 30 genes analyzed (TP53, TERTp, EGFR, ATRX, PDGFRA, CDKN2A, PTEN, and ACVR1). With immunohistochemistry, only 1 of 8 (12.5%) TERTp-mutated carcinomas lacked mismatch repair (MMR) protein expression compared to 6 of 21 (31.6%) of non-mutated ones. Sebaceous carcinomas with MMR protein expression had significantly higher frequency of total mutations and TP53 and TERTp mutations than MMR protein-deficient carcinomas. In conclusion, TERTp mutation has been detected in sebaceous carcinomas, and its presence could be useful to differentiate sebaceous carcinoma from sebaceoma, a difficult histopathological challenge.
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35
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Geueke A, Niemann C. Stem and progenitor cells in sebaceous gland development, homeostasis and pathologies. Exp Dermatol 2021; 30:588-597. [PMID: 33599012 DOI: 10.1111/exd.14303] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/04/2021] [Accepted: 02/14/2021] [Indexed: 12/11/2022]
Abstract
Sebaceous glands (SGs), typically associated with hair follicles, are critical for the homeostasis and function of mammalian skin. The main physiological function of SGs is the production and holocrine secretion of sebum to lubricate and protect the skin. Defective SGs have been linked to a variety of skin disorders, including acne, seborrheic dermatitis and formation of sebaceous tumors. Thus, a better understanding how SGs are formed and maintained is important to unravel the underlying molecular and cellular mechanisms of SG pathologies and to find better and effective therapies. Over the last two decades, research has come a long way from the initial identification of skin epithelial stem cells to the isolation and functional characterization of multiple stem cell pools as well as a better understanding of their unique and complex activities that drive skin homeostasis and operate in skin pathologies. Here, we discuss recent progress in unravelling cellular mechanisms underlying SG development, homeostasis and sebaceous tumor formation and assess the role of stem and progenitor cells in controlling SG physiology and disease processes. The development of elegant in vivo imaging as well as various in vitro and ex vivo stem cell and SG tissue models will advance mechanistic studies on SG function and allow drug screening and testing for efficient and successful targeting SG pathologies.
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Affiliation(s)
- Anna Geueke
- Center for Molecular Medicine Cologne, CMMC Research Institute, University of Cologne, Cologne, Germany
| | - Catherin Niemann
- Center for Molecular Medicine Cologne, CMMC Research Institute, University of Cologne, Cologne, Germany.,Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
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36
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Le Duc D, Hentschel J, Neuser S, Stiller M, Meier C, Jäger E, Abou Jamra R, Platzer K, Monecke A, Ziemer M, Markovic A, Bläker H, Lemke JR. In cis TP53 and RAD51C pathogenic variants may predispose to sebaceous gland carcinomas. Eur J Hum Genet 2020; 29:489-494. [PMID: 33319852 PMCID: PMC7940394 DOI: 10.1038/s41431-020-00781-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 11/07/2020] [Accepted: 11/17/2020] [Indexed: 11/22/2022] Open
Abstract
Pathogenic variants in TP53 have been classically thought to cause Li-Fraumeni syndrome (LFS), a cancer predisposition with high risks for various childhood- and adult-onset malignancies. However, increased genetic testing has lately revealed, that pathogenic variant carriers exhibit a broader range of phenotypes and that penetrance may be dependent both on variant type and modifiers. Using next generation sequencing and short tandem repeat analysis, we identified germline pathogenic variants in TP53 and RAD51C located in cis on chromosome 17 in a 43-year-old male, who has developed a rare sebaceous gland carcinoma (SGC) but so far no tumors of the LFS spectrum. This course mirrors a Trp53-Rad51c-double-mutant cis mouse-model, which similarly develops SGC, while the characteristic Trp53-associated tumor spectrum occurs with significantly lower frequency. Therefore, we propose that co-occurent pathogenic variants in RAD51C and TP53 may predispose to SGC, reminiscent of Muir-Torre syndrome. Further, this report supports the diversity of clinical presentations associated with germline TP53 alterations, and thus, the proposed expansion of LFS to heritable TP53-related cancer syndrome.
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Affiliation(s)
- Diana Le Duc
- Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany. .,Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, 04103, Leipzig, Germany.
| | - Julia Hentschel
- Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany
| | - Sonja Neuser
- Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany
| | - Mathias Stiller
- Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany.,Institute of Pathology, University of Leipzig Medical Center, 04103, Leipzig, Germany
| | - Carolin Meier
- Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany
| | - Elisabeth Jäger
- Department of Endocrinology, Nephrology, and Rheumatology, University of Leipzig Medical Center, 04103, Leipzig, Germany
| | - Rami Abou Jamra
- Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany
| | - Konrad Platzer
- Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany
| | - Astrid Monecke
- Institute of Pathology, University of Leipzig Medical Center, 04103, Leipzig, Germany
| | - Mirjana Ziemer
- Department of Dermatology, Venereology and Allergology, University of Leipzig Medical Center, 04103, Leipzig, Germany
| | - Aleksander Markovic
- Department of Dermatology, Venereology and Allergology, University of Leipzig Medical Center, 04103, Leipzig, Germany
| | - Hendrik Bläker
- Institute of Pathology, University of Leipzig Medical Center, 04103, Leipzig, Germany
| | - Johannes R Lemke
- Institute of Human Genetics, University of Leipzig Medical Center, 04103, Leipzig, Germany.
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Whole-exome sequencing for ocular adnexal sebaceous carcinoma suggests PCDH15 as a novel mutation associated with metastasis. Mod Pathol 2020; 33:1256-1263. [PMID: 31937901 DOI: 10.1038/s41379-020-0454-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 12/13/2019] [Accepted: 12/26/2019] [Indexed: 02/03/2023]
Abstract
Ocular adnexal sebaceous carcinoma (OASeC) is an aggressive eyelid carcinoma. Analysis of molecular-genetic drivers of this disease could reveal new prognostic markers and actionable targets for treatment. To identify somatically acquired genomic mutations in OASeC and explore their associations with metastasis, whole-exome sequencing on DNA extracted from retrospectively collected tumor samples was performed. Thirty-one patients in two orbital oncology centers with OASeC were included. Sequencing results were analyzed to detect mutations and explore their possible association with metastasis. The median patient age was 64 years. A total of 1780 candidate somatic mutations were identified with median mutation rate of 1.0/Mb (range, 0.2-13.6). The five most commonly mutated genes (as determined by MutSig; q value < 0.25) were TP53 (mutated in 22 cases), ZNF750 (13 cases), RB1 (12 cases), NOTCH1 (8 cases), and PCDH15 (5 cases). Mutations in ZNF750 or NOTCH1 pathway genes were present in 24 (77%) of the 31 cases; there was a trend toward mutual exclusivity of ZNF750 and NOTCH1 mutations. All eight tumors with NOTCH1 mutations also had TP53 and/or RB1 mutations. Four of the five PCDH15 mutations and all four PCDH15 missense mutations were identified in patients with metastatic disease, including one patient with distant metastasis and three with nodal metastasis. PCDH15 was significantly associated with metastasis (P = 0.01). We identified the most commonly mutated genes in a series of OASeCs and found a previously unreported mutation in OASeC, PCDH15 mutation, that was significantly associated with metastasis. NOTCH1 mutation is an actionable mutation; clinical trials targeting this mutation are available throughout the US and could be considered for patients with metastatic NOTCH1-mutant OASeC. TP53, ZNF750, RB1, and PCDH15 mutations are most likely loss-of-function mutations and may have diagnostic and prognostic importance.
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38
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Ferreira I, Wiedemeyer K, Demetter P, Adams DJ, Arends MJ, Brenn T. Update on the pathology, genetics and somatic landscape of sebaceous tumours. Histopathology 2020; 76:640-649. [PMID: 31821583 DOI: 10.1111/his.14044] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/25/2019] [Accepted: 12/06/2019] [Indexed: 01/17/2023]
Abstract
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.
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Affiliation(s)
- Ingrid Ferreira
- Université Libre de Bruxelles, Brussels, Belgium
- Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK
| | - Katharina Wiedemeyer
- Department of Dermatology, University Hospital of Heidelberg, Heidelberg, Germany
- Department of Pathology & Laboratory Medicine, The Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
| | - Pieter Demetter
- Department of Pathology, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium
| | - David J Adams
- Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Cambridge, UK
| | - Mark J Arends
- Division of Pathology, Cancer Research UK Edinburgh Centre, Institute of Genetics & Molecular Medicine, The University of Edinburgh, Edinburgh, UK
| | - Thomas Brenn
- Department of Pathology & Laboratory Medicine, The Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
- Division of Pathology, Cancer Research UK Edinburgh Centre, Institute of Genetics & Molecular Medicine, The University of Edinburgh, Edinburgh, UK
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Wu A, Rajak SN, Huilgol SC, James C, Selva D. Cutaneous sebaceous carcinoma. Australas J Dermatol 2020; 61:e283-e292. [PMID: 31956994 DOI: 10.1111/ajd.13234] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/03/2019] [Accepted: 12/14/2019] [Indexed: 12/19/2022]
Abstract
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.
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Affiliation(s)
- Albert Wu
- Department of Dermatology, Royal Adelaide Hospital, The University of Adelaide, Adelaide, South Australia, Australia
| | - Saul N Rajak
- Sussex Eye Hospital, Brighton and Sussex University Hospitals, Brighton, UK
| | - Shyamala C Huilgol
- Department of Dermatology, Royal Adelaide Hospital, The University of Adelaide, Adelaide, South Australia, Australia.,Adelaide Skin and Eye Centre, Adelaide, South Australia, Australia
| | - Craig James
- Clinpath Laboratories, Adelaide, South Australia, Australia
| | - Dinesh Selva
- Adelaide Skin and Eye Centre, Adelaide, South Australia, Australia.,South Australian Institute of Ophthalmology, Royal Adelaide Hospital, The University of Adelaide, Adelaide, South Australia, Australia
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40
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Eiger-Moscovich M, Eagle RC, Shields CL, Racher H, Lally SE, Silkiss RZ, Shields JA, Milman T. Muir-Torre Syndrome Associated Periocular Sebaceous Neoplasms: Screening Patterns in the Literature and in Clinical Practice. Ocul Oncol Pathol 2020; 6:226-237. [PMID: 33005611 DOI: 10.1159/000504984] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 11/25/2019] [Indexed: 11/19/2022] Open
Abstract
Background Muir-Torre syndrome (MTS) is defined clinically as the association of cutaneous sebaceous neoplasm and visceral malignancy. Ancillary tests are considered crucial for diagnosis. Although screening guidelines for MTS, including the Mayo MTS scoring system, have been proposed, there are no ophthalmic site-specific guidelines. Summary A literature review conducted by PubMed search for articles describing patients with periocular sebaceous neoplasm and MTS disclosed 31 publications describing 60 patients, 36 (60%) of whom fulfilled clinical criteria for MTS, 6 (10%) whose diagnosis was based on screening ancillary studies, 14 (23%) who fulfilled clinical criteria and had supporting screening ancillary studies, and 4 (7%) who fulfilled clinical criteria and had supporting diagnostic genetic testing. Most patients were male (34 vs. 15 females), with a median age of 59 years (range 37-79 years). The most common diagnosis was sebaceous carcinoma (40/60, 67%), followed by sebaceous adenoma (16/60, 27%), followed by other tumors with sebaceous differentiation (4/60, 6%). The periocular lesions were identified prior to visceral malignancy in 10 out of 45 (22%) cases, after visceral malignancy in 34 out of 45 (76%) cases, and concurrently with visceral malignancy in 1 out of 45 (2%) cases. Immunohistochemistry for mismatch repair proteins was performed in 41 out of 60 (68%) and 14 out of 38 (37%) of the tumors had lost MSH2. Based on Mayo-MTS scores of 2 or greater, and after removing visceral malignancies not included in their scoring algorithm, 26 out of 30 of patients (87%) with complete data were considered to be appropriate candidates for further work-up. A survey of current practice was conducted by questionnaires, distributed to ophthalmic pathologists, ocular oncologists, and oculoplastic surgeons from national and international professional societies. Of the 103 physicians who participated in the survey, 91 (88%) felt that MTS evaluation guidelines were not sufficiently clear. Key Messages Our findings suggest that Mayo MTS screening guidelines may be applicable to periocular sebaceous neoplasms. The uncertainty of ophthalmic specialists about optimal screening guidelines for MTS reflects the heterogeneity of defining criteria for MTS and limited molecular genetic data. Larger studies with detailed clinical, histopathologic, and molecular genetic data are required to formally assess screening guidelines for MTS in patients with periocular sebaceous neoplasms.
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Affiliation(s)
- Maya Eiger-Moscovich
- Department of Ophthalmic Pathology, Wills Eye Hospital, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Ralph C Eagle
- Department of Ophthalmic Pathology, Wills Eye Hospital, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Carol L Shields
- Ocular Oncology Service, Wills Eye Hospital, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Hilary Racher
- Impact Genetics/Dynacare, Bowmanville, Ontario, Canada
| | - Sara E Lally
- Ocular Oncology Service, Wills Eye Hospital, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Rona Z Silkiss
- Division of Ophthalmic Plastic, Reconstructive and Orbital Surgery, California Pacific Medical Center, San Francisco, California, USA
| | - Jerry A Shields
- Ocular Oncology Service, Wills Eye Hospital, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Tatyana Milman
- Department of Ophthalmic Pathology, Wills Eye Hospital, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA.,Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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41
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Owen JL, Kibbi N, Worley B, Kelm RC, Wang JV, Barker CA, Behshad R, Bichakjian CK, Bolotin D, Bordeaux JS, Bradshaw SH, Cartee TV, Chandra S, Cho NL, Choi JN, Council ML, Demirci H, Eisen DB, Esmaeli B, Golda N, Huang CC, Ibrahim SF, Jiang SB, Kim J, Kuzel TM, Lai SY, Lawrence N, Lee EH, Leitenberger JJ, Maher IA, Mann MW, Minkis K, Mittal BB, Nehal KS, Neuhaus IM, Ozog DM, Petersen B, Rotemberg V, Samant S, Samie FH, Servaes S, Shields CL, Shin TM, Sobanko JF, Somani AK, Stebbins WG, Thomas JR, Thomas VD, Tse DT, Waldman AH, Wong MK, Xu YG, Yu SS, Zeitouni NC, Ramsay T, Reynolds KA, Poon E, Alam M. Sebaceous carcinoma: evidence-based clinical practice guidelines. Lancet Oncol 2019; 20:e699-e714. [PMID: 31797796 DOI: 10.1016/s1470-2045(19)30673-4] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 09/12/2019] [Accepted: 09/13/2019] [Indexed: 12/18/2022]
Abstract
Sebaceous carcinoma usually occurs in adults older than 60 years, on the eyelid, head and neck, and trunk. In this Review, we present clinical care recommendations for sebaceous carcinoma, which were developed as a result of an expert panel evaluation of the findings of a systematic review. Key conclusions were drawn and recommendations made for diagnosis, first-line treatment, radiotherapy, and post-treatment care. For diagnosis, we concluded that deep biopsy is often required; furthermore, differential diagnoses that mimic the condition can be excluded with special histological stains. For treatment, the recommended first-line therapy is surgical removal, followed by margin assessment of the peripheral and deep tissue edges; conjunctival mapping biopsies can facilitate surgical planning. Radiotherapy can be considered for cases with nerve or lymph node involvement, and as the primary treatment in patients who are ineligible for surgery. Post-treatment clinical examination should occur every 6 months for at least 3 years. No specific systemic therapies for advanced disease can be recommended, but targeted therapies and immunotherapies are being developed.
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Affiliation(s)
- Joshua L Owen
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Nour Kibbi
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA
| | - Brandon Worley
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Division of Dermatology, The Ottawa Hospital, Ottawa, ON, Canada
| | - Ryan C Kelm
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Jordan V Wang
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Christopher A Barker
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ramona Behshad
- Department of Dermatology, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | | | - Diana Bolotin
- Section of Dermatology, The University of Chicago, Chicago, IL, USA
| | - Jeremy S Bordeaux
- Department of Dermatology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Scott H Bradshaw
- Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, Canada
| | - Todd V Cartee
- Division of Dermatology, Pennsylvania State University, Hershey, PA, USA
| | - Sunandana Chandra
- Division of Hematology and Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Nancy L Cho
- Department of Surgery, Brigham and Women's Hospital, Harvard University, Boston, MA, USA
| | - Jennifer N Choi
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - M Laurin Council
- Division of Dermatology, Center for Dermatologic and Cosmetic Surgery, Washington University in Saint Louis, Saint Louis, MO, USA
| | - Hakan Demirci
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA
| | - Daniel B Eisen
- Department of Dermatology, University of California Davis, Sacramento, CA, USA
| | - Bita Esmaeli
- Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nicholas Golda
- Department of Dermatology, University of Missouri School of Medicine, Columbia, MO, USA
| | - Conway C Huang
- Department of Dermatology, University of Alabama, Birmingham, AL, USA
| | - Sherrif F Ibrahim
- Department of Dermatology, University of Rochester, Rochester, NY, USA
| | - S Brian Jiang
- Department of Dermatology, University of California San Diego, San Diego, CA, USA
| | - John Kim
- Department of Plastic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Timothy M Kuzel
- Division of Hematology, Oncology and Cell Therapy, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA
| | - Stephen Y Lai
- Departments of Head and Neck Surgery and Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naomi Lawrence
- Department of Dermatology, Cooper Hospital, Rowan University, Camden, NJ, USA
| | - Erica H Lee
- Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Ian A Maher
- Department of Dermatology, University of Minnesota, Minneapolis, MN, USA
| | - Margaret W Mann
- Department of Dermatology, University Hospital, Cleveland, OH, USA
| | - Kira Minkis
- Department of Dermatology, Weill-Cornell Medical College, New York, NY, USA
| | - Bharat B Mittal
- Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Kishwer S Nehal
- Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Isaac M Neuhaus
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, USA
| | - David M Ozog
- Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA
| | - Brian Petersen
- Department of Dermatology, Colorado Permanente Medical Group, Denver, CO, USA
| | - Veronica Rotemberg
- Dermatology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sandeep Samant
- Department of Otolaryngology-Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Faramarz H Samie
- Department of Dermatology, Columbia University Medical Center, New York, NY, USA
| | - Sabah Servaes
- Department of Radiology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
| | - Carol L Shields
- Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, PA, USA
| | - Thuzar M Shin
- Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Joseph F Sobanko
- Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Ally-Khan Somani
- Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - William G Stebbins
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - J Regan Thomas
- Department of Otolaryngology-Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Valencia D Thomas
- Dermatology and Dermatopathology, Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David T Tse
- Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Abigail H Waldman
- Brigham and Women's Hospital Department of Dermatology, Harvard Medical School, Boston, MA, USA
| | - Michael K Wong
- Division of Cancer Medicine, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Y Gloria Xu
- Department of Dermatology, University of Wisconsin-Madison, Madison, WI, USA
| | - Siegrid S Yu
- Department of Dermatology, University of California at San Francisco, San Francisco, CA, USA
| | | | - Timothy Ramsay
- The Ottawa Health Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
| | - Kelly A Reynolds
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Emily Poon
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Murad Alam
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
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Kibbi N, Worley B, Owen JL, Kelm RC, Bichakjian CK, Chandra S, Demirci H, Kim J, Nehal KS, Thomas JR, Poon E, Alam M. Sebaceous carcinoma: controversies and their evidence for clinical practice. Arch Dermatol Res 2019; 312:25-31. [PMID: 31471636 DOI: 10.1007/s00403-019-01971-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/16/2019] [Accepted: 08/20/2019] [Indexed: 12/14/2022]
Abstract
Sebaceous carcinoma (SC) is a potentially aggressive malignancy of periocular or extraocular skin. It arises sporadically or is associated with Muir-Torre syndrome (MTS). Here, we review three controversial clinical conundra related to the diagnosis and treatment of SC and offer evidence-based recommendations. First, following a diagnosis of SC, deciding which patients to screen for MTS can be challenging. The Mayo MTS Risk Score is a clinical score that incorporates the key cutaneous findings in MTS but relies heavily on personal and family history that may not be available at the time of SC diagnosis, especially in young patients. Young patients, who have extraocular SC and are suspected to have MTS though do not meet criteria by Mayo MTS Risk Score, should have their tumors tested using immunohistochemistry for mismatch repair proteins. Second, sentinel lymph node biopsy (SLNB) is used in periocular SC to evaluate nodal disease. Patient selection is critical for SLNB. Periocular SC stage ≥ T2c (by American Joint Commission on Cancer, 8th edition) may be considered for SLNB given positivity rates over fifteen percent in expert hands. Lastly, treatment of metastatic SC is an area of active investigation. When possible, tumor profiling may be used to select targeted agents. Future research into these three key questions is needed.
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Affiliation(s)
- Nour Kibbi
- Department of Dermatology, Yale School of Medicine, New Haven, CT, USA
| | - Brandon Worley
- Division of Dermatology, The Ottawa Hospital, Ottawa, ON, Canada
| | - Joshua L Owen
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Ryan C Kelm
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | | | - Sunandana Chandra
- Division of Oncology, Department of Medicine, Northwestern University Medical Center, Chicago, IL, USA
| | - Hakan Demirci
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA
| | - John Kim
- Department of Plastic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Kishwer S Nehal
- Dermatology Service, Memorial Sloan Kettering, New York, NY, USA
| | - J Regan Thomas
- Department of Otolaryngology-Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Emily Poon
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Murad Alam
- Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. .,Department of Dermatology, Northwestern Memorial Hospital, Arkes Family Pavilion, 676 N Saint Clair Suite 1600, Chicago, IL, 60611, USA.
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43
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Potentially actionable FGFR2 high-level amplification in thymic sebaceous carcinoma. Virchows Arch 2019; 476:323-327. [PMID: 31401665 DOI: 10.1007/s00428-019-02644-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2019] [Revised: 07/30/2019] [Accepted: 08/02/2019] [Indexed: 10/26/2022]
Abstract
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.
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44
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North JP, Solomon DA, Golovato J, Bloomer M, Benz SC, Cho RJ. Loss of ZNF750 in ocular and cutaneous sebaceous carcinoma. J Cutan Pathol 2019; 46:736-741. [PMID: 31148199 DOI: 10.1111/cup.13516] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 05/24/2019] [Accepted: 05/28/2019] [Indexed: 01/13/2023]
Abstract
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.
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Affiliation(s)
- Jeffrey P North
- Department of Dermatology, University of California, San Francisco, San Francisco, California.,Department of Pathology, University of California, San Francisco, San Francisco, California
| | - David A Solomon
- Department of Pathology, University of California, San Francisco, San Francisco, California
| | | | - Michele Bloomer
- Department of Pathology, University of California, San Francisco, San Francisco, California.,Department of Ophthalmology, University of California, San Francisco, San Francisco, California
| | | | - Raymond J Cho
- Department of Dermatology, University of California, San Francisco, San Francisco, California
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Bao Y, Selfridge JE, Wang J, Zhao Y, Cui J, Guda K, Wang Z, Zhu Y. Mutations in TP53, ZNF750, and RB1 typify ocular sebaceous carcinoma. J Genet Genomics 2019; 46:315-318. [PMID: 31278009 DOI: 10.1016/j.jgg.2019.06.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 05/23/2019] [Accepted: 06/14/2019] [Indexed: 11/17/2022]
Affiliation(s)
- Yongyang Bao
- Department of Pathology, The Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - J Eva Selfridge
- Seidman Cancer Center, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA; Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Janet Wang
- Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Yiqing Zhao
- Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Junqi Cui
- Department of Pathology, The Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Kishore Guda
- Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA.
| | - Zhenghe Wang
- Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, 44106, USA.
| | - Yanbo Zhu
- Department of Pathology, The Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
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Vidal CI, Sutton A, Armbrect EA, Lee JB, Litzner BR, Hurley MY, Alam M, Duncan LM, Elston DM, Emanuel PO, Ferringer T, Fung MA, Hosler GA, Lazar AJ, Lowe L, Plaza JA, Robinson JK, Schaffer A. Muir‐Torre syndrome appropriate use criteria: Effect of patient age on appropriate use scores. J Cutan Pathol 2019; 46:484-489. [DOI: 10.1111/cup.13459] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 02/20/2019] [Accepted: 02/25/2019] [Indexed: 12/24/2022]
Affiliation(s)
| | - Claudia I. Vidal
- Department of DermatologySaint Louis University School of Medicine St. Louis Missouri
- Department of PathologySaint Louis University School of Medicine St. Louis Missouri
| | - Angela Sutton
- Department of DermatologySaint Louis University School of Medicine St. Louis Missouri
- Department of PathologySaint Louis University School of Medicine St. Louis Missouri
| | - Eric A. Armbrect
- Center for Health Outcomes ResearchSaint Louis University St. Louis Missouri
| | - Jason B. Lee
- Department of DermatologySidney Kimmel Medical College at Thomas Jefferson University Philadelphia Pennsylvania
- Department of Cutaneous BiologySidney Kimmel Medical College at Thomas Jefferson University Philadelphia Pennsylvania
| | - Brandon R. Litzner
- Department of DermatologyVia Christi Clinic, Ascension Medical Group Wichita Kansas
- Department of PathologyVia Christi Clinic, Ascension Medical Group Wichita Kansas
- Department of Family MedicineUniversity of Kansas Medical Center‐Wichita Wichita Kansas
| | - M. Yadira Hurley
- Department of DermatologySaint Louis University School of Medicine St. Louis Missouri
- Department of PathologySaint Louis University School of Medicine St. Louis Missouri
| | - Murad Alam
- Department of DermatologyFeinberg School of Medicine, Northwestern University Chicago Illinois
- Department of OtolaryngologyFeinberg School of Medicine, Northwestern University Chicago Illinois
- Department of SurgeryFeinberg School of Medicine, Northwestern University Chicago Illinois
| | - Lyn M. Duncan
- Pathology Service and Dermatopathology UnitMassachusetts General Hospital and Harvard Medical School Boston Massachusetts
| | - Dirk M. Elston
- Department of DermatologyDermatologic Surgery Medical University of SC Charleston South Carolina
| | | | - Tammie Ferringer
- Department of DermatologyGeisinger Medical Center Danville Pennsylvania
- Department of Laboratory MedicineGeisinger Medical Center Danville Pennsylvania
| | - Maxwell A. Fung
- Department of DermatologyUniversity of California, Davis School of Medicine Sacramento California
- Department of Pathology and Laboratory MedicineUniversity of California, Davis School of Medicine Sacramento California
| | - Gregory A. Hosler
- Division of Dermatopathology, ProPath Dallas Texas
- Department of DermatologyUniversity of Texas Southwestern Medical Center Dallas Texas
- Department of PathologyUniversity of Texas Southwestern Medical Center Dallas Texas
| | - Alexander J. Lazar
- Department of PathologyThe University of Texas MD Anderson Cancer Center Houston Texas
- Department of DermatologyThe University of Texas MD Anderson Cancer Center Houston Texas
- Department of Genomic MedicineThe University of Texas MD Anderson Cancer Center Houston Texas
| | - Lori Lowe
- Department of DermatologyUniversity of Michigan Medical Center Ann Arbor Michigan
- Department of PathologyUniversity of Michigan Medical Center Ann Arbor Michigan
| | - Jose A. Plaza
- Division of Dermatopathology, Miraca Life Sciences Irving Texas
| | - June K. Robinson
- Department of DermatologyNorthwestern University Chicago Illinois
| | - Andras Schaffer
- Division of Dermatopathology, Bay Dermatology and Cosmetic Surgery Spring Hill Florida
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Tetzlaff MT, North J, Esmaeli B. Update on sebaceous neoplasia: the morphologic spectrum and molecular genetic drivers of carcinoma. ACTA ACUST UNITED AC 2019. [DOI: 10.1016/j.mpdhp.2019.01.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Fulton EH, Kaley JR, Gardner JM. Skin Adnexal Tumors in Plain Language: A Practical Approach for the General Surgical Pathologist. Arch Pathol Lab Med 2019; 143:832-851. [PMID: 30638401 DOI: 10.5858/arpa.2018-0189-ra] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Skin adnexal tumors, those neoplasms deriving from hair follicles and sweat glands, are often a source of confusion amongst even experienced pathologists. Many well-described entities have overlapping features, tumors are often only partially sampled, and many cases do not fit neatly into well-established classification schemes. OBJECTIVES.— To simplify categorization of adnexal tumors for the general surgical pathologist and to shed light on many of the diagnostic dilemmas commonly encountered in daily practice. The following review breaks adnexal neoplasms into 3 groups: sebaceous, sweat gland-derived, and follicular. DATA SOURCES.— Pathology reference texts and primary literature regarding adnexal tumors. CONCLUSIONS.— Review of the clinical and histopathologic features of primary cutaneous adnexal tumors, and the diagnostic dilemmas they create, will assist the general surgical pathologist in diagnosing these often challenging lesions.
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Affiliation(s)
- Edward H Fulton
- From the Department of Pathology, University of Arkansas for Medical Sciences, Little Rock
| | - Jennifer R Kaley
- From the Department of Pathology, University of Arkansas for Medical Sciences, Little Rock
| | - Jerad M Gardner
- From the Department of Pathology, University of Arkansas for Medical Sciences, Little Rock
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Tetzlaff MT, Curry JL, Ning J, Sagiv O, Kandl TL, Peng B, Bell D, Routbort M, Hudgens CW, Ivan D, Kim TB, Chen K, Eterovic AK, Shaw K, Prieto VG, Yemelyanova A, Esmaeli B. Distinct Biological Types of Ocular Adnexal Sebaceous Carcinoma: HPV-Driven and Virus-Negative Tumors Arise through Nonoverlapping Molecular-Genetic Alterations. Clin Cancer Res 2018; 25:1280-1290. [DOI: 10.1158/1078-0432.ccr-18-1688] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/25/2018] [Accepted: 11/02/2018] [Indexed: 11/16/2022]
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Lee SH, Jung YH, Yoo JY, Park HJ. A Case Report of Recurrent Metastatic Sebaceous Carcinoma Which Showed Favorable Response Tt Non-Fluorouracil Based Chemotherapy. AMERICAN JOURNAL OF CASE REPORTS 2018; 19:1192-1196. [PMID: 30291222 PMCID: PMC6187987 DOI: 10.12659/ajcr.912552] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Patient: Female, 59 Final Diagnosis: Metastatic sebaceous carcinoma Symptoms: Palpable mass Medication: — Clinical Procedure: Chemotherapy Specialty: Oncology
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Affiliation(s)
- Shin Hee Lee
- Division of Hematology-Oncology, Department of Internal Medicine, Daejeon Sun Medical Center, Daejeon, South Korea
| | - Yun Hwa Jung
- Division of Hematology-Oncology, Department of Internal Medicine, Daejeon Sun Medical Center, Daejeon, South Korea
| | - Ji Yeon Yoo
- Division of Hematology-Oncology, Department of Internal Medicine, Daejeon Sun Medical Center, Daejeon, South Korea
| | - Hyo Jin Park
- Division of Hematology-Oncology, Department of Internal Medicine, Daejeon Sun Medical Center,, Daejeon, South Korea
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