Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2473 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Sebaceous carcinoma epidemiology and genetics: Emerging concepts and clinical implications for screening, prevention, and treatment Michael R. Sargen1, Gabriel J. Starrett2, Eric A. Engels3, Elizabeth K. Cahoon4, Margaret A. Tucker5, Alisa M. Goldstein1 1 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA 2 Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA 3 Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA 4 Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA 5 Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA Running Title: Sebaceous carcinoma epidemiology and genetics Keywords: sebaceous carcinoma; epidemiology; genetics; immunosuppression; treatment Corresponding Author: Michael R. Sargen, M.D. 1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2473 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Clinical Genetics Branch Division of Cancer Epidemiology and Genetics 9609 Medical Center Drive, Room 6E-542, Rockville, MD 20850 Phone: (240) 276-7354 | Fax: (623) 666-6616 | Email: [email protected] Conflicts of Interest: The authors declare no potential conflicts of interest. Word Count: 2,498 Figures: 1 Tables: 0 2 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2473 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract: Sebaceous carcinoma is an aggressive skin cancer with a 5-year overall survival rate of 78% for localized/regional disease and 50% for metastatic disease. The incidence of this cancer has been increasing in the United States for several decades, but the underlying reasons for this increase are unclear. In this article, we review the epidemiology and genetics of sebaceous carcinoma, including recent population data and tumor genomic analyses that provide new insights into underlying tumor biology. We further discuss emerging evidence of a possible viral etiology for this cancer. Lastly, we review the clinical implications of recent advances in sebaceous carcinoma research for screening, prevention, and treatment. 3 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2473 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Sebaceous carcinoma is a rare skin cancer that arises from the sebaceous oil gland. Individuals with this cancer have a 5-year overall survival rate of 78% for localized/regional disease and 50% for metastatic disease.(1-3) In addition to its aggressive behavior, treatment- related morbidity for sebaceous carcinoma can also be significant since tumors predominantly occur on the head and neck, with oncologic management often requiring complex facial reconstruction and radiation therapy.(1,2,4-6) Therefore, it is critically important to understand the epidemiology and biology of this rare cancer in order to improve early detection and to reduce morbidity and mortality for patients. In this article, we review the current state of sebaceous carcinoma research, including several recent studies highlighting the importance of ultraviolet radiation (UVR) and immunosuppression as risk factors for tumor development and the possibility of a viral etiology. We also summarize the clinical implications of this research for screening, prevention, and treatment of sebaceous carcinoma. Epidemiology Sebaceous carcinoma incidence has been increasing in the United States since 1973 when the Surveillance, Epidemiology, and End Results (SEER) cancer registries started collecting tumor data.(1,4,7) From 2000 through 2016, the overall incidence for sebaceous carcinoma was 2.4 cases per million persons, with an average of 800 cases per year in the United States.(7) Incidence is also higher for males (3.5 cases per million persons) than females (1.7 cases per million persons), and increases with age, with the highest incidence observed among individuals 4 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2473 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ≥80 years old (22.7 cases per million persons).(7) Seventy-eight percent of cases occur in non- Hispanic whites, who have approximately a 4-fold greater incidence than African Americans.(7) Sebaceous Carcinoma Risk Factors Figure 1 summarizes known and suspected risk factors for sebaceous carcinoma. DNA Mismatch Repair and Microsatellite Instability Pathogenic germline variants of DNA mismatch repair genes (MSH2, MSH6, MLH1) have been identified in 8-29% of individuals with sebaceous carcinoma.(8-11) These variants also cause hereditary nonpolyposis colorectal cancer syndrome, also known as Lynch syndrome, and affected individuals have an increased risk for additional malignancies affecting the skin (keratoacanthomas) and internal organs (gastrointestinal and genitourinary). Patients with sebaceous carcinoma and other cancers caused by germline mutations of DNA mismatch repair genes are classified as having a specific form of nonpolyposis colorectal cancer syndrome called Muir-Torre syndrome (OMIM 158320). Tumors in these patients are characterized by microsatellite instability.(12,13) Given the highly elevated risk for multiple cancer types in patients with Muir-Torre syndrome(12) and the relatively low incidence of sebaceous neoplasms in the general population, several prior studies(10,14,15) have recommended performing mismatch repair immunohistochemical staining of all sebaceous neoplasms to screen for possible underlying germline mutations.(10,14,15) Moreover, identifying tumors with these mutations may also have implications for treatment; the immune checkpoint inhibitor pembrolizumab (anti-PD1 antibody) is approved by the Food and Drug Administration (FDA) for the treatment of solid tumors in 5 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2473 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. adults and children with microsatellite instability caused by defective DNA mismatch repair.(16- 19) Ultraviolet Radiation Population and tumor data also implicate UVR as a risk factor for sebaceous carcinoma. In the United States, 73% of cases occur on chronically sun-exposed skin of the head and neck and 85% of tumors are diagnosed in white (Non-Hispanic, 78%; Hispanic, 7%) patients, who lack significant amounts of photoprotective melanin pigment in their skin.(7) Further, evaluation of ambient UVR exposure, as assessed by geographic location of residence, revealed an increased risk for sebaceous carcinoma among individuals with and without Muir-Torre syndrome.(7) In addition, one-third of tumors have been found to manifest significant solar damage with >25% of the mutations in these tumors exhibiting a UVR-mutational signature.(20) Despite the growing body of evidence implicating UVR in sebaceous carcinoma tumorigenesis, definitive evidence of an etiologic role will require larger tumor-based analyses to further evaluate UVR-mutational signatures and cancer driver genes as well as clinical studies demonstrating a reduction in sebaceous carcinoma risk with sun protective behavior (applying sunscreen, wearing a hat, etc.) among at-risk populations (eg. Muir-Torre syndrome). Immunosuppression Recently, immunosuppression has been identified as a strong risk factor for sebaceous carcinoma. Among individuals with acquired immunodeficiency syndrome (AIDS), there is an 8- fold elevation in risk for this cancer.(21) Similarly, an elevation in sebaceous carcinoma risk has also been observed for solid organ transplant recipients receiving immunosuppressive 6 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 9, 2020; DOI: 10.1158/1078-0432.CCR-20-2473 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. therapy.(22,23) D’Arcy and colleagues evaluated the incidence of rare cancer types among solid organ transplant recipients using data from the Transplant Cancer Match (TCM) Study, which links the United States solid organ transplant recipient registry with 18 population-based cancer registries(24,25),