Sebaceous Carcinoma Epidemiology and Genetics: Emerging Concepts and Clinical

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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.

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.

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Conflicts of Interest: The authors declare no potential conflicts of interest.

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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.

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

≥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

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

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), and identified 62 cases of sebaceous carcinoma among 262,455 transplant

recipients, which corresponded to a 34-fold elevation in risk compared to the general

population.(22) In a subsequent study using updated TCM Study data, which included 102 cases

of sebaceous carcinoma diagnosed among 301,075 transplant recipients and covering

approximately half of all United States transplant procedures performed from 1987 through

2017, we identified a slightly lower, but still highly elevated risk (25-fold) for sebaceous

carcinoma in this immunosuppressed population.(23) Among transplant patients, a post-

transplant diagnosis of cutaneous squamous cell carcinoma, longer time since transplant, and

induction therapy with thymoglobulin were each associated with an increased risk for sebaceous

carcinoma.(23) Moreover, the association between squamous cell carcinoma, caused by UVR- induced DNA damage, and increased sebaceous carcinoma risk suggests that UVR photodamage

of the skin contributes to sebaceous carcinoma tumorigenesis in transplant patients.

Possible Viral Etiology?

The strongly increased risk for sebaceous carcinoma among people with AIDS and solid

organ transplant recipients is similar to that of other virus-induced cancers such as Merkel cell

carcinoma(26,27) (caused by Merkel cell polyomavirus) and Kaposi’s sarcoma(24,28) (caused

by Kaposi's sarcoma-associated herpesvirus/human herpes virus 8), which suggests that

sebaceous carcinoma may also be caused by a viral infection. However, direct evidence

supporting a viral agent has been contradictory. The first evidence of viral involvement in

sebaceous carcinoma was reported in 1994 by Hayashi and colleagues, who identified HPV types

6, 11, 16, 18, 31, and 33 by DNA in situ hybridization (ISH) in 9 of 13 (62%) sebaceous carcinomas.(29) However, subsequent studies generally failed to identify HPV in sebaceous carcinomas, with only one HPV-positive case observed out of 85 (1.2%) examined by polymerase chain reaction, RNA ISH, or DNA ISH.(30-33) Very recently, 4 of 29 patients (14%) with TP53 and RB1 wildtype sebaceous carcinomas were reported to harbor “high-risk” HPV types, as detected by RNA ISH. Further, in two of these patients, RNA sequencing confirmed the presence of HPV16 and HPV18 with no other viruses detected.(34)

Further complicating the story of a potential viral etiology in sebaceous carcinoma is that multiple viruses have been implicated. Collisions between Merkel cell carcinomas and sebaceous carcinomas, where both tumors occur simultaneously at the same anatomic site, have been reported, raising the possibility of the involvement of Merkel cell polyomavirus.(35) Epstein-

Barr virus also was recently reported in 26% of sebaceous carcinomas in China, as detected by

ISH for the viral RNA, EBER.(36) Lastly, genus Beta papillomaviruses, also known as cutaneous papillomaviruses, have been proposed as suspects because of their potential involvement in the development of other non-melanoma skin cancers, especially in immunosuppressed patients.(37,38) Various studies in cell culture and mouse models have now demonstrated that the E6 and E7 oncoproteins of Beta papillomaviruses can tolerize cells to UV- mediated mutagenesis.(39,40) However, another report indicated that Beta papillomaviruses, which are a common component of normal skin flora, may be protective against non-melanoma skin cancers in immunocompetent individuals.(41)

Ultimately, due to the conflicting reports to date and the likely complexity of potential viral involvement in sebaceous carcinoma, several clear lines of evidence will be needed to bring

clarity. The first step towards resolution will require comprehensive identification and quantification of viral nucleic acids from tumors of immunocompetent and immunosuppressed sebaceous carcinoma patients by unbiased DNA and RNA sequencing. Candidate oncoviruses will have to be further validated for the expression of gene products spatially within tumors by either immunohistochemistry or RNA scope. Animal and cellular models will also need to be developed to study the mechanisms of virus-mediated sebaceous carcinoma oncogenesis with subsequent comparison of these results against patient data. Finally, conclusive evidence will come if prevention of the candidate oncovirus prevents the disease or its precursor especially in at-risk individuals.

Sebaceous Carcinoma Genomics

Although rare, several small case series have assessed the mutational profile of sebaceous carcinomas. North and colleagues performed whole exome sequencing of 32 sebaceous carcinomas (23 cutaneous tumors; 9 ocular [eyelid] tumors) and identified 3 molecular subtypes.(20) The first subtype, characterized by a prominent UVR mutational signature and a high tumor mutation burden (>50 mutations per Megabase), was observed in 10 cases (31%). A second subtype demonstrated prominent microsatellite instability and was observed in 9 tumors

(28%), of which seven had somatic mutations of mismatch repair genes (MLH1, MSH2, or

MSH6). In addition, one case with microsatellite instability also had a pathogenic germline mutation of MSH6. The last subtype (13 cases, 41%) consisted of pauci-mutational tumors with mutations of ZNF750 observed in 9 of the 13 cases (69%). The transcriptomes and anatomic distribution of UVR-mediated sebaceous carcinomas closely resembled those of cutaneous squamous cell carcinomas, leading the authors to postulate that epidermal keratinocytes (cell of

origin for cutaneous squamous cell carcinomas) may be the cell of origin for some sebaceous carcinomas. Further supporting this hypothesis was the identification of frequent mutations of

ZNF750, a lineage-specific tumor suppressor in squamous cell carcinoma(42), among pauci- mutational tumors.

Recently, Tetzlaff and colleagues performed next-generation sequencing for a targeted panel of 409 cancer-related genes in 29 primary or locally recurrent ocular adnexal (eyelid) sebaceous carcinomas.(34) Their analysis identified two molecular subtypes: tumors with TP53 mutations (19 cases, 66%) harboring concomitant genetic alterations of RB1 (13 of 19 cases with

TP53 mutations) and tumors that were wild type for both genes. In a subsequent study, Xu and colleagues performed whole exome sequencing of 31 ocular adnexal sebaceous carcinomas and also identified TP53 mutations in the majority of tumors (22 cases, 71%) with concomitant mutations of RB1 (10 cases), ZNF750 (10 cases), and NOTCH1 (7 cases) in a subset of cases.(43) Six tumors lacked mutations of all 4 genes (TP53, RB1, ZNF750, NOTCH1).

Mutations of PCDH15 were identified in 5 tumors (3 cases with TP53 mutations; 1 case lacking mutations of TP53, RB1, ZNF750, and NOTCH1), of which four subsequently metastasized.(43)

However, additional studies are necessary to validate PCDH15 as a prognostic biomarker including whether mutations of this gene are observed among non-ocular cases.

These genomic studies had several limitations. Each study analyzed a relatively small number of cases, and therefore may have been underpowered to detect less common, but biologically significant genetic alterations involved in tumor development and progression. In addition, two studies(34,43) were composed entirely of ocular cases; therefore, the genetic alterations identified may not be representative of non-ocular cases, which account for the

majority of tumors.(1,4,7) Lastly, none of the prior studies searched for differences in the genetic

alterations of tumors from immunocompetent and immunosuppressed patients.

Clinical Implications of Sebaceous Carcinoma Research

Management of Sebaceous Carcinoma

The first-line treatment for sebaceous carcinoma at all sites (periocular and extraocular) is

Mohs micrographic surgery or wide-local excision according to recently published clinical- practice guidelines developed by an expert panel of researchers and clinicians.(44) Periocular

tumors may require orbital exenteration if there is extensive involvement of underlying orbital or

periorbital structures.(44) A sentinel lymph node biopsy may also be performed for periocular

tumors to evaluate the extent of disease for tumors stage 2C or higher, which have a 15%

positivity rate for metastasis.(44,45) For cases with nodal metastasis, adjuvant radiotherapy is

sometimes used with unclear benefit to treat the nodal basin (46). In contrast, routine sentinel

lymph node biopsy is often not recommended for extraocular sebaceous carcinomas given the

low (<1% in SEER registries) positivity rate for metastasis.(44,47) Adjuvant radiotherapy can be

considered for individual cases of extraocular sebaceous carcinoma with perineural invasion,

positive surgical margins, or positive nodal basins, but evidence is insufficient regarding its

efficacy.(44) For advanced or unresectable tumors with microsatellite instability or a high tumor

mutation burden, the FDA has approved treatment with the immune checkpoint inhibitor

pembrolizumab.(17-19,48) However, treatments specifically approved by the FDA for sebaceous

carcinoma are lacking.

Reducing immunosuppression, such as lowering the dosage of anti-rejection medications

for transplant recipients and adjusting/starting antiretroviral therapy for individuals with HIV

infection to increase CD4 counts, may also slow down tumor growth and progression of disease.

However, for transplant patients, the potential benefit of reducing immunosuppression must be

balanced against the risk of graft rejection.

Screening and Prevention

Current management guidelines for Lynch syndrome patients, developed by a multi-

society task force in 2014, do not include skin cancer screening as part of long-term management

and follow-up.(49) However, several studies have recommended periodic skin cancer screening

for individuals with Lynch syndrome(12) given their highly elevated risk for sebaceous

carcinoma. Most guidelines(50) also recommend skin cancer screening following solid organ

transplantation because of the highly elevated risk for cutaneous squamous cell carcinoma,

however, the frequency of surveillance is often not specified. While performing total body skin

exams of transplant patients as part of their routine follow-up care, physicians should carefully

screen for sebaceous carcinoma, which may have a yellowish appearance because of the tumors

increased lipid content.(5) There should also be consideration of more frequent exams for

transplant recipients with multiple risk factors for sebaceous carcinoma. Factors influencing

screening frequency among transplant patients may include evidence of skin with severe

photodamage, prior history of skin cancer, duration of immunosuppression, exposure to

thymoglobulin, and exposure to photosensitizing medications such as voriconazole.(23,51)

Screening should also be considered for non-white patients, who may not be routinely surveilled

for skin cancer, if they have multiple risk factors for sebaceous carcinoma.

In addition, patients should be educated on the clinical appearance of sebaceous neoplasms (yellow/orange/red raised lesions, may ulcerate or bleed, often located on the

face)(52) in order to perform self-skin exams at home. Further, to reduce risk for sebaceous

carcinoma along with other skin cancer types, these high-risk populations (HIV positive, Muir-

Torre syndrome, solid organ transplant recipients) should be advised about the importance of sun

protection. HIV testing should also be considered for patients with newly diagnosed sebaceous

carcinoma, particularly when diagnoses occur before age 50 and when there are other risk factors

for HIV infection such as intravenous drug use. Lastly, if a virus is implicated in sebaceous

carcinoma tumor development, then it may be possible to develop a vaccine to prevent infection

and reduce cancer risk.

Conclusions

Recent studies have implicated ultraviolet radiation and immunosuppression in sebaceous

carcinoma tumorigenesis. Further studies are necessary to understand the biology underlying

these associations including whether a virus contributes to sebaceous gland neoplasia as well as

the genetic alterations contributing to tumor development and metastasis in immunocompetent

versus immunosuppressed populations. Since sebaceous carcinoma is a rare cancer it will be

necessary for institutions to share cases and data, which will allow for high-quality large-scale

clinical and genomic studies. Moreover, these types of collaborations will centralize research

efforts in a manner that will allow for translational studies, including clinical trials, to investigate

novel therapies to treat this aggressive cutaneous malignancy.

Acknowledgments: This work was supported by the Intramural Research Program of the

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of

Health. M.R. Sargen, E.A. Engels, E.K. Cahoon, M.A. Tucker, and A.M. Goldstein were

supported by intramural research funds from the Division of Cancer Epidemiology and Genetics,

National Cancer Institute, National Institutes of Health. The authors are also grateful to Chris

Buck for critical evaluation of the manuscript.

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Acad Dermatol 1995;33:1-15; quiz 6-8

Figure 1. Summary diagram of known and possible risk factors for sebaceous carcinoma.

Population data analyses have identified several risk factors for sebaceous carcinoma, which are listed in the above figure. The highly elevated risk for sebaceous carcinoma among immunosuppressed populations (solid organ transplant recipients; individuals with HIV infection), which is similar to the elevation observed for other virus-associated cancers (Kaposi sarcoma; Merkel cell carcinoma), suggests that sebaceous carcinoma may also be caused by a virus. In addition to causing cancer in immunosuppressed patients (pathway A), an oncogenic virus could also promote tumorigenesis in immunocompetent patients (pathway B). Among individuals with Muir-Torre syndrome, higher ambient ultraviolet radiation exposure is associated with an increased risk for sebaceous carcinoma in addition to being an independent risk factor for this cancer type.

Known risk factors

Ultraviolet radiation

Increasing age

Genetic susceptibility (Muir-Torre syndrome) Tumor cell Immunosuppression (HIV infection, solid organ transplantation) A HIV B Oncogenic virus?

Sebaceous carcinoma epidemiology and genetics: Emerging concepts and clinical implications for screening, prevention, and treatment

Michael R. Sargen, Gabriel J Starrett, Eric A. Engels, et al.

Clin Cancer Res Published OnlineFirst September 9, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-20-2473

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