CLINICAL CANCER RESEARCH | REVIEW

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, and
Alisa M. Goldstein1

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
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. Finally, we review the clinical implications of recent

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underlying reasons for this increase are unclear. In this article, advances in sebaceous carcinoma research for screening, preven-
we review the epidemiology and genetics of sebaceous carcinoma, tion, and treatment.

Introduction 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/
Sebaceous carcinoma is a rare skin cancer that arises from the
million persons) than females (1.7 cases/million persons), and
sebaceous oil gland. Individuals with this cancer have a 5-year overall
increases with age, with the highest incidence observed among indi-
survival rate of 78% for localized/regional disease and 50% for met-
viduals ≥80 years old (22.7 cases/million persons; ref. 7). Seventy-eight
astatic disease (1–3). In addition to its aggressive behavior, treatment-
percent of cases occur in non-Hispanic whites, who have approxi-
related morbidity for sebaceous carcinoma can also be significant
mately a 4-fold greater incidence than African Americans (7).
because tumors predominantly occur on the head and neck, with
oncologic management often requiring complex facial reconstruction
and radiotherapy (1, 2, 4–6). Therefore, it is critically important to Sebaceous Carcinoma Risk Factors
understand the epidemiology and biology of this rare cancer to
Figure 1 summarizes known and suspected risk factors for seba-
improve early detection and to reduce morbidity and mortality for
ceous carcinoma.
patients.
In this article, we review the current state of sebaceous carcinoma
DNA mismatch repair and microsatellite instability
research, including several recent studies highlighting the importance
Pathogenic germline variants of DNA mismatch repair genes
of ultraviolet radiation (UVR) and immunosuppression as risk factors
(MSH2, MSH6, and MLH1) have been identified in 8%–29% of
for tumor development and the possibility of a viral etiology. We also
individuals with sebaceous carcinoma (8–11). These variants also
summarize the clinical implications of this research for screening,
cause hereditary nonpolyposis colorectal cancer syndrome, also
prevention, and treatment of sebaceous carcinoma.
known as Lynch syndrome, and affected individuals have an increased
risk for additional malignancies affecting the skin (keratoacanthomas)
Epidemiology and internal organs (gastrointestinal and genitourinary). Patients with
sebaceous carcinoma and other cancers caused by germline mutations
Sebaceous carcinoma incidence has been increasing in the United
of DNA mismatch repair genes are classified as having a specific form
States since 1973 when the Surveillance Epidemiology and End Results
of nonpolyposis colorectal cancer syndrome called Muir–Torre syn-
(SEER) cancer registries started collecting tumor data (1, 4, 7). From
drome (OMIM 158320). Tumors in these patients are characterized by
2000 through 2016, the overall incidence for sebaceous carcinoma was
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
1
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, NCI, sebaceous neoplasms in the general population, several prior stud-
Rockville, Maryland. 2Laboratory of Cellular Oncology, Center for Cancer ies (10, 14, 15) have recommended performing mismatch repair IHC
Research, NCI, Bethesda, Maryland. 3Infections and Immunoepidemiology staining of all sebaceous neoplasms to screen for possible underlying
Branch, Division of Cancer Epidemiology and Genetics, NCI, Rockville, Maryland. germline mutations (10, 14, 15). Moreover, identifying tumors with
4
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics,
these mutations may also have implications for treatment; the immune
NCI, Rockville, Maryland. 5Human Genetics Program, Division of Cancer Epide-
miology and Genetics, NCI, Rockville, Maryland. checkpoint inhibitor, pembrolizumab (anti-PD-1 antibody), is
approved by the FDA for the treatment of solid tumors in adults and
Corresponding Author: Michael R. Sargen, NCI, 9609 Medical Center Drive,
children with microsatellite instability caused by defective DNA
Room 6E-542, Rockville, MD 20850. Phone: 240-276-7354; Fax: 623-666-6616;
E-mail: michael.sargen@nih.gov mismatch repair (16–19).
Clin Cancer Res 2021;27:389–93
UVR
doi: 10.1158/1078-0432.CCR-20-2473 Population and tumor data also implicate UVR as a risk factor for

2020 American Association for Cancer Research. sebaceous carcinoma. In the United States, 73% of cases occur on

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 Sargen et al.

Known risk factors

Ultraviolet radiation

Increasing age

Genetic susceptibility
(Muir-Torre syndrome)

Tumor
cell

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Immunosuppression
(HIV infection,
solid organ
transplantation) A
HIV
B
Oncogenic virus?

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 figure. The highly elevated risk for sebaceous carcinoma among immunosuppressed populations (solid organ transplant recipients and
individuals with HIV infection), which is similar to the elevation observed for other virus-associated cancers (Kaposi sarcoma and 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 UVR exposure is associated with
an increased risk for sebaceous carcinoma, in addition to being an independent risk factor for this cancer type.

chronically sun-exposed skin of the head and neck and 85% of tumors
are diagnosed in white (non-Hispanic, 78% and Hispanic, 7%)
patients, who lack significant amounts of photoprotective melanin
pigment in their skin (7). Furthermore, 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 muta-
tional 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 (e.g., Muir–Torre syndrome).
identified 62 cases of sebaceous carcinoma among 262,455 transplant
recipients, which corresponded to a 34-fold elevation in risk compared
with 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 approx-
imately half of all the U.S. 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 posttransplant diag-
nosis of cutaneous squamous cell carcinoma, longer time since trans-
plant, 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 sug-
gests that UVR photodamage of the skin contributes to sebaceous
carcinoma tumorigenesis in transplant patients.

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 U.S. solid organ transplant recipient
registry with 18 population-based cancer registries (24, 25), and
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 (caused by
Merkel cell polyomavirus; refs. 26, 27) and Kaposi sarcoma (caused by
Kaposi sarcoma–associated herpesvirus/human herpes virus 8;
refs. 24, 28), 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,

390 Clin Cancer Res; 27(2) January 15, 2021 CLINICAL CANCER RESEARCH

who identified human papillomavirus (HPV) types 6, 11, 16, 18, 31,
and 33 by DNA ISH in nine of 13 (62%) sebaceous carcinomas (29).
However, subsequent studies generally failed to identify HPV in
sebaceous carcinomas, with only one HPV-positive case observed of
85 (1.2%) examined by PCR, RNA ISH, or DNA ISH (30–33). Very
recently, 4 of 29 patients (14%) with TP53 and RB1 wild-type seba-
ceous carcinomas were reported to harbor “high-risk” HPV types, as
detected by RNA ISH. Furthermore, in 2 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). Finally, genus Beta papillomaviruses, also
known as cutaneous papillomaviruses, have been proposed as suspects
because of their potential involvement in the development of other
nonmelanoma 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 mutagene-
sis (39, 40). However, another report indicated that Beta papilloma-
viruses, which are a common component of normal skin flora, may be
protective against nonmelanoma 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 toward resolution will require comprehensive identification and
quantification of viral nucleic acids from tumors of immunocompetent
and immunosuppressed patients with sebaceous carcinoma by unbi-
ased DNA and RNA-sequencing. Candidate oncoviruses will have to
be further validated for the expression of gene products spatially within
tumors either by IHC 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 muta-
tional profile of sebaceous carcinomas. North and colleagues per-
formed whole-exome sequencing of 32 sebaceous carcinomas [23
cutaneous tumors and nine ocular (eyelid) tumors] and identified
three molecular subtypes (20). The first subtype, characterized by a
prominent UVR mutational signature and a high tumor mutation
burden (>50 mutations/Megabase), was observed in 10 cases (31%).
A second subtype demonstrated prominent microsatellite instability
and was observed in nine 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 path-
ogenic germline mutation of MSH6. The last subtype (13 cases,
41%) consisted of pauci-mutational tumors with mutations of
ZNF750 observed in nine of the 13 cases (69%). The transcriptomes
and anatomic distribution of UVR-mediated sebaceous carcinomas
closely resembled those of cutaneous squamous cell carcinomas,
AACRJournals.org
Sebaceous Carcinoma Epidemiology and Genetics
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 carci-
nomas (34). Their analysis identified two molecular subtypes: tumors
with TP53 mutations (19 cases, 66%) harboring concomitant genetic
alterations of RB1 (13/19 cases with TP53 mutations) and tumors that
were wild-type for both genes. In a subsequent study, Xu and collea-
gues performed whole-exome sequencing of 31 ocular adnexal seba-
ceous 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 (seven cases) in a subset of cases (43).
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Six tumors lacked mutations of all four genes (TP53, RB1, ZNF750, and
NOTCH1). Mutations of PCDH15 were identified in five tumors (three
cases with TP53 mutations; one 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 nonocular 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 repre-
sentative of nonocular cases, which account for the majority of
tumors (1, 4, 7). Finally, none of the prior studies searched for
differences in the genetic alterations of tumors from immunocompe-
tent and immunosuppressed patients.
Clinical Implications of Sebaceous
Carcinoma Research
Management of sebaceous carcinoma
The first-line treatment for sebaceous carcinoma at all sites (perio-
cular 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 stage IIC or higher tumors,
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 peri-
neural 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, treat-
ments specifically approved by the FDA for sebaceous carcinoma are
lacking.
Clin Cancer Res; 27(2) January 15, 2021 391
 Sargen et al.
Reducing immunosuppression, such as lowering the dosage of
antirejection medications for transplant recipients and adjusting/
starting antiretroviral therapy for individuals with human immuno-
deficiency virus (HIV) infection to increase CD4 counts, may also slow
down tumor growth and progression of disease. However, for trans-
plant patients, the potential benefit of reducing immunosuppression
must be balanced against the risk of graft rejection.
Screening and prevention
Current management guidelines for patients with Lynch syndrome,
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 transplanta-
tion because of the highly elevated risk for cutaneous squamous cell
carcinoma, however, the frequency of surveillance is often not spec-
ified. 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 tumor's 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 ulcer-
ate or bleed, and often located on the face; ref. 52) to perform self-skin
exams at home. Furthermore, to reduce risk for sebaceous carcinoma
along with other skin cancer types, these high-risk populations (HIV
positive individuals, individuals with Muir–Torre syndrome, and solid
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Authors’ Disclosures
No disclosures were reported.
Acknowledgments
This work was supported by the Intramural Research Program of the Division of
Cancer Epidemiology and Genetics, NCI, NIH. 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, NCI, NIH. The authors are also grateful
to Chris Buck for critical evaluation of the article.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
Received June 25, 2020; revised July 31, 2020; accepted September 3, 2020;
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