To our knowledge, this is the largest population-based study of cutaneous SC reported to date, enabling an evaluation of age-specific incidence patterns according to eyelid and non-eyelid sites. We found a predominance of cutaneous SC among males, Whites, and at non-eyelid sites. Many,3, 5, 21–24, 30–32
but not all,33, 34
studies of sebaceous tumors of the eyelid have reported a female predominance, often based on relative frequencies (which may reflect the generally longer lifespan in women). Surveys of extraocular SC have been limited by small numbers of cases.8–10
Although we did not find significant gender differences for eyelid SC in any age group, the incidence of non-eyelid SC was consistently higher among males, particularly at older ages. Eyelid and non-eyelid SC are considered biologically similar,1
however, the variation in incidence patterns by gender suggests etiologic heterogeneity.
We also observed a significantly lower incidence of both eyelid and non-eyelid SC among Blacks compared to Whites, which resembles the racial differences reported for keratinocyte-derived skin cancers as well as cutaneous melanoma.35, 36
Our findings suggest that the protective effects of cutaneous pigmentation on various forms of skin cancer may extend to sebaceous tumors of the eyelid and other sites.
Sebaceous carcinoma of the eyelid has been reported to occur more frequently30
and to comprise a greater proportion of eyelid tumors among Asian than Western populations.21
However, there are limited data on actual incidence rates for eyelid SC in Asia,22
and no information on incidence of non-eyelid SC. Our SEER population-based data revealed that, similar to Blacks, the risks of SC were significantly lower among APIs than Whites, but the deficit was limited to non-eyelid tumors. Taken together, the patterns in the U.S. point to racial differences in susceptibility to SC according to anatomic site.
Although the incidence trend for eyelid SC rose after the SEER Program began in 1973, the IRs seemed to plateau beginning in the mid-1980s, resembling the stable trend reported in Taiwan between 1979 and 1999.22
In contrast, the incidence of non-eyelid SC in SEER has continued to climb in both sexes. These findings may reflect site-specific differences in risk factors for SC and/or differential detection by medical specialists.
Our study is the first to quantitatively assess the risk of other cancers occurring in patients with SC. Several literature reviews of MTS have reported cancers occurring prior to, concurrently with, or subsequent to sebaceous tumors.13, 16, 19, 20
Most frequently reported have been colorectal and genitourinary cancers, accounting for 56% and 22% of cases, respectively.16
In our population-based study, patients with SC had a 43% significantly increased risk of developing a new malignancy compared to the general population. In the opposite direction, a significant 52% elevated risk of subsequent SC was seen among those diagnosed with other forms of cancer. Over all ages combined, we observed excess risks for cancers of the ureter, salivary gland, nasal cavities/middle ear, and eye/orbit following SC, while increased risks of SC were found after cancers of the colon, ovary, pharynx, and nasal cavities/middle ear, as well as NHL and CLL. In contrast to prior clinical surveys, colorectal cancer accounted for only 12% of cancers following SC and 28% of cancers associated with subsequent SC. This may reflect differences in the types of sebaceous tumors included in earlier studies (e.g., we did not assess sebaceous adenomas or epitheliomas) and/or reporting bias in the clinical literature. In addition, among patients previously reported with multiple cancers, 40–50% of SC have involved the eyelid,16, 19, 20
a slightly higher estimate than the 36% we observed in the SEER data. In the SEER population, however, we found that the risk of other cancers was significantly higher in association with non-eyelid than eyelid SC. Notably, individuals with SC in our study did not differ from the general population in their risk for several common cancers, such as breast, lung, and prostate.
It is noteworthy that, following cutaneous SC, risk of all subsequent cancers combined was markedly higher among those diagnosed with SC before rather than after age 50 years. In particular, individuals with early-onset SC had significantly increased risks of colon, uterine corpus, and pancreatic cancers, whereas those with early-onset cancers of the colon and ovary had significantly elevated risks of subsequent SC. In addition, individuals with late-onset SC had significantly increased risk of ureter cancer, while those with late-onset colon cancer had an excess of subsequent SC. Cancers of the colon, ureter, uterine corpus, ovary and, less commonly, pancreas have been reported in previous series of SC,13, 16, 19, 20
and all are considered HNPCC-related tumors.37
As with HNPCC, individuals with MTS often have germline mutations in mismatch repair genes (e.g., MLH1
) with resulting microsatellite instability (MSI) in all tumors, including SC.15, 38–42
In contrast, most sporadic sebaceous tumors have not been associated with MSI.38, 41, 43
In our study, the spectrum of early-onset cancers associated with SC, the greatly elevated risk estimates, and the reciprocal increases in the risks of colon cancer and SC, are consistent with the constellation of tumors reported in MTS.
In addition to MTS, genetic predisposition may contribute to the excess risk of SC of the eyelid reported in patients with retinoblastoma treated with radiotherapy.44
Furthermore, SC has been reported in immunosuppressed populations, including organ transplant recipients and patients infected with human immunodeficiency virus (HIV),45–47
which suggests that immunologic impairment may have contributed to the 3-fold or greater risks of SC that we observed following NHL, CLL, and melanoma at age 50 or older. Since immune alterations predispose to infectious agents, further consideration in SC should be given to the possible role of oncogenic viruses.48, 49
Ultraviolet radiation may also play a role in the development of SC, as suggested by the racial disparities in our study, and the predominance of tumors occurring on the head and neck, although sebaceous glands are also more common in this area.2, 45
Cancers of the salivary gland, nasal cavities/middle ear, and eye/orbit have been reported rarely in surveys of SC.7, 16, 50
It is uncertain whether the excess risks we observed for these cancer sites reflect a true association or are due to misclassified metastases,2, 4
multicentric tumors,5, 7
or radiotherapy administered for the initial cancer. Although none of the cancers associated with SC in our series were reported to have sebaceous histology, the ability of SC to masquerade as other neoplasms must be considered.2, 4, 5, 33
The population-based design and magnitude of our study allowed us to estimate with some precision the incidence patterns and cancer risks associated with SC, while avoiding the biases that may result from clinical series. Limitations included the lack of centralized pathology review, particularly given diagnostic challenges associated with SC; however, the SEER database has high reliability and 93% of patients with multiple primary cancers have microscopic confirmation.28
We included ICD-O-3 topography codes for other and unspecified parts of the face (C443) and unspecified skin site (C449) within the non-eyelid category, which may have resulted in eyelid lesions being included within the non-eyelid category. Nevertheless, misclassification of tumor site would have yielded attenuated risk differences between eyelid and non-eyelid SC. Our analysis also included multiple comparisons, and small numbers were involved in several risk estimates, so that some of the observed associations may represent chance findings.
In summary, this population-based study of SC revealed a higher incidence in Whites than Blacks or APIs, consistent with the racial differences seen with other forms of skin cancer. In contrast to the patterns for eyelid SC, the non-eyelid tumors predominated among males, rose steadily over time, and were associated with significantly increased risk of other primary cancers, either preceding or following a diagnosis of SC. The associations with SC were most pronounced for early-onset cancers of the colon, uterine corpus, ovary, and pancreas, as well as late-onset ureter cancer, all of which are components of MTS, a variant of HNPCC (Lynch syndrome). In addition, a role for immunologic factors was suggested by the elevated risks of SC following NHL, CLL, and cutaneous melanoma, consistent with previous reports of SC following organ transplantation and HIV infection. Further studies of SC by site of origin should clarify the genetic, immunologic, and environmental determinants of this tumor and help design screening programs aimed at the early detection of SC and visceral cancers associated with MTS.