Background
Sebaceous gland carcinoma is an aggressive, uncommon, cutaneous tumor first well-described by Allaire in 1891. [1] This tumor is thought to arise from sebaceous glands in the skin and, thus, may arise anywhere on the body where these glands exist, including the genitalia. [2, 3, 4, 5] Approximately 75% of these tumors arise in the periocular region, an area rich in a variety of types of sebaceous glands. [6, 7] This tumor exhibits an aggressive clinical course, with a significant tendency for both local recurrence and distant metastasis.
Diagnosis and therapy tend to be delayed because sebaceous carcinoma is frequently mistaken for more common benign entities, further complicating treatment of this aggressive malignancy. [8, 9, 10, 11] In addition, a varied histologic appearance may occur, and delayed diagnosis or misdiagnosis following a biopsy is not uncommon. [8, 9, 10]
When arising in the periocular region, the clinical presentation is often variable, and sebaceous gland carcinoma is often not initially suspected. Instead, patients may receive multiple courses of incision and drainage for chalazion before a definitive biopsy is performed. [8, 12, 13]
Most sebaceous gland carcinomas have no obvious etiology. Only a few are associated with Muir-Torre syndrome. Although sebaceous adenoma and epithelioma are more specific markers for Muir-Torre syndrome, an evaluation for this syndrome is advisable once sebaceous gland carcinoma is diagnosed. [14] Extraocular sebaceous carcinoma has been suggested to have a higher risk of Muir-Torre syndrome. [15] In approximately 40% of cases, patients with Muir-Torre syndrome develop some type of sebaceous tumor before or concurrent with visceral malignancy. [16]
Pathophysiology
Sebaceous gland carcinoma resembles normal sebaceous glands. [17] One may reasonably speculate that sebaceous gland carcinoma arises from mature sebaceous glands. Histologic studies have suggested that periocular sebaceous gland carcinomas arise from the sebaceous glands in this region. The following 5 types of sebaceous glands are seen in the periocular region [6, 7] :
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Meibomian glands of the tarsal plate
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Glands of Zeis of the cilia
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Sebaceous glands of the eyebrows
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Glands of the caruncle
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Glands of the fine hair follicles of the eyelid surface
In one histologic series, 51% of cases reportedly arose from a specialized sebaceous gland of the eyelid, the meibomian gland. Indeed, sebaceous gland carcinoma is sometimes referred to as meibomian gland carcinoma. In the same series, 10% of cases arose from the glands of Zeis, less than 10% of cases arose from the caruncle and the eyebrow each, and 12% were multicentric with no obvious source of origin. [18]
Isolated case reports describe sebaceous gland carcinoma limited to the epithelium, with no obvious connection to the underlying sebaceous glands. [19] In these rare cases, the sebaceous gland carcinoma may fill the conjunctival epithelium and create the appearance of squamous cell carcinoma in situ. Whether these tumors truly have an epithelial origin or whether the dermal connection has been lost is simply unappreciated is unknown.
Approximately 30 case reports have described the development of sebaceous carcinoma in a sebaceous nevus of Jadassohn. [20, 21, 22, 23, 24, 25] Sebaceous carcinoma arising from a nevus sebaceous is more common in women and elderly persons, described as a nodule or ulcerated tumor that usually demonstrates rapid growth prior to diagnosis. [22] Although generally larger in diameter, this distinct entity tends to possess more benign features and follow a more favorable course. [26] Controversy exists regarding the prophylactic removal of a nevus sebaceous, but when malignant neoplasms are suspected, removal is warranted regardless. [27]
Several molecular markers have been identified that may help elucidate the pathophysiologic progression of sebaceous carcinoma. Promotion of tumor metastasis and a poor clinical outcome have been associated with epigenetic inactivation of E-cadherin and subsequent loss of cell-to-cell adhesion in sebaceous carcinoma. [28] Hormonal receptors may also play a significant role. Increased expression of androgen receptor in the nucleus of periocular sebaceous carcinoma may indicate a greater likelihood of recurrence and help distinguish this entity from squamous cell and basal cell carcinomas. [29, 30] In addition, HER2 gene amplification and protein overexpression have been demonstrated in sebaceous carcinoma and may serve as potential therapeutic targets. [31] Future studies are needed to clarify these mechanisms.
Sebaceous carcinomas have also been associated with previous radiation, immunosuppression, genetic conditions such as Muir-Torre syndrome and retinoblastoma, production of nitrosamines, and photosensitization from diuretic use. [32]
Etiology
The etiology of sebaceous gland carcinoma remains unclear. No association with ultraviolet radiation has been documented, but a history of ionizing radiation has been reported. Reports of prior radiation therapy for a variety of benign and malignant conditions include radiation for cavernous hemangioma, barber's itch, retinoblastoma, and uterine cancer. [33, 34, 35]
In one series of 20 patients with sebaceous gland carcinoma, 8 patients had a history of diuretic use, and a possible association was suggested. [9]
Sebaceous gland carcinoma seems to be more common in Asian populations than in other populations, and involvement of human papillomavirus (HPV) has been suggested as a possible etiologic factor in these populations. One paper from Japan reported the presence of HPV DNA in some sebaceous gland carcinomas, as well as an overexpression of TP53. [36] A study from the United States failed to detect HPV, but it did find overexpression of TP53. [37]
Sebaceous carcinoma may occur in greater frequency in immunocompromised patients. Cases of sebaceous carcinoma in HIV-infected and cardiac and renal transplant patients have been reported. Although more controlled studies are needed, the authors emphasized the need for awareness of sebaceous carcinoma in long-term dermatologic follow-up in organ transplant patients. [38] Calcineurin inhibitors such as cyclosporine and tacrolimus have been implicated in propagating sebaceous carcinomas through increasing activity of transforming growth factor-beta and interleukin 6. [39] Switching to sirolimus may suppress new sebaceous neoplasms in organ transplant patients. [40] Although an association between immunosuppression and sebaceous carcinomas has been identified, one report of six patients showed that sebaceous carcinoma may not behave more aggressively in Non-Hodgkin lymphoma and chronic lymphocytic leukemia. [41]
Experimental evidence in animals has implicated chalazia as a possible factor in the development of sebaceous gland carcinoma. Chalazia are caused by inflammation of the meibomian glands or glands of Zeis that results in the formation of a hard, usually painless, nodule in the eyelid. Histologically, chalazia contain granulomatous inflammation, areas of caseation necrosis, and an unsaturated 8-carbon fatty acid called oleic acid. Animal studies have suggested possible carcinogenicity with exposure to oleic acid, and prolonged exposure to this molecule within chalazia may induce dysplastic growth in glandular structures.
Genetic factors play a role, and sebaceous gland carcinomas are part of the genodermatosis, Muir-Torre syndrome. Muir-Torre syndrome is a rare autosomal dominant condition with variable penetrance characterized by skin manifestations, including benign and malignant sebaceous neoplasms, keratoacanthomas, and internal manifestations (eg, colonic polyps, visceral malignancies). [14] A diagnosis of Muir-Torre syndrome requires the presence of both an internal malignancy and a sebaceous neoplasm. [14] The sebaceous neoplasms encompass a spectrum from well-differentiated sebaceous hyperplasia through undifferentiated sebaceous gland carcinoma. [14]
In one literature review of 120 patients with Muir-Torre syndrome, 29 had sebaceous gland carcinoma, 50% of which were ocular. [16] Sebaceous neoplasms developed before or concurrent with visceral malignancies in 41% of patients in one series. [16] Colorectal carcinoma is the most common internal malignancy in Muir-Torre syndrome, followed by genitourinary malignancy. [16] A variety of internal malignancies, including head and neck, small bowel, and hematologic, occur less frequently in Muir-Torre syndrome. Sebaceous gland carcinoma is clearly part of Muir-Torre syndrome. However, the percentage of patients with sebaceous gland carcinoma who will develop Muir-Torre syndrome is not clear. [14] All patients with sebaceous gland carcinoma should be evaluated for Muir-Torre syndrome.
Epidemiology
Frequency
United States
Sebaceous gland carcinoma is a rare tumor. Approximately 75% of sebaceous gland carcinomas occur in the periocular region. [6] In this region, sebaceous gland carcinoma represents 1-5.5% of eyelid malignancies, fourth after basal cell carcinoma, squamous cell carcinoma, and melanoma. [18, 42, 43] The overall incidence has been increasing, by an annual percentage change of 3.31% from 2000-2012 to 0.23 cases per 100,000 person-years, especially in white males. [44] According to a 2016 Surveillance, Epidemiology, and End Results (SEER) program, 25% of sebaceous carcinomas are periorbital. [44]
International
Sebaceous gland carcinoma seems to occur with greater frequency relative to other skin cancers in Asian populations. In a large retrospective series from China, sebaceous gland carcinoma was the second most common periocular tumor after basal cell carcinoma, reported to represent 33% of eyelid malignancies. [43]
Sex
Historically, women were reported to be affected somewhat more often than men, with 57-77% of patients being women in several large series. [8, 17, 18, 45, 46, 47] However, a SEER Program analysis from 2000-2012 reported that males (0.32 per cases per 100,000 person-years) had a higher incidence than females (0.16 cases per 100,000 person-years). [44]
Age
Most patients present in their sixth or seventh decade of life, although the range is from early childhood through the nineties. [17, 33] The youngest reported case arose in a 3-year-old child. [48]
Prognosis
Sebaceous gland carcinoma is an aggressive tumor, with a tendency for both local recurrence and distant metastasis. Reported local recurrence rates range from 9-36%, with larger series reporting recurrence rates in the 30% range. Local recurrence tends to occur within 5 years. [6, 10]
The rate of metastasis in extraocular and ocular sebaceous carcinoma is thought to be similar, occurring in 14-25% of cases, first to the draining lymph nodes and then to distant sites. [8, 18, 49] Sites of distant metastasis include the liver, lungs, bones, and brain. [8, 18, 50] Nodal metastasis has not been shown to be an independent prognostic factor in sebaceous carcinoma. [51] Metastasis has been reported to occur as late as 5 years after the initial diagnosis, lending support to the continual surveillance of patients with sebaceous carcinoma. [46]
Reported clinicopathological features associated with a poor prognosis include orbital invasion, upper and lower eyelid involvement, poor differentiation, [52] lacrimal gland involvement, [52] tumor diameter greater than 10 mm, [53] pagetoid spread, and symptom duration greater than 6 months. [18] Patients aged 80 years or older at the time of diagnosis may also have reduced 5-year-disease specific survival. [51]
One Korean study of 40 patients found that T staging by the American Joint Committee on Cancer (AJCC) yielded important prognostic value and that patients with sebaceous carcinoma of at least stage T2b (>10 mm in size or involving full-thickness eyelid) had an increased rate of metastasis. [54] Another study of 50 patients reported an AJCC stage T3a (>20 mm in size, invasion of adjacent ocular or orbital structures, or perineural invasion) was correlated with distant metastasis and death from disease. [55] A 2016 study of 191 patients found that orbital tumor extension and perivascular invasion was associated with systemic metastasis, but only orbital tumor extension correlated with death due to systemic metastasis. [56]
The 5-year mortality rate for patients with metastatic disease is reportedly 71.1% (standard error, 1.5%) and the 10-year survival rate is 45.9% (standard error, 2.1%). [57]
A 2016 SEER database report showed sebaceous carcinoma mortality has been decreasing despite increased incidence, with a 5-year 78.2% observed survival rate and a 10-year 61.2% observed survival rate. However, male sex, black race, and extraocular occurrences were associated with significantly greater mortality. [44]
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Irregular lobules and sheets of atypical sebaceous cells (20x magnification).
