AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Background

Sebaceous gland carcinoma is an aggressive, uncommon, cutaneous tumor. 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. Approximately 75% of these tumors arise in the periocular region, an area rich in a variety of types of sebaceous glands. 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. In addition to its varied clinical appearance, a varied histologic appearance may occur, and delayed diagnosis or misdiagnosis following a biopsy is not uncommon.

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.

Most sebaceous gland carcinomas have no obvious etiology. Only a few are associated with Muir-Torre syndrome. Despite the low probability, an evaluation for Muir-Torre syndrome is advisable once sebaceous gland carcinoma is diagnosed. In about 40% of cases, patients with Muir-Torre syndrome develop some type of sebaceous tumor before or concurrent with visceral malignancy.

Pathophysiology

Modern tumor classification schemes name tumors for the type of normal adult tissue toward which the tumor appears to be differentiating. The cell of origin is often not known. Sebaceous gland carcinoma clearly resembles normal sebaceous glands. One may reasonably speculate that in fact 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. Five types of sebaceous glands are seen in the periocular region.

• Meibomian glands of the tarsal plate
• Glands of Zeis of the cilia
• Sebaceous glands of the eyebrows
• Glands of the caruncle
• Glands of the fine hair follicles of the eyelid surface

In one histologic series, it appeared that 51% of cases arose from a specialized sebaceous gland of the eyelid, the meibomian gland. Indeed, one may see sebaceous gland carcinoma referred to as meibomian gland carcinoma in some sources. 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.

Isolated case reports describe sebaceous gland carcinoma limited to the epithelium, with no obvious connection to the underlying sebaceous glands. 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 or is simply unappreciated is unknown.

Frequency

United States

Sebaceous gland carcinoma is a rare tumor. Approximately 75% of sebaceous gland carcinomas occur in the periocular region. In this region, sebaceous gland carcinoma represents 1-5.5% of eyelid malignancies, fourth after basal cell carcinoma, squamous cell carcinoma, and melanoma.

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 28% of eyelid tumors.

Mortality/Morbidity

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.
• Metastasis occurs in 14-25% of cases, first to the draining lymph nodes and then to distant sites. Sites of distant metastasis include the liver, the lungs, the bones, and the brain. The 5-year mortality for patients with metastatic disease is reportedly 50-67%.

Sex

Women tend to be affected somewhat more often than men, with 57-77% of patients being women in several large series.

Age

Most patients present in their sixth or seventh decade of life, although the range is from early childhood through the nineties. The youngest reported case arose in a 3-year-old child.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

History

• The presentation of sebaceous gland carcinoma is often nonspecific, and a noncancerous condition of the periocular area may be mistakenly assumed. A biopsy-confirmed diagnosis is typically delayed for months and even years after the patient becomes aware of the condition.
• Most often, a painless nodule of the eyelid develops, and the patient receives treatment for the far more common benign chalazion.

Physical

Sebaceous gland carcinoma has a varied clinical presentation that often results in delayed diagnosis.

• Tumors of the upper lid are 2-3 times more common than lesions of the lower lid.
• The most common presentation is a firm, slowly enlarging nodule of the upper eyelid, often mistaken for a chalazion.
• • Patients are not uncommonly treated for many months for recurrent chalazia before a biopsy is performed.
  • In a variety of series, the delay in diagnosis following presentation ranges from 1-3 years.
• Loss of cilia is a clinical clue that the lesion is malignant.
• Clinical presentation can mimic keratoconjunctivitis, blepharoconjunctivitis, squamous cell carcinoma, basal cell carcinoma, cutaneous horn, sarcoidosis, ocular pemphigoid, and a variety of benign and malignant ocular tumors.
• Extraocular sebaceous gland carcinoma represents 25% of reported tumors.
• The head and the neck are where most extraocular sebaceous gland carcinomas occur, with the parotid gland alone representing 20% of cases.
• Rare reports exist of tumors arising in virtually every area of the body, including the genitalia.
• The clinical presentation is nonspecific and is usually described as a nodule that is pink to yellow-red.

Causes

The cause 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, and retinoblastoma.

• One series of 20 patients with sebaceous gland carcinoma reported that 8 patients had a history of diuretic use, and a possible association was suggested.
• 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.
  • A recent study from the United States failed to detect HPV, but it did find overexpression of TP53.
• 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 clearly play a role, as sebaceous gland carcinomas are part of the genodermatosis, Muir-Torre syndrome.
• • Muir-Torre syndrome is an autosomal dominant condition with variable penetrance characterized by skin manifestations, including benign and malignant sebaceous neoplasms, keratoacanthomas, and internal manifestations (eg, colonic polyps, low-grade visceral malignancies).
  • The sebaceous neoplasms encompass a spectrum from well-differentiated sebaceous hyperplasia through undifferentiated sebaceous gland carcinoma.
  • In one series of 120 patients with Muir-Torre syndrome, 29 had sebaceous gland carcinoma, 50% of which were ocular.
  • Sebaceous neoplasms developed before or concurrent with visceral malignancies in 41% of patients in one series.
  • Colorectal carcinoma is the most common internal malignancy in Muir-Torre syndrome, followed by genitourinary malignancy.
  • A variety of internal malignancies, including head and neck, small bowel, and hematologic, occur less frequently in Muir-Torre syndrome.
  • The visceral malignancies tend to be low grade, and prolonged survival is generally the course.
  • Sebaceous gland carcinoma is clearly part of Muir-Torre syndrome. However, the percentage of patients with sebaceous gland carcinoma who will have Muir-Torre syndrome is not clear.
  • All patients with sebaceous gland carcinoma should be evaluated for Muir-Torre syndrome.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Chalazion
Keratoconjunctivitis
Blepharoconjunctivitis
Conjunctival carcinoma in situ
Leukoplakia
Ocular pemphigoid
Granulomatous inflammation from syphilis or tuberculosis
Central retinal artery occlusion and proptosis
Lacrimal gland tumors
Exophthalmos
Benign adnexal tumors

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Lab Studies

• Baseline studies include liver function tests, electrolyte levels, and a complete blood cell count to rule out metastatic disease and to establish a baseline for future care. Normal results of these tests also help to rule out any tumors associated with Muir-Torre syndrome
• More detailed studies can be directed by these findings.

Imaging Studies

• Chest radiography to rule out metastatic disease and to establish a baseline for future care may be performed.

Other Tests

• A systemic evaluation includes a complete medical and family history and a physical examination, including a detailed ophthalmologic examination, palpation of the lymph nodes, a thorough skin examination, and a review of systems.
• Evaluation for Muir-Torre syndrome includes a preliminary rectal examination, colonoscopy or barium enema, and a first morning urine for cytologic analysis.
• • Colorectal carcinoma is the most common visceral malignancy in Muir-Torre syndrome. Most of these malignancies occur proximal to the splenic flexure and, thus, digital examination and flexible sigmoidoscopy would be inadequate to aid in the diagnosis.
  • The urine cytologic analysis is used to screen for genitourinary malignancy.

Procedures

• Successful diagnosis results from suspecting this rare tumor in the first place and performing an adequate biopsy.
• A full-thickness eyelid biopsy is generally recommended in cases in which a papular or nodular primary tumor is evident.
• Some authors have recommended fine needle aspiration for primary and metastatic sebaceous gland carcinoma, but a full-thickness surgical biopsy is mandatory if the results are negative or equivocal.
• Approximately 50% of patients have clinically inapparent extension of tumor cells in the surrounding epidermis, termed pagetoid spread. This may extend considerable distances beyond the main body of the tumor. Conjunctival map biopsies are recommended to delineate the presence and extent of pagetoid spread.

Histologic Findings

Sebaceous gland carcinoma may exhibit clinically inapparent extension beyond the obvious tumor within the adjacent epithelia. Cells seen in the adjacent epithelia, often appearing to be separate from the main tumor, are known as pagetoid spread. This typically occurs within the conjunctivae, but it can also occur in the adjacent skin or the cornea. This phenomenon is seen in approximately 40-80% of reported series. The significance of these intraepithelial cells in unclear, with some authors reporting a worse prognosis when present, and others reporting no significant difference in outcome when present. Given the possibility that these cells represent tumor infiltration rather than premalignant or reactive cells, a conjunctival map biopsy to delineate the presence and the extent of pagetoid spread seems warranted.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical Care

Sebaceous gland carcinoma is an aggressive tumor with a tendency for both local recurrence and metastasis. Delay in diagnosis may contribute to the poor outcome in this tumor. Therefore, a high degree of suspicion when eyelid lesions occur and a willingness to perform a biopsy will most likely contribute to a better prognosis for this tumor. Radiation therapy has traditionally been considered palliative and not curative.

• In a small series of 6 patients, all 6 experienced a relapse 2 months to 2 years following radiation therapy, but they remained tumor-free following subsequent surgery.
• Rao et al reported a mortality rate of 78% in patients treated primarily with radiation therapy in contrast to a rate of 7% for those treated with wide excision; however, a recent case report describes 2 patients who refused surgery who were successfully treated with radiation therapy.
• Drawing conclusions from only 2 cases is premature, but the possibility exists that advancements in radiation technology and technique may make this a viable therapeutic option in the future.
• While the significance of pagetoid spread is debated, most authors agree treatment of this epithelioid spread is warranted. It has been suggested, but not studied, that topical chemotherapy to the involved conjunctivae following surgical excision of the invasive tumor may be beneficial.

Surgical Care

Sebaceous gland carcinoma remains a dangerous tumor and produces significant morbidity and mortality. Heightened awareness by the clinician and early biopsy may impact management of this rare tumor. Therapeutically, cryosurgery and surgical excision have been used for this tumor.

• Cryosurgery has been useful for a variety of cutaneous tumors and holds the theoretic advantage of treating large areas of conjunctivae if pagetoid spread is present. Long-term studies evaluating the use of cryosurgery for sebaceous gland carcinoma with pagetoid spread need to be performed.
• Surgery has been and remains the primary treatment modality for sebaceous gland carcinoma. When orbital involvement is documented, therapy has traditionally been orbital exenteration. Without orbital involvement, surgical therapy typically involves excision of the visible tumor plus 5-6 mm of normal-appearing tissue in all directions, followed by either frozen section or permanent section histologic analysis. This approach has not been completely satisfying, as local recurrence occurs in about one third of patients.
• The use of the fresh tissue Mohs technique has been successfully used in a number of case reports; however, these reports are limited to 1-3 cases each for a total of 12 cases in the literature, and the findings cannot be considered definitive. Nonetheless, these reports added together state that 2 of 12 patients had lesions recur, for a recurrence rate of 16.7%, and that 2 of 12 patients had positive margins at reconstruction, so presumably these lesions may have recurred as well.
• This author has treated 18 patients with periocular sebaceous gland carcinoma using the fresh tissue Mohs technique, with an average follow-up period of 37 months. Two of these 18 patients had lesions recur, for a recurrence rate of 11.1%, and one of these patients also developed metastatic disease to the parotid lymph nodes, for a metastatic rate of 5.6% (Spencer, 2001). This is a significant improvement over the local recurrence rate of 32% reported following conventional surgery. Given our current understanding of the treatment of sebaceous gland carcinoma, excision using the Mohs technique may become the treatment of choice.
• The treatment of tumors with pagetoid spread remains controversial. Some authorities have suggested that complete excision of involved epithelia is necessary, while others have suggested only frank invasive tumor needs to be treated, after which only careful clinical observation of the involved epithelia is warranted. Given the aggressive nature of this tumor, treating pagetoid spread as direct tumor extension and continuing surgical excision until all margins are clear, including clear of pagetoid spread, are wise. In this author's series of 18 patients, 9 had pagetoid spread, and surgery was continued until the conjunctivae was clear because pagetoid spread can be seen on frozen sections. Future larger series are needed to better delineate the true significance of pagetoid spread.

Consultations

Referral to an internist and gastroenterologist is warranted in patients diagnosed with sebaceous carcinoma in order to evaluate for the presence of internal (internist) and bowel (gastroenterologist) lesions associated with Muir-Torre syndrome.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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.
• Metastasis occurs in 14-25% of patients. It first spreads to the draining lymph nodes and then to distant sites. Sites of distant metastasis include the liver, the lungs, the bones, and the brain.
• The 5-year mortality rate for patients with metastatic disease is reportedly 50-67%.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Misdiagnosis as a more common benign entity may cause delay in appropriate treatment. However, delayed diagnosis or misdiagnosis is not uncommon with this clinically subtle tumor.
• Failure to evaluate patients with a diagnosis of sebaceous carcinoma for Muir-Torre syndrome is a pitfall.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Oct 2, 2006