Are You Confident of the Diagnosis?
What you should be alert for in the history
Characteristic findings on physical examination
Sebaceous carcinoma (SC) has been termed the “great masquerader” of adnexal tumors. Its diverse clinical presentation does not allow for a characteristic illustration. Yet clinical awareness and diagnostic acumen are paramount given its aggressive and malignant nature and its negative impact on morbidity and mortality when not treated in an effective and timely manner.
A classical presentation of a sebaceous carcinoma is a gradually enlarging, painless papule, nodule or plaque on the upper or lower eyelid. A retrospective review of 1349 cases of sebaceous carcinomas recorded in the National Cancer Institute Surveillance, Epidemiology and End Results (NCI SEER) database between 1973 and 2004 revealed that the eyelids were the involved site for 38.7% of sebaceous carcinomas. The remainder were found, in order of incidence, on the face, trunk, scalp/neck, upper limb/shoulder, external ear, lower limb/hip and lip (Figure 1).
They can also occur on the genitalia and reproductive organs. Essentially, sebaceous carcinoma can be found on any hair-bearing skin, as well as nonskin site of the head and neck such as the Meibomian glands. In a review of 40 cases of sebaceous carcinomas patients presented anywhere from less than 1 year to more than 4 years after the onset of symptoms.
Therefore, obtaining clues from a thorough history can be as insightful as the physical examination. Specifically, a high index of suspicion is warranted in patients who present with recurrent or treatment-resistant chalazion (obstruction and inflammation of the Meibomian or Zeis glands that commonly presents as a nontender nodule on the inner eyelid), blepharoconjunctivitis (inflammation of both conjunctiva and eyelids that present with erythema, edema and crusting of the eyelid margins with pink conjunctiva) or keratoconjunctivitis (inflammation of the cornea and conjunctiva with associated epithelial keratitis).
Additionally, a personal or family history of visceral malignancy may aid in the diagnosis of sebaceous carcinoma given its association with Muir-Torre syndrome, an autosomal dominant genodermatosis that predisposes affected individuals to sebaceous neoplasms and visceral cancers.
Expected results of diagnostic studies
The diagnosis of sebaceous carcinoma is made histopathologically. On histology sebaceous carcinoma presents with disorderly invasion of the dermis by basaloid or squamoid cells and includes poorly differentiated sebaceous cells in ill-defined lobules. Moderate to severe atypia is prominent, including hyperchromatism and pleomorphism with many abnormal mitotic figures and foamy cytoplasm. In contrast, sebaceous adenoma appears distinct from sebaceous carcinoma in that it is typically a distinctly circumscribed lobular tumor with mature sebocytes and basaloid germinative cells in the periphery. Cytologic atypia is minimal (Figure 2).
However, in reality, diagnosis can be challenging, particularly when sebaceous areas are subtle and focal, and additional immunohistochemical stains may be necessary. Epidermal membrane antigen (EMA), a glycoprotein found in secretary mammary cells, can be used to help differentiate SC from basal cell carcinoma with sebaceous differentiation, as it would be negative to more weakly positive in the latter.
CAM5.2 (lower molecular weight keratin) would be positive in SC but negative in squamous cell carcinoma. Also, up to 50% of sebaceous carcinomas can involve pagetoid spread and may be missed depending on biopsy technique and section of tissue sample studied. This can contribute to the propensity of sebaceous carcinoma to recur and metastasize. Oil-red-O and Sudan black stains can be used to highlight sebaceous cells. This requires frozen tissue samples to properly preserve the integrity of the lipids in the sample. Also, Leu-M1 immunohistochemical stain can be used to identify sebaceous carcinoma.
The choice between an incisional and excisional biopsy is not always straightforward, although it may be aided by the location of the lesion and extent of tissue involvement. The latter may be an option when the lesion is well circumscribed on an area where tissue sparing is not a significant factor to consider. However, incisional biopsy is preferred when referral for further management, pending biopsy results, is expected and when the carcinoma involves an area where tissue sparing would be beneficial to the patient (such as the eyelid or other areas of the face).
Also, incisional biopsy is recommended when signs of blepharoconjunctivitis are present (crusted eyelids, injected conjunctiva). Fine needle aspiration has been used to sample lesions, although its use is limited by the sparse amount of tissue that is garnered and because it can potentially miss pagetoid areas.
If a sebaceous carcinoma involves the eyelid, orbital imaging can aid in determining the extent of the tumor, particularly if the conjunctiva are involved or there appears to be extensive involvement of the eyelid. At this stage, an ophthalmology consult would be prudent.
There is no classification system in place to correlate tumor burden with prognosis. The TNM classification system has been applied to 21 cases of sebaceous carcinoma demonstrating that diameter greater than 10 mm, classified as T4, indicated a grave prognosis compared with smaller tumors. Despite this, a formal systematic staging system is not in place for sebaceous carcinoma.
Given the diverse clinical presentation of sebaceous carcinoma reported, the list of differential diagnosis is long. It includes basal cell carcinoma, squamous cell carcinoma, cutaneous horn, unilateral conjunctivitis, chalazion blepharoconjunctivitis, Merkel cell carcinoma, cutaneous metastatic cancer including renal cell carcinoma, granulomatous lesions such as sarcoidosis, syphilis or tuberculosis, clear-cell eccrine hidradenoma, ocular pemphigoid, conjunctival carcinoma in situ and lacrimal gland tumors. Histology and immunohistochemistry aid in distinguishing sebaceous carcinoma from each of the above entities, as discussed previously.
Who is at Risk for Developing this Disease?
In the largest review to date of 1379 cases of sebaceous carcinoma reported in the NCI SEER database between 1973 and 2004, age of presentation ranged from 13 to 102, with median age of 73, similar to other published studies. There is a reported case of a 12-year-old who developed fatal ocular sebaceous carcinoma 11 years after curative radiotherapy of bilateral retinoblastoma.
Sebaceous carcinoma has been considered to occur more frequently in women, although the review found a marginal male preponderance (54%). Incidence varied slightly among the different races in the United States, ranging from 0.5 to 2 cases per million per year. Also, Asians and Southeast Asians do not appear any more or less susceptible to developing sebaceous carcinoma.
The SEER database between 1973 and 2004 represented 26.1% of the US population and 53.3% of the Asian population. Even so, the incidence of sebaceous carcinoma among the Asian population was not greater. It appears that eyelid lesions are more likely to be sebaceous carcinoma in the Asian population because they are less likely to develop lesions more commonly found on Caucasian skin, such as basal cell carcinoma, squamous cell carcinoma and melanoma. As such, in the United States, sebaceous carcinoma is the fourth most common eyelid malignancy behind the three above.
Overall survival rate relative to population matched survival rate is 91.9% at 5 years and 79.2% 10 years. Survival does not significantly differ between periorbital and extraorbital sebaceous carcinoma.
Risk factors for sebaceous carcinoma include previous radiation therapy, increased age, an immunosuppressed state and genetic predisposition. There are reports of sebaceous carcinoma occurring in patients who had undergone irradiation for childhood retinoblastoma, as well as for eczema and cosmetic epilation. Also, there is a report of increased incidence of sebaceous carcinoma in patients who had undergone renal transplantation. Finally, a family history of Muir-Torre syndrome presents a significant risk of developing sebaceous neoplasms, including sebaceous carcinoma.
What is the Cause of the Disease?
The majority of sebaceous carcinomas arise spontaneously and de novo. In the periocular region, they arise from sebaceous glands, most commonly the Meibomian glands and the glands of Zeis. Other sebaceous glands in this region include the sebaceous glands of the eyebrows (follicular), sebaceous glands of the fine hairs of the eyelids and lacrimal glands, and sebaceous glands of the caruncle. In the extracutaneous sites, sebaceous carcinomas do not appear to arise from sebaceous glands, making their origin debatable.
There have been reports of sebaceous carcinoma arising from a nevus sebaceous. Also, animal studies have shown that they can arise from primitive, multipotent stem cells that have the potential to differentiate along several lineages. In summary, the pathophysiology of sebaceous carcinomas that arise de novo is not well known and difficult to study given its rarity.
A minority of sebaceous carcinomas occur in patients with Muir-Torre syndrome, providing clues that mutations in tumor suppressor genes can be causative. Muir-Torre syndrome is an autosomal dominant disease with high penetrance and variable expressivity. Afflicted individuals develop multiple visceral cancers and multiple sebaceous neoplasms. By definition, a combination of one visceral cancer and one sebaceous neoplasm is sufficient to make the diagnosis, which can be confirmed by immunohistochemical staining of tissue with MSH-1 and MLH-2; however, Schwartz and Torre describe that the presence of these genetic mutations is not a necessary criterion for diagnosis.
MSH-1 and MLH-2 are genes important for the repair of DNA mismatch. Germline mutations in these genes lead to microsatellite instability in DNA and in the process lead to inactivation of tumor suppressor genes. Animal studies have corroborated that knockout or suppression of these genes leads to marked tumorigenesis and reduced apoptotic response to a particular type of DNA damage.
The invasion of sebaceous carcinoma is believed to occur by direct extension into subdermal and/or epithelial tissues (epitheliotropism), multifocal proliferation into intradermal and subcutaneous tissues, and by oncophoresis whereby cancer cells are hypothetically “shed and transplanted.” In periocular lesions, tumor cells that originate in sebaceous glands are thought to migrate into the ductal epithelial lining and ascend the infundibulum to involve the conjunctiva or epidermis.
There can also be direct intraepidermal extension by pagetoid spread. Up to 50% of recurrent periocular sebaceous carcinomas may involve pagetoid spread and 100% in exenterated specimens. Pagetoid spread is reported to be much less common in extraocular sebaceous carcinoma.
Systemic Implications and Complications
The timely recognition and diagnosis of SC is paramount because of its aggressive nature and tendency to locally invade and metastasize. This is associated with significant morbidity and mortality with diminished overall survival rate. In particular, periocular lesions that are not treated in time may extend to the orbit and require orbital exenteration.
SC has been reported to metastasize to regional parotid, submandibular, preauricular and cervical lymph nodes. There are also reports of periocular SC with distant metastasis to the lung, bone, liver and brain with mortality rate as high as 30%. In the United States prior to 1970, mortality rate was reportedly as high as 24% to 33%. It now appears to be declining, reportedly 9% to 15% at 5 years, due to earlier recognition and monitoring of surgical margins by frozen sections using the Mohs micrographic technique.
The diagnosis of SC can help identify patients with Muir-Torre syndrome and help initiate cancer screening as early as possible in the course of their disease.
In 41% of cases of Muir-Torre syndrome, SC either precedes or occurs simultaneously as a visceral malignancy. They include colorectal adenocarcinoma (most common), genitourinary cancer including bladder cancer, breast carcinoma, lung cancer, hematologic disorders, endometrial carcinoma and gastric carcinoma. The primary care physician should become involved for routine thorough medical workup, including an annual breast or testicular examination, a digital rectal examination and thyroid examination.
Laboratory workup for malignancy includes obtaining a complete blood count (CBC), complete metabolic panel including liver function tests, CEA and ESR. Recommendations have included annual colonoscopy beginning at age 25 as well as less aggressive surveillance by colonoscopy or barium enema every 3 to 5 years.
Annual chest X ray, computed tomography (CT) scan of the abdomen and pelvis, mammography and endometrial biopsy may be judicious. However, since the progression of these malignancies is not known, controversy remains about the optimal frequency for screening tests, especially considering the potential hazards of cumulative radiation exposure.
Of note, it is thought that SC associated with Muir-Torre syndrome is less likely to exhibit a pagetoid nature and therefore less likely to metastasize. Additionally, visceral malignancy associated with Muir-Torre syndrome is not as aggressive as its nonsyndromic counterpart although it still has an overall 60% likelihood of metastasis.
Schwartz and Torre reported a 50% survival rate at 12 years from diagnosis, and therefore, timely removal of primary tumors and even metastatic lesions confer to the patient a greater likelihood to be curative and a positive impact overall survival rate. As such, routine and close follow-up of patients and patient education are important. Furthermore, detection of affected family members and genetic counseling for family planning are also important.
Table 1. Treatment options for sebaceous carcinoma
|Medical Treatment||Surgical Procedures||Physical modalities|
|Systemic chemotherapy||Mohs micrographic surgery||Adjunctive radiotherapy|
|Topical chemotherapy||Wide excision with 5-6 mm margin|
Optimal Therapeutic Approach for this Disease
Treatment options are summarized in the
Table 1. Historically, the surgical treatment of choice in cases without obvious orbital involvement was wide excision with 5 to 6 mm margins. The 5-year recurrence rate has been reported to be as high as 36% with an associated 5-year mortality rate of 18% to 30%. More recent studies looking at the outcome of Mohs micrographic surgeries (MMS) revealed a more favorable outcome, including a decrease in recurrence rate to 8% to 11%.
MMS also offers a more optimal cosmetic outcome as a result of the tissue-sparing nature of the technique. In theory, however, the particular technique of evaluating frozen tissue sections for margins in Mohs has the potential to miss pagetoid islands that can skip sections of tissue and serve as potential nidus for recurrence.
MMS is often performed under local anesthesia where tissue is excised in layers and processed as frozen sections for histologic analysis. This allows complete peripheral and deep margin examination for malignant cells. Useful tools in managing periocular SC include a chalazion clamp to provide hemostasis, an eye shield to protect the cornea, special ophthalmic micro-instrumentation, thermo- and electrocautery hemostasis, and if necessary tetracaine eyedrops in addition as an injectable anesthetic.
After tumor control, wounds may be left to heal by secondary intention, primarily closed, repaired with flaps or referred to oculoplastics for reconstruction.
Orbital exenteration is recommended when there is orbital involvement without metastasis, extensive involvement of the eyelids or involvement of the tarsus and bulbar conjunctiva. Conjunctival map biopsy and/or orbital imaging may be useful in determining the extent of ocular involvement. Whenever there is ocular involvement, an ophthalmology consult is also advised.
Involvement of regional lymph nodes can be managed with neck dissection followed by adjuvant radiotherapy. Although sentinel node mapping has been performed in patients with sebaceous carcinoma and may be of value in staging the extent of the malignancy, its exact role in managing the disease remains to be defined Radiotherapy is also an option in those who have had extirpation of the eye and present with recurrence.
Metastatic disease warrants both adjuvant radiotherapy and chemotherapy. There is a report of a patient who presented with periocular sebaceous carcinoma of 2 to 3 years’ duration who then underwent MMS. Upon recurrence 2 years later, she underwent orbital exenteration with adjuvant radiation therapy. About 5 years later, she developed pulmonary metastasis, for which chemotherapy, including carboplatin, doxetaxel and bevaczimab, was administered; the patient continued to undergo treatment at the time of publication 2 years later.
There are reports of adjuvant cryotherapy and topical chemotherapy with mitomycin C. However, given the small number of cases, more studies would be needed to make any conclusions about their long-term efficacy.
Patients should be made aware that sebaceous carcinoma is a malignant cutaneous neoplasm that has the potential to recur even after surgical treatment. Local recurrence rate at 5 years has been reported to be 8% to 11% after Mohs micrographic surgery and as high as 36% after wide excision with 4 to 5mm margins. Also, SC can cause extensive local tissue damage when not treated in a timely manner, travel along the angiolymphatic pathway to seed neighboring and distant lymph nodes, and metastasize to visceral organs.
Both periocular and extraocular SC carry similar recurrence rates, risk for regional lymph node and distant metastasis, and effects on overall survival outcome.
Therefore, patients should be followed closely for several years after surgical treatment. Reviews of ocular sebaceous carcinoma report recurrences occurring anywhere between 0 to 5 years after initial surgical management. Risk factors included long duration of lesion prior to diagnosis. Lymph node metastasis, when present, has been reported to occur within a mean of 4.5 months after surgical management. Therefore, physical examination should include palpation of regional lymph nodes. There is a report of metastatic lymph node development only 1 month after surgical treatment.
Poor prognostic factors include involvement of both upper and lower eyelids, lymphovascular invasion, multicentric disease, poorly differentiated tumors, tumor diameter greatater than 10 mm, pagetoid spread or infiltrative tumor particularly into the conjunctiva, cornea or skin, persistence of symptoms for more than 6 months at the time of presentation, and previous irradiation.
Good prognostic factors include association with Muir-Torre syndrome, size less than 6mm and presentation of symptoms for less than 6 months at diagnosis.
Unusual Clinical Scenarios to Consider in Patient Management
Although the involvement is characteristically on the eyelids, sebaceous carcinoma may occur at very unusual sites, including the tongue. Collision tumors of SC and seborrheic keratoses have been reported. SC in situ has also been noted.
What is the Evidence?
Dasgupta, T, Wilson, LD, Yu, JB. “A retrospective review of 1349 cases of sebaceous carcinoma”. Cancer. vol. 115. 2009. pp. 158-65. (The largest review of sebaceous carcinoma compiled by retrospective review of the National Cancer Institute’s Surveillance, Epidemiology, and End Results database from 1973 through 2004. It provides important insight into the epidemiology, demographics and survival outcome of this rare malignancy.)
Doxanas, MT, Green, WR. “Sebaceous gland carcinoma: review of 40 cases”. Arch Ophthalmol. vol. 102. 1984. pp. 245-9. (A historical review of sebaceous gland carcinomas that highlights their diverse clinical and histopathologic nature)
Berlin, AL, Amin, SP, Goldberg, DJ. “Extraocular sebaceous carcinoma treated with Mohs micrographic surgery: report of a case and review of literature”. Dermatol Surg. vol. 34. 2008. pp. 254-7. (There is limited literature available on the management and prognosis of extraocular sebaceous carcinoma compared with periocular SC. This article illustrates the potentially more efficacious nature of MMS compared with standard surgical excision in the management of extraocular SC and the need for further studies.)
Pereira, PR, Odashiro, AN, Rodrigues-Reyes, AA, Correa, Z, Filho, J, Burnier, MN. “Histopathological review of sebaceous carcinoma of the eyelid”. J Cutan Pathol. vol. 32. 2005. pp. 496-501. (An insightful review of the histopathology of ocular sebaceous carcinoma that illustrates the often challenging job of identifying SC on histology, particularly differentiating it from basal cell carcinoma and squamous cell carcinoma.)
Husain, A, Blumenschein, G, Esmaeli, B. “Treatment and outcomes for metastatic sebaceous cell carcinoma of the eyelid”. Int J Dermatol. vol. 47. 2008. pp. 276-9. (A report of four cases of metastatic eyelid SC, their management and survival outcome. The article highlights the aggressive and unpredictable nature of this rare malignancy and the importance of close follow-up of patients.)
Schwartz, RA, Torre, DP. “The Muir-Torre syndrome: a 25-year retrospect”. J Am Acad Dermatol. vol. 33. 1995. pp. 90-104. (A historical review of Muir-Torre syndrome by one of the physicians for whom the disease is named. It includes the history of the disease, clinical presentation, histopathologic findings, differential diagnosis, course and prognosis.)
Cohen, PR, Kohn, SR, Kurzrock, R. “Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome”. Am J Med. vol. 90. 1991. pp. 606-13. (A detailed retrospective review of Muir-Torre syndrome that examined the relationship between internal malignancy and sebaceous gland tumors. It provides a detailed outline of a diagnostic treatment plan for patients with Muir-Torre syndrome and their families.)
Ponti, G, Ponz de, LM. “Muir-Torre syndrome”. Lancet Oncol. vol. 6. 2005. pp. 980-7. (A more recent review of Muir-Torre syndrome, including pathophysiology and recommendations to aid in diagnosis and clinical management.)
Snow, SN, Larson, PO, Lucarelli, MJ, Lemke, BN, Madjar, DD. “Sebaceous carcinoma of the eyelids treated by Mohs micrographic surgery: report of nine cases with review of the literature”. Dermatol Surg. vol. 28. 2002. pp. 623-31. (A review of nine cases of periocular sebaceous carcinoma treated by MMS between 1987-2001 at the University of Wisconsin Surgery Clinic and additional review of 40 cases from the literature. The authors provide useful details about management by MMS and delve thoroughly into recurrence rate, metastatic rate and survival outcome in support of MMS over standard surgical excision for periocular SC.)
Spencer, JM, Nossa, R, Tse, DT, Sequeira, M. “Sebaceous carcinoma of the eyelid treated with Mohs micrographic surgery”. J Am Acad Dermatol. vol. 44. 2001. pp. 1004-9. (A report of 18 patients with SC who underwent MMS between 1988 and 1998 at the University of Miami Department of Dermatology and Cutaneous Surgery, supporting the lower recurrence and metastatic rates when compared with standard surgical excision.)
Buttrago, W, Joseph, AK. “Sebaceous carcinoma: the great masquerader”. Dermatologic Therapy. vol. 21. 2008. pp. 459-66. (A thorough and thoughtful review of the sebaceous carcinoma literature.)
Ho, VH, Ross, MI, Prieto, VG, Khaleq, A, Kim, S, Esmaeli, B. “Sentinel lymph node biopsy for sebaceous cell carcinoma and melanoma of the ocular adnexa”. Arch Otolaryngol Head Neck Surg. vol. 133. 2007. pp. 820-6. (The exact role of the use of sentinel lymph node biopsy for managing patients with sebaceous carcinoma warrants further study.)
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