Dermatologic Manifestations of Sebaceous Carcinoma 

Updated: Mar 22, 2019
Author: Wesley Wu, MD; Chief Editor: Dirk M Elston, MD 

Overview

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] :

  • 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, 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]

 

Presentation

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.[10, 46]

Most often, a painless nodule develops on the eyelid, and the patient receives treatment for the far more common benign chalazion.[6, 8, 12]

Physical Examination

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.[6, 18, 45, 47] The most common presentation is a firm, slowly enlarging, yellow to red-brown plaque or nodule of the upper eyelid, owing to its greater density of meibomian glands, and is often mistaken for a chalazion.[6, 8, 12] The surface of the lesion may be friable, crusted, or ulcerated.

In a variety of series, the delay in diagnosis following presentation ranges from 1-5 years.[10, 46] Loss of cilia is a clinical clue that the lesion is malignant.[47]

One study reported 7 of 31 patients presented with a characteristic “tigroid” pattern of the conjunctiva, described as yellow streaks (lipid material from the meibomian glands) within an area of papillary hypertrophy.[10] Clinical presentation can mimic keratoconjunctivitis,[8, 12] squamous cell carcinoma, basal cell carcinoma, cutaneous horn,[58] sarcoidosis, ocular pemphigoid, and a variety of benign and malignant ocular tumors.[6, 10]

Extraocular sebaceous gland carcinoma represents 75% of reported tumors, which are more common in men.[44] The head and the neck are where most extraocular sebaceous gland carcinomas occur, with the parotid gland alone representing 30% of cases.[59] Rare reports describe tumors arising in virtually every area of the body. Unusual anatomical locations reported in association with sebaceous carcinoma include the genitalia,[3, 6] the parotid gland,[60] the ear canal,[61] the breast,[62, 63] and the intraoral cavity.[2]

An Australian report characterized the dermatoscopic features of extraocular sebaceous carcinoma to have polymorphous vessels, asymmetry, and ulcerated areas with a variable yellow background.[64] The vasculature may be variable given different array of microvessels between the epidermis and tumor. Yellowish structures represent sebaceous differentiation. A Japanese publication suggested also dermatoscopically examining whitish pink areas that represented telangiectases, inflammatory infiltrate, and fibrosis.[65] An Indian study also focused on irregular abruptly ending borders and various colors in a single dermoscopic field indicating a high suspicion for extraocular sebaceous carcinoma.[66] The findings may be relatively nonspecific, but they should raise suspicion for the diagnosis.

Pagetoid intraepithelial spread may obfuscate diagnosis given generalized ocular signs, including eyelid thickening and conjunctival irritation, and may occur in 26-51% of sebaceous carcinomas.[67]

 

DDx

Differential Diagnoses

 

Workup

Approach Considerations

If a sebaceous carcinoma is initially suspected, a biopsy should be performed. After histopathologic diagnosis of a sebaceous carcinoma, various risk factors should be reviewed, including pagetoid spread, multicentricity, size, growth pattern, lymphovascular and perineural spread, and involvement of one or both eyelids. If high-risk features are present, multidisciplinary consultation is recommended as well as consideration of staging.

Moreover, Muir-Torre syndrome should be suspected in all sebaceous carcinomas, and this can be evaluated by family history of early visceral malignancies and immunohistochemistry staining of biopsy specimens for loss-of-mismatch-repair genes. If either of these two is positive, it should be suggested that the patient consider geneticist consultation. Regardless, all patients with sebaceous carcinoma should undergo age-appropriate cancer screening.[68]

Laboratory Studies

To rule out metastatic disease, baseline studies including liver function tests, electrolyte levels, and a complete blood cell count may be considered and may help 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

No formal guidelines exist regarding the role of imaging in further evaluating sebaceous carcinoma. Chest radiography may be performed to rule out metastatic disease and to establish a baseline for future care. Isolated reports recommend the use of computed tomography (CT) scanning, magnetic resonance imaging (MRI), or positron emission tomography (PET) scannning for patients with clinically or histologically aggressive features, frank regional lymphadenopathy, or a positive sentinel lymph node biopsy.[69, 70, 71, 72] Suspicion for lymph node and orbital involvement may warrant orbital CT scanning or MRI; ultrasonography of the parotid, submandibular, and cervical nodes; and fine-needle aspiration biopsy of frank lymph nodes.[73]

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.

A scoring system developed by Roberts et al may be useful in identifying patients with sebaceous neoplasms at risk for Muir-Torre syndrome, weighing in age at diagnosis, number of sebaceous neoplasms, and personal or family history of Lynch syndrome–related cancer.[74]

Deletion or mutation of mismatch repair genes MLH1, MSH2, MSH6, PMS2, and EPCAM may be tested on tumors via immunohistochemistry, similar to sebaceous adenoma. However, their sensitivity in sebaceous carcinoma has been reported to be less than that of other sebaceous neoplasms.[74, 75]

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.[16] 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.

An autosomal recessive subtype of Muir-Torre syndrome, accounting for up to 35% of tumors in syndromic patients, has been described.[76] In Muir-Torre syndrome type II, biallelic inactivation of MYH, a base excision repair gene, leads to later-onset development of internal malignancy and gastrointestinal polyposis.[77] Unlike the predominant form of Muir-Torre syndrome, genetic analysis in this second subtype does not show microsatellite instability and would require referral to a geneticist for further workup and surveillance.

Noninvasively, meibography may be helpful in differentiating chalazion from sebaceous carcinoma and mapping the latter. The carcinoma has been shown to have higher reflectivity over an irregular and marginated lesion around the nodule, especially when pagetoid spread is present.[78]

Procedures

Successful diagnosis results from clinic suspicion 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.[11, 79]

Some authors have recommended fine-needle aspiration for primary and metastatic sebaceous gland carcinoma,[80, 81] but a full-thickness surgical biopsy is mandatory if the results are negative or equivocal.[82]

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.[83]

Histologic Findings

Histology is the criterion standard for diagnosis of sebaceous carcinoma. Sebaceous gland carcinoma demonstrates disordered invasion of the dermis by lobules of poorly defined sebaceous cells (see image below) or basaloid and squamoid growth patterns.[84] Lobules may form sheets of basaloid tumor cells, but no peripheral palisading or clefting is present. The lesions have atypical mitosis, asymmetry, poor circumscription, and infiltrative borders. Necrosis in lobule centers may be prominent.[85] Four patterns may be recognized: lobular, comedocarcinoma, papillary, and mixed.[32]

Irregular lobules and sheets of atypical sebaceous Irregular lobules and sheets of atypical sebaceous cells (20x magnification).

Sebocytes tend to have multivacuolated clear cytoplasm, causing the nucleus to be scalloped from the lipid invasion.[17] In many cases, moderate-to-severe atypia can be found, as well as a high nuclear/cytoplasm ratio and a perinuclear halo, identified in all 30 cases presented by Izumi et al.[17] Pleomorphism is not uncommon, and large, bizarre, multinucleated cells may be randomly distributed throughout the lesion.[85] In some cases, well-developed sebocytes can be identified; in a smaller number of cases, sebaceous duct differentiation can be seen.[17]

Sebaceous carcinoma can be stained positively with oil red-O or Sudan black, which are specific for cytoplasmic fat, but epithelial membrane antigen (EMA) immunoperoxidase staining may be a better supplemental stain for confirming sebaceous differentiation.[86] Adipophilin, a monoclonal antibody against an intracellular lipid droplet surface protein, was found to have a greater ability to highlight cytoplasmic lipid vesicles than Oil Red O, and a sensitivity of 82-100%, depending on the differentiation of the sebaceous carcinoma. A membranous vesicular staining pattern of adipophilin is the most specific for sebaceous neoplasms and was shown to be negative in 100% of basal cell and squamous cell carcinomas in 43 control cases.[85] An annular staining of adipophilin in immature sebaceous cells contrasts with a more granular staining pattern in basal cell and squamous cell carcinomas.[87] In addition, cytokeratin, Ber-EP4, cyclooxygenase 2, peroxisome proliferator-activated receptor gamma, and androgen-receptor stains are positive. Sebaceous carcinomas also express more proliferation markers like p53 and Ki-67, but reduced antiapoptotic markers such as bcl-2 and p21. Sebaceous carcinomas do not express carcinoembryonic antigen, S100 protein, or gross cystic disease fluid protein.[87, 88]

In evaluating for Muir-Torre Syndrome, microsatellite mismatch repair gene instability is evaluated. Germline mutations include MSH2 (>90%), MLH-1 (< 10%), MSH-6, and PMS-2.[89] Cystic histopathologic changes have also been associated with Muir-Torre Syndrome.[90]

Sebaceous gland carcinoma may also 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. Intraepithelial cells exhibit nuclei that are larger than neighboring keratinocytes. 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.[11] The significance of these pagetoid cells is unclear, with some authors reporting a worse prognosis when present[18] 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.[83]

 

Treatment

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 patients with this tumor. Radiation therapy has traditionally been considered palliative but not curative. Chemotherapy has also been used in aggressive cases with mixed results and requires further study.

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.[91]

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[18] ; however, one case report describes two patients who refused surgery who were successfully treated with radiation therapy[92] and another case series describes two patients who underwent radiation therapy as well, with no recurrence after 27 and 36 months, respectively. Radiotherapy is useful in patients who are not candidates for surgery. One study of 13 patients with stage T3 sebaceous carcinoma reported reduced recurrence rates in those who received adjuvant radiotherapy (28%) compared with those who did not (83.3%).[93]

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.[45, 47] Mitomycin 0.04% four times daily for 1 week repeated every 2 weeks for 6 weeks has been reported to be effective for pagetoid lesions in case studies.[94]

Systemic chemotherapy may be an option for sebaceous carcinoma refractory to surgical excision and radiotherapy. Case studies have reported variable results with use of 5-fluorouracil, cisplatin, docetaxel, capecitabine, paclitaxel, and doxorubicin (Adriamycin) for aggressive tumors. These reports have suggested its potential use as a preoperative neoadjuvant therapy.[95, 96, 97, 98, 99]

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 sebaceous carcinoma.[47]

Cryotherapy 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. Targeting margins and the scleral bed may reduce recurrence rates.[100] 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.[79] Without orbital involvement, surgical therapy typically involves excision of the visible tumor plus 5-6 mm of healthy-appearing tissue in all directions, followed by either frozen section or permanent section for histologic analysis.[101] This approach has not been completely satisfying, because local recurrence occurs in approximately one third of patients,[6] with a 5-year mortality rate reported to range from 18-30%.[101]

The use of the fresh-tissue Mohs technique has been successful in a number of case reports. Spencer et al treated 18 patients with periocular sebaceous gland carcinoma using the Mohs technique, with an average follow-up period of 37 months. The recurrence rate was 11.1%, one of which also developed metastatic disease to the parotid lymph nodes.[101] Similarly, a retrospective review of 49 cases of sebaceous carcinoma treated by the Mohs technique revealed a local recurrence rate of 12% (6 of 49) and a metastatic rate of 8%.[102] In a retrospective study at the Mayo clinic comparing wide local excision with the Mohs technique in 52 patients with 70 sebaceous carcinomas, the Mohs group had a recurrence rate of 1 case in 35 at 6 years postoperatively and 1 case in 24 in the wide local excision group (median margin 1 cm) at 4 months after surgery.[103] Washington University published a retrospective review of 37 patients with 45 sebaceous carcinomas with an average follow up of 3.6 years, reporting zero instances of local recurrences, metastases, or disease-specific deaths.[68] Most recently, a Chinese study published a 360-patient multicenter cohort study with 5-year follow-up, showing improved recurrence, metastatic, and disease-specfic death rates for Mohs micrographic surgery (15.7%, 7.8%, and 5.2%) compared with wide local excision (39.6%, 15.5%, and 8.6%, respectively). However, in patients with pagetoid intraepithelial neoplasia, the recurrence, metastasis, and tumor-related mortality rates were significantly higher.[104] Although recurrence rates may be attributed to discontiguous growth, Mohs micrographic surgery seems to offer a reduced recurrence rate compared with standard excision, with some proponents arguing it is the treatment of choice for nonpagetoid sebaceous carcinomas not involving the orbit.

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. It is recommended that patients with signs of pagetoid spread such as diffuse eyelid thickening and conjunctival inflammation should consider multiple conjunctival map biopsies and adjuvant therapy such as cryotherapy and mitomycin C. 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, is wise.[105]

One retrospective study from England using “slow Mohs,” or delayed reconstruction after complete excision with paraffin section control for 17 patients, reported improved evaluation of pagetoid spread with paraffin-embedded sections and local recurrence of 18% and mortality of 12% after an average follow-up of 5 years.[106]

Future larger series are needed to better delineate the true significance of pagetoid spread.

Given that lymph node involvement may be seen in 15-21% of cases, prophylactic lymph node excision or sentinel lymph node biopsy may be considered in conjunction with surgical excision of sebaceous carcinoma. However, neither of these options has been recommended by a sufficient body of evidence.[107, 108]

Based on the Surveillance, Epidemiology, and End Results Program (SEER) reported rates of regional and distant metastasis for ocular sebaceous carcinoma (4.4%) and extraocular head and neck sebaceous carcinoma (0.9%),[108] Chang et al suggest sentinel lymph node biopsy for ocular sites and routine reginal lymph node surveillance for extraocular head and neck sites.[72] In addition, the authors in a retrospective study of 50 patients with ocular sebaceous carcinoma concluded that a sentinel lymph node biopsy or strict regional lymph node surveillance may be appropriate for ocular sebaceous carcinomas greater than 10 mm.[55]

Parotidectomy has also been reported in cases of sebaceous carcinoma with regional lymphadenopathy or metastasis.[10] Given the potential for metastasis to the parotid gland, further evaluation is warranted, particularly with an upper eyelid sebaceous carcinoma.[7, 45, 59]

Consultations

Referral to an internist, urologist, 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. A geneticist is also recommended for further workup of syndromic associations.

An ophthalmologist or oculoplastic surgeon may also be considered if there is orbital involvement and possible need for exenteration. Of note, if corneal involvement is suspected, the patient should avoid cataract surgery to avoid seeding tumor into the globe.

For systemic disease, an oncologist is necessary for chemotherapy. A radiation oncologist referral may be helpful for tumors in patients who are poor surgical candidates, and this can be used as adjuvant radiotherapy.

Complications

Radiotherapy can result in chronic dry eyes, trichiasis, exposure keratopathy, conjunctival keratinization, cataract, optic neuropathy, retinopathy, and permanent loss of visual acuity.