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Sebaceous carcinoma

Sebaceous carcinoma
Literature review current through: Jan 2024.
This topic last updated: Aug 25, 2023.

INTRODUCTION — Sebaceous carcinoma is a rare, malignant tumor of the sebaceous glands [1]. It can occur in any body site where sebaceous glands are present but is most commonly found in the head and neck region, particularly in the periocular area [2]. Sebaceous carcinoma of the eyelid (picture 1) may be mistaken for inflammatory lesions, such as chalazion or blepharoconjunctivitis, resulting in a delayed diagnosis and poorer prognosis [3].

Sebaceous carcinomas can occur sporadically or may be associated with Muir-Torre syndrome, a variant of the hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome) characterized by single or multiple sebaceous neoplasms, keratoacanthomas, and internal malignancy (particularly malignancy of the gastrointestinal or genitourinary system) [4,5].

This topic will review the pathogenesis, clinical presentation, diagnosis, and treatment of sebaceous carcinoma. Muir-Torre syndrome and Lynch syndrome are discussed separately.

(See "Muir-Torre syndrome".)

(See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

(See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management".)

EPIDEMIOLOGY — Sebaceous carcinoma is a rare tumor, with an estimated incidence rate of approximately 1 to 2 per 1,000,000 per year [2,4,6-8]. However, sebaceous carcinoma is the most common eyelid malignancy after basal cell carcinoma and squamous cell carcinoma [9,10]. In a review of the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2012 that identified 2201 cases of sebaceous carcinoma, the incidence rate among White Americans was almost three times higher than among Black Americans and other ethnic groups, and more than 98 percent of cases were older than 40 years, with a peak incidence between the ages of 60 to 79 years [8]. Outcomes of White and Asian patients with sebaceous carcinoma are similar, but Black individuals have a markedly lower five-year relative survival rate compared with White patients [11]. Finally, sebaceous carcinoma is exceedingly rare in children, with only a few cases reported [12,13].

In a small subgroup of patients, typically younger than 60 years [14], sebaceous carcinoma may be a marker of Muir-Torre syndrome, an autosomal dominant disorder considered a variant of hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome). In an analysis of the National Cancer Institute SEER registry from 2000 to 2012 including 3299 cases of sebaceous carcinoma, 64 patients (1.9 percent) had Muir-Torre syndrome [15]. (See "Muir-Torre syndrome" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

PATHOGENESIS — Ocular sebaceous carcinomas arise from the meibomian (tarsal), Zeis (eyelash), or sebaceous glands of the eyelid and caruncle. There are several reports of sebaceous carcinoma arising within a nevus sebaceous [16]. The origin of extraocular sebaceous carcinoma is less clear. The observation of sebaceous carcinoma in association with actinic keratosis or Bowen disease suggests that extraocular sebaceous carcinoma may originate from a pre-existing intraepidermal neoplasia or that ultraviolet radiation plays a role in the pathogenesis of some of these tumors in sun-exposed areas [17-19].

The molecular pathogenesis of sebaceous carcinoma is incompletely understood [20]. Loss of expression of mismatch repair genes MSH2, MSH6, or MLH1 and microsatellite instability (MSI) are seen in sebaceous carcinomas associated with Muir-Torre syndrome as well as in other cancers associated with the hereditary Lynch syndrome [21]. Loss of expression of MSH2 and MSI have also been detected in sebaceous carcinomas in organ transplant recipients, suggesting that immunosuppression may unmask a Muir-Torre phenotype [22,23]. (See "Muir-Torre syndrome" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Genetics'.)

Sporadic sebaceous carcinomas may show somatic variants in the mismatch repair genes MLH1 and MSH2 as well as in TP53 and other genes potentially involved in tumorigenesis [24-26]. A whole-exome sequencing study of 32 sebaceous carcinomas identified three genetically distinct groups of sebaceous carcinomas (based on the predominant somatic mutation pattern): tumors harboring TP53 ultraviolet-damage signature variants with high numbers of CC > TT dinucleotide transitions (10 of 32), tumors harboring MSI signatures (9 of 32), and a group of 13 paucimutational tumors with no dominant mutational signature, of which six showed truncating variants in the ZNF750 transcription factor gene (an epidermal differentiation regulator) [24].

Hypermethylation of the CDKN2A promoter region has also been found with high frequency in periocular sebaceous carcinoma occurring at a younger age [27].

Studies have suggested a role for the Wnt/beta-catenin (a 92-kDa molecule involved in cell-cell adhesion in adherens junctions) pathway and the downstream target lymphoid enhancer binding factor-1 (LEF-1) in the pathogenesis of sebaceous carcinoma, irrespective of the microsatellite status [21,28,29].

Trophoblast cell surface antigen 2 (TROP2), a cell-surface glycoprotein involved in several intracellular signaling pathways, is highly expressed in various human cancers, including basal cell carcinoma and squamous cell carcinoma of the skin. Strong expression of TROP2 has been detected in sebaceous carcinoma and sweat gland carcinoma, suggesting a potential therapeutic role for sacituzumab govitecan, an antibody-drug conjugate that targets the cell-surface antigen TROP2 [30].

Immunohistochemical studies have demonstrated strong and frequent expression of NECTIN4 and TROP2 in sebaceous carcinoma, suggesting that NECTIN4- and TROP2-targeted antibody-drug conjugates, such as enfortumab vedotin and sacituzumab govitecan, respectively, may have efficacy in systemic disease as well [30,31]. Additionally, epidermal growth factor receptor (EGFR) is expressed in most cases of sebaceous carcinoma and could be a therapeutic target in metastatic cases [32].

As with other nonmelanoma skin cancers, the development of sebaceous carcinoma has also been described in a patient on ruxolitinib therapy [33]. Additionally, immunosuppression significantly increases one's risk for the development of sebaceous carcinoma [34].

CLINICAL PRESENTATION — Sebaceous carcinoma typically presents as a firm, gradually enlarging subcutaneous nodule (picture 2). Approximately 80 percent of cases occur in the skin of the head or neck, and approximately 40 percent involve the eyelids [2].

Eyelid sebaceous carcinoma — Eyelid sebaceous carcinoma is the third most common malignant tumor of the eyelid after basal cell carcinoma and squamous cell carcinoma [35]. It typically presents in older patients as a painless, rounded nodule, most often located on the upper eyelid. This is in contrast to periocular basal cell carcinoma and squamous cell carcinoma, which are most commonly located on the lower lid. Occasionally, the lesion can be inflamed and painful and may be clinically mistaken for a chalazion (picture 4B), leading to a delay in diagnosis and appropriate treatment. A lesion with visible, superficial vessels that alters the eyelid margin and the eyelash line should raise suspicion of sebaceous carcinoma (picture 1). The second most common presentation is a diffuse, unilateral thickening of the eyelid accompanied by an inflammatory reaction that simulates blepharoconjunctivitis [36].

Eyelid sebaceous carcinoma may spread locally to involve the palpebral and bulbar conjunctiva and cornea. Unilateral signs of blepharoconjunctivitis, with thickening of the eyelids, loss of cilia, diffuse erythema, thickening of the conjunctiva, and superficial vascularity of the cornea, suggest epithelial involvement due to pagetoid spread of the tumor [37]. Isolated primary sebaceous gland carcinoma of the bulbar conjunctiva has been described, although the lesion typically begins on the eyelid margin and palpebral conjunctiva [38]. In advanced cases, the tumor can invade the orbital soft tissue, bone, and intracranial cavity.

Extraocular sebaceous carcinoma — Extraocular sebaceous carcinoma usually presents as a yellowish-tan nodule, often ulcerated, located on the head and neck in most cases or, less frequently, on the trunk or extremities. Rarely, sebaceous carcinomas may develop in extracutaneous sites, such as the parotid gland, nasal cavity, breast, large bowel, ovary, and prostate [39-41].

Metastasis — Metastasis occurs in approximately 12 percent of patients with eyelid sebaceous carcinoma, with an average time to metastasis of 20.5 months [35]. Among patients with extraocular sebaceous carcinoma from registries of the Surveillance, Epidemiology, and End Results (SEER) database, the rate of nodal or distant metastases was 1.4 percent [42]. Regional lymph nodes are the most common site of metastasis [43]. Tumors located on the upper eyelid tend to metastasize to preauricular and parotid nodes; tumors of the lower eyelid tend to metastasize to submandibular and cervical nodes [37]. Distant metastasis may involve the parotid gland, liver, lung, and bone [43-45].

DIAGNOSIS — The diagnosis of sebaceous carcinoma is suspected in older patients with a history of recalcitrant chalazion or unilateral blepharoconjunctivitis that does not respond to standard treatment (picture 1). Clinical misdiagnosis and failure to perform a biopsy results in delay in diagnosis and poor outcome [46]. The average diagnostic delay is approximately 15 months [35].

Biopsy — An excisional biopsy or a deep incisional biopsy is required to establish the diagnosis [46]. Immunohistochemistry is helpful to diagnose sebaceous carcinoma with indeterminate features and to distinguish poorly differentiated sebaceous carcinoma from basal cell carcinoma and squamous cell carcinoma. (See 'Histopathology' below.)

Histopathology — Routine histopathologic examination with hematoxylin and eosin shows neoplastic cells (basaloid, basosquamous, and epidermoid) with various degrees of differentiation arranged in lobules or sheets of cells separated by a fibrovascular stroma (picture 3) [9]. In eyelid lesions, upward migration and spreading to the surface epidermis or conjunctiva in a pagetoid pattern is often seen:

Well-differentiated tumors may contain sebocyte-like cells with vacuolated, foamy cytoplasm. In frozen specimens, an Oil Red O stain can demonstrate intracytoplasmic lipid [47]. Differential diagnoses are multilineage adnexal tumors with partly sebaceous differentiation, sebaceous changes as a component of benign cystic lesions or epidermal tumors, clear cell squamous cell carcinoma, nevus sebaceous, and the commonly encountered sebaceous hyperplasia [46,48,49].

Poorly differentiated lesions usually show both a sebaceous and squamous differentiation and may be confused with squamous cell carcinoma. Nuclear pleomorphism, prominent nucleoli, and mitotic figures are usually present.

Immunohistochemistry — Positive immunostaining with nuclear factor XIIIa (clone AC-1A1 mouse monoclonal), epithelial membrane antigen (EMA), adipose differentiation-related protein (adipophilin) and perilipin, androgen receptor, and cytokeratin AE1/AE3 antibody confirms sebaceous differentiation and differentiates sebaceous carcinoma from basal cell carcinoma and squamous cell carcinoma [46,50-52].

Markers that are typically negative in sebaceous carcinoma include carcinoembryonic antigen, S100, HMB45, SOX10, CD5, GCDFP-15, D2-40, and Ber-EP4 (occasionally positive) [46].

Screening for Muir-Torre syndrome — Although most sebaceous carcinomas occur sporadically, in a small subgroup of patients, these tumors are a marker of Muir-Torre syndrome, an autosomal dominant disorder considered a variant of hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome). Muir-Torre syndrome is characterized by the development of sebaceous tumors in association with visceral neoplasms [53]. (See "Muir-Torre syndrome" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

Based on recommendations in published expert guidelines [46], genetic testing for Muir-Torre syndrome is recommended in patients with extraocular sebaceous carcinoma and/or a Mayo Muir-Torre syndrome overall risk score ≥2 [54]. The Mayo Muir-Torre syndrome score is calculated by adding the scores associated with the following four variables:

Age <60 years at first presentation of sebaceous carcinoma (score = 1)

≥2 sebaceous tumors (score = 2)

Personal history of any Lynch syndrome-related cancers (score = 1)

Family history of any Lynch syndrome-related cancers, such as colorectal cancer and endometrial cancer (score = 1)

For patients with sebaceous carcinoma and suspected Muir-Torre syndrome who do not fulfill the Mayo Muir-Torre syndrome clinical criteria (eg, patients <60 years with a first extraocular sebaceous carcinoma [score = 1]), immunohistochemical tumor testing for loss of mismatch repair proteins is appropriate to identify patients who are candidates for genetic testing [55,56]. (See "Muir-Torre syndrome", section on 'Tumor testing'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of sebaceous carcinoma includes several benign and malignant conditions, including [36,47,57]:

Inflammatory lesions – Sebaceous carcinoma may mimic chalazion (picture 4A-C), blepharoconjunctivitis, or keratoconjunctivitis. Inflammatory eye conditions that are unilateral and fail to respond to standard treatment should be biopsied and sent for histopathologic examination. Additionally, sebaceous carcinoma masquerading as orbital cellulitis has been reported [58]. (See "Eyelid lesions".)

Benign sebaceous neoplasms – Benign sebaceous neoplasms (eg, sebaceous adenoma (picture 5), sebaceoma) are not common in the periocular region. The finding of sebaceous differentiation in an eyelid lesion should raise the suspicion of malignancy. (See "Cutaneous adnexal tumors", section on 'Tumors with sebaceous differentiation'.)

Basal cell carcinoma – Nodular basal cell carcinoma is more common on the lower eyelid but may occur on the upper eyelid (picture 6) and tends to ulcerate at an early stage, whereas ulceration is uncommon in sebaceous carcinoma. The morpheaform variant of basal cell carcinoma may also simulate sebaceous carcinoma, but conjunctival involvement is uncommon.

Immunohistochemical staining for epithelial membrane antigen (EMA) and adipophilin are negative in basal cell carcinoma but positive in nearly all sebaceous carcinomas [50,51]. Ber-EP4 is typically positive in basal cell carcinoma but may be positive or negative in sebaceous carcinoma. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis".)

Squamous cell carcinoma – Squamous cell carcinoma may occur on the upper eyelid, and clear cell squamous cell carcinoma can mimic sebaceous carcinoma [46].

Immunohistochemical staining for EMA may be positive in squamous cell carcinoma, but adipophilin and androgen receptor are consistently negative [50,51]. (See "Cutaneous squamous cell carcinoma (cSCC): Clinical features and diagnosis".)

Merkel cell carcinoma – Merkel cell carcinoma may present as a red lesion on the eyelid. Histologic examination can clarify the diagnosis. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma".)

Cutaneous clear cell tumors, including epidermoid carcinoma with sebaceous differentiation, clear cell acanthoma, trichilemmoma, and balloon cell melanoma, may be confused histologically with sebaceous carcinoma.

STAGING — The staging of periocular sebaceous carcinomas is performed according to the staging system for eyelid carcinoma outlined in the eighth edition of the American Joint Committee on Cancer Staging Manual (table 1) [59-63]. Extraocular sebaceous carcinoma in the head and neck region shares the same staging system as cutaneous squamous cell carcinoma of the head and neck (table 2) [59].

Physical examination — Patients diagnosed with sebaceous carcinoma should receive a careful examination of the tumor site to assess the clinical extent of the tumor. Palpation of the regional lymph nodes should be performed to assess for enlarged lymph nodes that may indicate regional metastasis.

Ophthalmologic examination — Patients with sebaceous carcinoma of the eyelids should be referred to an ophthalmologist for the evaluation of conjunctival involvement. Slit lamp biomicroscopy and conjunctival map biopsies are used to determine the presence and extent of intraepithelial disease [37].

Imaging — Ultrasonography or computerized tomography (CT) scan of regional lymph nodes is indicated to complete tumor staging for larger or more aggressive tumors [46,64]. In patients with large tumors located in the periorbital area, CT or magnetic resonance imaging (MRI) should be performed to evaluate for invasion of orbital soft tissue, bone, or intracranial cavity. Positron emission tomography (PET) scan should be considered for patients with confirmed nodal metastasis or Muir-Torre syndrome [46,65].

Sentinel lymph node biopsy — Sentinel lymph node biopsy (SLNB) is generally not indicated for extraocular sebaceous carcinoma, which is associated with a low risk of nodal and distant metastases [66]. Among 867 patients with extraocular sebaceous carcinoma from the National Cancer Institute's registries of the Surveillance, Epidemiology, and End Results (SEER) database, the rate of nodal or distant metastases was 1.4 percent [42]. However, SLNB along with imaging may be indicated for complete tumor staging of larger or more aggressive periocular tumors (ie, eyelid tumor stage T2c or higher) [42,46,67,68].

Data on the rate of positive sentinel lymph node are sparse. In a series of 100 patients with periocular sebaceous carcinoma, 5 of 30 patients (16.7 percent) who underwent SLNB had positive sentinel lymph node, and two were false negative [67]. A review of the United States National Cancer Database revealed that SLNB was performed in 149 of 1320 patients with periocular and extraocular seborrheic carcinoma (10.7 percent) [68]. A positive SLNB was found in 11 cases (7.4 percent). The benefit of SLNB on disease-specific survival is unknown.

MANAGEMENT

Goals of treatment — Sebaceous carcinoma is a locally aggressive tumor that can metastasize to locoregional lymph nodes and distant sites. The primary goal of management is the complete surgical removal of the tumor. Local recurrence is due to incomplete excision in most cases (due to the multifocal nature of the tumor), with discontinuous intraepithelial involvement and pagetoid spread of malignant sebocytes along the conjunctiva [35]. (See 'Prognosis' below.)

For periocular lesions, additional management goals include the identification and treatment of subclinical intraepithelial neoplasia, vision salvage, avoidance of exenteration, and acceptable cosmetic outcome [36,37].

Local disease

Surgical treatment — Surgical excision with peripheral and deep en face margin assessment (PDEMA), also called excision with complete circumferential peripheral and deep margin assessment (CCPDMA), or Mohs micrographic surgery (if available) are the first-line treatments for sebaceous carcinoma of the head and neck region (including eyelid tumors) [2,36,69]. For extraocular sebaceous carcinoma, if Mohs surgery or CCPDMA are not available, wide local excision (WLE) with peripheral 1 cm margin down to the deep fascial plane can be performed [46].

Because the interpretation of frozen sections may be problematic (eg, in differentiating vacuolating cytoplasm from freezing artifacts in conjunctival margins), some experts advocate the use of frozen and permanent paraffin-embedded sections for margin control [70]. (See "Mohs surgery".)

Studies on large case series indicate that Mohs surgery is associated with lower rates of local recurrence and better overall survival than WLE:

In a series of 1265 patients with sebaceous carcinoma from the United States National Cancer Database of whom 234 were treated with Mohs surgery and 1031 were treated with WLE, patients who underwent Mohs surgery had a longer overall five-year survival than those who underwent surgical excision (75 versus 66 percent, respectively) [71]. On multivariable regression analysis, Mohs surgery was associated with better overall survival than surgical excision after adjusting for other prognostic factors, such as tumor size and clinical stage (hazard ratio [HR] 0.70, 95% CI 0.50-0.99).

In a multicenter, cohort study that included 360 patients with eyelid sebaceous carcinoma (115 patients [32 percent] treated with Mohs surgery and 245 patients [68 percent] treated with WLE), the local recurrence rate was lower in the Mohs surgery group than in the WLE group (15.7 versus 39.6 percent, respectively) [72].

A study of 554 patients with localized sebaceous carcinoma from the United States National Cancer Database who underwent WLE (n = 243) or Mohs surgery (n = 311) between 2004 and 2015 showed a similar overall survival at five years for the two groups (65.8 and 61.4 percent, respectively) [73].

Conjunctival involvement — Conjunctival epithelial involvement may be treated with surgical resection, cryotherapy, and/or topical mitomycin [37,46]. Posterior lamellar resection, a surgical technique that entails removing the entire tarsal plate and palpebral conjunctiva, has been described as having lower morbidity and lower risk of metastases than lumpectomy [74]. For tumors with extensive intraorbital involvement, surgical management may include orbital exenteration.

Radiation therapy — Radiation therapy (RT) may be used as primary treatment for both periocular and extraocular tumors in patients who are not surgical candidates and in patients who have tumors or nodal metastases that are surgically unresectable [46]. Postsurgical adjuvant RT is used for tumors excised with positive margin or tumors with histopathologic evidence of perineural invasion. RT is also used for palliation or after resection of local recurrence.

The general principles of RT for skin cancer also apply to sebaceous carcinoma, with the higher dose of up to 66.6 to 70 Gy applied to larger lesions. However, high doses to the upper eyelid are associated with severe complications, including keratitis. RT doses for definitive treatment of periocular sebaceous carcinoma are 56 to 70 Gy in two Gy fractions, with margins varying depending on the surrounding sensitive structures [46]. A total of 50 to 70 Gy in two Gy fractions with 2 cm margin has been used in case reports of extraocular sebaceous carcinoma [75]. Postoperative adjuvant RT doses of 50 to 60 Gy are recommended for perineural invasion.

Radiation oncologists should use a smaller fraction size to decrease long-term complications and improve cosmetic outcome, especially in areas with poor blood supply. An orthovoltage machine (if available) is preferred to electron treatment because the RT fields are smaller due to a narrow penumbra, and shielding is easier (a 6 MeV electron beam produces bremsstrahlung radiation, and the cornea receives a small RT dose behind the eye shield). Moreover, it is less expensive (linear accelerator machines required to produce electrons are more costly), has a higher relative biologic effectiveness, and provides better local control. The electron dose should be higher by 10 percent to be as effective as orthovoltage.

Eye drops with a local anesthetic and steroid should be applied before inserting the eye shield. The patient should wear an eye patch one to two hours after RT each day.

A few small studies have reported the use of RT as the primary treatment for sebaceous carcinoma of the eyelid [76-78]:

In one study, eight patients with eyelid sebaceous carcinoma were treated with high-dose rate interstitial brachytherapy (a total of 39 Gy in six fractions in six days) as initial treatment [76]. All patients showed a complete response, with a five-year, disease-free survival rate of 57 percent.

In another study that included 23 patients with eyelid carcinoma, 16 patients with histologically confirmed sebaceous carcinoma were treated with a median dose of 60 Gy (range 50 to 66.6 Gy) delivered in 18 to 37 fractions [77]. The reported five-year overall and local progression-free rates were 80 and 93 percent, respectively.

Plaque brachytherapy (50 Gy) instead of exenteration has been used for tumors involving the lacrimal gland or orbit [79,80].

Contraindications and adverse effects — Contraindications for RT include previous RT in the same area and genetic conditions predisposed to skin malignancies (eg, xeroderma pigmentosum). RT should be used with caution in patients with connective tissue diseases.

Common acute side effects of RT are conjunctivitis (from local anesthetic eye drops and RT), eyelid erythema and edema, and conjunctival congestion and chemosis. Long-term side effects of RT include loss of eyelashes; deformities of the eyelid, including ectropion or entropion (eyelashes growing outside and inside, respectively); dry eye due to RT dose to lacrimal gland; keratitis; epiphora or tearing due to fibrosis of lacrimal duct; and cataract. Radiation-induced cataract has been reported in 3 out of 23 patients in one series [77].

Adjuvant therapies — Cryotherapy, topical mitomycin, and RT have been used in small series of patients as postsurgical adjuvant therapy for sebaceous carcinoma of the eyelid showing pagetoid spread to the conjunctiva and/or regional lymph node involvement:

Cryotherapy – Cryotherapy is frequently used as an adjunctive treatment after surgical excision of sebaceous carcinoma of the eyelid, particularly for the management of pagetoid invasion of conjunctiva [81]. However, cryotherapy may be associated with serious adverse effects, including symblepharon and corneal erosions.

Topical mitomycin – Topical mitomycin has been used in a small number of patients for the treatment of pagetoid spread to the conjunctiva and cornea with varying results [36,82-84]. Complications of topical mitomycin treatment include persistent keratoconjunctivitis, epiphora secondary to punctal stenosis, allergic reaction, and limbal stem cell deficiency [85].

Radiation therapy – The use of radiation therapy (RT) as an adjuvant therapy after surgery has been evaluated in a small, retrospective study of 13 patients with locally advanced tumors, 10 of whom had regional lymph node involvement [86]. A recurrence occurred in two of seven patients who had received adjuvant RT postoperatively and in five of six patients who did not receive RT.

Neoadjuvant therapies — Successful use of neoadjuvant systemic chemotherapy with fluorouracil and cisplatin or carboplatin has been described in small case series of locally advanced eyelid tumors [87,88]. In a single case report of mismatch repair-deficient sebaceous carcinoma of bilateral eyelids, immunotherapy with the programmed death receptor-1 (PD-1) inhibitor pembrolizumab (two doses of 400 mg six weeks apart) reduced tumor burden, allowing for a smaller defect post-Mohs surgery and better reconstructive outcome [88].

Nodal and distant metastatic disease — The management of patients with metastatic sebaceous carcinoma should be discussed in a multidisciplinary tumor board with expertise in the treatment of such tumors. Data on the treatment of locoregional or distant metastasis of sebaceous carcinoma are limited to small case series and case reports [89,90]. If enlarged lymph nodes are detected, lymph node biopsy via fine needle aspiration or surgical removal of the enlarged lymph node is indicated.

Regional nodal involvement can be treated with lymph node dissection and/or RT [86,91,92]. Adjuvant RT has also been given to the nodal basin after lymph node dissection identified additional nodal disease, although the benefit is uncertain [46]. RT or completion nodal dissection can be considered for microscopic regional metastasis in periocular sites [46].

Pembrolizumab, fluorouracil, cisplatin or carboplatin, capecitabine, taxane, and RT have been successfully used in a few patients with metastatic sebaceous carcinoma [89,93-96]. Pembrolizumab has also been successfully used in three patients with advanced/metastatic tumors without microsatellite instability (MSI) [96-98].

PROGNOSIS — Local recurrence due to incomplete removal of the primary tumor is a major unfavorable determinant of prognosis. It is associated with more aggressive pathologic features and surrounding tissue invasion [99].

In a United States study using data from the National Cancer Database that included 2039 patients treated for sebaceous carcinoma between 2004 and 2017, 150 patients (7.4 percent) had a positive surgical margin [100]. Compared with patients with negative surgical margins, those with positive margins had a poorer five-year overall survival (70 versus 55 percent, respectively). Risk factors for margin positivity included head and neck location (especially the lip, ear, and periocular area), tumor size >2 cm, low-volume facility, and age >74 years.

In a meta-analysis of 24 observational studies that included 1333 patients with sebaceous carcinoma of the eyelid followed up for an average of 42 months, the overall recurrence rate was 16 percent, the metastasis rate was 12 percent (with an average time to metastasis of 20.5 months), and the tumor-related mortality rate was 6 percent [35]. In the Surveillance, Epidemiology, and End Results (SEER) database, the 5- and 10-year overall survival rates were 71 and 46 percent, respectively [2]. Tumor stage T2 or worse, older age, poorly differentiated tumors, and distant (but not nodal) metastasis are unfavorable prognostic factors [101].

Patients with sebaceous carcinoma and Muir-Torre syndrome have a worse prognosis. An analysis of SEER data on over 3000 patients with sebaceous carcinoma (of whom 64 had Muir-Torre syndrome) found that the five-year, cause-specific survival rates among patients with and without Muir-Torre syndrome were 53 and 78 percent, respectively [15].

Additional prognostic factors for eyelid sebaceous carcinoma include [46,102]:

Pagetoid spread – Periocular tumors showing pagetoid spread are more likely to be poorly differentiated, to be recurrent, have distant metastases, and to require exenteration [67,103].

High androgen receptor staining – Periocular tumors showing androgen receptor staining of >50 percent with moderate intensity are more likely to be recurrent and develop metastases [46].

Programmed death receptor-1 (PD-1) expression – Tumors with PD-1 expression in tumor-infiltrating lymphocytes tend to have higher T stage and poor survival [104].

Location – Lower eyelid or orbital extension are associated with a higher mortality rate.

Vimentin overexpression – Vimentin overexpression in eyelid sebaceous carcinoma is associated with advanced stage, nodal metastases, pagetoid spread, and poor survival [105].

FOLLOW-UP — All patients with sebaceous carcinoma should undergo an extended follow-up after the initial treatment, every six months for three years and annually thereafter. Ultrasound nodal imaging, CT, or positron emission tomography (PET) can be arranged as indicated by initial stage for high-risk patients, especially those with periocular tumors [46]. Late relapses (pagetoid, nodal, or distant) have been reported 5 to 11 years after the excision of the primary sebaceous carcinoma [91,92,106,107].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sebaceous carcinoma and Muir-Torre syndrome".)

SUMMARY AND RECOMMENDATIONS

Epidemiology – Sebaceous carcinoma is a rare, malignant tumor of the sebaceous glands, with an estimated incidence rate of approximately 1 to 2 per 1,000,000 per year. It most commonly occurs in the head and neck region and, particularly, on the eyelids of older individuals. Although sporadic in most cases, in a small subgroup of patients, usually younger than 60 years, sebaceous carcinoma may be a marker of Muir-Torre syndrome, a variant of the hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome). (See 'Introduction' above and 'Epidemiology' above.)

Clinical presentation:

Eyelid sebaceous carcinoma – Eyelid sebaceous carcinoma typically presents as a painless, rounded nodule, most often located on the upper eyelid (picture 1). The second most common presentation is a diffuse, unilateral thickening and inflammation of the eyelid.

Extraocular sebaceous carcinoma – Extraocular sebaceous carcinoma usually presents as a yellowish-tan nodule, often ulcerated, located on the head and neck in most cases or, less frequently, on the trunk or extremities. (See 'Clinical presentation' above.)

Diagnosis – The diagnosis of sebaceous carcinoma is suspected in older patients with a history of recalcitrant chalazion or unilateral blepharoconjunctivitis that does not respond to standard treatment. A lesion biopsy for histopathologic examination is required to establish the diagnosis. Immunostaining for nuclear factor XIIIa, androgen receptor, and adipophilin and perilipin may be useful to confirm the diagnosis in poorly differentiated tumors. (See 'Diagnosis' above.)

Screening for Muir-Torre syndrome – Genetic testing for Muir-Torre syndrome is indicated in younger patients (<60 years) who have two or more sebaceous tumors or a first sebaceous carcinoma and a personal or family history of any Lynch syndrome-related cancers (Mayo Muir-Torre syndrome risk score ≥2). (See 'Screening for Muir-Torre syndrome' above.)

Staging – The evaluation of patients with sebaceous carcinoma should include a careful examination of the tumor site and palpation of the regional lymph nodes. Ultrasonography or CT scan of regional lymph nodes may be indicated for patients with large or aggressive periocular tumors. Enlarged lymph nodes should be biopsied. Patients with sebaceous carcinoma of the eyelids should be referred to an ophthalmologist for slit lamp biomicroscopy and conjunctival map biopsies to evaluate for intraepithelial disease. The staging of periocular sebaceous carcinomas is performed according to the staging system for eyelid carcinoma outlined in the eighth edition of the American Joint Committee on Cancer Staging Manual (table 1). (See 'Staging' above.)

Management:

Surgery – We suggest surgical excision with complete circumferential peripheral and deep margin assessment (CCPDMA) or Mohs micrographic surgery as the first-line treatment for sebaceous carcinoma of the head and neck region (including eyelid tumors) (Grade 2C). When Mohs surgery or CCPDMA are not available, wide local excision (WLE) with peripheral 1 cm margin down to the deep fascial plane can be an alternative approach for extraocular tumors. (See 'Surgical treatment' above.)

Radiation therapy – Radiation therapy (RT) may be used as primary treatment for both periocular and extraocular tumors in patients who are not surgical candidates and in patients who have tumors or nodal metastases that are surgically unresectable. There are limited data on the benefit of postsurgical adjuvant RT for tumors excised with positive margin or tumors with histopathologic evidence of perineural invasion. (See 'Radiation therapy' above.)

Follow-up and prognosis – All patients with sebaceous carcinoma should undergo an extended follow-up after the initial treatment, every six months for three years and annually thereafter. For eyelid tumors, the estimated overall recurrence, metastasis, and tumor-related mortality rates over an average follow-up time of 42 months were approximately 16, 12, and 6 percent, respectively. (See 'Follow-up' above and 'Prognosis' above.)

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Topic 97893 Version 19.0

References

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