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 [4].

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 [2,4-7]. However, sebaceous carcinoma is the most common eyelid malignancy after basal cell carcinoma and squamous cell carcinoma [8,9]. 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 [7]. Sebaceous carcinoma is exceedingly rare in children, with only a few cases reported [10,11].

In a small subgroup of patients, typically younger than 60 years, sebaceous carcinoma may be a marker of Muir-Torre syndrome (MTS), 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 (1.9 percent) had MTS [12]. (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 [13]. 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 [14-16].

The molecular pathogenesis of sebaceous carcinoma is incompletely understood [17]. Loss of expression of mismatch repair genes MSH2, MSH6, or MLH1 and microsatellite instability (MSI) is seen in sebaceous carcinomas associated with Muir-Torre syndrome as well as in other cancers associated with the hereditary Lynch syndrome [18]. 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 [19,20]. (See "Muir-Torre syndrome" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Genetics'.)

Sporadic sebaceous carcinomas may show somatic mutations in the mismatch repair genes MLH1 and MSH2 as well as in TP53 and other genes potentially involved in tumorigenesis [21-23]. 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 mutations 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 6 showed truncating mutations in the ZNF750 transcription factor gene, an epidermal differentiation regulator [21].

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 [18,24]. Hypermethylation of the CDKN2A promoter region has also been found with high frequency in periocular sebaceous carcinoma occurring at a younger age [25].

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 typically presents as a painless, rounded nodule, most often located on the upper eyelid. Occasionally, the lesion can be inflamed and painful (picture 1) and may be clinically mistaken for a chalazion (picture 6B), leading to a delay in diagnosis and appropriate treatment. The second most common presentation is a diffuse, unilateral thickening of the eyelid accompanied by an inflammatory reaction that simulates blepharoconjunctivitis [26].

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, and thickening of the conjunctiva, and superficial vascularity of the cornea suggest epithelial involvement due to pagetoid spread of the tumor (picture 3) [27]. 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 in most cases on the head and neck 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 [28,29].

Metastasis — Regional lymph nodes are the most common site of metastasis [30]. 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 [27]. Distant metastasis may involve the parotid gland, liver, lung, and bone [30,31].

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). Misdiagnosis results in delay in diagnosis and poor outcome [32]. An excisional biopsy or a deep incisional biopsy to the deep dermis extending into subcutaneous fat is required to establish the diagnosis [32]. Immunohistochemistry may be performed to differentiate 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 4) [8]. Well-differentiated tumors may contain sebocyte-like cells with vacuolated, foamy cytoplasm. In frozen specimens, an oil red-O stain can demonstrate intracytoplasmic lipid [33]. 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 [32,34,35].

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. Upward migration and spreading to the surface epidermis or conjunctiva in a pagetoid pattern is often seen in eyelid lesions.

Immunohistochemistry — Positive immunostaining with nuclear factor XIIIa (clone AC-1A1 mouse monoclonal), epithelial membrane antigen (EMA), adipose differentiation-related protein (adipophilin [ADP]) and perilipin, androgen receptor (AR), and cytokeratin AE1/AE3 antibody confirms sebaceous differentiation and differentiates sebaceous carcinoma from basal cell carcinoma and squamous cell carcinoma [32,36-38].

Markers that are typically negative in sebaceous carcinoma included carcinoembryonic antigen, S100, HMB45, SOX10, CD5, GCDFP-15, D2-40, and Ber-EP4 (occasionally positive) [32].

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 (MTS), an autosomal dominant disorder considered a variant of hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome). MTS is characterized by the development of sebaceous tumors in association with visceral neoplasms [39]. (See "Muir-Torre syndrome" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

Based on recommendations in published expert guidelines [32], genetic testing for MTS is recommended in patients with extraocular sebaceous carcinoma and a Mayo MTS overall risk score ≥2 [40]. The Mayo MTS 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-related cancers (score = 1)

●Family history of any Lynch-related cancers (score = 1)

For patients with sebaceous carcinoma and suspected MTS who do not fulfill the Mayo MTS clinical criteria (eg, patients <60 years with a first extraocular sebaceous carcinoma [score = 1]), immunohistochemical tumor testing for loss of mismatch repair proteins may be appropriate to identify patients who are candidates for genetic testing [41,42]. (See "Muir-Torre syndrome", section on 'Tumor testing'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of sebaceous carcinoma includes several benign and malignant conditions, including [26,33,43]:

●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'.)

●Inflammatory lesions – Sebaceous carcinoma may mimic chalazion (picture 6A-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. (See "Eyelid lesions".)

●Basal cell carcinoma – Nodular basal cell carcinoma (BCC) is more common on the lower eyelid (picture 7) and tends to ulcerate at an early stage, whereas ulceration is uncommon in sebaceous carcinoma. The morpheaform variant of BCC may also simulate sebaceous carcinoma, but conjunctival involvement is uncommon. Immunohistochemical staining for epithelial membrane antigen (EMA) and adipophilin (ADP) are negative in BCC but positive in nearly all sebaceous carcinomas [36,37]. (See "Epidemiology, pathogenesis, and clinical features of basal cell carcinoma".)

●Squamous cell carcinoma – Squamous cell carcinoma (SCC) may occur on the upper eyelid, and clear cell SCC can mimic sebaceous carcinoma [32]. Immunohistochemical staining for EMA may be positive in SCC, but ADP and androgen receptor (AR) are consistently negative [36,37]. (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 — 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. Ultrasonography or computerized tomography (CT) scan of regional lymph nodes may be indicated to complete tumor staging for larger or more aggressive periocular tumors [32,44]. If enlarged lymph nodes are detected, lymph node biopsy via fine needle aspiration or surgical removal of the enlarged lymph node is indicated.

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 [27]. In patients with large tumors located in the periorbital area, CT or magnetic resonance imaging (MRI) is useful 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 [32,45].

The staging of periocular sebaceous carcinomas is performed according to the staging system for eyelid carcinoma, outlined in the eight edition of the American Joint Committee on Cancer Staging Manual (table 1) [46-48]. 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) [46].

MANAGEMENT — 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. For periocular lesions, additional goals include the identification and treatment of subclinical intraepithelial neoplasia, vision salvage, avoidance of exenteration, and acceptable cosmetic outcome [26,27].

Local disease

Surgical treatment — Surgical excision with complete circumferential peripheral and deep margin assessment (CCPDMA) or, if available, Mohs micrographic surgery are the first-line treatments for sebaceous carcinoma of the head and neck region, including eyelid tumors [2,26,49]. 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 performed for extraocular sebaceous carcinoma [32].

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 [50]. (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 with WLE, 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) [51].

●In a multicenter, cohort study that included 360 patients with eyelid sebaceous carcinoma (115 [32 percent] treated with Mohs surgery and 245 [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) [52].

●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 (36.2 and 27.6 percent, respectively) [53].

Conjunctival epithelial involvement may be treated with surgical resection of the bulbar epithelium, cryotherapy, and/or topical mitomycin [27,32]. For tumors with extensive intraorbital involvement, surgical management may include orbital exenteration.

Radiation therapy — Radiation therapy (RT) may be given as primary treatment for both periocular and extraocular tumors or nodal metastases that are surgically unresectable [32]. 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 surrounding sensitive structures [32]. 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 [54]. 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, shielding is easier (a 6 MeV electron beam produces bremsstrahlung radiation and the cornea receives a small RT dose behind the eye shield), less expensive (since linear accelerator machines required to produce electrons are more costly), with a higher relative biologic effectiveness, and local control is better. The electron dose should be higher by 10 percent to be as effective as orthovoltage.

Eye drops with 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 [55-57]:

●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 [55]. 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) delivered in 18 to 37 fractions [56]. The reported five-year overall and local progression-free rates were 80 and 93 percent, respectively.

In periocular sites, RT or completion nodal dissection can be considered for microscopic regional metastasis [32]. Adjuvant RT has been given to the nodal basin after lymph node dissection identified additional nodal disease, although the benefit is uncertain [32]. Plaque brachytherapy (50 Gy) instead of exenteration has been used for tumors involving the lacrimal gland or orbit [58,59].

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 [56].

Adjuvant therapies — Cryotherapy or topical mitomycin are used for focal positive margins or local recurrence of the conjunctiva:

●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 [60]. However, cryotherapy may be associated with serious adverse effects, including symblepharon and corneal erosions.

●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 [26,61-63]. Complications of topical mitomycin treatment include persistent keratoconjunctivitis, epiphora secondary to punctal stenosis, allergic reaction, and limbal stem cell deficiency [64].

The use of 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 [65]. A recurrence occurred in two of seven patients who had received adjuvant RT postoperatively and five of six patients who did not receive RT.

Nodal and distant metastatic disease — Sentinel lymph node (SLN) biopsy and imaging to complete tumor staging may be indicated for larger or more aggressive periocular tumors (ie, eyelid tumor stage T2c or higher) [32,66,67]. In a series of 100 patients with periocular sebaceous carcinoma, 5 of 30 patients (16.7 percent) who underwent SLN biopsy had positive SLN, and 2 were false negative [67]. However, the benefit of SLN biopsy on disease-specific survival is unknown.

SLN biopsy is generally not indicated for extraocular sebaceous carcinoma, which is associated with a low risk of nodal and distant metastases. In a series of 1836 patients with sebaceous carcinomas from the National Cancer Institute's 17 registries of the Surveillance, Epidemiology, and End Results (SEER) database, the rate of nodal or distant metastases among 867 patients with extraocular sebaceous carcinoma was 1.4 percent [66].

Data on the management of locoregional or distant metastasis of sebaceous carcinoma are limited to small case series and case reports [68,69]. Patients with regional nodal involvement are treated with lymph node dissection and/or RT [65,70,71].

There are isolated reports of successful use of fluorouracil, cisplatin, capecitabine, taxane, and RT for the management of metastatic sebaceous carcinoma [68,72-74]. Immunotherapy with pembrolizumab, a programmed death receptor-1 (PD-1) inhibitor, has been successfully used in two patients with advanced disease [75,76].

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 [77]. Local recurrence has been reported in 9 to 36 percent of patients, with distant metastasis occurring in 3 to 25 percent [78-80]. In a series of 60 patients with sebaceous carcinoma of the eyelids, local recurrence occurred in 18 percent of patients and metastasis in 8 percent of patients [26].

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 [81].

Other prognostic factors include [32]:

●Pagetoid spread for periocular sebaceous carcinoma – More likely to be poorly differentiated, recurrent, with distant metastases, and require exenteration [67,82].

●High androgen receptor staining of >50 percent with moderate intensity for periocular sebaceous carcinoma – More likely to be recurrent and develop metastases [32].

●Programmed death receptor-1 (PD-1) expression in tumor-infiltrating lymphocytes of periocular sebaceous carcinoma – Tends to have higher T stage and poor survival [83].

●Location – Lower eyelid or orbital extension tend to have higher mortality.

●Vimentin overexpression in eyelid sebaceous carcinoma is associated with advanced stage, nodal metastases, pagetoid spread, and poor survival [84].

Patients with sebaceous carcinoma and Muir-Torre syndrome (MTS) have a worse prognosis. An analysis of SEER data on over 3000 patients with sebaceous carcinoma, of whom 64 had MTS, found that the five-year, cause-specific survival rates among patients with and without MTS were 53 and 78 percent, respectively [12].

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, computerized tomography (CT), or positron emission tomography (PET) can be arranged as indicated by initial stage for high-risk patients, especially those with periocular tumors [32]. Late relapses (pagetoid, nodal, or distant) have been reported 5 to 11 years after the excision of the primary sebaceous carcinoma [70,71,85,86].

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

●Sebaceous carcinoma is a rare, malignant tumor of the sebaceous glands, most commonly found in the head and neck region and particularly on the eyelids of older individuals. It occurs sporadically in most cases. However, 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.)

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

●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.)

●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-related cancers (Mayo Muir-Torre syndrome risk score ≥2). (See 'Screening for Muir-Torre syndrome' above.)

●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 computerized tomography (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 eight edition of the American Joint Committee on Cancer Staging Manual (table 1). (See 'Staging' above.)

●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. Conjunctival epithelial involvement may be treated with surgical resection of the bulbar epithelium, cryotherapy, and/or topical mitomycin. (See 'Management' above.)