Sebaceous carcinoma — Double trouble

By Warren R. Heymann, MD, FAAD
July 23, 2025
Vol. 7, No. 29

Sebaceous carcinoma (SC, aka sebaceous gland carcinoma) is double trouble — the cancer itself and its potential association with the Muir-Torre syndrome (MTS).

SC is an aggressive malignancy that develops from the sebaceous glands. SC is most common in the periocular area, head, and neck but can occur anywhere sebaceous glands are present. SC occurs in older patients, most frequently in the 7th and 8th decades. (1) The epidemiology of SC is controversial. While studies from Japan report a frequency of eyelid SC in 54% of all eyelid tumors in Japan and 43%-56% in India, it is only 1-3% in Western countries. (2)

Tripathi and Bordeaux state, “The etiology of sebaceous carcinoma is complex. Immunosuppression in the setting of solid organ transplant is associated with a 25-fold increase in SC incidence, with potential explanatory factors including viral oncogenesis, underlying medical conditions, drug-induced phototoxicity, T-cell deficiency/dysfunction, and chronic inflammation. There are likely numerous predisposing factors which are differentially present in distinct patient populations — the combination of multiple such ‘hits’ may be necessary for the onset of SC.” Previously, SC was believed to be more aggressive in patients with MTS; however, larger cohorts in the Surveillance, Epidemiology, and End Results (SEER) database suggest that SC-specific mortality is not greater in MTS. (3) In a study of 4,997 patients with SC from the SEER program, including 116 with MTS, Joshi and Ranario demonstrated that of the 1,308 patients who died, 75.8% (992) died from non-cancer causes, such as cardiovascular disease, cerebrovascular disease, diabetes mellitus, nephritis/nephrotic syndrome, and pneumonia/influenza. The increased risk of mortality from these causes was in patients without MTS. MTS patients’ mortality risk was attributed to colorectal and small bowel malignancies. (4)

Periocular sebaceous carcinoma (PSC) may mimic benign disorders (chalazion, stye, blepharitis, pyogenic granuloma) and malignancies (basal cell carcinoma, squamous cell carcinoma). PSC involves the upper eyelid (63%), lower eyelid (27%), or both contemporaneously (5%). The diagnosis may be delayed if the lesion is mistakenly considered benign. (5) Extraocular SCs account for approximately 25% of all SCs, appearing on the trunk, extremities, breast, genitalia, salivary glands, and lungs. (6) A National Cancer Database analysis of 3211 SC cases demonstrated that 26% of sebaceous carcinomas were found on the trunk and extremities. Tumors on the trunk and extremities tended to be larger than tumors on the head and neck, with 8% being greater than 50 mm (P < .001). Tumors on the trunk and extremities were more likely to be well differentiated (P < .001) and have fewer lymph node metastases (P < .001).

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The diagnosis of SC requires histologic confirmation, although initial assessments may include dermoscopy, reflectance confocal microscopy, and optical coherence tomography. High-risk PSC includes tumors larger than 10 mm, locally advanced lesions, recurrent disease, or those with high-risk histopathological features, including the pagetoid pattern, poor differentiation, and lymphovascular or perineural invasion. Lesions with these features are candidates for sentinel lymph node biopsy; those without these features are considered low-risk. (5) Appropriate staging will determine the tailored therapeutic approach. Surgery (wide local excision, Mohs micrographic surgery [MMS]) is primary. (1) In their systematic review (which the authors acknowledge was limited by the heterogeneity of the studies) Yadlapati et al. concluded that MMS cases demonstrate a superior outcome for local, regional, and distant recurrence, making it a good option managing SC. (8) Depending on the tumor stage, radiation, chemotherapy (5-fluorouracil, taxanes), and immunotherapy (pembrolizumab, potentially Hedgehog inhibition) may be warranted. (5)

The question of whether the patient has MTS is raised when a diagnosis of SC is rendered. As stated by Cohen and Kurzrock, “Muir-Torre syndrome, a subtype of Lynch syndrome, is characterized by a germline mutation of one or more mismatch repair genes such as MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS1 Homolog 2, mismatch repair system component (PMS2) resulting in microsatellite instability and at least one malignancy and a minimum of one syndrome-associated sebaceous neoplasm such as a sebaceous adenoma, epithelioma, or carcinoma. The syndrome has an autosomal dominant mode of inheritance detectable with germline sequencing of normal body elements such as blood, saliva, or normal skin for a mismatch repair gene mutation. Sebaceous neoplasms can occur before, concurrent with, or following Muir-Torre syndrome-related cancer. Immunohistochemistry, microsatellite instability testing, and next-generation sequencing of tumor tissue can evaluate malignancies such as colorectal and endometrial cancer and sebaceous neoplasms for somatic mismatch repair gene defects. However, these tests cannot differentiate somatic (acquired) versus germline alterations, and immunohistochemistry and microsatellite stability assessment can produce false negatives.” (9) In his editorial on sebaceous neoplasms and MTS, Elston asserts that most patients do not have germline mutations and emphasizes that testing for germline mutations is the gold standard for MTS diagnosis. (10)

Significant false-negative results with immunohistochemistry analysis for microsatellite instability and next-generation sequencing of tumor tissue have been found. Because of this and their inability to definitively differentiate an inherited germline mutation from an acquired somatic genomic aberration of the mismatch repair genes, Cohen and Kurzrock propose that germline testing (on normal elements such as blood, saliva, or a normal skin biopsy) for a mismatch repair gene mutation should be the initial evaluation of a patient with even a single new Muir-Torre syndrome-associated sebaceous neoplasm. (9)

Point to Remember: Sebaceous carcinoma may appear de novo or as part of the Muir-Torre syndrome. Germline testing for Muir-Torre syndrome is the gold standard for diagnosis.

Our experts’ viewpoint

Philip R. Cohen, MD, FAAD
Department of Dermatology, University of California, Davis Medical Center, Sacramento, California
Touro University California College of Osteopathic Medicine, Vallejo, California
Maples Center for Forensic Medicine, University of Florida College of Medicine, Gainesville, Florida

Razelle Kurzrock, MD
Department of Medicine, Medical College of Wisconsin Cancer Center and Genome Sciences and Precision Medicine Center, Milwaukee, Wisconsin
Chief Medical Officer and Chair, Clinical Trials Unit, Worldwide Innovative Network (WIN) for Personalized Cancer Therapy, Villejuif, France
Adjunct Professor, University of Nebraska, Omaha, Nebraska

The development of certain sebaceous tumors (adenomas, epitheliomas, and carcinomas) can be a component of an autosomal genodermatosis with malignant potential: the Muir-Torre syndrome (which is a subtype of Lynch syndrome). (11,12) Lynch syndrome can be due to germline alterations in the MLHL1, MSH2, MSH6, PMS2, or EPCAM genes. The syndrome is associated with one or more visceral malignancies, most commonly colorectal, endometrial, ovarian, small bowel, urinary tract (renal pelvis and ureter), and biliary tract (gallbladder and bile ducts) cancers. (13,14) Lynch syndrome includes sebaceous carcinoma not only of the ocular adnexa but also non-ocular tumors. (15,16)

Our investigative journey regarding this syndrome began in 1991. We reviewed the world literature of published cases and proposed a cancer workup for patients with a syndrome-related sebaceous neoplasm and a malignancy evaluation for members of the patient’s family. At that time, cancer-related immunohistochemistry was in its infancy, and aberration of the mismatch repair genes had not been associated with the syndrome. Also, microsatellite instability, next-generation sequencing, and germline testing evaluation had not been conceived. (17)

Currently, most individuals with colorectal carcinomas or endometrial carcinomas are evaluated for Lynch syndrome. The tumors are assessed for syndrome-related mismatch repair gene mutations using immunohistochemistry or polymerase chain reaction studies (for microsatellite instability). Next generation sequencing (NGS) may also be performed. Referral for genetic consultation and germline studies should be requested if either test is positive. (18)

How should a dermatologist evaluate individuals with a newly diagnosed sebaceous tumor that can be associated with the Muir-Torre syndrome? The prognosis for the patient and their family depends on whether only the tissue shows a somatic mutation of the mismatch repair genes or if normal body elements (such as blood, saliva, or normal skin) demonstrate a germline mutation for these genes. If the patient only has an acquired, non-inherited somatic mutation, only that individual needs to be evaluated for malignancy. However, if there is a germline genetic aberration, the patient’s parents, siblings, and children should be evaluated with germline testing and cancer screening. (9) Whether or not the mutation is germline cannot be established with certainty without germline testing of normal body elements such as blood.

We recently summarized the literature regarding benign and malignant sebaceous neoplasms occurring in immunocompetent individuals and immunosuppressed patients; the latter group include solid organ transplant patients following the initiation of treatment with immunosuppressive therapy or patients with HIV infection. (9,19) We observed that, in both groups of patients with sebaceous neoplasms, not only did the Mayo Muir-Torre syndrome risk score algorithm produce occasional false-negative results, but also immunohistochemistry analysis and microsatellite instability testing of sebaceous tumors could have discordant results. (9,19) In conclusion, after proper patient consent, germline testing of mismatch repair genes should be part of the initial evaluation of both immunocompetent individuals and immunocompromised patients with a Muir-Torre syndrome-associated cutaneous sebaceous neoplasm. (9,19)

Philip R. Cohen declares no conflicts of interest. Razelle Kurzrock has received research funding from Genentech, Merck Serono, Pfizer, Boehringer Ingelheim, TopAlliance, Takeda, Incyte, Debiopharm, Medimmune, Sequenom, Foundation Medicine, Konica Minolta, Grifols, Omniseq, and Guardant, as well as consultant and/or speaker fees and/or advisory board for X-Biotech, Caris, Datar Cancer Genomics, Neomed, Pfizer, Actuate Therapeutics, and Roche, has an equity interest in IDbyDNA and CureMatch Inc, serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch.

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References

1. Gall R, Ortiz-Perez S. Sebaceous Gland Carcinoma. 2023 Aug 14. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 32965894.

2. Thagaard MS, Vest SD, Heegaard S, Marcussen N. Eyelid sebaceous gland carcinoma: a protocol for a systematic review and meta-analysis of clinicopathological studies of prevalence. BMJ Open. 2024 Jun 12;14(6):e086213. doi: 10.1136/bmjopen-2024-086213. PMID: 38866573; PMCID: PMC11177665.

3. Tripathi R, Bordeaux JS. Mortality in Sebaceous Carcinoma and Directions for Future Research (REPLY to MS# JAAD-D-24-01697R1). J Am Acad Dermatol. 2024 Dec 6:S0190-9622(24)03328-0. doi: 10.1016/j.jaad.2024.11.052. Epub ahead of print. PMID: 39647705.

4. Joshi TP, Ranario JS. Overall drivers of mortality in sebaceous carcinoma patients with and without Muir-Torre syndrome: a population-based analysis. J Am Acad Dermatol. 2024 Dec 9:S0190-9622(24)03327-9. doi: 10.1016/j.jaad.2024.07.1537. Epub ahead of print. PMID: 39662525.

5. Dini F, Susini P, Nisi G, Cuomo R, Grimaldi L, Massi D, Innocenti A, Doni L, Mazzini C, Santoro N, De Giorgi V. Periocular sebaceous carcinoma: updates in the diagnosis, treatment, staging, and management. Int J Dermatol. 2024 Jun;63(6):726-736. doi: 10.1111/ijd.17045. Epub 2024 Feb 13. PMID: 38351466.

6. Chica J, Cuevas L, Fuentes O, Ardila D, Sánchez E. Sebaceous carcinoma of the back: a case report and literature review. J Med Case Rep. 2024 Nov 26;18(1):570. doi: 10.1186/s13256-024-04779-7. PMID: 39593180; PMCID: PMC11590488.

7. Grunvald M, Chang R, Terranella S, Ritz E, Goyal PK, O'Donoghue C. Sebaceous carcinoma of the trunk and extremities: Epidemiology and treatment patterns in the United States. JAAD Int. 2024 Mar 28;16:34-38. doi: 10.1016/j.jdin.2024.03.012. PMID: 38774346; PMCID: PMC11107211.

8. Yadlapati S, Rosa-Nieves PM, Mehta N, Merritt BG, Carrasquillo OY. Treatment of sebaceous carcinoma with Mohs micrographic surgery versus wide local excision: a systematic review. Int J Dermatol. 2024 Oct;63(10):1357-1362. doi: 10.1111/ijd.17283. Epub 2024 Jun 10. PMID: 38856083.

9. Cohen PR, Kurzrock R. Germline Testing of Mismatch Repair Genes Is Needed in the Initial Evaluation of Patients With Muir-Torre Syndrome-Associated Cutaneous Sebaceous Neoplasms: A Case Series. Cureus. 2023 Jan 19;15(1):e33975. doi: 10.7759/cureus.33975. PMID: 36824550; PMCID: PMC9941027.

10. Elston DM. Sebaceous neoplasms and the Muir-Torre syndrome. J Am Acad Dermatol. 2023 Dec;89(6):1123. doi: 10.1016/j.jaad.2023.05.012. Epub 2023 May 10. PMID: 37172735.

11. Cohen PR. Diagnosing the Muir-Torre syndrome. J Oral Maxillofac Surg. 1992;50(6):660.

12. Grimshaw EC, Cohen PR. What is the cause of these nasal papules? Muir-Torre syndrome [DermDx]. The Dermatologist 2012;20(8):46-50.

13. Cohen PR, Kohn SR, Davis DA, Kurzrock R. Muir-Torre syndrome. Dermatol Clin. 1995;13(1):79-89.

14. Davis DA, Cohen PR. Genitourinary tumors in men with the Muir-Torre syndrome. J Am Acad Dermatol. 1995;33(5 Pt 2):909-912.

15. Cohen PR. Sebaceous carcinomas of the ocular adnexa and the Muir-Torre syndrome. J Am Acad Dermatol. 1992;27(2 Pt 1):279-280.

16. Cohen PR. Muir-Torre syndrome inpatients with hematologic malignancies. Am J Hematol. 1992;40(1):64-65.

17. Cohen PR, Kohn SR, Kurzrock R. Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome. Am J Med. 1991;90(50):606-613.

18. Usha L, Dewdney SB, Buckingham LE. Tumor screening and DNA testing in the diagnosis of Lynch syndrome. JAMA. 2016;316(1):93-94.

19. Cohen PR, Kurzrock R. Patients with a new-onset cutaneous sebaceous neoplasm following immunosuppression should be evaluated for Muir-Torre syndrome with germline mismatch repair gene mutation analysis: case reports. Dermatol Online J. 2024;30(1). doi: 10.5070/D330163287.

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