Targeted therapy

In recent years, targeted therapy has had an emerging role in the treatment of refractory tumors, such as advanced melanoma.60 For patients with metastatic or locally advanced BCC or SCC, targeted therapy against the Hedgehog pathway or epidermal growth factor receptor has been shown to be fairly efficacious in preventing disease progression.30,61 In a series of current studies, an overexpression of HER2 is observed in SC,23,62 thus suggesting the possibility of targeted therapy with monoclonal antibodies trastuzumab and cetuximab.61 Confirmation of frequent PI3K signaling pathway activation provides a strong rationale for the application of mammalian target of rapamycin inhibitors in targeted therapy of ocular SC.25

Continue Reading

The management of metastasis

Up to 25% of SCs metastasize.17 For lymph node and distant metastases, combination treatments, including lymph node and neck dissection, radiation therapy, and systemic chemotherapy, should be considered.61,63,64

Two case reports on the management of recurrent, locally advanced, or metastatic SC of the eyelids showed neoadjuvant cisplatin and fluorouracil for 1 cycle in 1 case report and carboplatin and 5-fluorouracil for 3 cycles in the other with favorable responses and stable residual disease.63Neoadjuvant chemotherapy may enable local resection of advanced tumors, thus avoiding disfiguring procedures, such as exenteration.64,65

Orbital exenteration refers to a surgical procedure involving removal of the eyeball and intraorbital contents. This morbific surgery is usually reserved for SC that involves most of the conjunctiva and has invaded the orbit or for potentially life-threatening SC.66–68 Gerring et al67 demonstrated that orbital exenteration offered a 2-year mean disease-free survival of 39.2% among advanced SC cases.


In the past, ocular SC has led to cancer-specific mortality in ~18%–30% of patients.17,69 Fortunately, more attention has been paid to this tumor, and the mortality has decreased to 3%–7.3% due to comprehensive therapy.6,10,12,50

The indicators for prognosis have been disputed. On the basis of a retrospective study, the T category was significantly associated with lymph node metastasis and disease-specific survival, especially among patients with a T category of T3a or worse.27 Orbital involvement was once considered to be associated with worsened prognosis, while it has been challenged in a contemporary retrospective review of 1,394 cases of SC.1 Other histological markers of poor prognosis in previous reports include pagetoid spread, multicentric origin, tumor size >10 mm, tumor growth pattern,16 and invasion of vascular, lymphatic, and perineural structures. In addition, other poor prognostic indicators consist of delayed diagnosis (>6 months), involvement of both eyelids,27 and the presence of metastatic disease at the time of diagnosis.4 However, Takahashi et al16 found that the interval between the appearance of symptoms and referral to medical center did not significantly affect local recurrence or metastasis. Different patient characteristics may provide a possible explanation.

Compared to traditional isolated risk factors, the development of a new model for individualized prediction of tumor-related survival may pave the way for prognostic stratification.


Ocular SC is an uncommon, but aggressive malignancy with great potential to spread to regional lymph nodes and beyond. As its clinical presentation is nonspecific, definite diagnosis of this tumor relies on histopathologic confirmation, which can be challenging. Special efforts should be made to unveil the mechanism of ocular SC in order to provide evidence for targeted therapy. The existing literature related to the treatment of ocular SC primarily consists of small- to medium-sized case series and isolated case reports, impeding the possibility to reach a clinical consensus. As a result, surgical excision with a tumor-free margin continues to be the best choice for ocular SC that is discovered early. Adjuvant treatment options, including radiation therapy, cryotherapy, and topical therapy are adapted based on the extent of the tumor. Larger studies with longer follow-up periods are essential for clarifying the long-term effects of different treatment modalities. For the management of late-stage cases, multicenter clinical trials may be an appropriate solution to accrue adequate patient numbers. Patients with ocular SC require long-term follow-up with careful clinical examination for at least 5 years after radical antitumor therapy, regardless of tumor stage or anatomic location.


This work was supported by the Scientific Research Program of National Health and Family Planning Commission of China (201402014), the Science and Technology Commission of Shanghai (17DZ2260100) and the National Natural Science Foundation of China (Grant No 81500757).

Author contributions

RBJ and XQF are senior authors on this paper. YFX prepared the first draft of the manuscript; FL contributed to the design and writing of the manuscript. RBJ and XQF critically reviewed and revised the manuscript. All authors read and approved the final manuscript. All authors contributed toward data acquisition and analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.


The authors report no conflicts of interest in this work.

Yangfan Xu,1,2,* Fang Li,1,2,* Renbing Jia,1,2 Xianqun Fan1,2
1Department of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, People’s Republic of China

*These authors contributed equally to this work 


1. Dasgupta T, Wilson LD, Yu JB. A retrospective review of 1,349 cases of sebaceous carcinoma. Cancer. 2009;115(1):158–165.

2. Kuzel P, Metelitsa AI, Dover DC, Salopek TG. Epidemiology of sebaceous carcinoma in Alberta, Canada, from 1988 to 2007. J Cutan Med Surg. 2012;16(6):417–423.

3. Dores GM, Curtis RE, Toro JR, Devesa SS, Fraumeni JF Jr. Incidence of cutaneous sebaceous carcinoma and risk of associated neoplasms: insight into Muir-Torre syndrome. Cancer. 2008;113(12):3372–3381.

4. Tryggvason G, Bayon R, Pagedar NA. Epidemiology of sebaceous carcinoma of the head and neck: implications for lymph node management. Head Neck. 2012;34(12):1765–1768.

5. Shields JA, Saktanasate J, Lally SE, Carrasco JR, Shields CL. Sebaceous carcinoma of the ocular region: the 2014 Professor Winifred Mao lecture. Asia Pac J Ophthalmol. 2015;4(4):221–227.

6. Tripathi R, Chen Z, Li L, Bordeaux JS. Incidence and survival of sebaceous carcinoma in the United States. J Am Acad Dermatol. 2016;75(6):1210–1215.

7. Shields JA, Demirci H, Marr BP, Eagle RC Jr, Shields CL. Sebaceous carcinoma of the ocular region: a review. Surv Ophthalmol. 2005;50(2):103–122.

8. Lin HY, Cheng CY, Hsu WM, Kao WH, Chou P. Incidence of eyelid cancers in Taiwan: a 21-year review. Ophthalmology. 2006;113(11):2101–2107.

9. Muqit MM, Foot B, Walters SJ, Mudhar HS, Roberts F, Rennie IG. Observational prospective cohort study of patients with newly-diagnosed ocular sebaceous carcinoma. Br J Ophthalmol. 2013;97(1):47–51.

10. Shields JA, Demirci H, Marr BP, Eagle RC Jr, Shields CL. Sebaceous carcinoma of the eyelids: personal experience with 60 cases. Ophthalmology. 2004;111(12):2151–2157.

11. Pe’er J. Pathology of eyelid tumors. Indian J Ophthalmol. 2016;64(3):177–190.

12. Song A, Carter KD, Syed NA, Song J, Nerad JA. Sebaceous cell carcinoma of the ocular adnexa: clinical presentations, histopathology, and outcomes. Ophthal Plast Reconstr Surg. 2008;24(3):194–200.

13. Mahipathy SR, Durairaj AR, Kothandaraman K, Rajamanohar VC, Prabakaran A. Sebaceous gland carcinoma of the lower eyelid reconstructed with a composite flap: a case report. J Clin Diagn Res. 2016;10(6):PD16–PD18.

14. Bernardini FP. Management of malignant and benign eyelid lesions. Curr Opin Ophthalmol. 2006;17(5):480–484.

15. Kiratli H, Tarlan B, Firat P. Primary sebaceous carcinoma of the lacrimal gland. Orbit. 2012;31(5):352–354.

16. Takahashi Y, Takahashi E, Nakakura S, Kitaguchi Y, Mupas-Uy J, Kakizaki H. Risk factors for local recurrence or metastasis of eyelid sebaceous gland carcinoma after wide excision with paraffin section control. Am J Ophthalmol. 2016;171:67–74.

17. Slutsky JB, Jones EC. Periocular cutaneous malignancies: a review of the literature. Dermatol Surg. 2012;38(4):552–569.

18. Stockl FA, Dolmetsch AM, Codere F, Burnier MN Jr. Sebaceous carcinoma of the eyelid in an immunocompromised patient with Muir-Torre syndrome. Can J Ophthalmol. 1995;30(6):324–326.

19. Hoss E, Nelson SA, Sharma A. Sebaceous carcinoma in solid organ transplant recipients. Int J Dermatol. 2017;56(7):746–749.

20. Kaliki S, Ayyar A, Dave TV, Ali MJ, Mishra DK, Naik MN. Sebaceous gland carcinoma of the eyelid: clinicopathological features and outcome in Asian Indians. Eye. 2015;29(7):958–963.

21. Bell WR, Singh K, Rajan Kd A, Eberhart CG. Expression of p16 and p53 in intraepithelial periocular sebaceous carcinoma. Ocul Oncol Pathol. 2015;2(2):71–75.

22. Kiyosaki K, Nakada C, Hijiya N, et al. Analysis of p53 mutations and the expression of p53 and p21WAF1/CIP1 protein in 15 cases of sebaceous carcinoma of the eyelid. Invest Ophthalmol Vis Sci. 2010;51(1):7–11.

23. Kwon MJ, Shin HS, Nam ES, et al. Comparison of HER2 gene amplification and KRAS alteration in eyelid sebaceous carcinomas with that in other eyelid tumors. Pathol Res Pract. 2015;211(5):349–355.

24. Liau JY, Liao SL, Hsiao CH, Lin MC, Chang HC, Kuo KT. Hypermethylation of the CDKN2A gene promoter is a frequent epigenetic change in periocular sebaceous carcinoma and is associated with younger patient age. Hum Pathol. 2014;45(3):533–539.

25. Tetzlaff MT, Singh RR, Seviour EG, et al. Next-generation sequencing identifies high frequency of mutations in potentially clinically actionable genes in sebaceous carcinoma. J Pathol. 2016;240(1):84–95.

26. Yang PT, Tucker NA, Rootman DB, Rootman DS, McGowan H, Chan CC. Pagetoid spread of sebaceous cell carcinoma to the cornea. Can J Ophthalmol. 2012;47(6):e46–e47.

27. Esmaeli B, Nasser QJ, Cruz H, Fellman M, Warneke CL, Ivan D. American Joint Committee on Cancer T category for eyelid sebaceous carcinoma correlates with nodal metastasis and survival. Ophthalmology. 2012;119(5):1078–1082.

28. Spencer JM, Nossa R, Tse DT, Sequeira M. Sebaceous carcinoma of the eyelid treated with Mohs micrographic surgery. J Am Acad Dermatol. 2001;44(6):1004–1009.

29. Chao AN, Shields CL, Krema H, Shields JA. Outcome of patients with periocular sebaceous gland carcinoma with and without conjunctival intraepithelial invasion. Ophthalmology. 2001;108(10):1877–1883.

30. Yin VT, Merritt HA, Sniegowski M, Esmaeli B. Eyelid and ocular surface carcinoma: diagnosis and management. Clin Dermatol. 2015;33(2):159–169.

31. Ha A, Kim N. Sebaceous gland carcinoma of tarsus can be misdiagnosed as intratarsal keratinous cyst. Can J Ophthalmol. 2016;51(3):e99–e101.

32. Jayaraj P, Sen S, Bhattacharya T, et al. Clinical relevance of cyclooxygenase 2 and peroxisome proliferator-activated receptor gamma in eyelid sebaceous gland carcinoma. Histopathology. 2016;69(2):268–275.

33. Schmitz EJ, Herwig-Carl MC, Holz FG, Loeffler KU. Sebaceous gland carcinoma of the ocular adnexa – variability in clinical and histological appearance with analysis of immunohistochemical staining patterns. Graefes Arch Clin Exp Ophthalmol. 2017;255(11):2277–2285.

34. Cabral ES, Auerbach A, Killian JK, Barrett TL, Cassarino DS. Distinction of benign sebaceous proliferations from sebaceous carcinomas by immunohistochemistry. Am J Dermatopathol. 2006;28(6):465–471.

35. Na HY, Choe JY, Shin SA, et al. Proposal of a provisional classification of sebaceous carcinoma based on hormone receptor expression and HER2 status. Am J Surg Pathol. 2016;40(12):1622–1630.

36. Ostler DA, Prieto VG, Reed JA, Deavers MT, Lazar AJ, Ivan D. Adipophilin expression in sebaceous tumors and other cutaneous lesions with clear cell histology: an immunohistochemical study of 117 cases. Mod Pathol. 2010;23(4):567–573.

37. While B, Salvi S, Currie Z, Mudhar HS, Tan JH. Excision and delayed reconstruction with paraffin section histopathological analysis for periocular sebaceous carcinoma. Ophthal Plast Reconstr Surg. 2014;30(2):105–109.

38. Chang HH, Suh E, Fortes BH, Zheng F, Cheng AM. Forehead galeal pericranial flap for single-staged total upper eyelid reconstruction in sebaceous gland carcinoma excision. Int Med Case Rep J. 2017;10:309–312.

39. Savar A, Oellers P, Myers J, et al. Positive sentinel node in sebaceous carcinoma of the eyelid. Ophthal Plast Reconstr Surg. 2011;27(1):e4–e6.

40. Nijhawan N, Ross MI, Diba R, Ahmadi MA, Esmaeli B. Experience with sentinel lymph node biopsy for eyelid and conjunctival malignancies at a cancer center. Ophthal Plast Reconstr Surg. 2004;20(4):291–295.

41. Kingham TP, Panageas KS, Ariyan CE, Busam KJ, Brady MS, Coit DG. Outcome of patients with a positive sentinel lymph node who do not undergo completion lymphadenectomy. Ann Surg Oncol. 2010;17(2):514–520.

42. Knackstedt T, Samie FH. Sebaceous carcinoma: a review of the scientific literature. Curr Treat Options Oncol. 2017;18(8):47.

43. Tolkachjov SN. Adnexal carcinomas treated with Mohs micrographic surgery: a comprehensive review. Dermatol Surg. 2017;43(10):1199–1207.

44. Snow SN, Larson PO, Lucarelli MJ, Lemke BN, Madjar DD. Sebaceous carcinoma of the eyelids treated by mohs micrographic surgery: report of nine cases with review of the literature. Dermatol Surg. 2002;28(7):623–631.

45. Callahan EF, Appert DL, Roenigk RK, Bartley GB. Sebaceous carcinoma of the eyelid: a review of 14 cases. Dermatol Surg. 2004;30(8):1164–1168.

46. Arora A, Barlow RJ, Williamson JM, Olver JM. Eyelid sebaceous gland carcinoma (SGC) treated with “slow” Mohs’ micrographic surgery. Eye. 2004;18(8):854–855.

47. Thomas CJ, Wood GC, Marks VJ. Mohs micrographic surgery in the treatment of rare aggressive cutaneous tumors: the Geisinger experience. Dermatol Surg. 2007;33(3):333–339.

48. Brady KL, Hurst EA. Sebaceous carcinoma treated with Mohs micrographic surgery. Dermatol Surg. 2017;43(2):281–286.

49. Kyllo RL, Brady KL, Hurst EA. Sebaceous carcinoma: review of the literature. Dermatol Surg. 2015;41(1):1–15.

50. Erovic BM, Goldstein DP, Kim D, et al. Sebaceous gland carcinoma of the head and neck: the Princess Margaret Hospital experience. Head Neck. 2013;35(3):316–320.

51. Dowd MB, Kumar RJ, Sharma R, Murali R. Diagnosis and management of sebaceous carcinoma: an Australian experience. ANZ J Surg. 2008;78(3):158–163.

52. Pushker N, Batra J, Meel R, Bajaj MS, Chawla B, Ghose S. Lateral eyelid rotation flap: a novel technique for reconstruction of full thickness eyelid defect. Int Ophthalmol. 2015;35(6):793–799.

53. Belaid A, Nasr C, Benna M, et al. Radiation therapy for primary eyelid cancers in Tunisia. Asian Pac J Cancer Prev. 2016;17(7):3643–3646.

54. Connor M, Droll L, Ivan D, et al. Management of perineural invasion in sebaceous carcinoma of the eyelid. Ophthal Plast Reconstr Surg. 2011;27(5):356–359.

55. Deo SV, Shukla NK, Singh M, Jha D, Khanna P, Kallianpur A. Locally advanced sebaceous cell carcinoma (T3) of eyelid: incidence and pattern of nodal metastases and combined modality management approach. Orbit. 2012;31(3):150–154.

56. Hsu A, Frank SJ, Ballo MT, et al. Postoperative adjuvant external-beam radiation therapy for cancers of the eyelid and conjunctiva. Ophthal Plast Reconstr Surg. 2008;24(6):444–449.

57. Hata M, Koike I, Omura M, Maegawa J, Ogino I, Inoue T. Noninvasive and curative radiation therapy for sebaceous carcinoma of the eyelid. Int J Radiat Oncol Biol Phys. 2012;82(2):605–611.

58. Shields CL, Naseripour M, Shields JA, Eagle RC Jr. Topical mitomycin-C for pagetoid invasion of the conjunctiva by eyelid sebaceous gland carcinoma. Ophthalmology. 2002;109(11):2129–2133.

59. Galor A, Karp CL, Oellers P, et al. Predictors of ocular surface squamous neoplasia recurrence after excisional surgery. Ophthalmology. 2012;119(10):1974–1981.

60. Ribas A, Hamid O, Daud A, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315(15):1600–1609.

61. Della Vittoria Scarpati G, Perri F, Pisconti S, et al. Concomitant cetuximab and radiation therapy: a possible promising strategy for locally advanced inoperable non-melanoma skin carcinomas. Mol Clin Oncol. 2016;4(4):467–471.

62. Cho KJ, Khang SK, Koh JS, Chung JH, Lee SS. Sebaceous carcinoma of the eyelids: frequent expression of c-erbB-2 oncoprotein. J Korean Med Sci. 2000;15(5):545–550.

63. Priyadarshini O, Biswas G, Biswas S, Padhi R, Rath S. Neoadjuvant chemotherapy in recurrent sebaceous carcinoma of eyelid with orbital invasion and regional lymphadenopathy. Ophthal Plast Reconstr Surg. 2010;26(5):366–368.

64. Gogia A, Pushker N, Sen S, Bakhshi S. Avoidance of exenteration in orbital sebaceous gland carcinoma with neoadjuvant chemotherapy. Graefes Arch Clin Exp Ophthalmol. 2013;251(10):2479–2480.

65. Kaliki S, Ayyar A, Nair AG, Mishra DK, Reddy VA, Naik MN. Neoadjuvant systemic chemotherapy in the management of extensive eyelid sebaceous gland carcinoma: a study of 10 cases. Ophthal Plast Reconstr Surg. 2016;32(1):35–39.

66. Shields JA, Shields CL, Demirci H, Honavar SG, Singh AD. Experience with eyelid-sparing orbital exenteration: the 2000 Tullos O. Coston lecture. Ophthal Plast Reconstr Surg. 2001;17(5):355–361.

67. Gerring RC, Ott CT, Curry JM, Sargi ZB, Wester ST. Orbital exenteration for advanced periorbital non-melanoma skin cancer: prognostic factors and survival. Eye. 2017;31(3):379–388.

68. Ali MJ, Pujari A, Dave TV, Kaliki S, Naik MN. Clinicopathological profile of orbital exenteration: 14 years of experience from a tertiary eye care center in South India. Int Ophthalmol. 2016;36(2):253–258.

69. Sinard JH. Immunohistochemical distinction of ocular sebaceous carcinoma from basal cell and squamous cell carcinoma. Arch Ophthalmol. 1999;117(6):776–783.

Source: OncoTargets and Therapy.
Originally published June 27, 2018.