Saudi Journal of Ophthalmology (2013) 27, 159–165
Ocular Oncology Update
Periocular sebaceous gland carcinoma: A comprehensive review Kaustubh Mulay, DNB a; Ekta Aggarwal, MS b; Valerie A. White, MD, MHSc, FRCPC c,⇑
Abstract Sebaceous gland carcinoma (SGC) is a rare tumour occurring at periocular and extra-ocular sites. SGC can be a challenging diagnosis for both clinicians and pathologists. High recurrence rates and a tendency for intra-epithelial spread, locoregional and distant metastases make it important for SGC to be suspected and be included in the differential diagnosis of an eyelid lesion. Early diagnosis, that may sometimes need ancillary testing, and prompt management using a multimodal approach can help reduce morbidity and mortality in patients with SGC. Keywords: Periocular, Sebaceous gland, Carcinoma Ó 2013 Production and hosting by Elsevier B.V. on behalf of Saudi Ophthalmological Society, King Saud University. http://dx.doi.org/10.1016/j.sjopt.2013.05.002
Introduction The sebaceous glands are microscopic glands in the skin that secrete sebum. In humans, they are found abundantly in the face and scalp although they are distributed throughout all skin sites except palms and soles. Sebaceous glands are associated with the hair follicle, arising at the junction of the inferior portion of the follicle infundibulum and the isthmus.1 Sebaceous gland proliferations include senile sebaceous gland hyperplasia, sebaceoma, sebaceous adenoma and sebaceous gland carcinoma.2 First described by Allaire in 1891, sebaceous gland carcinoma (SGC) accounts for less than 1% of all cutaneous malignancies.3,4 SGC can masquerade as other inflammatory lesions, and benign and malignant tumours thus delaying diagnosis possibly leading to inappropriate management and an increase in morbidity and/or mortality. The purpose of this review is to summarize in a multifaceted manner the data available in the literature regarding
the epidemiology, aetiology, clinicopathological features, molecular advancements, differential diagnosis, management and prognosis of patients with periocular SGC.
Surgical anatomy The eyelid can be divided into anterior and posterior lamellae. The skin, orbicularis muscle, eyelashes, and their follicles are present in the anterior lamella while the posterior lamella contains the mucocutaneous junction, meibomian gland orifices, and tarsal plate. Sebaceous glands are found in the tarsal plate (upper and lower), caruncle and eye brow. The glands of Zeis open into the hair follicles at the base of eyelashes.
Epidemiology SGC can occur in either the periocular location or at extraocular sites with the periocular sites accounting for 75% of all
Available online 13 June 2013 a
National Reporting Centre for Ophthalmic Pathology, Centre For Sight, Hyderabad, India Department of Ophthalmic Plastics, Vasan Eye Care Hospitals, Hyderabad, India c Department of Pathology and Laboratory Medicine and Ophthalmology and Visual Sciences, University of British Columbia and Vancouver General Hospital, Canada b
⇑ Corresponding author. Address: Department of Pathology and Laboratory Medicine, Vancouver General Hospital, 910 West 10th Avenue, Vancouver, BC V5Z4E3, Canada. Tel.: +1 (604)875-4111. e-mail address: [email protected] (V.A. White). Peer review under responsibility of Saudi Ophthalmological Society, King Saud University
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160 SGC.5,6 Periocular SGC usually arise from the meibomian glands, the glands of Zeis and the sebaceous glands of the eyelid skin, with the former being most frequent. SGC arise two to three times more frequently in the upper eyelid than its lower counterpart due to the presence of more meibomian glands in the upper eyelid compared to the lower eyelid.7 Other periocular sites include the eye-brow, caruncle, lacrimal gland and conjunctiva.6–10 The rate of SGC varies according to the ethnicity of the population. In Caucasians, SGC are rare accounting for less than 1–5.5% of eyelid malignancies.11,12 On the contrary, in the Chinese and Japanese population, SGC is the second most common eyelid malignancy with the highest reported rates being 39% and 37.5% respectively.13,14 Similar studies in the Indian population and in Singapore report rates of 31.2% and 10.2% respectively.15,16 The reason for higher rates of SGC in the Asian population could be genetic or racial in nature. Alternatively, the rates of SGC could be higher due to the lower incidence of other eyelid malignancies. The absolute incidence in non-Caucasians is unknown. SGC is considered to be a tumour of the older age group, mostly arising between the sixth and eighth decades of life, although it can occur in younger age groups as well.1,15 Some reports suggest a female preponderance while others report no gender predilection.6,7,17,18
Aetiology The aetiology of SGC is largely unknown. Several risk factors have been associated with this tumour. Asian race is reported to be significantly associated with SGC.19–21 However, recent reports suggest a contradictory observation of the tumour being more common in whites thus suggesting the role of sunlight exposure.17 Muir–Torre syndrome (MTS), a rare genodermatologic disorder characterized by autosomal dominant non-polyposis colorectal carcinoma, sebaceous gland tumours and visceral malignancies is a risk factor for SGC.22,23 Other reported associations include Rb and p53 mutations, HIV and HPV.24–27
Clinical features The upper lid is more frequently involved by SGC than the lower lid.7 It masquerades not only as various inflammatory conditions such as blepharoconjunctivitis or chalazion but also as premalignant lesions and other benign or malignant tumours.28–31 The nodular form of SGC presents as a discrete, hard, immobile nodule commonly located in the upper tarsal plate having a yellowish appearance (Fig. 1A). The pagetoid variety of SGC occurs with intraepithelial infiltration of the lid margin and/or conjunctiva causing diffuse thickening and loss of eyelashes resembling chronic blepharoconjunctivitis (Fig. 1B).32,33
Diagnosis, microscopy and immunostaining It is important to include SGC in the differential diagnosis of all eyelid lesions, particularly in populations with a higher reported frequency. Microscopic examination is the gold standard in diagnosis and confirmation of SGC. Most patients have a moderately differentiated tumour.34 The tumour cells are arranged in the form of sheets or lobules, sometimes with central comedo necrosis (Fig. 1C). Individual tumour
K. Mulay et al. cells have distinct cell membranes, clear to vacuolated cytoplasm and vesicular nuclei with prominent nucleoli, numerous mitoses and apoptotic cells (Fig. 1D). The demonstration of intracytoplasmic lipid vacuoles by Oil red O or Sudan IV stains, performed on frozen sections of fresh or formalinfixed tissues is reported to aid in the diagnosis of SGC, but is rarely necessary and has largely been superseded by adipophilin (see below).6 Studies have reported a missed diagnosis on light microscopy in 23–77% cases of poorly differentiated SGC.35–37 Sometimes, the tissues are extremely small or SGC may not be suspected before light microscopic examination. In such situations, immunohistochemical staining helps in the diagnosis. A recent study reported that more than 75% SGC stained positively for anti-CK5 and anti CK-15 and were negative with anti-CK1, CK10, CK15, CK17, CK18 and CK20 antibodies.38 Antibodies to phosphinothricin-Nacetyl transferase (PAT) or perilipin family have been used to demonstrate proteins associated with lipid droplets (Fig. 1E).39 Adipophilin (ADP) had a lower specificity (77%) but higher sensitivity (88.5%) as compared to perilipin (specificity 100%, sensitivity 45.5%) and tail-interacting protein of 47 kDa (TIP47, specificity 100%, sensitivity 8.3%).39 This study also suggested that ADP was a more sensitive marker of lipid droplets in SGC than Oil red O.39 However, a similar staining pattern for ADP is also seen in xanthomatous lesions and metastatic renal cell carcinoma.40 SGC are immunoreactive for epithelial membrane antigen (EMA) with staining being restricted to the centre of cell nests.34 BRST-1 antibody stains most SGC, either focally or diffusely. It is negative in basal cell carcinoma (BCC) but can be focally positive in squamous cell carcinoma (SCC).34 Cam 5.2, an anti-low molecular weight keratin antibody, is positive in most cases of SGC.34,41 It can be positive in BCC but is negative in SCC.34 Immunostaining for androgen receptor (AR) in SGC has been extensively described in the recent literature suggesting AR to be a reliable marker of sebaceous differentiation (Fig. 1F).42–46 A panel of antibodies comprising carcinoembryonic antigen (CEA), EMA, AR, Ber-EP4, ADP, CA15-3 and CA19-9 has been suggested to differentiate SGC from SCC and BCC (Table 1).39,40,43,46,47 Intra-epithelial spread, a common cause of misdiagnosis, is a characteristic feature of SGC seen in up to 39% patients.31 Intra-epithelial spread can have a Bowenoid, pagetoid or mixed pattern. Reports in the literature describe the Bowenoid and pagetoid patterns in up to 35% and 47% of SGC respectively.36,48
Molecular pathology Muir-Torre syndrome and mismatch repair genes Several studies have investigated the relationship between MTS and SGC.1,22,23,49 A subset of patients with clinical or phenotypic MTS have a defect in the DNA mismatch repair (MMR) genes and are at a risk for developing a future malignancy.49 An MMR defect results in the accumulation of replication errors or unstable microsatellite sequences.50 In MTS, germline mutation in one of the MMR-genes is complemented by a second somatic molecular alteration in a neoplasm. A sebaceous lesion is present either before or concurrent with the first visceral malignancy in 63% patients with MMR-deficient MTS.51 Diagnosis of SGC or a benign sebaceous neoplasm should prompt the clinician to carry
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Periocular sebaceous carcinoma a review
Figure 1. Clinicopathological features of sebaceous gland carcinoma. Nodular form of sebaceous carcinoma involving both fornices (Fig. 1A) and pagetoid variety presenting as diffuse thickening of the eyelid (Fig. 1B). Lobules of tumour cells with central comedo necrosis (Fig. 1C, haematoxylin and eosin 40). Tumour cells with vacuolated cytoplasm and vesicular nuclei having prominent nucleoli (Fig. 1D, haematoxylin and eosin 400). Tumour cells showing cytoplasmic staining for adipophilin (Fig. 1E, 400) and nuclear staining for androgen receptor (Fig. 1F, 400).
Table 1. Antibody panel that may be helpful in the differential diagnosis of sebaceous gland carcinoma, basal cell carcinoma and squamous cell carcinoma. Antibody
Sebaceous gland carcinoma
CEA46 ADP39,40,43,46–48 AR43,46 EMA46,47 Ber-EP446 CA19-946 CA15-346 BRST134 CAM5.234,47
± + + + ± + + +
Basal cell carcinoma
Squamous cell carcinoma
± + + ± ± ± ±
CEA, carcinoembryonic antigen; ADP, adipophilin; AR, androgen receptor; EMA, epithelial membrane antigen.
out a thorough history and physical examination to rule out a visceral malignancy. It should also prompt the laboratory to perform immunostaining for the commonly absent MMR proteins (MSH2, MLH1, PMS1 and PMS2). One-third of patients with clinical MTS demonstrate failure to express normal MMR proteins.49 Mutations in MSH2 and MLH1 are more frequent than those in MSH6, MSH3, MLH3, PMS2 and PMS1.1 Many cell signalling pathways have been shown to be dysregulated in SGC (Table 2 and Fig. 2).
sence of Wnt, glycogen synthase kinase 3 (GSK-3) constitutively phosphorylates the b-catenin protein. Overexpression of b-catenin has been demonstrated in SGC thus suggesting a possible dysregulation of the Wnt/b-catenin pathway.52–54 Further, it was also shown that reduced membranous expression of b-catenin correlated with invasion and metastasis, especially at the site of invasion.54
TP53 Wnt/b-catenin pathway The Wnt/b-Catenin pathway regulates stem cell pluripotency and cell fate decisions during development. In the ab-
p53 Mutations in SGC, as demonstrated by overexpression, suggest a possible role of UV radiation and subsequent signal alterations.25
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Table 2. Signalling pathways and proteins involved in periocular sebaceous gland carcinoma. Study group
Protein involved
Protein function
Signal pathway
Expression change
Prognostic significance
Jayaraj et al.51 Jayaraj et al.53
b-catenin
Co-ordination of cell–cell adhesion and gene transcription
Wnt/bcatenin
Correlated with tumour size >2 cm Invasion and metastasis
Shalin et al.25
p53
p53
McBride et al.54
p21WAF1
Apoptosis tumour suppressor inhibits angiogenesis DNA repair cell cycle arrest Cyclin-dependent kinase inhibitor.
Overexpression Reduced membranous expression Overexpression
p53/p21 p53 independent
Loss of compartmentalization Down regulation
Preserved in benign and normal sebaceous glands Lymph node metastasis
Sonic hedgehog NA
Overexpression
Metastatic disease Aggressiveness
Increased activity
Inhibits p53 expression and p53 activity.
Wnt/ bcatenin/TCF
Lower expression
Poor tumour differentiation and high proliferation rate Reduced disease-free survival, size >2 cm, lymphnode metastases, poor differentiation
Kiyosaki et al.55 Kim et al.52 Rokhlin et al.59, Nantermet et al.60 Li et al.76 Jayaraj et al.
Shh ABCG2 Androgen receptor E-cadherin
53
Cell-cycle regulation Prevents cell proliferation Maintenance of stem cells in adult tissues Regulation of gene expression
Suppressor of invasion and growth of epithelial cancers. Cell–cell adhesion
Promoter methylation
Correlates with tumour type and tumour location
Figure 2. Sonic hedgehog and Wnt/b-catenin signalling pathways in sebaceous gland carcinoma.78.
p21/WAF1
Androgen receptor
p21WAF1, a cyclin-dependent kinase inhibitor, regulates G1-S transition and mediates G1 cell cycle arrest. It can be transcriptionally upregulated by p53 but may be activated independently. Compartmentalization of p21WAF1 in the differentiated component of the gland, seen in normal sebaceous glands and benign sebaceous lesions, is lost in SGC.55 A recent study associated downregulation of p21 with lymph node metastasis in SGC.56
AR has been identified as a MYC target gene in mouse epidermis.57 p53 can inhibit AR gene expression by direct association with AR promoter58 and by inhibiting AR protein activity.59 On the other hand, strong AR activity can inhibit p53 expression60 and p53 activity.61 Thus, the expressions of AR and p53 are inversely related to each other in SGC.62
Sonic hedgehog pathway The sonic hedgehog (Shh) signalling pathway is also altered in SGC with Shh and ABCG2 proteins being overexpressed in patients with a metastatic disease.53 This study thus suggested that activation of Wnt and Shh signalling pathways is associated with higher cumulative incidences of lymph node and distant metastasis in SGC.53
E-cadherin E-cadherin promoter hypermethylation has been associated with poor clinical outcome.54,63
Treatment As discussed earlier, SGC may be a difficult clinical diagnosis to make due to its masquerading nature and thus, might delay diagnosis and appropriate management. Local
163
Periocular sebaceous carcinoma a review excision, orbital exenteration, radiotherapy and chemotherapy are various methods used to manage patients with SGC based on tumour stage at presentation. Wide excision with at least 4 mm margin and radical neck dissection is necessary in patients with locoregional metastases.64 However, 32% cases recur even with a margin clearance of 5– 6 mm.65 Frozen section and Mohs’ micrographic surgery are now used in specialized centres. Definitive margin excision and minimal loss of surrounding normal tissue are advantages of Mohs’ surgery. A recent study suggested the use of ‘slow’’ Mohs’ surgery which uses paraffin embedded sections to identify pagetoid spread that is otherwise difficult or impossible to identify on frozen sections.66 A recurrence rate of 11.1% has been reported after Mohs’ surgery.65 Exenteration is the treatment of choice for patients with extensive or multifocal tumour or extensive pagetoid spread.67 Radical neck dissection is indicated in patients of SGC with regional nodal metastases.7,64 The role of radiotherapy in SGC has been extensively studied and found to have variable results.36,68–70 Radiation of 50–66.6 Gy administered with a curative intent has been effective in achieving a prolonged survival and good tumour control in addition to facilitating functional and cosmetic preservation of the eyelid.68 Radiotherapy given post-operatively following orbital exenteration provides a better disease control as compared to treatment by exenteration only.69 Radiation is best avoided due to the various complications associated with it such as blepharoconjunctivitis, lid atrophy, dry eye, ectropion, epiphora, cataract and keratopathy.32 Cryotherapy may be used as a coadjuvant.32 The role of Mitomycin C, a non-cell cycle specific alkylating agent, is controversial.71 It has been used in patients with SGC and pagetoid spread to reduce the need for further invasive management.72 More recently, neoadjuvant chemotherapy using carboplatin and 5-fluorouracil has been shown to reduce morbidity in a patient with metastatic nodal disease.73 Recent studies on expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) suggest a potential role of hormonal therapy in patients with SGC.42,43,74
Prognosis Various clinicopathological factors are reported to indicate a poor prognosis in SGC and include lymphovascular and orbital invasion, involvement of both upper and lower eyelids, poor differentiation, multicentric origin, long duration of symptoms, large tumour size, an infiltrative pattern and pagetoid invasion of epithelia of the skin or conjunctiva.7 The 7th edition of AJCC classification for eyelid tumours has been shown to be prognostically useful in one study by Esmaeli et al.75 and is in the process of being validated in a larger cohort of patients. Tumours originating from the glands of Zeis have a better prognosis.76 Also, origin from the upper lids is associated with an adverse prognosis compared to origin from lower lids.76 Human telomerase RNA (hTR) has been shown to be a marker of malignant degree in SGC.77 The overall mortality rate in SGC is 5–10%.32 Locoregional metastases and recurrence are seen in 6–29% cases.18,21,62,76 14– 25% patients develop metastases, either in the form of lymphatic spread to the lymph nodes and/or haematogenous spread to the liver, lungs, brain, and bones.7,35,37,62,76
Conclusion Sebaceous gland carcinoma is a rare tumour of the eyelids that can mimic many inflammatory and neoplastic lesions. Accurate diagnosis by light microscopy and immunostaining followed by appropriate management with a multimodal approach using surgical advances and adjuvant treatment provide good tumour control to reduce the morbidity and mortality in these patients.
Conflict of interest The authors declared that there is no conflict of interest.
Acknowledgment We would like to acknowledge Mr. C. Jangaiah for his help with photography.
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gland carcinoma of the eyelid with regional lymph node metastasis. Ophthal Plast Reconstr Surg 2005;21(4):307–9. Kariya Y, Moriya T, Suzuki T, Chiba M, Ishida K, Takeyama J, et al. Sex steroid hormone receptors in human skin appendage and its neoplasms. Endocr J 2005;52(3):317–25. 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):1078–82. Jakobiec FA, Rao NA, McLean IW, Zimmerman LE. Sebaceous carcinoma of the eyelid and caruncle:correlation of clinicopathologic features with prognosis. In: Jakobiec FA, editor. Ocular and adnexal tumors. Birmingham, AL: Aesculapius; 1978. p. 461–76. Li B, Li N, Cheng G, Sun X, Xu X, Shi J, et al. Correlation of the expression of telomerase RNA with risk factors for recurrence of sebaceous gland carcinoma. Graefes Arch Clin Exp Ophthalmol 2006;244(4):480–4. Shahi MH, Diaz E. Transcription factor targets as treatment for medulloblastoma. In: Abujamra AL editor, Brain tumours – current and emerging therapeutic strategies, InTech; 2011. DOI: 10.5772/ 21658. Available from: http://www.intechopen.com/books/braintumors-current-and-emerging-therapeutic-strategies/transcriptionfactor-targets-as-treatment-for-medulloblastoma.
Ocular Oncology Update
Periocular sebaceous gland carcinoma: A comprehensive review Kaustubh Mulay, DNB a; Ekta Aggarwal, MS b; Valerie A. White, MD, MHSc, FRCPC c,⇑
Abstract Sebaceous gland carcinoma (SGC) is a rare tumour occurring at periocular and extra-ocular sites. SGC can be a challenging diagnosis for both clinicians and pathologists. High recurrence rates and a tendency for intra-epithelial spread, locoregional and distant metastases make it important for SGC to be suspected and be included in the differential diagnosis of an eyelid lesion. Early diagnosis, that may sometimes need ancillary testing, and prompt management using a multimodal approach can help reduce morbidity and mortality in patients with SGC. Keywords: Periocular, Sebaceous gland, Carcinoma Ó 2013 Production and hosting by Elsevier B.V. on behalf of Saudi Ophthalmological Society, King Saud University. http://dx.doi.org/10.1016/j.sjopt.2013.05.002
Introduction The sebaceous glands are microscopic glands in the skin that secrete sebum. In humans, they are found abundantly in the face and scalp although they are distributed throughout all skin sites except palms and soles. Sebaceous glands are associated with the hair follicle, arising at the junction of the inferior portion of the follicle infundibulum and the isthmus.1 Sebaceous gland proliferations include senile sebaceous gland hyperplasia, sebaceoma, sebaceous adenoma and sebaceous gland carcinoma.2 First described by Allaire in 1891, sebaceous gland carcinoma (SGC) accounts for less than 1% of all cutaneous malignancies.3,4 SGC can masquerade as other inflammatory lesions, and benign and malignant tumours thus delaying diagnosis possibly leading to inappropriate management and an increase in morbidity and/or mortality. The purpose of this review is to summarize in a multifaceted manner the data available in the literature regarding
the epidemiology, aetiology, clinicopathological features, molecular advancements, differential diagnosis, management and prognosis of patients with periocular SGC.
Surgical anatomy The eyelid can be divided into anterior and posterior lamellae. The skin, orbicularis muscle, eyelashes, and their follicles are present in the anterior lamella while the posterior lamella contains the mucocutaneous junction, meibomian gland orifices, and tarsal plate. Sebaceous glands are found in the tarsal plate (upper and lower), caruncle and eye brow. The glands of Zeis open into the hair follicles at the base of eyelashes.
Epidemiology SGC can occur in either the periocular location or at extraocular sites with the periocular sites accounting for 75% of all
Available online 13 June 2013 a
National Reporting Centre for Ophthalmic Pathology, Centre For Sight, Hyderabad, India Department of Ophthalmic Plastics, Vasan Eye Care Hospitals, Hyderabad, India c Department of Pathology and Laboratory Medicine and Ophthalmology and Visual Sciences, University of British Columbia and Vancouver General Hospital, Canada b
⇑ Corresponding author. Address: Department of Pathology and Laboratory Medicine, Vancouver General Hospital, 910 West 10th Avenue, Vancouver, BC V5Z4E3, Canada. Tel.: +1 (604)875-4111. e-mail address: [email protected] (V.A. White). Peer review under responsibility of Saudi Ophthalmological Society, King Saud University
Production and hosting by Elsevier
Access this article online: www.saudiophthaljournal.com www.sciencedirect.com
160 SGC.5,6 Periocular SGC usually arise from the meibomian glands, the glands of Zeis and the sebaceous glands of the eyelid skin, with the former being most frequent. SGC arise two to three times more frequently in the upper eyelid than its lower counterpart due to the presence of more meibomian glands in the upper eyelid compared to the lower eyelid.7 Other periocular sites include the eye-brow, caruncle, lacrimal gland and conjunctiva.6–10 The rate of SGC varies according to the ethnicity of the population. In Caucasians, SGC are rare accounting for less than 1–5.5% of eyelid malignancies.11,12 On the contrary, in the Chinese and Japanese population, SGC is the second most common eyelid malignancy with the highest reported rates being 39% and 37.5% respectively.13,14 Similar studies in the Indian population and in Singapore report rates of 31.2% and 10.2% respectively.15,16 The reason for higher rates of SGC in the Asian population could be genetic or racial in nature. Alternatively, the rates of SGC could be higher due to the lower incidence of other eyelid malignancies. The absolute incidence in non-Caucasians is unknown. SGC is considered to be a tumour of the older age group, mostly arising between the sixth and eighth decades of life, although it can occur in younger age groups as well.1,15 Some reports suggest a female preponderance while others report no gender predilection.6,7,17,18
Aetiology The aetiology of SGC is largely unknown. Several risk factors have been associated with this tumour. Asian race is reported to be significantly associated with SGC.19–21 However, recent reports suggest a contradictory observation of the tumour being more common in whites thus suggesting the role of sunlight exposure.17 Muir–Torre syndrome (MTS), a rare genodermatologic disorder characterized by autosomal dominant non-polyposis colorectal carcinoma, sebaceous gland tumours and visceral malignancies is a risk factor for SGC.22,23 Other reported associations include Rb and p53 mutations, HIV and HPV.24–27
Clinical features The upper lid is more frequently involved by SGC than the lower lid.7 It masquerades not only as various inflammatory conditions such as blepharoconjunctivitis or chalazion but also as premalignant lesions and other benign or malignant tumours.28–31 The nodular form of SGC presents as a discrete, hard, immobile nodule commonly located in the upper tarsal plate having a yellowish appearance (Fig. 1A). The pagetoid variety of SGC occurs with intraepithelial infiltration of the lid margin and/or conjunctiva causing diffuse thickening and loss of eyelashes resembling chronic blepharoconjunctivitis (Fig. 1B).32,33
Diagnosis, microscopy and immunostaining It is important to include SGC in the differential diagnosis of all eyelid lesions, particularly in populations with a higher reported frequency. Microscopic examination is the gold standard in diagnosis and confirmation of SGC. Most patients have a moderately differentiated tumour.34 The tumour cells are arranged in the form of sheets or lobules, sometimes with central comedo necrosis (Fig. 1C). Individual tumour
K. Mulay et al. cells have distinct cell membranes, clear to vacuolated cytoplasm and vesicular nuclei with prominent nucleoli, numerous mitoses and apoptotic cells (Fig. 1D). The demonstration of intracytoplasmic lipid vacuoles by Oil red O or Sudan IV stains, performed on frozen sections of fresh or formalinfixed tissues is reported to aid in the diagnosis of SGC, but is rarely necessary and has largely been superseded by adipophilin (see below).6 Studies have reported a missed diagnosis on light microscopy in 23–77% cases of poorly differentiated SGC.35–37 Sometimes, the tissues are extremely small or SGC may not be suspected before light microscopic examination. In such situations, immunohistochemical staining helps in the diagnosis. A recent study reported that more than 75% SGC stained positively for anti-CK5 and anti CK-15 and were negative with anti-CK1, CK10, CK15, CK17, CK18 and CK20 antibodies.38 Antibodies to phosphinothricin-Nacetyl transferase (PAT) or perilipin family have been used to demonstrate proteins associated with lipid droplets (Fig. 1E).39 Adipophilin (ADP) had a lower specificity (77%) but higher sensitivity (88.5%) as compared to perilipin (specificity 100%, sensitivity 45.5%) and tail-interacting protein of 47 kDa (TIP47, specificity 100%, sensitivity 8.3%).39 This study also suggested that ADP was a more sensitive marker of lipid droplets in SGC than Oil red O.39 However, a similar staining pattern for ADP is also seen in xanthomatous lesions and metastatic renal cell carcinoma.40 SGC are immunoreactive for epithelial membrane antigen (EMA) with staining being restricted to the centre of cell nests.34 BRST-1 antibody stains most SGC, either focally or diffusely. It is negative in basal cell carcinoma (BCC) but can be focally positive in squamous cell carcinoma (SCC).34 Cam 5.2, an anti-low molecular weight keratin antibody, is positive in most cases of SGC.34,41 It can be positive in BCC but is negative in SCC.34 Immunostaining for androgen receptor (AR) in SGC has been extensively described in the recent literature suggesting AR to be a reliable marker of sebaceous differentiation (Fig. 1F).42–46 A panel of antibodies comprising carcinoembryonic antigen (CEA), EMA, AR, Ber-EP4, ADP, CA15-3 and CA19-9 has been suggested to differentiate SGC from SCC and BCC (Table 1).39,40,43,46,47 Intra-epithelial spread, a common cause of misdiagnosis, is a characteristic feature of SGC seen in up to 39% patients.31 Intra-epithelial spread can have a Bowenoid, pagetoid or mixed pattern. Reports in the literature describe the Bowenoid and pagetoid patterns in up to 35% and 47% of SGC respectively.36,48
Molecular pathology Muir-Torre syndrome and mismatch repair genes Several studies have investigated the relationship between MTS and SGC.1,22,23,49 A subset of patients with clinical or phenotypic MTS have a defect in the DNA mismatch repair (MMR) genes and are at a risk for developing a future malignancy.49 An MMR defect results in the accumulation of replication errors or unstable microsatellite sequences.50 In MTS, germline mutation in one of the MMR-genes is complemented by a second somatic molecular alteration in a neoplasm. A sebaceous lesion is present either before or concurrent with the first visceral malignancy in 63% patients with MMR-deficient MTS.51 Diagnosis of SGC or a benign sebaceous neoplasm should prompt the clinician to carry
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Periocular sebaceous carcinoma a review
Figure 1. Clinicopathological features of sebaceous gland carcinoma. Nodular form of sebaceous carcinoma involving both fornices (Fig. 1A) and pagetoid variety presenting as diffuse thickening of the eyelid (Fig. 1B). Lobules of tumour cells with central comedo necrosis (Fig. 1C, haematoxylin and eosin 40). Tumour cells with vacuolated cytoplasm and vesicular nuclei having prominent nucleoli (Fig. 1D, haematoxylin and eosin 400). Tumour cells showing cytoplasmic staining for adipophilin (Fig. 1E, 400) and nuclear staining for androgen receptor (Fig. 1F, 400).
Table 1. Antibody panel that may be helpful in the differential diagnosis of sebaceous gland carcinoma, basal cell carcinoma and squamous cell carcinoma. Antibody
Sebaceous gland carcinoma
CEA46 ADP39,40,43,46–48 AR43,46 EMA46,47 Ber-EP446 CA19-946 CA15-346 BRST134 CAM5.234,47
± + + + ± + + +
Basal cell carcinoma
Squamous cell carcinoma
± + + ± ± ± ±
CEA, carcinoembryonic antigen; ADP, adipophilin; AR, androgen receptor; EMA, epithelial membrane antigen.
out a thorough history and physical examination to rule out a visceral malignancy. It should also prompt the laboratory to perform immunostaining for the commonly absent MMR proteins (MSH2, MLH1, PMS1 and PMS2). One-third of patients with clinical MTS demonstrate failure to express normal MMR proteins.49 Mutations in MSH2 and MLH1 are more frequent than those in MSH6, MSH3, MLH3, PMS2 and PMS1.1 Many cell signalling pathways have been shown to be dysregulated in SGC (Table 2 and Fig. 2).
sence of Wnt, glycogen synthase kinase 3 (GSK-3) constitutively phosphorylates the b-catenin protein. Overexpression of b-catenin has been demonstrated in SGC thus suggesting a possible dysregulation of the Wnt/b-catenin pathway.52–54 Further, it was also shown that reduced membranous expression of b-catenin correlated with invasion and metastasis, especially at the site of invasion.54
TP53 Wnt/b-catenin pathway The Wnt/b-Catenin pathway regulates stem cell pluripotency and cell fate decisions during development. In the ab-
p53 Mutations in SGC, as demonstrated by overexpression, suggest a possible role of UV radiation and subsequent signal alterations.25
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Table 2. Signalling pathways and proteins involved in periocular sebaceous gland carcinoma. Study group
Protein involved
Protein function
Signal pathway
Expression change
Prognostic significance
Jayaraj et al.51 Jayaraj et al.53
b-catenin
Co-ordination of cell–cell adhesion and gene transcription
Wnt/bcatenin
Correlated with tumour size >2 cm Invasion and metastasis
Shalin et al.25
p53
p53
McBride et al.54
p21WAF1
Apoptosis tumour suppressor inhibits angiogenesis DNA repair cell cycle arrest Cyclin-dependent kinase inhibitor.
Overexpression Reduced membranous expression Overexpression
p53/p21 p53 independent
Loss of compartmentalization Down regulation
Preserved in benign and normal sebaceous glands Lymph node metastasis
Sonic hedgehog NA
Overexpression
Metastatic disease Aggressiveness
Increased activity
Inhibits p53 expression and p53 activity.
Wnt/ bcatenin/TCF
Lower expression
Poor tumour differentiation and high proliferation rate Reduced disease-free survival, size >2 cm, lymphnode metastases, poor differentiation
Kiyosaki et al.55 Kim et al.52 Rokhlin et al.59, Nantermet et al.60 Li et al.76 Jayaraj et al.
Shh ABCG2 Androgen receptor E-cadherin
53
Cell-cycle regulation Prevents cell proliferation Maintenance of stem cells in adult tissues Regulation of gene expression
Suppressor of invasion and growth of epithelial cancers. Cell–cell adhesion
Promoter methylation
Correlates with tumour type and tumour location
Figure 2. Sonic hedgehog and Wnt/b-catenin signalling pathways in sebaceous gland carcinoma.78.
p21/WAF1
Androgen receptor
p21WAF1, a cyclin-dependent kinase inhibitor, regulates G1-S transition and mediates G1 cell cycle arrest. It can be transcriptionally upregulated by p53 but may be activated independently. Compartmentalization of p21WAF1 in the differentiated component of the gland, seen in normal sebaceous glands and benign sebaceous lesions, is lost in SGC.55 A recent study associated downregulation of p21 with lymph node metastasis in SGC.56
AR has been identified as a MYC target gene in mouse epidermis.57 p53 can inhibit AR gene expression by direct association with AR promoter58 and by inhibiting AR protein activity.59 On the other hand, strong AR activity can inhibit p53 expression60 and p53 activity.61 Thus, the expressions of AR and p53 are inversely related to each other in SGC.62
Sonic hedgehog pathway The sonic hedgehog (Shh) signalling pathway is also altered in SGC with Shh and ABCG2 proteins being overexpressed in patients with a metastatic disease.53 This study thus suggested that activation of Wnt and Shh signalling pathways is associated with higher cumulative incidences of lymph node and distant metastasis in SGC.53
E-cadherin E-cadherin promoter hypermethylation has been associated with poor clinical outcome.54,63
Treatment As discussed earlier, SGC may be a difficult clinical diagnosis to make due to its masquerading nature and thus, might delay diagnosis and appropriate management. Local
163
Periocular sebaceous carcinoma a review excision, orbital exenteration, radiotherapy and chemotherapy are various methods used to manage patients with SGC based on tumour stage at presentation. Wide excision with at least 4 mm margin and radical neck dissection is necessary in patients with locoregional metastases.64 However, 32% cases recur even with a margin clearance of 5– 6 mm.65 Frozen section and Mohs’ micrographic surgery are now used in specialized centres. Definitive margin excision and minimal loss of surrounding normal tissue are advantages of Mohs’ surgery. A recent study suggested the use of ‘slow’’ Mohs’ surgery which uses paraffin embedded sections to identify pagetoid spread that is otherwise difficult or impossible to identify on frozen sections.66 A recurrence rate of 11.1% has been reported after Mohs’ surgery.65 Exenteration is the treatment of choice for patients with extensive or multifocal tumour or extensive pagetoid spread.67 Radical neck dissection is indicated in patients of SGC with regional nodal metastases.7,64 The role of radiotherapy in SGC has been extensively studied and found to have variable results.36,68–70 Radiation of 50–66.6 Gy administered with a curative intent has been effective in achieving a prolonged survival and good tumour control in addition to facilitating functional and cosmetic preservation of the eyelid.68 Radiotherapy given post-operatively following orbital exenteration provides a better disease control as compared to treatment by exenteration only.69 Radiation is best avoided due to the various complications associated with it such as blepharoconjunctivitis, lid atrophy, dry eye, ectropion, epiphora, cataract and keratopathy.32 Cryotherapy may be used as a coadjuvant.32 The role of Mitomycin C, a non-cell cycle specific alkylating agent, is controversial.71 It has been used in patients with SGC and pagetoid spread to reduce the need for further invasive management.72 More recently, neoadjuvant chemotherapy using carboplatin and 5-fluorouracil has been shown to reduce morbidity in a patient with metastatic nodal disease.73 Recent studies on expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) suggest a potential role of hormonal therapy in patients with SGC.42,43,74
Prognosis Various clinicopathological factors are reported to indicate a poor prognosis in SGC and include lymphovascular and orbital invasion, involvement of both upper and lower eyelids, poor differentiation, multicentric origin, long duration of symptoms, large tumour size, an infiltrative pattern and pagetoid invasion of epithelia of the skin or conjunctiva.7 The 7th edition of AJCC classification for eyelid tumours has been shown to be prognostically useful in one study by Esmaeli et al.75 and is in the process of being validated in a larger cohort of patients. Tumours originating from the glands of Zeis have a better prognosis.76 Also, origin from the upper lids is associated with an adverse prognosis compared to origin from lower lids.76 Human telomerase RNA (hTR) has been shown to be a marker of malignant degree in SGC.77 The overall mortality rate in SGC is 5–10%.32 Locoregional metastases and recurrence are seen in 6–29% cases.18,21,62,76 14– 25% patients develop metastases, either in the form of lymphatic spread to the lymph nodes and/or haematogenous spread to the liver, lungs, brain, and bones.7,35,37,62,76
Conclusion Sebaceous gland carcinoma is a rare tumour of the eyelids that can mimic many inflammatory and neoplastic lesions. Accurate diagnosis by light microscopy and immunostaining followed by appropriate management with a multimodal approach using surgical advances and adjuvant treatment provide good tumour control to reduce the morbidity and mortality in these patients.
Conflict of interest The authors declared that there is no conflict of interest.
Acknowledgment We would like to acknowledge Mr. C. Jangaiah for his help with photography.
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