Introduction
Sebaceous gland carcinoma (SGC) is an uncommon, slow growing tumor. It is the most aggressive and lethal malignant tumor after cutaneous malignant melanoma. The tumor is predominantly seen in the periorbital region. Ocular SGC is relatively rare in the western population (4-5% of all eyelid malignancies) while in the Asian-Indian population, it is the most common eyelid malignancy accounting for 28-60%.1, 2, 3, 4, 5 SGC of the eyelid tends to occur in the 6th -7th decade of life and it predominates in females.6 Clinically, it masquerades as benign and inflammatory conditions like chalazion and chronic blepharitis or blepharoconjunctivitis which may lead to delay in diagnosis, metastasis and poor prognosis.7 It may involve fornicial and bulbar conjunctiva with diffuse thickening of the eyelid and caruncle area. A high rate of recurrence (9-36%) and nodal metastasis (17-28%) have been reported.8 The diagnosis and management of ocular SGC is often challenging because of its masquerading and aggressive nature. In this review we highlight the latest diagnostic techniques ,treatment & therapeutic options based on existing literature.
Origin and Clinical Patterns of Ocular SGC:
Sebaceous carcinoma develops from some specific glands and periorbital area including the gland of Zeis, meibomian glands, glands associated with hair follicles, caruncle, conjunctiva, and sebaceous glands with the eyebrow. The gland of Zies is a unilobular sebaceous gland located on the margin of the eyelid that produces an oily substance, during abnormal conditions, this gland gives rise to 10% of sebaceous carcinoma.9 The meibomian glands (tarsal glands) are exocrine glands located along the rim of the eyelids (Figure 1). The meibomian glands are abundantly present at the upper lid (63%) as compared to the lower lid (27%) hence SGC of the eyelid is more profound at the upper eyelid. The incidence of sebaceous carcinoma arising from caruncle is very low, reported to be around 5-10%.9
SGC is the most aggressive tumor of the eyelid and associated with a high mortality rate, thus its early & accurate diagnosis and appropriate treatment are important. Sebaceous carcinoma of the eyelid is the most notorious tumor which can masquerade as a benign condition (“masquerade syndrome”) like chalazion, chronic blepharitis / blepharo conjunctivitis & keratoconjunctivitis , etc., often resulting in difficulty or delay in diagnosis.10 This in turn can increase the chances of local recurrence, metastasis, and death. Ocular sebaceous carcinoma has a varied clinical presentation. The most common presentation is a painless, sessile / nodular yellowish tumor involving the eyelid margin (from the gland of Zeis) with loss of eyelid architecture and cilia (Figure 1, Figure 2). SGC may sometimes grow outward and become pedunculated with keratinization and also possess a cutaneous horn-like appearance.11, 12 Less commonly, SGC may ulcerate and have an appearance like squamous cell carcinoma / basal cell carcinoma. The second most common manifestation is a diffuse pseudo-inflammatory lesion that is marked as a diffuse unilateral thickening of the eyelid (Figure 4, Figure 5). This presentation is more likely to extend to the epithelium of nearby structures such as the cornea and conjunctiva. The lack of a typical nodular appearance causes the clinician to suspect an inflammatory condition. 13, 14 It is also suggested that SGC must be ruled out in unilateral blepharitis in an elderly patient that does not respond to standard treatment, and thus a biopsy is indicated. SGC may develop as a gradually progressive yellowish-red mass involving the medial canthus. (Figure 5, Figure 6).15 Often SGC may originate as a sebaceous cyst of the eyebrow. Caruncular SGC is uncommon. (Figure 7). Primary sebaceous carcinoma is rarely found in the lacrimal gland, 16, 17 rather seen as extensive invasion of eyelids, conjunctiva, cornea, and anterior orbital tissue. 15
Figure 1
Large nodular type of sebaceous gland carcinoma arising from meibomian glands of the right lower eyelid involving the medial aspect of the lid. Note irregular yellowish mass with loss of cilia and multiple telangiectatic vessels.
Figure 2
Nodular sebaceous carcinoma arising from the lateral aspect of the tarsus of the left lower eyelid.
Figure 3
Diffuse thickening of the lateral half of left upper eyelid with irregular loss of cilia due to sebaceous gland carcinoma in a 40 year male.
Figure 4
Nodular swelling with diffuse thickening of right lower eyelid due to sebaceous gland carcinoma in 70-year female.
Figure 5
Advanced ulcero-nodular sebaceous gland carcinoma of the medial half of left upper eyelid with extensive involvement of medial canthus and infero-medial bulbar conjunctiva.
Figure 6
Advanced ulcero-nodular sebaceous gland carcinoma of the medial half of left upper eyelid with extensive involvement of medial canthus and infero-medial bulbar conjunctiva .
Figure 7
Multilobulated pedunculated mass arising from left caruncle that was histopathologically proven as sebaceous gland carcinoma.
American joint committee on Cancer (AJCC) recommendation defined TNM (tumor node metastasis) to access the tumor staging. AJCC classification on the recent staging of SGC based on the eighth edition is given below in Table 1: 18
Table 1
JCC cancer staging manual giving details on each part of the TNM system for eyelid cancer (eighth edition)
Tumor spread
Diagnosis and management of ocular SGC is always challenging mainly due to its masquerading nature and tendency to spread beyond its primary site of origin. It can spread through local invasion, regional metastasis and distant metastasis. SGC tends to have a multicentric origin and pagetoid invasion. It has been reported that 18% of advanced sebaceous carcinomas are having multicentric origin. 16, 19 Eyelid sebaceous carcinoma can locally invade the adjacent orbital soft tissue, lacrimal system, and intracranial contents. Regional metastasis of ocular SC occurs via lymphatic spread in about 30% of cases. 20, 21 The SC of the upper eyelid tends to metastasize to preauricular lymph node (Figure 8) & parotid gland while lower eyelid carcinoma tends to metastasize to submandibular and cervical lymph nodes. 22, 23 The majority of the deaths associated with ocular SC is due to distant metastasis. The most common organs involved are the brain, liver, lung bone etc.
Pathology
Histopathology
A gross specimen of eyelid biopsy of SGC may have a yellow appearance due to the presence of lipids. Microscopic histopathologic examination is the gold standard in confirmation of SGC. Normal Sebaceous gland presents as a peripheral border of basaloid cells which after maturation became lipid-laden cells. In SGC there is a loss of the normal maturation architecture of the gland. SGC is characterized by pleomorphic cells with prominent vacuolated or clear cytoplasm, vesicular nuclei with prominent nucleoli, and numerous mitosis(Figure 9, Figure 10). The intracytoplasmic lipid vacuoles can be demonstrated by oil red O or Sudan IV Stains. The four histopathological patterns of SGC are (i) Lobular (ii) papillary (iii) Comedocarcinama and (iv) mixed type. 16, 22, 24 The lobular pattern is most frequent and characterized by peripheral normal- looking, sebaceous gland architecture, and control well differentiated lipid- producing cells (Figure 11). Rao et al reported a comedocarcinoma variant characterized by large central necrosis surrounded by peripheral viable cells. 25 However papillary pattern mostly present as small conjunctival tumors having papillary projections with sebaceous differentiation. Histopathologically SGC can be classified as well-differentiated, moderately differentiated and poorly or undifferentiated type.
Rao et al also described infiltrative features of SGC categories as minimal, moderate and highly infiltrative patterns. Minimally infiltrative type tumors are predominantly composed of lobules with minimal stromal invasion while highly infiltrative type have diffuse infiltrating cords of tumor cells in the stroma. Higher degrees of stromal infiltration is associated with a high mortality rate.
Cavanagh et al described the multicentric origin of SGC and which is also an important cause of misdiagnosis 26 Another causes of misdiagnosis is its ability to exhibit intraepithelial spread reported in about 39% patients, which may be Bowenoid, pagetoid and mixed pattern. 23, 27, 28
Imprint cytology of tissue and fine needle aspiration cytology of lymph node may suggests earliest pathological diagnosis of SGC (Figure 12).
Figure 9
Lobular growth pattern of sebaceous gland carcinoma of eyelid showing cytoplasmic vacuoles and mitotic activity (A. Hematoxylin-eosin X 4 & B. Hematoxylin-eosin X 100).
Figure 10
Localized sebaceous gland carcinoma near the eyelid margin arising from the gland of Zeis (Hematoxylin-eosin X 4 & 10X)
Immunohistochemistry
Missed histopathological diagnosis on light microscopy is very common with in the case of poorly differentiated SGC. Insufficient biopsy specimens also lead to misdiagnosis. In such conditions, immunohistochemistry helps in diagnosis. Sinard et al used immunohistochemistry to differentiate SGC from other eyelid cancer. 29 SGC is immunoreactive to epithelial membrane antigen (EMA), Cytokeratin Cant-C-K-S & ant-CK-15). Ber-EP4 and Adipophilin (ADP) are more sensitive marker of lipid droplets in SGC than oil red O.30 Basal cell carcinoma never express EMA. An EMA –positive, Ber-EP4-positive immune-staining supports diagnosis of SGC while EMA-positive, Ber-EP4-negative supports squamous cell carcinoma and EMA-negative, Ber-EP4-positive result supports basal cell carcinoma. (Figure 13, Figure 14, Figure 15). SGC expresses high p53 and Kil17 (proliferation markers) and decreased expression of DCL-2 and p21 in serum (anti-apoptotic markers).31 Recently it has been demonstrated that SGC is highly positive for androgen receptor (AR) Immunostaining AR may be a reliable marker of sebaceous differentiation(Figure :14). 32, 33, 34 Monoclonal antibodies like BRST -1 and CAM52 are positive in most of the SGC cases. 29, 35
Figure 13
Tumour cell showing strong immune reactivity to Anti-epithelial membrane antigen (EMA) in sebaceous gland carcinoma of eyelid. (EMA 10X & 40X)
Sentinel Lymph Node Biopsy
Sentinel lymph node biopsy (SLNB) can be done to identify occult or sub clinical, microscopic nodal spread of SGC. SLNB or strict node surveillance has been recommended for large tumors (> 10mm size), T2b or worse tumors, suspected lymphadenopathy, tumors having poorly differentiated histology and tumors having perineural invasion. 36, 37, 38 In SLNB technetium- labeled sulfur colloid is used as a tracer molecule that reaches local lymph nodes through the lymphatic system. The site of tracer collection can be detected by a handheld gamma probe. The single or multiple nodes containing tracer are then excised for histopathological examination.
Conjunctival Map Biopsy
Ocular SGC tends to show microscopic pagetoid spread leading to diffuse eyelid and conjunctival involvement. In such cases, it is difficult to visualize tumors grossly. Conjunctival map biopsies (CMB) are recommended to determine the extent of the tumor and to decide the definitive treatment for SGC having diffuse conjunctival involvement. 39, 40, 41 Shield C.L. advised pretreatment and post-treatment conjunctival map biopsy while treating SGC by topical mitomycin C. 42 In CMB 10-14 biopsies should be taken from bulbar conjunctiva (superonasal, inferonasal, superotemporal and inferotemporal quadrants), on the tarsal conjunctiva (medial, lateral and mid portion) of both eyelids and from plica semilunaris. 43 Careful labeling and numbering of each biopsy should be done before submitting the specimen for histopathological examination.
Molecular basis of sebaceous gland Carcinoma:
The molecular basis of tumorigenesis of sebaceous gland carcinoma (SGC) is very little known. Muir-Torre Syndrome (MTS) often associated with SGC and other visceral malignancies, occur due to genetic alterations. MTS have a germline mutation in the DNA mismatch repair (MMR) gene and commonly absent MMR proteins are MLH1, PMS2, MSH6, and MSH2. 44, 45 The cell signaling pathways that have been dysregulated in SGC are many like TP53, Went / β-catenin, p21/WAFT1 and Sonic hedgehog (Shh) pathway etc.46 Kim et al reported a higher incidence of lymph node and distant metastasis in SGC associated with the activation of Wint and Shh singling pathways. 47 Bladen JC also observed Hedgehog (Hh) upregulation specially Gli2 more in SGC than BCC.48 Kumar A et al found dysregulation of two major pathways in meibomian gland carcinoma of the eyelid: MAPK (mitogen-activated protein kinase) and JAK/STAT(Janus kinase / signal transducers and activators of transcription) by microarray analysis.49 Tumor suppressor gene p53 helps in maintaining cellular integrity and differentiation. The presence of mutational inactivation of the p53 genes may lead to the progression of SGC and has been associated with a poor prognosis.29, 50 Bladen JC et al have identified aberrant miRNAs and their gene targets in sebaceous gland carcinoma. He demonstrated overexpression of has-miR-205 and down regulation of has-miR-199a in invasive pagetoid variants of SGC. 51
Management
Wide local excision (WLE)
Full-thickness excision (with posterior lamellar) of the eyelid tumor with intraoperative margin control by frozen section or chemosurgery is the gold standard treatment for localized / circumscribed SGC. Wide local with ≥ 5mm normal appearing tissue is recommended where a frozen section biopsy facility is not available. 1, 2, 52, 53 For the SGC with suspected pagetoid spread, scheduled map biopsies at the time of WLE should be done. Dogru M reported 36% recurrence when 1-3 mm margins were taken and no recurrence if margins were ≥ 5mm. 54 Local recurrence and metastasis after wide excision have been reported in SGC having the involvement of both eyelids, diffuse growth pattern, multicentric origin, large tumor (T3a) and non-tubular histopathological patterns.1, 3, 7, 52, 55, 56
To get good functional and aesthetic outcomes appropriate eyelid reconstruction is to be performed after WLE. Reconstructive techniques may be two-staged e.g. Cutler Beard or single-staged procedures like Tanzel’s rotational flap or Mastarde’s cheek rotational flap etc.
Mohs micrographic surgery (MMS
Mohs micrographic surgery consists of removal and extemporaneous analysis of every skin stratum until the identification of disease-free margins With the advent of MMS, ophthalmologists can intraoperatively assess the surgical margins while ensuring maximal preservation of healthy tissue. 53 MMS is the appropriate choice for SGC in all locations, except the inner and outer canthus and cases with orbital involvement. A series of retrospective studies from 2001 to 2017 summarizes that MMS is associated with lower local recurrence rates (6.4%–11%) than wide local excision (11%–36%).3, 11, 55, 57 Overall, MMS has very good outcomes for tumor control and should be considered for all patients with ocular SGC.58 The rarity of this tumor precludes large-scale comparative studies, but the existing studies may have provided some clues. Circumstances might be different in the UK, where MMS is not frequently considered in ophthalmic/oculoplastic services.
Topical Chemotherapy
Topical and systemic chemotherapy can be useful in SGC for the reduction of tumor size and prevention of micrometastasis. Tumuluri et al recommended topical mitomycin-C 0.02% four times a day for two weeks followed by two weeks interval therapy as adjuvant therapy after surgical excision of SGC with pagetoid spread.59 In a pilot study conducted by Shield et al. mitomycin 0.04 % four times a day for one week followed by 1week interval found complete clearance of intraepithelial pagetoid invasion. 60 Larger studies with longer follow-up are necessary to establish the efficacy of topical mitomycin –C.
Neoadjuvant systemic chemotherapy
Recently systemic Chemotherapy has been recommended for patients with metastatic or locally advanced periocular SGC. Combination chemotherapy can be used in different ways in eyelid carcinomas. Neoadjuvant chemotherapy is given before to surgery to reduce the tumor bulk hence allowing less extensive surgery, eradicates micro-metastasis and improve disease free survival. Adjuvant chemotherapy given for localized tumour after primary surgery to "mop-up" the micro surgical residual tumour thus reducing loco-regional relapse. Palliative systemic chemotherapy is given in recurrent cases or advanced SGC with systemic metastasis (Figure 16). The chemotherapeutic regimen used for eyelid and periocular SGC are:
cis-platin 100 mg/m² on day 1 and
5 FU 1000 mg/m² on day 1-5. Repeated every 21 days cycle. Kaliki et al used cisplatin and 5 FU combination neoadjuvant chemotherapy in 10 cases of advanced stage SGC of eyelid and observed 74% reduction in tumor basal diameter.61
Radiotherapy
Radiation therapy, especially brachytherapy, has been proven as an efficient treatment of ocular SGC. It facilitates functional and cosmetic preservation of the eyelid with good local control and acceptable levels of toxicity. However, the tumor is generally regarded as resistant to radiation therapy, and higher recurrence rates have been reported.17, 18, 62, 63 Radiation is only employed as adjuvant therapy for locally advanced (stage T3a or higher) or high-risk (pagetoid spread) periorbital SGC,58, 64, 65 perineural invasion, nodal metastasis, or palliative treatment. 24, 65 Till date, numerous case series and case reports have demonstrated a good response to radiation therapy in patients who were either poor surgical candidates or who refused surgical treatment. In a study of 13 patients with T3 SGC, the local recurrence rate was lower in the patients who received adjuvant radiotherapy (28%) than among those who did not (83.3%).22 Complications from radiotherapy can be quite extensive and it includes chronic dry eye, conjunctival keratinization, blepharitis, trichiasis, exposure keratopathy, cataract, optic neuropathy, retinopathy, and even permanent loss of visual acuity.58, 65 The risk should be minimized with appropriate shielding and balancing against the obvious morbidity of orbital exenteration.
Cryotherapy
Cryotherapy has a certain effect on ocular SGC with pagetoid spread to the conjunctiva or cornea. 23 For elderly patients where conservative approaches are preferred, these seem to be the feasible choices. In a retrospective case series identifying predictors of ocular surface squamous neoplasm recurrence after surgical resection, the addition of cryotherapy to the margins and the scleral bed have shown to cause a dramatic reduction in recurrence rates,66 which may be significant in ocular SGC. The side effects of cryotherapy include permanent loss of visual acuity, corneal ulceration, and chronic dry eye. The use of this method is somewhat controversial and is largely surgeon dependent at this point.58
Targeted therapy
In recent years, targeted therapy is having an emerging role in the treatment of refractory tumors such as advanced melanoma 44 It is very efficacious in preventing disease progression in patients with metastatic or locally advanced BCC or SCC as in these cases targeted therapy against the Hedgehog pathway or epidermal growth factor receptor is used.45, 67 In a series of current studies, overexpression of HER2 is observed in SGC, 68, 69 which suggests the possibility of targeted therapy with monoclonal antibodies trastuzumab and cetuximab.67 Frequent PI3K signaling pathway activation provides a strong rationale for the application of target rapamycin inhibitors in targeted therapy of ocular SGC. 70, 71
Orbital Exenteration
This is a psychologically and anatomically disfiguring procedure. It is usually reserved for the treatment of extensive SGC or those tumours that have invaded the orbital soft tissue and are relentlessly progressive despite other treatments (Figure 17). Recently, as an alternative to exenteration, surgeons employed several variations of complete posterior lamellar removal of the eyelids followed by reconstruction using tarsal graft (usually from buccal mucosa) or amniotic membrane graft.72 This procedure has been done primarily in older patients who had minimal residual disease and good vision in the affected eye. The above technique was employed with the tumor involving only the conjunctiva and eyelid tissue and was not used if there was any clinical or radiologic involvement of deeper orbital soft tissue.72 However, a few patients still required exenteration because their tumors were extensive or had invaded the orbital soft tissue.
Prognosis
The prognosis of periocular SGC depends on duration, extent, type of tumor and its histological characteristics. Well differentiated tumors, localized tumors, originating from glands of Zies have better prognosis. Reported poor prognostic indicators of periocular SGC are delayed diagnosis (symptoms > 6 months duration), tumour larger than 10 mm, involvement of both eyelids, presence of metastasis. 22, 73 In addition, other histological biomarkers of poor prognosis included poor differentiation, multicentric origin, pagetoid spread, highly infiltrative growth patterns, orbital extension and vascular, lymphatic and perineural invasion. 74 The hyperexpression of tumor suppresser gene p53 is one of the important molecular genetic factor associated with recurrence, metastasis and poor prognosis. 50
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