Recent updates on the management of ocular sebaceous gland carcinoma

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]).

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]

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.

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.