Squamous Cell Carcinoma of the Eyelid and Ocular Surface

Abstract

Squamous cell carcinoma that arises from the eye and its adnexa has gained more attention as the incidence rises globally. The malignancy has a broad spectrum of clinical manifestations and, if not properly treated, may affect both vision and life. In this chapter, we will go over the squamous cell carcinoma that occurs on the ocular surface and its adnexa, including the eyelid and lacrimal apparatus. We would like to introduce the epidemiology, pathophysiology, diagnosis methods, recurrence and prognosis of this squamous neoplasm. Furthermore, we review most of the current treatment strategies for squamous cell carcinoma of the eyelid and ocular surface ranging from medical to surgical measures.

1. Introduction

Squamous cell carcinoma (SCC) of the eye is an invasive epithelial malignancy and involves the periocular skin, ocular surface and lacrimal apparatus [1]. Over the past four decades, there has been a progressive rise in the global incidence of SCC on account of increased exposure to carcinogens such as ultraviolet (UV) radiation, cigarette smoking, immunosuppressive drugs or human papillomavirus (HPV) infection [1, 2, 3]. The tumor comprises a large and diverse spectrum of conditions and threatens both vision and life. Diagnosis and management of patients with such malignant ophthalmic tumors present additional challenges.

2. Epidemiology

Eyelid SCC is the second most common periocular skin malignancy, far exceeded by basal cell carcinoma (BCC) which is 10–13 times more common [4, 5]. The reported incidence of SCC of the eyelid is 0.09 to 2.42 cases per 100,000 persons per year, representing 3.4–12.6% of all types of malignant eyelid neoplasms [6]. A longitudinal study in England has shown that the age-standardized incidence of SCC has increased approximately 2% per year between 2000 and 2014 [3]. It mainly presents in the seventh decade of life with a male predominance (1.83:1) [7].

Ocular surface SCC is the most common primary ocular neoplasm with reported incidence from 0.3 to 1.9 per 100,000 persons per year, accounting 4–29% of all oculo-orbital tumors [8, 9, 10].

Primary lacrimal sac/duct malignancies are very rare with SCC being the most frequently reported neoplasm [11]. In one study, only 38 out of 3865 (0.98%) specimens of lacrimal sac biopsy showed malignant [12].

3. Demographics and risk factors

SCC is prevalent in the elderly and more frequent among men than women [1, 3]. Typically, SCC affects individuals with a fair complexion and a history of chronic sunlight exposure, which is reflected in an increased risk in white populations [3]. Advanced age and cumulative UV radiation are the major risk factors for SCC formation [6, 13, 14]. There is a doubling in the incidence of SCC with each 10-degree reduction in latitude and every decade increase over the age of sixty [3, 15]. Ionizing radiation, exposure to chemicals (arsenic, polycyclic hydrocarbons and psoralen), high fat diet, cigarette smoking, and infection of HPV also contribute to the formation of SCC [5]. Higher rate of SCC development has been observed in those with immunosuppression secondary to organ transplantation and acquired immunodeficiency syndrome (AIDS) [16, 17]. Studies have shown that the risk of developing SCC varies with the types of transplants and the time intervals following transplantation [17, 18, 19]. Other intrinsic factors predisposing to SCC include preexisting skin neoplasms, chronic cutaneous inflammatory lesions (such as nonhealing wounds, ulcers, burns, scars and sinus tracts), and genetic skin disorders (such as xeroderma pigmentosum, epidermodysplasia verruciformis and albinism) [1, 7, 20].

4. Pathogenesis and pathology

SCC may arise de novo or from preexisting actinic keratosis or carcinoma in situ (Bowen disease) [1, 7, 21]. Conjunctival intraepithelial neoplasia (CIN) refers to varying degrees of conjunctival epithelial dysplasia. CIN that involves the entire epithelium is referred to as carcinoma in situ. In some cases of squamous cell papilloma, they have been found to grow quite large, covering the surface of the cornea and simulating a squamous cell carcinoma. Most cases of squamous cell papilloma are benign tumor, but its potential for malignant transformation has yet to be studied (Figures 1 and 2). Development of such malignancy undergoes a multi-step process of carcinogenesis involving mutations of genes (such as TP53, CDKN2A, NOTCH1 and NOTCH2, EGFR and TERT) and molecular pathways (RAS–RAF–MEK–ERK and PI3K-AKT–mTOR), epigenetic modifications, viral oncogenesis, and microenvironmental changes [18, 22]. Inactivation of the p53 tumor suppressor gene results in altered apoptosis and clonal proliferation of keratinocytes [1, 18]. Moreover, upregulation of matrix metalloproteinases (MMPs) and other factors account for the invasive activity associated with tumor progression [22].

Figure 1.

Periocular squamous cell papilloma with focal mild dysplasia.

Figure 2.

Diffused type of conjunctival squamous cell carcinoma (conjunctival intraepithelial neoplasm). a, gross view. b, high magnification (X2 original).

Histologically, SCC is characterized by full-thickness atypia of squamous cells with increased mitotic activity, pleomorphism, and prominent nuclei. The tumor is classified as carcinoma in situ when it is confined to the basement membrane, and as invasive SCC when it extends deep to the dermis or stroma. In a well-differentiated tumor, the cells form nests and strands and exhibit polygonal with abundant eosinophilic cytoplasm and hyperchromatic nuclei. Dyskeratosis, keratin pearls, intercellular bridges are more prominent. Poorly differentiated SCC presents high pleomorphism with anaplastic cells, little keratinization and loss of intercellular bridges. Other variants include spindle and adenoid SCC [1]. Immunohistochemical studies may be useful in diagnosis as cells are positive for epithelial membrane antigen (EMA), cytokeratin, prekeratin, AE1/AE3, MNF16, p63 [5, 23, 24]. Stains for CAM5.2, Ber-EP4, adipophilin, lysozyme, S100 protein and desmin are negative [5, 24, 25].

5. Clinical presentation

5.1 Cutaneous SCC of the eyelid and periocular skin

The appearance of cutaneous SCC (cSCC) has a broad spectrum and may be indistinguishable from various benign and malignant lesions. Collision tumor, a neoplastic lesion comprised of two or more distinct cell populations that maintain distinct borders, which is rare but well documented in the eyelid (Figure 3) [23]. Studies had reported that the accuracy of preoperative clinical diagnosis of cSCC is 51–62.7% [6, 7, 26]. The tumor has a predilection for the lower eyelid and medial can thus, similar to basal cell carcinomas (BCCs). However, cSCC is more likely to involve the upper eyelid than is BCC (Figure 4). SCC of the eyelids grows more rapidly and aggressively than does BCC. The tumor typically appears as a slightly raised nodule or plaque with irregular margins and overlying scaling, crusting, induration, keratinization, or ulceration. Some may feature cutaneous horn, papillomatous lesion, and large fungating growth. The periocular architecture may be distorted and madarotic. The surface vascularization or telangiectasia is usually absent.

Figure 3.

Collision tumor of squamous cell carcinoma and sebaceous cell carcinoma coincident in a single mass. a, preoperative photograph. b, postoperative status with reconstruction.

Figure 4.

Cutaneous SCC of the eyelid. a, preoperative photograph. b, postoperative status with reconstruction.

Eyelid SCC has potential for local extension with tissue destruction and perineural infiltration which may facilitate intraorbital and intracranial spread with associated cranial neuropathies. This occurs in 4–8% of cases [7, 27]. Unlike BCC, SCC tends to metastasize to regional lymph nodes and distant sites through lymphatic and haematogenous routes. The rate of metastasis ranges from 1–24% depending on tumor size, length of follow up and underlying risk factors [28, 29].

5.2 SCC of conjunctiva and cornea

Conjunctival or corneal SCC belongs to the disease spectrum of ocular surface squamous neoplasia (OSSN). It appears as a fleshy, elevated plaque-like lesion usually at the limbus and bulbar conjunctiva within the interpalpebral fissure zone [30]. There are three common morphologic patterns: leukoplakic, papillomatous and gelatinous [31]. Superficial feeder vasculature and pigmentation of the lesion may be prominent, but some tumors may appear avascular. The tumor may cause ocular irritation, foreign body sensation, pruritus, conjunctival congestion, decreased vision and even diplopia.

Although, the metastatic disease is rare, local invasion through corneoscleral lamella into the anterior chamber occurs in about 40% of cases [32, 33]. Mucoepidermoid carcinoma and spindle cell carcinoma (Figure 5) are other rare variants of conjunctival SCC which tend to be more aggressive and more likely to invade the globe or orbit [30, 34]. The incidence of intraocular spread by conjunctival SCC is reported up to 13% and orbital invasion about 12–16% [35, 36, 37].

Figure 5.

Advanced spindle squamous cell carcinoma. A, primary site. B, after one year without treatment. C, submandibular lymph node metastasis.

5.3 SCC of lacrimal drainage system

The clinical manifestations of lacrimal sac tumors are featureless such as chronic epiphora and recurrent dacryocystitis. However, a firm, nonreducible, nontender mass with insidious growth above the medial canthal tendon should prompt the suspicion of possible malignancy [38, 39]. The tumor may invade the skin and produce ulceration and spontaneous bleeding.

Metastasis to regional lymph nodes may also occur. When regional or distant metastases are present in all types of ophthalmic SCC, the prognosis is poor, and the mortality is high [1].

6. Tumor staging

To achieve minimizing the rate of recurrence, a complete pre-op assessment must be made, including a highly precise clinical approach to the diagnostic: whether the lesion is circumscribed or diffuse, bilateral or unilateral, suspected to be pre-cancerous or malign. The extension of the tumor must also be assessed, determining the existence of intra-ocular and/or intra-orbital invasion, carrying out palpation of regional lymphatics and, when considered appropriate, a systemic extension study for detecting metastasis.

Clinical staging is based on the assessment of cancer by inspection; slit-lamp examination, palpation of regional nodes, and clinical photography are used, as well as preoperative ultrasound biomicroscopy (UBM) and (Optical Coherence Tomograph) OCT when the intraocular invasion is suspected. Radiological examination (CT, magnetic resonance imaging [MRI], and PET/CT) can be used to examine regional node status, paranasal sinuses, orbit, brain, and chest. Ongoing studies are designed to clarify the role of sentinel node biopsy in the accurate staging of invasive squamous cell carcinoma [40].

TNM staging also includes clinical classification and pathological classification as outlined by the American Joint Committee on Cancer (AJCC), this staging applies to squamous carcinomas with the natural history of lymphatic spread to regional nodes, the possibility of hematogenous metastases, as well as subsequent locoregional disease and metastatic disease. Tables 1 and 2 are the staging of eyelid SCC and ocular surface SCC, respectively.

Category		Definition
Primary tumor (T)
TX		Primary tumor cannot be assessed
T0		No evidence of primary tumor
Tis		Carcinoma in situ
T1		Tumor ≤10 mm in greatest dimension
T1a		Tumor does not invade the tarsal plate or eyelid margin
T1b		Tumor invades the tarsal plate or eyelid margin
T1c		Tumor involves full thickness of the eyelid
T2		Tumor >10 mm but ≤20 mm in greatest dimension
T2a		Tumor does not invade the tarsal plate or eyelid margin
T2b		Tumor invades the tarsal plate or eyelid margin
T2c		Tumor involves full thickness of the eyelid
T3		Tumor >20 mm but ≤30 mm in greatest dimension
T3a		Tumor does not invade the tarsal plate or eyelid margin
T3b		Tumor invades the tarsal plate or eyelid margin
T3c		Tumor involves full thickness of the eyelid
T4		Any eyelid tumor that invades adjacent ocular, orbital, or facial structures
T4a		Tumor invades ocular or intraorbital structures
T4b		Tumor invades (or erodes through) the bony walls of the orbit or extends to the paranasal sinuses or invades the lacrimal sac / nasolacrimal duct or brain
Regional lymph nodes (N)
NX		Regional lymph nodes cannot be assessed
N0		No evidence of lymph node involvement
N1		Metastasis in a single ipsilateral regional lymph node, ≤ 3 cm in greatest dimension
N1a		Metastasis in a single ipsilateral regional lymph node based on clinical evaluation or imaging findings
N1b		Metastasis in a single ipsilateral regional lymph node based on lymph node biopsy
N2		Metastasis in a single ipsilateral regional lymph node, > 3 cm in greatest dimension, or in bilateral or contralateral lymph nodes
N2a		Metastasis documented based on clinical evaluation or imaging findings
N2b		Metastasis documented based on microscopic findings on lymph node biopsy
Distant metastasis (M)
M0		No distant metastasis
M1		Distant metastasis
AJCC, American Joint Committee on Cancer.

Table 1.

Staging for eyelid carcinoma according to AJCC 8th edition.

Category		Definition
Primary tumor (T)
TX		Primary tumor cannot be assessed
T0		No evidence of primary tumor
Tis		Carcinoma in situ
T1		Tumor ≤5 mm. Or less in greatest dimension
T2		Tumor >5 mm. In greatest dimension, without invasion of adjacent structures
T3		Tumor invades adjacent structures (excluding the orbit)
T4		Tumor invades the orbit with or without further extension
T4a		Tumor invades the orbital soft tissues, without bone invasion
T4b		Tumor invades bone
T4c		Tumor invades adjacent paranasal sinuses
T4d		Tumor invades brain
Regional lymph nodes (N)
NX		Regional lymph nodes cannot be assessed
N0		No regional lymph node metastasis
N1		Regional lymph node metastasis
Distant metastasis (M)
M0		No distant metastasis
M1		Distant metastasis
AJCC, American Joint Committee on Cancer.

Table 2.

Staging for conjunctival carcinoma according to AJCC 7th edition.

7. Management

7.1 Surgical treatment

7.1.1 Conjunctival SCC treatment

The management of CIN or SCC in the ocular surface varies with the extent or recurrence of the lesion. To completely destroy or extirpate the tumor through surgery and adjuvating treatments (cryotherapy, topical chemotherapy, radiotherapy) remains the widely accepted treatment strategy for primary lesion after precise histopathological confirmation.

Most of the primary conjunctival squamous cell carcinoma arises in the interpalpebral area near the limbus and the surgical technique for limbal tumors is different than that for forniceal tumors [41, 42, 43, 44].

In general, for tumors that are circumscribed, limbar or conjunctival bulbar, complete extirpation (excisional biopsy) with the smallest possible amount of manipulation and a resection margin of 3–5 mm could be sufficient treatment. Limbal neoplasms possibly can invade through the corneal epithelium and sclera into the anterior chamber and through the soft tissues into the orbit. Thus, it is often necessary to remove a thin lamella of the cornea or sclera to achieve tumor-free margins and to decrease the chance for tumor recurrence. The management of limbal lesions could involve alcohol epitheliectomy or corneal epitheliectomy with a beaver blade for the corneal component and partial lamellar scleroconjunctivectomy with wide margins for the conjunctival component followed by freeze–thaw cryotherapy to the remaining adjacent bulbar conjunctiva. Bowman’s layer should be respected because its removal would facilitate the intraocular penetration of any recurrence [43, 44].

In all cases, the full conjunctival component along with the underlying Tenon’s fascia should be excised totally. Those tumors in the forniceal region can be managed by wide local resection and cryotherapy. In diffuse and extended lesions where complete resection is difficult, the largest possible extirpation must be made which must also allow for a precise histopathological diagnostic.

Because cells from these friable tumors can seed into adjacent tissues, a gentle technique without touching the tumor (no-touch technique) is advised. Additionally, the operative field should be left dry to minimize the seeding of cells. In some cases, microscopically controlled excision (Mohs surgery) is performed at the time of surgery to ensure tumor-free margins [45].

7.1.1.1 Incisional biopsy

An extensive suspicious tumor that is symptomatic or suspected to be malignant can be approached by incisional wedge biopsy or punch biopsy. In general, it should be concerned if tumors occupy 4 clock hours or less on the bulbar conjunctiva, excisional biopsy is preferable to incisional biopsy. Incisional biopsy is also appropriate for lesions that are ideally treated with radiotherapy, chemotherapy, or other topical medications. These include metastatic tumors, and some cases of squamous cell carcinoma that are unsuitable for surgical management [44].

7.1.1.2 Excisional biopsy

Primary excisional biopsy is appropriate for relatively smaller tumors (≦4 clock hours limbal tumor or≦15 mm basal dimension) that are symptomatic or suspected to be malignant. In these situations, excisional biopsy is preferred over incisional biopsy to avoid inadvertent tumor seeding [44].

7.1.2 Eyelid SCC treatment

Surgery remains the main modality for the management of periocular cancer. Unlike other treatment modalities, it allows histological confirmation of the diagnosis. Furthermore, examination of the excision margin assesses the adequacy of tumor clearance. To minimize the risk of incomplete excision, the larger safe margin of excision with at least 4–6 mm for SCC was recommended [46, 47].

Margin control can be achieved using frozen sections, but there are inherent inaccuracies in frozen-section techniques, and it is not unusual for frozen sections to be clear with involved margins on paraffin-fixed specimens. Confirmation of tumor clearance is essential before undertaking periocular reconstruction. Routine paraffin fixed specimens take several days to be processed, but the specimens can be processed within 24–48 h by prior arrangement with the local pathologist, allowing delayed reconstruction.

As it allows three-dimensional assessment of the tumor margins, Mos micrographic surgery (MMS) has excellent cure rates for non-melanoma skin cancers and is widely regarded as the gold standard for tumor excision [27].

Supplemental cryotherapy, topical chemotherapy and irradiation should be applied if the tumor margin is unclear or if there is residual involvement of bulbar conjunctiva.

7.1.3 Reconstruction after surgical excision

Eyelid or periocular malignancies require different considerations from other cutaneous malignancies of the same pathohistological cell type. It needs unique anatomic considerations to preserve the functional impact of ocular protection and vision after wide excision and reconstruction.

For a small conjunctival lesion, double layers closure with Tenon’s fascia first and then conjunctiva over wound by primary suture may be enough. In cases where excessive conjunctiva is sacrificed, autologous conjunctival or buccal mucosa grafts, or amniotic membrane graft may be employed for reconstruction. For eyelid lesion, the primary suture is suitable for a small lesion, but an autologous graft or rotational flap may be needed for the extensive lesion.

7.2 Topical adjuvating treatments

Mitomycin C (MMC) is an antineoplastic and antibiotic agent. 5-fluorouracil (5FU) is an anticancer drug that interrupts DNA replication and cell growth. These agents are often used by an ophthalmologist in glaucoma and pterygium surgery to prevent inappropriate scar formation, especially MMC.

In cases with positive margins related to inadequate surgical excision, extensive tumors, higher recurrence, or more local invasion especially those with the extensive corneal component, treatment with topical MMC, 5FU, or interferon α (IFNα) and interferon 2b (IFN2b) as an adjuvant after surgical removal have been employed [48, 49, 50, 51].

Topical chemotherapy enables to treat the entire ocular surface and is not dependent upon surgical margins. It may be preferred as primary treatment over the surgery by some patients who are inadequate to surgery or refuse surgery.

Subconjunctival and perilesional injections to treat OSSN have also been proposed, however, the evidence is limited and requires more studies [52].

In general, the adverse effects are minimal and tolerance in 5FU and IFN. The ocular surface toxicity and other serious adverse effects are much greater in MMC than in 5FU or IFN-b. It is the main drawback of MMC. To relieve the side effects, preservative-free artificial tears, or short-term use of the topical steroid to minimize ocular surface irritation could be used as needed. Applying petroleum jelly to the lower eyelid skin is recommended to reduce skin irritation and toxicity. Additionally, it may be instructed to occlude the punctum briefly after applying the medication to minimize the risk of punctal stenosis [53].

7.2.1 Mitomycin C (MMC)

Using topical 0.02–0.04% MMC eyedrops are very effective which show high-resolution rates ranging from 76–100% and low recurrence rates ranging from 0–20% [54, 55, 56, 57, 58]. Alvarez had recommended MMC in 4 week cycles of 0.04% four times a day for 1 week, followed by 3 weeks of no treatment, with cycles repeated until resolution [53]. Others may use MMC with shorter breaks, such as topically 4 times daily for a 1-week period followed by a 1-week hiatus to allow the ocular surface to recover, and this cycle is repeated once again.

Its propensity for causing ocular surface toxicity and other serious adverse effects is much greater than 5FU or IFN-b. These include allergy, itching, pain, conjunctival hyperaemia, punctate staining of the cornea, punctal stenosis corneal-scleral melting, disturbance of tear film stability, goblet cell loss, squamous metaplasia and limbal stem cells deficiency [53, 59, 60, 61].

Chemoreduction with topical MMC followed by interferon alfa 2b (1 million IU/mL) 4 times daily, or topical Cyclosporine A (0,05%) combined with a topical low dose of MMC (0,01%) had also been prescribed as the effective treatments in extensive CIN cases where surgical resection with safety margins is infeasible and corneal extension resection and the repetitive cycles of MMC adjunctive could cause a depletion of limbal stem cells and other commented side effects on the ocular surface [62].

7.2.2 5-fluorouracil (5FU)

1% of 5FU used as topical eye-drops shows very effective in treating OSSN with high-resolution rates of 82–100% and low recurrence rates of 10–14% [58, 62, 63, 64, 65].

It is recommended four times a day for 1 week, and then stop the drug for 3 weeks. This protocol could continue until resolution [62, 63, 64].

Side effects of 5FU are generally mild and well-tolerated. These may include pain, tearing, redness, eyelid edema and keratopathy [63]. It is reported that short-term complications include lid toxicity in 52% of patients, keratopathy in 11% and epiphora in 5% [66].

7.2.3 Interferon (IFN α-2b)

IFN can be used as topical eye-drops, subconjunctival perilesional injections, or both [67, 68]. Both forms have shown great success in treating OSSN.

In cases of CIN, the combination of subconjunctival and topical treatment of IFN α-2b showed the average time to complete tumor response at mean of 5.5 weeks (range 2–12). For INF α-2b topical treatment, the average time to complete tumor response is 11 weeks (range 2–59). Injection treatment had the benefit of rapid tumor resolution [67].

Topical IFN α-2b, 1 million IU/ ml, four times daily, until resolution following with at least 1–3 months have been recommended. Weekly subconjunvtival injection of 3 million IU in 0.5ml of IFN α-2b until tumor resolution is an alternative [69].

The resolution rates showed 81–100% in topical administration and 87–100% in injections [68, 70, 71, 72]. IFN eye-drops also have remarkably low recurrence rates ranging from 0–4% [58, 71, 72].

Topical IFN eye-drops are very well tolerated by patients and nearly without side effects or discomfortable. Some follicular conjunctivitis was found [71]. Injections of IFN are also well-tolerated, but patients typically experience mild flu-like symptoms for about 24 hours following the injection [71].

7.3 Cryotherapy

Intraoperative cryotherapy by a double freeze-slow thaw method applied on conjunctival margins of the excised area has proved to diminish recurrences significantly after surgical excision in pre-cancerous and SCC in situ, but not suitable for invasive cancers [73].

The advantages of cryotherapy include the elimination of subclinical or microscopic malignant tumor cells and the prevention of recurrence. The adverse effects include conjunctival chemosis, cataract formation, uveitis, thinning scleral and corneal. Frozen globe and risk of phthisis bulbi could unexpectedly develop if cryotherapy had been excessively used [74].

It is also safe and useful for cutaneous SCC in situ in patients who refuse surgery, poor surgical candidates or with bleeding disorders.

7.4 Radiation therapy

Radiotherapeutic treatment has been limited to brachytherapy techniques either alone for whom surgery is risky, or as adjuvant therapy after surgical resection for whom the disease has spread to nerves/lymph nodes or with poorly defined margins.

When conjunctival SCC invades deeply into the sclera or into the globe, topical chemotherapeutic agents and cryotherapy might be ineffective due to not penetrating the sclera or into the eye, and enucleation is often necessary [68, 75]. To preserve vision and salvage eyeball, plaque radiotherapy had been reported as reliable alternative treatment without globe removal for conjunctival SCC demonstrating scleral invasion and/or intraocular involvement.

Using Beta radiation with strontium-90 source as adjunctive therapy to control residual microscopic tumor following surgical resection of conjunctival SCC had been reported. It revealed excellent control rates with only 3 in total 131 patients indicating recurrent after a 30-Gy dose [76], Similar results have been observed with ruthenium-106 after a total 320-Gy dose delivered at the surface without recurrence at 22 months [77]. Gamma radiotherapy using I125 has also been explored as an adjunctive treatment to excision for invasive conjunctival SCC because it has a deeper penetrability compared with beta radiation [78].

Arepalli and Shields had explored an alternative to enucleation using plaque radiotherapy with a gamma source of I125 for invasive conjunctival SCC. Plaque radiotherapy can be an effective alternative to enucleation for residual scleral-invasive conjunctival SCC following resection. In final, total globe salvage was achieved in 10 cases from their total 15 SCC patients with scleral (all cases) and anterior chamber invasion (3 cases). However, 4 cases showed further distant conjunctival tumor recurrence (remote of the radiotherapy site) with orbital involvement at 5 months after plaque radiotherapy, necessitating enucleation (n = 2) or orbital exenteration (n = 2). Complications included cataract (n = 13), iris telangiectasia (n = 5), corneal epithelial defect (n = 4), corneal edema (n = 3), and glaucoma (n = 1). One patient required enucleation due to a nonhealing epithelial defect and chronic ocular irritation [79].

In the management of eyelid malignancies, adjuvant radiotherapy has been recommended for eyelid malignancies with aggressive histologic subtype, perineural invasion, or nodal metastasis at presentation [80]. Radiotherapy is used as an adjunct to surgery in cases of incomplete tumor excision and/or perineural invasion [81, 82]. Although, radiotherapy alone is also an alternative to surgery for patients who are not candidates for surgery, there are several drawbacks. The recurrence rates are higher after radiotherapy alone than surgery [83]. Furthermore, when recurrence occurs, it is usually difficult to manage and definitively diagnose [84]. Unlike surgery, radiation therapy does not readily demonstrate histological evidence of tumor clearance. It is also noted that a large dose of radiotherapy may cause ocular complications leading to visual disturbance.

7.5 Chemotherapy

Systemic chemotherapy is recommended for patients in the advanced stage with distant metastasis and can be considered for patients with extensive nodal disease.

7.6 Other treatment modalities

Other treatment modalities currently with favorable outcomes include radiotherapy, surgical excision in combination with absolute alcohol, vitamin A, excimer laser, topical imiquimod 5% cream, and adjuvant topical or perilesional chemotherapy [50].

7.7 Management of Intraocular or/and infraorbital invasion

Orbital invasion by eyelid SCC occurs in 4–8% of cases [7, 27]. Conjunctival SCC can represent 0 ~ 13% of intraocular and/or 1–6% of orbital local invasion. The orbital invasion should be suspected if a patient with a current or previously treated periocular malignancy presents with a palpable orbital mass, globe displacement, limitation of eye movement, numbness, or pain in the distribution of the trigeminal nerve (Figure 6) [85, 86]. If Intraocular or/and infraorbital invasion occurs, it has devastating visual consequences [32, 33, 35].

Figure 6.

A patient with squamous cell carcinoma of the right eyelid with orbital metastasis: Periocular mass, proptosis, facial numbness and palsy.

The intraocular spread tends to follow recurrence of the conjunctival lesion after attempted excision. Modes of invasion may include direct invasion through the sclera, along the tract of the anterior ciliary vessels, or inoculation through intraocular surgery incision [87].

Although, there have been reports of local control achieved with globe-sparing surgeries [79, 88], enucleation or exenteration is usually required to manage intraocular or/and intra-orbital invasion with or without adjunctive radiotherapy.

Local tumor clearance is usually possible by orbital exenteration with or without adjunctive radiotherapy. However, the perineural invasion occurs commonly in such cases, and increases the risk of incomplete excision even after exenteration [85]. Furthermore, perineural invasion worsens the prognosis because of extensive orbital, and sometimes intracranial involvement. A meta-analysis of 9 publications on large series of exenterations between 1954 and 2005 indicated that 89/559 (16%) cases were for conjunctival SCC and required exenteration for advanced disease [89].

Orbital exenteration rates are 6% at 5 years in the US, but are higher in HIV endemic areas, with 13/23 cases (56%) reported in a case series in Zimbabwe [33]. Risk factors predictive of orbital exenteration were positive margins at primary resection, perineural invasion, positive nodal status, and medial canthal tumor location [89].

7.8 Target therapy

The discovery of overexpression of the epidermal growth factor receptor (EGFR, a transmembrane tyrosine kinase receptor in the ErbB family) in SCC has opened the door to consideration of targeted therapy in inoperable cases of advanced BCC or cutaneous SCC of the orbit and periocular region [90].

Recently, both Yin’s group and El-Sawy’s group show successful outcomes after oral erlotinib (EGFR inhibitor) treatment in some patients who have advanced SCC with orbital invasion and regional lymph nodes metastasis [91, 92]. However, several reports also show that patients often acquire resistance. Several publications point out that despite EGFR inhibition, there are multiple downstream signaling pathways that serve as alternatives and that are found to be persistently activated, thus permitting cancer resistance to EGFR-inhibitors [93, 94]. Additionally, less than 5% of head and neck cancers contain EGFR mutations, which may partially explain the limited efficacy in using EGFR inhibitors and the current lack of FDA-approved for HNSCC [93, 95]. For the efficacy of EGFR inhibitor in the treatment of cutaneous SCC, more studies are needed to further conform.

In 2018, designated by the FDA as a breakthrough therapy, cemiplimab-rwlc, a PD-1–blocking antibody, became the first drug to receive FDA approval for the treatment of patients with advanced cutaneous SCC. Of the 75 patients with metastatic CSCC, 46.7% achieved an objective response; of the 33 patients with locally advanced CSCC, 48.5% achieved an objective response. Furthermore, 60% of patients with metastatic CSCC and 63% of patients with locally advanced CSCC maintained a response to treatment for ≥6 months [96].

With the Libtayo approval, the FDA has approved six immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway for treating a variety of tumors, from the bladder to head and neck cancer, and now advanced cutaneous squamous-cell carcinoma.

8. Regional lymph nodes and distant organ metastasis

Early diagnosis and adequate treatment of the eyelid SCC is very important, because of its ability to invade the orbital and intracranial legions and metastasis to the lymph nodes and distant organs. Regional lymph nodes are generally believed to be the most common first site of metastasis for SCC of the eyelid. The incidence of regional lymph node metastasis of eyelid SCC varies widely from 10% to 24.3% [97]. with most regional metastases occurring in the parotid, preauricular, and submandibular nodes. Distant metastasis is much less common, reported in 6.2% of cases [28].

Radical dissection with sentinel lymph node biopsy for patients with extensive lesions especially with perineurial invasion and recurrent lesions may get benefit if there is a ruling out distant metastasis. A high degree of suspicion for the orbital invasion along sensory nerves should be maintained. Perineural spread of cutaneous SCC is associated with an increased risk of local recurrence and distant metastasis, but may also be the direct cause of death when the primary tumor on the head and face gains access to the intracranial cavity via the cranial nerves [98, 99]. Risk factors have been found to correlate with the increased death and poor prognosis for cutaneous SCC, including prior treatments, lesion size ≥2 cm, increased depth, poor histopathological differentiation and immunosuppression [100]. In Nasser’s study, patients who had a lymph node metastasis at presentation or during follow-up had tumors that were stage T2C (according to AJCC, 9th edition; or T2b in AJCC, 8th edition) or higher at and ≥ 18 mm in greatest dimension at presentation. This finding will help practitioners select patients for closer surveillance for nodal metastasis or possibly for SLN biopsy [101].

9. Recurrence

Recurrence rates in OSCC range from 5–50% [33, 102, 103, 104, 105]. Galor et al. found that the 1-year recurrence rate was 10% and the 5-year recurrence rate was 21%, with a mean time to recurrence of 2.5 years when analyzing 389 excised OSSN lesions [73]. In Savino’s study, the overall recurrence rate was significantly higher (64%) in their advanced ocular surface squamous cell carcinoma (OSSC, T3 and T4 stage) cases series after long-term follow-up (median: 31 months, range: 6–120 months) [106].

In advanced, OSCC involving periocular tissues and/or orbit is an aggressive disease with a high recurrence rate. Multicentric disease, positive surgical margins, inferior tarsus localization, and surgery without adjuvant therapies are strong predictors of recurrence and are the main factors affecting prognosis [105].

The type of treatment is also correlated with the recurrence rate. Sudesh et al. reported a recurrence rate of 28.5% with surgical excision alone and 7.7% with surgical excision and cryotherapy [107]. Adjuvant topical therapy showed effectiveness in decreasing recurrence rates, particularly in patients with positive margins, histological high-risk SCC, tarsal, and multicentric pattern anatomical involvement [73, 108].

The presence of positive margins can increase the risk of recurrence by as much as 10-fold, from 5–50% [35].

The microscopic and histologic information of cutaneous and periocular SCC is helpful to evaluate the recurrence, perineural invasion, local invasion, and metastasis. Histological well-differentiated tumors are associated with a lower risk of subclinical tumor extension, recurrence, and orbital invasion [27, 100]. Histologic specimens should be carefully examined for evidence of perineural invasion when facing cases of particularly aggressive tumors or in patients with symptoms of trigeminal pain, trigeminal-distribution sensory deficit, facial palsy, orbital pain, or biopsy of the supraorbital orbital nerve [28, 109]. Perineural invasion is associated with high local invasion, recurrence, and distant metastasis [98, 99].

The local recurrence rates for SCC range from 2.4% to 36.9% at 5 years [7, 28]. The perineural invasion has been found to be present in approximately 8–14% of cases of facial and periorbital SCC [7, 110].

10. Conclusions

Squamous cell carcinoma of the eyelid and ocular surface is an aggressive malignancy and maybe vision- and life-threatening although it grows slowly. Precise diagnosis along with appropriate management is a prerequisite.

Conflict of interest

The authors declare no conflict of interest.